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WO2022255765A1 - Novel fluorine-substituted flavonoid derivative, and pharmaceutical composition for preventing or treating allergic diseases, comprising same - Google Patents

Novel fluorine-substituted flavonoid derivative, and pharmaceutical composition for preventing or treating allergic diseases, comprising same Download PDF

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WO2022255765A1
WO2022255765A1 PCT/KR2022/007713 KR2022007713W WO2022255765A1 WO 2022255765 A1 WO2022255765 A1 WO 2022255765A1 KR 2022007713 W KR2022007713 W KR 2022007713W WO 2022255765 A1 WO2022255765 A1 WO 2022255765A1
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chromen
hydroxyphenyl
methyl
oxo
benzoate
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PCT/KR2022/007713
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French (fr)
Korean (ko)
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변영주
전영호
안명환
최도영
손상현
김은지
김호순
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주식회사 에즈큐리스
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/304—Foods, ingredients or supplements having a functional effect on health having a modulation effect on allergy and risk of allergy
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to novel fluorine-substituted flavonoid derivatives, and more particularly, to novel fluorine-substituted flavonoid derivatives exhibiting preventive or therapeutic effects on allergic diseases.
  • Bronchodilators or anti-inflammatory drugs used in the treatment of allergic inflammatory diseases are drugs that are mainly applied symptomatically and can temporarily relieve symptoms, but cannot fundamentally treat the disease because it is impossible to control the allergic disease in the fundamental stage. has the disadvantage of not being able to Environmental diseases such as bronchial asthma, atopic skin disease, and allergic rhinitis are known as immune diseases, and Th2 cells are well known to play a pivotal role in inducing allergic reactions.
  • TSLP thymic stromal lymphoprotein
  • type 2 cytokines such as IL-4, these cells differentiate into Th2 and induce an allergic response.
  • cytokines include TSLP, IL-25, IL-33, etc., and among them, TSLP is expected to play the most effective role. For example, it has been shown that suppression of TSLP secretion in animal models makes it difficult to generate and activate Th2 cells and thus does not cause disease in animals. Inhibition of TSLP in diseased animals has also been reported to cure disease. there is a bar Taken together, TSLP is an important cytokine that acts on both the differentiation and activation of Th2 cells, and its control is recognized as important for the treatment of allergic diseases.
  • An object to be solved by the present invention is to provide a novel fluorine-substituted flavonoid derivative that can be used as a treatment for allergic diseases such as asthma or atopy.
  • an object of the present invention is to provide a method for preparing the novel fluorine-substituted flavonoid derivative.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating thymic stromal lymphoprotein (TSLP)-related diseases, comprising the novel fluorine-substituted flavonoid derivative as an active ingredient.
  • TSLP thymic stromal lymphoprotein
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating allergic diseases comprising the novel fluorine-substituted flavonoid derivative as an active ingredient.
  • the problem to be solved by the present invention is to treat at least one allergy selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis, containing the novel fluorine-substituted flavonoid derivative as an active ingredient.
  • sexually transmitted disease at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis;
  • a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
  • the problem of the present invention is to treat asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneity, including the step of administering the novel fluorine-substituted flavonoid derivative to a subject in need thereof.
  • at least one allergic disease selected from urticaria and anaphylaxis
  • at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis
  • one or more allergic diseases selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And to provide a use of the novel fluorine-substituted flavonoid derivative to prepare a medicament for use in preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
  • an object of the present invention is to provide a functional health food composition for improving symptoms of allergic diseases, which includes the novel fluorine-substituted flavonoid derivative.
  • a fluorine-substituted flavonoid derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided.
  • R a and R b are hydrogen or linked to each other to form a single bond
  • X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, or OCO-alkyl;
  • Z is hydrogen, halogen, or OCO-alkyl
  • R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
  • R 2 is hydrogen or COO-R c ;
  • R c is hydrogen or C 1 -C 4 straight or branched chain alkyl.
  • a treatment for thymic stromal lymphoprotein (TSLP)-related diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • TSLP thymic stromal lymphoprotein
  • a fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is used as an active ingredient for preventing or treating allergic diseases.
  • a pharmaceutical composition is provided.
  • a fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient asthma, allergic rhinitis, chronic sinusitis
  • a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.
  • the step of administering the fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof one or more allergic diseases selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.
  • allergic diseases selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis
  • at least one autoimmune disease selected from Graves' disease,
  • the fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is used for asthma, allergic rhinitis, chronic sinusitis, and allergic contact dermatitis.
  • atopic dermatitis chronic spontaneous urticaria, and at least one allergic disease selected from anaphylaxis
  • a use for preparing a medicament for use in the prevention or treatment of one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.
  • a health functional food composition for improving the symptoms of allergic diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. is provided.
  • the novel fluorine-substituted flavonoid derivative compound provided in one aspect of the present invention controls intracellular signal transduction by TSLP (thymic stromal lymphoprotein) to exert an effect of inhibiting intracellular STAT5 phosphorylation and reacts with TSLP and TSLP receptors By exhibiting an excellent inhibitory effect on, it can be usefully used as a pharmaceutical composition for preventing or treating allergic diseases such as asthma or atopy.
  • TSLP thymic stromal lymphoprotein
  • 1 is a 1 H 1D NMR spectrum showing the oxidation of baicalein over time.
  • baicalein quinone produced by oxidation of baicalein shows baicalein quinone produced by oxidation of baicalein.
  • Figure 4 is a schematic diagram schematically showing an ELISA test method for measuring inhibition of TSLP and TSLP receptor (TSLPR) binding.
  • 5 is a dose-response graph measuring IC 50 values of compound 7.
  • the present invention provides a fluorine-substituted flavonoid derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • R a and R b are hydrogen or linked to each other to form a single bond
  • X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, or OCO-alkyl;
  • Z is hydrogen, halogen, or OCO-alkyl
  • R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
  • R 2 is hydrogen or COO-R c ;
  • R c is hydrogen or C 1 -C 4 straight or branched chain alkyl.
  • alkyl is a straight-chain or branched hydrocarbon, which may contain single, double or triple bonds, and is preferably C 1 -C 10 alkyl.
  • the alkyl includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, acetylene, vinyl, trifluoromethyl, and the like.
  • alkoxy means an alkyloxy having from 1 to 10 carbon atoms.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • the fluorine-substituted flavonoid derivative compound represented by Formula 1 may be a compound represented by Formula 1a below.
  • X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, or halogen;
  • Z is hydrogen or halogen
  • R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
  • R 2 is hydrogen or COO-R c ;
  • R c is C 1 -C 4 straight or branched chain alkyl.
  • the fluorine-substituted flavonoid derivative compound represented by Formula 1 may be a compound represented by Formula 1b below.
  • X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, or OCO-alkyl;
  • Z is hydrogen, halogen, or OCO-alkyl
  • R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
  • R 2 is hydrogen or COO-R c ;
  • R c is hydrogen or C 1 -C 4 straight or branched chain alkyl.
  • X and Y may independently be hydrogen, methyl, methoxy, F, Cl, hydroxy, or acetate.
  • the Z can be hydrogen, F, or acetate.
  • R 1 can be hydrogen, methoxy, hydroxy, carboxyl, or methyl carboxylate.
  • R 2 can be hydrogen, carboxyl, or methyl carboxylate.
  • fluorine-substituted flavonoid derivative compounds are as follows:
  • the compound represented by Formula I according to the present invention can be used in the form of a prodrug, hydrate, solvate, or pharmaceutically acceptable salt in order to improve absorption or solubility in vivo
  • the prodrug, Hydrates, solvates and pharmaceutically acceptable salts are also within the scope of this invention.
  • prodrug refers to a substance that is transformed into the parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may obtain bioactivity by oral administration whereas the parent agent may not. A prodrug may also have improved solubility in a pharmaceutical composition than the parent drug.
  • a prodrug may be an in vivo hydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof.
  • Another example of a prodrug would be a short peptide (polyamino acid) attached to an acid group that is metabolized to reveal an active site.
  • hydrate refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or a salt thereof.
  • solvate refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.
  • isomers refers to compounds of the present invention or salts thereof that have the same chemical formula or molecular formula but differ structurally or sterically. These isomers include both structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, and stereoisomers such as geometric isomers (trans, cis). All these isomers and mixtures thereof are also included within the scope of the present invention.
  • pharmaceutically acceptable salt refers to a salt form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.
  • the pharmaceutical salt is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbonic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric
  • carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N- organic salts such as methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine; and the like.
  • the compounds of formula (I) according to the present invention may be converted into their salts by conventional methods.
  • Fluorine-substituted flavonoid derivatives of formula (I) of the present invention can be synthesized according to Scheme 1 and Scheme 2 described below.
  • the method for preparing the compound of Formula I according to the present invention is not limited to the method for preparing the compound of Formula I according to the present invention.
  • the preparation methods of Reaction Scheme 1 and Reaction Scheme 2 are only examples, and it is obvious that they can be easily modified by a person skilled in the art according to specific substituents.
  • the present invention also relates to prevention or treatment of thymic stromal lymphoprotein (TSLP)-related diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for use.
  • TSLP thymic stromal lymphoprotein
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of allergic diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • the present invention also relates to asthma, allergic rhinitis, chronic sinusitis, and allergic contact, comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • At least one allergic disease selected from sexual dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis
  • at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis
  • it provides a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
  • the present invention also provides a step of administering a fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof to a subject in need thereof, one or more allergic diseases selected from allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And it provides a method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
  • allergic diseases selected from allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis
  • at least one autoimmune disease selected from Graves'
  • the present invention also relates to a fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, for asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, at least one allergic disease selected from chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; and chronic obstructive pulmonary disease.
  • a fluorine-substituted flavonoid derivative compound represented by Formula I for asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, at least one allergic disease selected from chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease,
  • the present invention also provides a health functional food composition for improving symptoms of allergic diseases, comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  • the additives may include pharmaceutically acceptable carriers or diluents, and oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterilization according to conventional methods, respectively. It can be formulated in the form of an injection solution.
  • the pharmaceutically acceptable carrier is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil; and the like.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants are included.
  • Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose. ), gelatin, and the like, and may include lubricants such as magnesium stearate and talc.
  • Oral liquid preparations include suspensions, internal solutions, emulsions, syrups, and the like, and may include diluents such as water and liquid paraffin, wetting agents, sweeteners, aromatics, and preservatives.
  • Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, lyophilized preparations, and suppositories, and non-aqueous solvents and suspensions include vegetable oils, injectable esters such as ethyl oleate, and the like.
  • a base for the suppository witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
  • the dose of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of active ingredient, the route and period of administration, and may be appropriately adjusted according to the patient.
  • the active ingredient may be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 100 mg/kg, and the administration may be administered once or several times a day.
  • the pharmaceutical composition of the present invention may include the active ingredient in a weight percentage of 0.001 to 90% based on the total weight of the composition.
  • the pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans through various routes, for example, oral, dermal, abdominal, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebral vascular (intracerebroventricular) It may be administered by injection.
  • Scheme 1 describes the synthesis of flavonoid derivatives in which two phenyl rings of the compound are substituted with various functional groups.
  • the acetophenone compounds 2a-2c and 2g-2i were commercially available and used as starting materials. However, compounds 2d-2f having two substituents were synthesized in two steps (see Scheme 1).
  • starting material 1a was reacted with acetyl chloride in the presence of pyridine in dichloromethane at room temperature. After monitoring the progress of the reaction by TLC, aluminum chloride was added to the reaction mixture and a subsequent reaction was conducted at 150° C. to obtain compound 2d .
  • Compounds 3a-3z were obtained via the Claisen-Schmidt condensation reaction of compounds 2a-2i with appropriate aldehydes, and for 3a-3h with barium hydroxide in methanol (or ethanol) at 40 °C-50 °C. for 1-17 hours, or for 3i-3z in a 25% (w/v) NaOMe solution in THF from 0°C to room temperature for 12 hours.
  • Compounds 4a-4h were obtained in 47%-97% yields through intramolecular cyclization by reacting compounds 3a-3h with iodine in DMSO at 110 °C for 6-24 hours.
  • Reaction Scheme 2 shows the synthetic process of flavonoid derivatives having an acetyl group of the A ring.
  • 5,6,7-Trihydroxyflavone ( 6 ) [Trihydroxyflavone ( 6 )] was commercially available and was used as the starting material.
  • 5,6,7-trihydroxyflavone ( 6 ) was reacted with acetyl chloride in the presence of diisopropylethylamine as base in DMF at 0°C to room temperature. After monitoring the reaction progress by TLC, it was concentrated with toluene and purified by silica gel column chromatography to obtain compound 7 in 93% yield.
  • Compound 3a is 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2a ; 200 mg, 1.3 mmol) [ 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ], Benzaldehyde (159 ⁇ L, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) were stirred in methanol (8.0 mL) at 50 ° C. for 1 hour, followed by the same method as described in Synthesis Example 2, yielding 72% as a yellow powder. was obtained with The crude residue was purified by column chromatography on silica gel.
  • Compound 3b was 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2a ; 200 mg, 1.3 mmol), p-anisaldehyde ( p- anisaldehyde, 190 ⁇ L, 1.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was stirred in methanol (10 mL) at 50 °C for 17 hours to obtain a yellow powder in 44% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3c was 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one ( 2b ; 200 mg, 1.3 mmol), benzaldehyde (159 ⁇ L, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) was stirred in methanol (8.0 mL) at 50 °C for 1 hour to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3d was 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2b ; 200 mg, 1.3 mmol), p-anisaldehyde (190 ⁇ L, 2.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was used in methanol (10 mL) at 40° C. for 4 hours to obtain a yellow powder in 76% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3e was 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one ( 2c ; 166 ⁇ L, 1.3 mmol), benzaldehyde (159 ⁇ L, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) was stirred in methanol (8.0 mL) at 50 °C for 3 hours to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3f was 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one ( 2c ; 200 mg, 1.3 mmol), p-anisaldehyde (190 ⁇ L, 1.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was used in methanol (10 mL) at 50 °C for 6 hours to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3g was 1-(2,4-difluoro-6-hydroxyphenyl)ethan-1-one ( 2d ; 200 mg, 1.2 mmol), benzaldehyde (142 ⁇ L, 1.4 mmol) and barium hydroxide (398 mg, 2.3 mmol) was used in methanol (8.0 mL) at 50 °C for 2 hours to obtain a yellow powder in 95% yield in the same manner as described in Synthesis Example 2. The crude residue was used in the next step without further purification.
  • Compound 3i was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 200 mg, 1.2 mmol), benzaldehyde (142 ⁇ L, 1.7 mmol) and sodium methoxide solution (397.8 ⁇ L, 1.7 ⁇ L). mmol) in THF (7.5 mL) at room temperature for 24 hours to obtain a yellow powder in 57% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane.
  • Compound 3j was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 300 mg, 1.7 mmol), p-anisaldehyde (254 ⁇ L, 2.6 mmol) and sodium methoxide solution (596.8 ⁇ L, 2.6 mmol) was stirred in THF (11 mL) at room temperature for 5 hours to obtain a yellow powder in 90% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane.
  • Compound 3k was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethenone ( 2e ; 300 mg, 1.7 mmol), hydroxybenzaldehyde (173 mg, 2.6 mmol) and sodium methoxide solution (398 ⁇ L, 2.6 mmol) was used in THF (7.5 mL) at room temperature to 50 ° C. for 24 hours to obtain a yellow powder in 12% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3l is 1- (4,5-difluoro-2-hydroxyphenyl) ethanone ( 2e ; 150 mg, 0.87 mmol), methyl-3-formylbenzoate (methyl-3-formylbenzoate, 171 mg, 1.3 mmol) and sodium methoxide solution (298 ⁇ L, 1.3 mmol) were stirred in THF (5.7 mL) at room temperature for 5 hours to obtain a yellow powder in 23% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from EtOH.
  • Compound 3m is 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 350 mg, 2.0 mmol), methyl terephthalaldehydate (400 mg, 3.0 mmol) and sodium methoxide
  • the solution (696 ⁇ L, 3.0 mmol) was stirred in THF (13 mL) at room temperature for 5 hours to obtain a yellow powder in 28% yield in the same manner as described in Synthesis Example 2.
  • the crude residue was purified by column chromatography on silica gel.
  • Compound 3p was prepared from 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 200 mg, 0.98 mmol), hydroxybenzaldehyde (182 mg, 1.5 mmol) and sodium methoxide solution (334 ⁇ L). , 1.5 mmol) was used in THF (6.3 mL) at room temperature to 70 ° C. for 24 hours to obtain a yellow powder in 15% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3t was prepared by mixing 2'-hydroxy-4',5'-dimethoxyacetophenone ( 2 g ; 1.0 g, 5.1 mmol), methyl terephthalaldehyde (1.0 g, 6.1 mmol) and sodium methoxide solution (1.4 mL, 6.1 mmol) was used in THF (40 mL) at room temperature for 12 hours to obtain a yellow powder in 50% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3v was prepared by mixing 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), benzaldehyde (0.22 mL, 2.2 mmol) and sodium methoxide solution (0.6 mL, 2.6 mmol). was stirred in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 73% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from ethanol.
  • Compound 3w was 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), p-anisaldehyde (0.27 mL, 2.2 mol) and sodium methoxide solution (0.6 mL, 2.6 mL). mmol) in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 95% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 3x was 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), methyl terephthalaldehyde (361 mg, 2.2 mmol) and sodium methoxide solution (0.6 mL, 2.6 mL). mmol) in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 57% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel.
  • Compound 4a was (E)-1-(4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3a ; 194 mg, 0.80 mmol) and iodine (20.3 mg, 0.08 mmol) was used in DMSO (6.0 mL) and stirred for 24 hours to obtain a white powder in 90% yield in the same manner as described in Synthesis Example 3.
  • the crude residue was purified by column chromatography on silica gel.
  • Compound 4b was (E)-1-(4-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3b ; 137 mg, 0.50 mmol) And iodine (12.7 mg, 0.05 mmol) was stirred in DMSO (7.0 mL) for 16 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4c was (E)-1-(5-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3c ; 304 mg, 1.3 mmol) and iodine (31.7 mg, 0.13 mmol) was used in DMSO (6.0 mL) and stirred for 15 hours to obtain a white powder in 91% yield in the same manner as described in Synthesis Example 3.
  • the crude residue was purified by column chromatography on silica gel.
  • Compound 4e was (E)-1-(2-fluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3e ; 200 mg, 0.83 mmol) and iodine (21.1 mg, 0.08 mmol) was used in DMSO (5.0 mL) and stirred for 20 hours to obtain a white powder in 86% yield in the same manner as described in Synthesis Example 3.
  • the crude residue was purified by column chromatography on silica gel.
  • Compound 4g was (E)-1-(2,4-difluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3g ; 280 mg, 0.96 mmol) and iodine ( 24.4 mg, 0.09 mmol) was stirred in DMSO (10 mL) for 14 hours to obtain a white powder in 88% yield in the same manner as described in Synthesis Example 3.
  • the crude residue was purified by column chromatography on silica gel.
  • Compound 4h is (E)-1-(2,4-difluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3h ; 270 mg, 0.93 mmol) and iodine (23.6 mg, 0.09 mmol) were stirred in DMSO (6.0 mL) for 10 hours to obtain a white powder in 47% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4i is (E)-1-(4,5-difluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3i ; 100 mg, 0.38 mmol) and iodine ( 106.6 mg, 0.42 mmol) was stirred in DMSO (5.6 mL) at 100° C. for 24 hours to obtain a white powder in 89% yield in the same manner as described in Synthesis Example 3.
  • the crude residue was purified by column chromatography on silica gel.
  • Compound 4j is (E)-1-(4,5-difluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3j ; 100 mg, 0.38 mmol) and iodine (107 mg, 0.42 mmol) were stirred in DMSO (5.6 mL) at 100 ° C. for 24 hours to obtain a white powder in 89% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4k is (E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3l ; 100 mg , 0.31 mmol) and iodine (87.5 mg, 0.35 mmol) were stirred in DMSO (4.6 mL) at 100 ° C. for 16 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4l is (E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3m ; 100 mg , 0.31 mmol) and iodine (87.5 mg, 0.35 mmol) were stirred in DMSO (4.6 mL) at 100 ° C. for 16 hours to obtain a white powder in 88% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4m is (E)-1-(4,5-dichloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3n ; 100 mg, 0.34 mmol) and iodine (95 mg, 0.37 mmol) was stirred in DMSO (5.0 mL) at 100 °C for 24 hours to obtain a white powder in 67% yield in the same manner as described in Synthesis Example 3.
  • Compound 4n was (E)-1-(4,5-dichloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3o ; 100 mg, 0.34 mmol) and iodine (95 mg, 0.37 mmol) in DMSO (5.0 mL) and stirred at 100 °C for 24 hours to obtain a white powder in 67% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4o is (E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3q ; 100 mg; 0.29 mmol) and iodine (79.5 mg, 0.31 mmol) were stirred in DMSO (4.2 mL) at 100 ° C. for 24 hours to obtain a white powder in 96% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4p is (E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3r ; 100 mg, 0.29 mmol) and iodine (79.5 mg, 0.31 mmol) were stirred in DMSO (4.2 mL) at 100 ° C. for 24 hours to obtain a white powder in 96% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4r is (E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3t ; 200 mg , 0.58 mmol) and iodine (178 mg, 0.70 mmol) in DMSO (5.0 mL) and stirred at 100 ° C. for 24 hours to obtain a brown powder in 62% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 4w was (E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3y ; 120 mg, 0.39 mmol) and iodine (118 mg, 0.46 mmol) in DMSO (3.0 mL) and stirred at 100 °C for 24 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel.
  • Compound 5a was distilled using 7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4b ; 76 mg, 0.28 mmol) and boron tribromide (3.4 mL, 3.4 mmol). It was stirred in chloromethane (30 mL) at 50 °C for 18 hours to obtain a brown powder in quantitative yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel.
  • Compound 5d was prepared by combining 5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4h ; 100 mg, 0.35 mmol) and boron tribromide (4.2 mL, 4.2 mmol). was stirred in dichloromethane (30 mL) at 50 °C for 14 hours to obtain a white powder in 94% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel.
  • Example 56 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5f) [ 4-(6,7-Difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5f)]
  • Compound 5g was prepared by combining 6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4j ; 65 mg, 0.23 mmol) and boron tribromide (0.6 mL, 3.8 mmol). was stirred in dichloromethane (2.6 mL) at 60 °C for 24 hours to obtain a white powder in 13% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel.
  • Compound 5k was prepared from methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4r ; 100 mg, 0.29 mmol) and 1 N NaOH in methanol (5.0 mL) ( 0.60 mL, 0.59 mmol) was used and stirred at 70° C. for 2 hours to obtain an ivory-colored powder in 54% yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water.
  • Example 64 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5n) [ 4-(6,7-Dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5n)]
  • Example 65 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5o) [ 3-(6,7-Dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5o)]
  • compound 5e was substituted with fluorine groups instead of hydroxyl groups at positions 6 and 7 so that it could not be oxidized to quinone, so it did not undergo structural transformation by oxidation in solution, and as a result, 26 It was confirmed that no change in the 1D NMR signal was observed even with time, and the same structure was maintained (see FIG. 3).
  • FIG. 4 schematically shows an ELISA test method for measuring inhibition of TSLP and TSLP receptor (TSLPR) binding.
  • TSLP receptor TSLP receptor
  • 1X coating buffer Biolegend
  • Samples containing 100 nM of TSLP wildtype human recombinant protein and 10 ⁇ M or 100 ⁇ M of each of the example compounds were prepared, put into the same volume, and reacted at room temperature for 2 hours or longer.
  • the anti-TSLP (Abcam) antibody was diluted 1:7500 and reacted at room temperature for 1 hour or longer.
  • TMB substrate solution (Thermo) was added and reacted for 5 minutes or more. After stopping the reaction by adding 1 N HCl (Samchun), orbital shaking was performed for 5 seconds using a Microplate reader (Tecan, Spark ® ), and the absorbance value was obtained at 450 nm.
  • the result values derived from the program linked with the microplate reader were analyzed using the Excel program.
  • the average of the three values obtained through triplicate is obtained and the vehicle value is converted to 100% to obtain the binding % or the vehicle value is converted to 100% to obtain the TSLP-TSLPR binding % saved
  • the binding rate (%) value of each compound was obtained by subtracting the TSLP-TSLPR binding % from 100%, and the error range of triplicate was also obtained, which was reflected when deriving the compound inhibition rate graph.

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Abstract

The present invention provides a fluorine-substituted flavonoid derivative compound, and a pharmaceutical composition for preventing or treating allergic diseases, comprising same. A fluorine-substituted flavonoid derivative compound of the present invention controls intracellular signaling mediated by TSLP, so as to exhibit the effect of inhibiting the phosphorylation of intracellular STAT5 and exhibit an excellent inhibitory effect on reactions of TSLP and TSLP receptors, and that can be effectively used as a pharmaceutical composition for preventing or treating allergic diseases such as asthma or atopic dermatitis.

Description

신규 불소-치환 플라보노이드 유도체 및 이를 포함하는 알러지성 질환의 예방 또는 치료용 약학적 조성물Novel fluorine-substituted flavonoid derivative and pharmaceutical composition containing the same for preventing or treating allergic diseases
본 발명은 신규 불소-치환 플라보노이드 유도체에 관한 것으로, 더욱 상세하게는 알러지성 질환의 예방 또는 치료 효과를 나타내는 신규 불소-치환 플라보노이드 유도체에 관한 것이다.The present invention relates to novel fluorine-substituted flavonoid derivatives, and more particularly, to novel fluorine-substituted flavonoid derivatives exhibiting preventive or therapeutic effects on allergic diseases.
알러지성 염증 질환의 치료에 사용되는 기관지 확장제 혹은 항염증제는 대증 요법 위주로 적용되는 약물로서 증상 완화에 일시적으로는 효과를 볼 수 있지만, 알러지 질환의 근본적인 단계에서의 제어가 불가능하여 질병을 근원적으로 치료하지 못한다는 단점을 갖는다. 기관지 천식, 아토피성 피부질환, 알러지성 비염 등의 환경 질환은 면역 질환으로 알려져 있고, Th2 세포는 알러지 반응을 유발하는데 중추적인 역할을 하는 것으로 잘 알려져 있다. CD4 T 세포가 림프구에서 항원에 자극을 받을 때 동시에 인식하는 사이토카인 (cytokine)에 따라서 여러 종류의 Th 세포로 분화가 가능하며, 이때 인식하는 사이토카인이 흉선 기질 림프단백질 (thymic stromal lymphoprotein, TSLP) 또는 IL-4 등과 같은 타입 2 사이토카인일 경우에 이러한 세포들은 Th2로 분화하여 알러지 반응을 유발한다.Bronchodilators or anti-inflammatory drugs used in the treatment of allergic inflammatory diseases are drugs that are mainly applied symptomatically and can temporarily relieve symptoms, but cannot fundamentally treat the disease because it is impossible to control the allergic disease in the fundamental stage. has the disadvantage of not being able to Environmental diseases such as bronchial asthma, atopic skin disease, and allergic rhinitis are known as immune diseases, and Th2 cells are well known to play a pivotal role in inducing allergic reactions. When CD4 T cells are stimulated by antigens in lymphocytes, they can differentiate into various types of Th cells depending on the cytokines they simultaneously recognize, and the cytokines recognized at this time are thymic stromal lymphoprotein (TSLP). Alternatively, in the case of type 2 cytokines such as IL-4, these cells differentiate into Th2 and induce an allergic response.
이러한 다양한 사이토카인들에는 TSLP, IL-25, IL-33 등이 포함되며, 이 중에서도 특히 TSLP가 가장 효과적인 역할을 하는 것으로 예상되고 있다. 예를 들어, 동물 모델에서 TSLP의 분비를 억제하면 Th2 세포의 생성 및 활성이 어려워 동물이 질병을 유발하지 않는 것으로 밝혀진 바도 있으며, 질병이 진행중인 동물들에서도 TSLP를 억제하면 질병이 치료되는 것으로 보고된 바 있다. 종합하면, TSLP는 Th2 세포의 분화 및 활성화에 모두 작용을 하는 중요한 사이토카인으로서, 이를 제어하는 것이 알러지 질환 치료에 중요한 것으로 인식되고 있다.These various cytokines include TSLP, IL-25, IL-33, etc., and among them, TSLP is expected to play the most effective role. For example, it has been shown that suppression of TSLP secretion in animal models makes it difficult to generate and activate Th2 cells and thus does not cause disease in animals. Inhibition of TSLP in diseased animals has also been reported to cure disease. there is a bar Taken together, TSLP is an important cytokine that acts on both the differentiation and activation of Th2 cells, and its control is recognized as important for the treatment of allergic diseases.
본 발명이 해결하고자 하는 과제는 천식 또는 아토피 등의 알러지성 질환 치료제로 사용 가능한 신규 불소-치환 플라보노이드 유도체를 제공하는 것이다.An object to be solved by the present invention is to provide a novel fluorine-substituted flavonoid derivative that can be used as a treatment for allergic diseases such as asthma or atopy.
또한, 본 발명의 해결 과제는 상기 신규 불소-치환 플라보노이드 유도체의 제조 방법을 제공하는 것이다.In addition, an object of the present invention is to provide a method for preparing the novel fluorine-substituted flavonoid derivative.
또한, 본 발명의 해결 과제는 상기 신규 불소-치환 플라보노이드 유도체를 유효성분으로 포함하는 TSLP (thymic stromal lymphoprotein) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.In addition, an object of the present invention is to provide a pharmaceutical composition for preventing or treating thymic stromal lymphoprotein (TSLP)-related diseases, comprising the novel fluorine-substituted flavonoid derivative as an active ingredient.
또한, 본 발명의 해결 과제는 상기 신규 불소-치환 플라보노이드 유도체를 유효성분으로 포함하는 알러지성 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating allergic diseases comprising the novel fluorine-substituted flavonoid derivative as an active ingredient.
또한, 본 발명의 해결 과제는 상기 신규 불소-치환 플라보노이드 유도체를 유효성분으로 포함하는, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.In addition, the problem to be solved by the present invention is to treat at least one allergy selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis, containing the novel fluorine-substituted flavonoid derivative as an active ingredient. sexually transmitted disease; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And to provide a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
또한, 본 발명의 해결 과제는 상기 신규 불소-치환 플라보노이드 유도체를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료방법을 제공하는 것이다.In addition, the problem of the present invention is to treat asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneity, including the step of administering the novel fluorine-substituted flavonoid derivative to a subject in need thereof. at least one allergic disease selected from urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And to provide a method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
또한, 본 발명의 해결 과제는 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료에 사용하기 위한 약제 (medicament)를 제조하기 위한, 상기 신규 불소-치환 플라보노이드 유도체의 용도(use)를 제공하는 것이다.In addition, one or more allergic diseases selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And to provide a use of the novel fluorine-substituted flavonoid derivative to prepare a medicament for use in preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
또한, 본 발명의 해결 과제는 상기 신규 불소-치환 플라보노이드 유도체를 포함하는 알러지성 질환의 증상 개선용 건강기능식품 조성물을 제공하는 것이다.In addition, an object of the present invention is to provide a functional health food composition for improving symptoms of allergic diseases, which includes the novel fluorine-substituted flavonoid derivative.
본 발명이 해결하고자 하는 과제는 이상에서 언급한 해결 과제로 제한되지 않으며, 언급되지 않은 또 다른 기술적 과제들은 아래의 기재로부터 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.The problem to be solved by the present invention is not limited to the above-mentioned problem, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.
상기 과제를 해결하기 위하여, 본 발명의 일 측면에 따라, 하기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염이 제공된다.In order to solve the above problems, according to one aspect of the present invention, a fluorine-substituted flavonoid derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided.
<화학식 Ⅰ><Formula Ⅰ>
Figure PCTKR2022007713-appb-img-000001
Figure PCTKR2022007713-appb-img-000001
상기 식에서, In the above formula,
Ra 및 Rb는 수소이거나 서로 연결되어 단일결합을 형성하고,R a and R b are hydrogen or linked to each other to form a single bond,
X 및 Y는 독립적으로 수소, C1-C4 직쇄 또는 분지쇄 알킬, C1-C4 알콕시, 할로겐, 히드록시, 또는 OCO-알킬이고,X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, or OCO-alkyl;
Z는 수소, 할로겐, 또는 OCO-알킬이고,Z is hydrogen, halogen, or OCO-alkyl;
R1은 수소, C1-C4 알콕시, 히드록시, 또는 COO-Rc이고,R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
R2는 수소 또는 COO-Rc이고,R 2 is hydrogen or COO-R c ;
상기 Rc는 수소, 또는 C1-C4 직쇄 또는 분지쇄 알킬이다.R c is hydrogen or C 1 -C 4 straight or branched chain alkyl.
본 발명의 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 TSLP (thymic stromal lymphoprotein) 관련 질환의 예방 또는 치료용 약학적 조성물이 제공된다.According to another aspect of the present invention, a treatment for thymic stromal lymphoprotein (TSLP)-related diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for prevention or treatment is provided.
본 발명의 또 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알러지성 질환의 예방 또는 치료용 약학적 조성물이 제공된다.According to another aspect of the present invention, a fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is used as an active ingredient for preventing or treating allergic diseases. A pharmaceutical composition is provided.
본 발명의 또 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료용 약학적 조성물이 제공된다.According to another aspect of the present invention, a fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient, asthma, allergic rhinitis, chronic sinusitis At least one allergic disease selected from allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.
본 발명의 또 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료방법이 제공된다.According to another aspect of the present invention, the step of administering the fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof one or more allergic diseases selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.
본 발명의 또 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염의, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료에 사용하기 위한 약제 (medicament)를 제조하기 위한 용도(use)가 제공된다.According to another aspect of the present invention, the fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is used for asthma, allergic rhinitis, chronic sinusitis, and allergic contact dermatitis. , atopic dermatitis, chronic spontaneous urticaria, and at least one allergic disease selected from anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a use for preparing a medicament for use in the prevention or treatment of one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.
본 발명의 또 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 포함하는 알러지성 질환의 증상 개선용 건강기능식품 조성물이 제공된다.According to another aspect of the present invention, a health functional food composition for improving the symptoms of allergic diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. is provided.
본 발명의 일 측면에서 제공되는 신규 불소-치환 플라보노이드 유도체 화합물은 TSLP (thymic stromal lymphoprotein)에 의한 세포 내 신호 전달을 제어하여 세포내 STAT5의 인산화를 억제하는 효과를 발휘하고 TSLP와 TSLP 수용체와의 반응에 대하여 우수한 저해 효과를 나타냄으로써, 천식 또는 아토피 등의 알러지성 질환의 예방 또는 치료용 약학적 조성물로 유용하게 사용될 수 있다.The novel fluorine-substituted flavonoid derivative compound provided in one aspect of the present invention controls intracellular signal transduction by TSLP (thymic stromal lymphoprotein) to exert an effect of inhibiting intracellular STAT5 phosphorylation and reacts with TSLP and TSLP receptors By exhibiting an excellent inhibitory effect on, it can be usefully used as a pharmaceutical composition for preventing or treating allergic diseases such as asthma or atopy.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 설명 또는 특허청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.The effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be inferred from the description of the present invention or the configuration of the invention described in the claims.
도 1은 바이칼레인의 시간에 따른 산화를 나타낸 1H 1D NMR 스펙트럼이다. 1 is a 1 H 1D NMR spectrum showing the oxidation of baicalein over time.
도 2는 바이칼레인의 산화에 의해 생성되는 바이칼레인 퀴논 (Baicalein quinone)을 나타낸 것이다. 2 shows baicalein quinone produced by oxidation of baicalein.
도 3은 NMR을 활용하여 화합물 5e의 안정성을 평가한 결과이다. 3 is a result of evaluating the stability of compound 5e using NMR.
도 4는 TSLP와 TSLP 수용체 (TSLPR) 결합의 억제를 측정하는 ELISA실험 방법을 개략적으로 나타낸 모식도이다. Figure 4 is a schematic diagram schematically showing an ELISA test method for measuring inhibition of TSLP and TSLP receptor (TSLPR) binding.
도 5는 화합물 7의 IC50 값을 측정한 용량-반응 그래프이다. 5 is a dose-response graph measuring IC 50 values of compound 7.
본 발명은 하기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a fluorine-substituted flavonoid derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
<화학식 Ⅰ><Formula Ⅰ>
Figure PCTKR2022007713-appb-img-000002
Figure PCTKR2022007713-appb-img-000002
상기 식에서, In the above formula,
Ra 및 Rb는 수소이거나 서로 연결되어 단일결합을 형성하고,R a and R b are hydrogen or linked to each other to form a single bond,
X 및 Y는 독립적으로 수소, C1-C4 직쇄 또는 분지쇄 알킬, C1-C4 알콕시, 할로겐, 히드록시, 또는 OCO-알킬이고,X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, or OCO-alkyl;
Z는 수소, 할로겐, 또는 OCO-알킬이고,Z is hydrogen, halogen, or OCO-alkyl;
R1은 수소, C1-C4 알콕시, 히드록시, 또는 COO-Rc이고,R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
R2는 수소 또는 COO-Rc이고,R 2 is hydrogen or COO-R c ;
상기 Rc는 수소, 또는 C1-C4 직쇄 또는 분지쇄 알킬이다.R c is hydrogen or C 1 -C 4 straight or branched chain alkyl.
본 명세서를 통하여 화학식 Ⅰ의 화합물을 정의함에 있어서는 다음과 같은 치환체에 대해 정의된 개념들이 사용된다.In defining the compound of Formula I throughout this specification, the concepts defined for the following substituents are used.
용어 "알킬"은 직쇄형 또는 분지형 탄화수소로서, 단일결합, 이중결합 또는 삼중결합을 포함할 수 있고, C1-C10　알킬이 바람직하다. 예를 들어, 상기 알킬은 메틸, 에틸, n-프로필, iso-프로필, n-부틸, iso-부틸, tert-부틸, 아세틸렌, 비닐, 트리플루오로메틸 등을 포함하지만, 이에 한정되는 것은 아니다.The term “alkyl” is a straight-chain or branched hydrocarbon, which may contain single, double or triple bonds, and is preferably C 1 -C 10 alkyl. For example, the alkyl includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, acetylene, vinyl, trifluoromethyl, and the like.
용어 "알콕시"는 달리 정의하지 않는 한 1 내지 10개의 탄소원자를 가지는 알킬옥시를 의미한다.The term "alkoxy", unless otherwise defined, means an alkyloxy having from 1 to 10 carbon atoms.
용어 "할로겐" 또는 "할로"는 불소(F), 염소(Cl), 브롬(Br) 또는 요오드(I)를 나타낸다.The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
일 구현예에서, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물은 하기 화학식 Ⅰa로 표시되는 화합물일 수 있다.In one embodiment, the fluorine-substituted flavonoid derivative compound represented by Formula 1 may be a compound represented by Formula 1a below.
<화학식 Ⅰa><Formula Ia>
Figure PCTKR2022007713-appb-img-000003
Figure PCTKR2022007713-appb-img-000003
상기 식에서,In the above formula,
X 및 Y는 독립적으로 수소, C1-C4 직쇄 또는 분지쇄 알킬, C1-C4 알콕시, 또는 할로겐이고,X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, or halogen;
Z는 수소 또는 할로겐이고,Z is hydrogen or halogen;
R1은 수소, C1-C4 알콕시, 히드록시, 또는 COO-Rc이고,R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
R2는 수소 또는 COO-Rc이고,R 2 is hydrogen or COO-R c ;
상기 Rc는 C1-C4 직쇄 또는 분지쇄 알킬이다.R c is C 1 -C 4 straight or branched chain alkyl.
일 구현예에서, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물은 하기 화학식 Ⅰb로 표시되는 화합물일 수 있다.In one embodiment, the fluorine-substituted flavonoid derivative compound represented by Formula 1 may be a compound represented by Formula 1b below.
<화학식 Ⅰb><Formula Ib>
Figure PCTKR2022007713-appb-img-000004
Figure PCTKR2022007713-appb-img-000004
상기 식에서,In the above formula,
X 및 Y는 독립적으로 수소, C1-C4 직쇄 또는 분지쇄 알킬, C1-C4 알콕시, 할로겐, 히드록시, 또는 OCO-알킬이고,X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, or OCO-alkyl;
Z는 수소, 할로겐, 또는 OCO-알킬이고,Z is hydrogen, halogen, or OCO-alkyl;
R1은 수소, C1-C4 알콕시, 히드록시, 또는 COO-Rc이고,R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
R2는 수소 또는 COO-Rc이고,R 2 is hydrogen or COO-R c ;
상기 Rc는 수소, 또는 C1-C4 직쇄 또는 분지쇄 알킬이다.R c is hydrogen or C 1 -C 4 straight or branched chain alkyl.
일 구현예에서, 상기 X 및 Y는 독립적으로 수소, 메틸, 메톡시, F, Cl, 히드록시, 또는 아세테이트일 수 있다.In one embodiment, X and Y may independently be hydrogen, methyl, methoxy, F, Cl, hydroxy, or acetate.
일 구현예에서, 상기 Z는 수소, F, 또는 아세테이트일 수 있다.In one embodiment, the Z can be hydrogen, F, or acetate.
일 구현예에서, 상기 R1은 수소, 메톡시, 히드록시, 카르복실, 또는 메틸 카르복실레이트일 수 있다.In one embodiment, R 1 can be hydrogen, methoxy, hydroxy, carboxyl, or methyl carboxylate.
일 구현예에서, 상기 R2는 수소, 카르복실, 또는 메틸 카르복실레이트일 수 있다.In one embodiment, R 2 can be hydrogen, carboxyl, or methyl carboxylate.
본 발명에 따른 불소-치환 플라보노이드 유도체 화합물의 구체적인 예는 다음과 같다:Specific examples of the fluorine-substituted flavonoid derivative compounds according to the present invention are as follows:
(E)-1-(4-플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3a),(E) -1- (4-fluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3a );
(E)-1-(4-플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3b),(E) -1- (4-fluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3b ),
(E)-1-(5-플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3c),(E) -1- (5-fluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3c ),
(E)-1-(5-플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3d),(E)-1-(5-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3d );
(E)-1-(2-플루오로-6-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3e),(E) -1- (2-fluoro-6-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3e );
(E)-1-(2-플루오로-6-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3f),(E) -1- (2-fluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3f ),
(E)-1-(2,4-다이플루오로-6-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3g),(E) -1- (2,4-difluoro-6-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3g ),
(E)-1-(2,4-다이플루오로-6-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3h),(E) -1- (2,4-difluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3h ),
(E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3i),(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3i ),
(E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3j),(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3j ),
(E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-(4-히드록시페닐)프로프-2-엔-1-온 (3k),(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one ( 3k ),
(E)-메틸 3-(3-(4,5-다이플루오로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3l),(E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3l ),
(E)-메틸 4-(3-(4,5-다이플루오로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3m),(E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3m );
(E)-1-(4,5-다이클로로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3n),(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3n ),
(E)-1-(4,5-다이클로로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3o),(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3o ),
(E)-1-(4,5-다이클로로-2-히드록시페닐)-3-(4-히드록시페닐)프로프-2-엔-1-온 (3p),(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one ( 3p ),
(E)-메틸 3-(3-(4,5-다이클로로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3q),(E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3q );
(E)-메틸 4-(3-(4,5-다이클로로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3r),(E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3r );
(E)-1-(2-히드록시-4,5-다이메톡시페닐)-3-페닐프로프-2-엔-1-온 (3s),(E) -1- (2-hydroxy-4,5-dimethoxyphenyl) -3-phenylprop-2-en-1-one ( 3s ),
(E)-메틸 4-(3-(2-히드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3t),(E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3t ),
(E)-메틸 3-(3-(2-히드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3u),(E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3u );
(E)-1-(2-히드록시-4,5-다이메틸페닐)-3-페닐프로프-2-엔-1-온 (3v),(E) -1- (2-hydroxy-4,5-dimethylphenyl) -3-phenylprop-2-en-1-one ( 3v ),
(E)-1-(2-히드록시-4,5-다이메틸페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3w),(E) -1- (2-hydroxy-4,5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3w ),
(E)-메틸 4-(3-(2-히드록시-4,5-다이메틸페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3x),(E)-methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3x );
(E)-메틸 3-(3-(2-히드록시-4,5-다이메틸페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3y),(E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3y );
(E)-메틸 4-(3-(2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3z),(E)-methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3z );
7-플루오로-2-페닐-4H-크로멘-4-온 (4a),7-fluoro-2-phenyl-4H-chromen-4-one ( 4a );
7-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4b),7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4b );
6-플루오로-2-페닐-4H-크로멘-4-온 (4c),6-fluoro-2-phenyl-4H-chromen-4-one ( 4c );
6-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4d),6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4d );
5-플루오로-2-페닐-4H-크로멘-4-온 (4e),5-fluoro-2-phenyl-4H-chromen-4-one ( 4e );
5-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4f),5-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4f );
5,7-다이플루오로-2-페닐-4H-크로멘-4-온 (4g),5,7-difluoro-2-phenyl-4H-chromen-4-one ( 4g );
5,7-다이플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4h),5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4h );
6,7-다이플루오로-2-페닐-4H-크로멘-4-온 (4i),6,7-difluoro-2-phenyl-4H-chromen-4-one ( 4i );
6,7-다이플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4j),6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4j );
메틸 3-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조에이트 (4k),methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4k );
메틸 4-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조에이트 (4l),methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4l );
6,7-다이클로로-2-페닐-4H-크로멘-4-온 (4m),6,7-dichloro-2-phenyl-4H-chromen-4-one ( 4m );
6,7-다이클로로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4n),6,7-dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4n );
메틸 3-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조에이트 (4o),methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4o );
메틸 4-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조에이트 (4p),methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4p );
6,7-다이메톡시-2-페닐-4H-크로멘-4-온 (4q),6,7-dimethoxy-2-phenyl-4H-chromen-4-one ( 4q );
메틸 4-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (4r),methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4r );
메틸 3-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (4s),methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4s );
6,7-다이메틸-2-페닐-4H-크로멘-4-온 (4t),6,7-dimethyl-2-phenyl-4H-chromen-4-one ( 4t );
2-(4-메톡시페닐)-6,7-다이메틸-4H-크로멘-4-온 (4u),2-(4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 4u );
메틸 4-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조에이트 (4v),methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4v );
메틸 3-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조에이트 (4w),methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4w );
메틸 4-(4-옥소-4H-크로멘-2-일)벤조에이트 (4x),methyl 4-(4-oxo-4H-chromen-2-yl)benzoate ( 4x );
7-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5a),7-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5a );
6-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5b),6-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5b );
5-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5c),5-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5c );
5,7-다이플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5d),5,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5d );
3-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조산 (5e),3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5e );
4-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조산 (5f),4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5f );
6,7-다이플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5g),6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5g ),
3-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조산 (5h),3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5h );
4-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조산 (5i),4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5i );
6,7-다이히드록시-2-페닐-4H-크로멘-4-온 (5j)6,7-dihydroxy-2-phenyl-4H-chromen-4-one ( 5j )
4-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조산 (5k)4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 5k )
3-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조산 (5l)3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 5l )
2-(4-히드록시페닐)-6,7-다이메틸-4H-크로멘-4-온 (5m)2-(4-hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 5m )
4-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조산 (5n)4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid ( 5n )
3-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조산 (5o)3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid ( 5o )
4-(4-옥소-4H-크로멘-2-일)벤조산 (5p),4-(4-oxo-4H-chromen-2-yl)benzoic acid ( 5p );
4-옥소-2-페닐-4H-크로멘-5,6,7-트리일 트리아세테이트 (7).4-oxo-2-phenyl-4H-chromene-5,6,7-triyl triacetate ( 7 ).
본 발명에 따른 상기 화학식 Ⅰ로 표시되는 화합물은 생체내 흡수를 증진시키거나 용해도를 증가시키기 위하여 프로드럭, 수화물, 용매화물 및 약제학적으로 허용되는 염의 형태로 만들어 사용할 수 있으므로, 상기의 프로드럭, 수화물, 용매화물 및 약제학적으로 허용되는 염 역시 본 발명의 범위에 속한다.Since the compound represented by Formula I according to the present invention can be used in the form of a prodrug, hydrate, solvate, or pharmaceutically acceptable salt in order to improve absorption or solubility in vivo, the prodrug, Hydrates, solvates and pharmaceutically acceptable salts are also within the scope of this invention.
용어 "프로드럭(prodrug)"은 생체내에서 모 약제(parent drug)로 변형되는 물질을 의미한다. 프로드럭은, 몇몇 경우에 있어서, 모 약제보다 투여하기 쉽기 때문에 종종 사용된다. 예를 들어, 이들은 구강 투여에 의해 생활성을 얻을 수 있음에 반하여, 모 약제는 그렇지 못할 수 있다. 프로드럭은 또한 모 약제보다 제약 조성물에서 향상된 용해도를 가질 수도 있다. 예를 들어, 프로드럭은, 본 발명에 따른 화합물의 생체 내 가수분해 가능한 에스테르 및 이의 제약상 허용되는 염일 수 있다. 프로드럭의 또 다른 예는 펩티드가 활성 부위를 드러내도록 물질 대사에 의해 변환되는 산기에 결합되어 있는 짧은 펩티드(폴리아미노산)일 수 있다.The term “prodrug” refers to a substance that is transformed into the parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may obtain bioactivity by oral administration whereas the parent agent may not. A prodrug may also have improved solubility in a pharmaceutical composition than the parent drug. For example, a prodrug may be an in vivo hydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug would be a short peptide (polyamino acid) attached to an acid group that is metabolized to reveal an active site.
용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecular force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다.The term "hydrate" refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or a salt thereof.
용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.The term “solvate” refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.
용어 "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 이성질체에는 호변 이성질체(tautomer) 등의 구조 이성질체와, 비대칭 탄소 중심을 가지는 R 또는 S 이성체, 기하이성질체(트랜스, 시스) 등의 입체 이성질체가 모두 포함된다. 이들 모든 이성체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.The term “isomer” refers to compounds of the present invention or salts thereof that have the same chemical formula or molecular formula but differ structurally or sterically. These isomers include both structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, and stereoisomers such as geometric isomers (trans, cis). All these isomers and mixtures thereof are also included within the scope of the present invention.
용어 "약학적으로 허용가능한 염"은, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 화합물의 염의 형태를 의미한다. 상기 약학적 염은, 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어, 염산, 황산, 질산, 인산, 브롬화수소산, 요드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플로로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리신산 등과 같은 유기 카본산, 메탄설폰산, 에탄술폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 예를 들어, 약제학적으로 허용되는 카르복실산 염에는, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 금속염 또는 알칼리 토금속 염, 라이신, 아르기닌, 구아니딘 등의 아미노산 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸)메틸아민, 디에탄올아민, 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다. 본 발명에 따른 화학식 Ⅰ의 화합물은 통상적인 방법에 의해 그것의 염으로 전환시킬 수도 있다.The term “pharmaceutically acceptable salt” refers to a salt form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salt is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbonic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed with sulfonic acids and the like are included. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N- organic salts such as methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine; and the like. The compounds of formula (I) according to the present invention may be converted into their salts by conventional methods.
본 발명의 화학식 Ⅰ의 불소-치환 플라보노이드 유도체는 이하 설명될 반응식 1 및 반응식 2에 따라 합성할 수 있다. 본 발명의 화학식 Ⅰ의 화합물의 제조방법으로 예시된 반응식 1 및 2의 제조방법이 본 발명에 따른 화학식 Ⅰ의 화합물의 제조방법을 한정하는 것은 아니다. 반응식 1 및 반응식 2의 제조방법은 예시일 뿐이며, 특정 치환체에 따라 통상의 기술자에 의해 용이하게 변형될 수 있음은 자명하다.Fluorine-substituted flavonoid derivatives of formula (I) of the present invention can be synthesized according to Scheme 1 and Scheme 2 described below. The method for preparing the compound of Formula I according to the present invention is not limited to the method for preparing the compound of Formula I according to the present invention. The preparation methods of Reaction Scheme 1 and Reaction Scheme 2 are only examples, and it is obvious that they can be easily modified by a person skilled in the art according to specific substituents.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 TSLP (thymic stromal lymphoprotein) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also relates to prevention or treatment of thymic stromal lymphoprotein (TSLP)-related diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for use.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알러지성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for the prevention or treatment of allergic diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also relates to asthma, allergic rhinitis, chronic sinusitis, and allergic contact, comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. at least one allergic disease selected from sexual dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And it provides a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료방법을 제공한다.The present invention also provides a step of administering a fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof to a subject in need thereof, one or more allergic diseases selected from allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And it provides a method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염의, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스 중에서 선택되는 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염 중에서 선택되는 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택되는 1 이상의 질환의 예방 또는 치료에 사용하기 위한 약제 (medicament)를 제조하기 위한 용도(use)를 제공한다.The present invention also relates to a fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, for asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, at least one allergic disease selected from chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; and chronic obstructive pulmonary disease.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 포함하는 알러지성 질환의 증상 개선용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for improving symptoms of allergic diseases, comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염과, 약제학적으로 허용가능한 첨가제를 포함하는 것을 특징으로 하는 약학적 조성물을 제공한다.The present invention also relates to a pharmaceutical composition comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. provides
상기 첨가제는 약제학적으로 허용가능한 담체 또는 희석제를 포함할 수 있으며, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제제화될 수 있다.The additives may include pharmaceutically acceptable carriers or diluents, and oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterilization according to conventional methods, respectively. It can be formulated in the form of an injection solution.
상기 약제학적으로 허용가능한 담체는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 포함한다. 또한, 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함한다. 경구용 고형 제제는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 포함할 수 있으며, 마그네슘 스테아레이트, 탈크 같은 윤활제 등을 포함할 수 있다. 경구용 액상 제제는 현탁제, 내용액제, 유제, 시럽제 등을 포함하며, 물, 리퀴드 파라핀 등의 희석제, 습윤제, 감미제, 방향제, 보존제 등을 포함할 수 있다. 비경구용 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 크림제, 동결건조 제제, 좌제를 포함하며, 비수성 용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르류 등을 포함한다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The pharmaceutically acceptable carrier is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil; and the like. In addition, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants are included. Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose. ), gelatin, and the like, and may include lubricants such as magnesium stearate and talc. Oral liquid preparations include suspensions, internal solutions, emulsions, syrups, and the like, and may include diluents such as water and liquid paraffin, wetting agents, sweeteners, aromatics, and preservatives. Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, lyophilized preparations, and suppositories, and non-aqueous solvents and suspensions include vegetable oils, injectable esters such as ethyl oleate, and the like. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
본 발명의 약학 조성물에 함유되는 유효성분의 투여량은 환자의 상태 및 체중, 질병의 정도, 유효성분 형태, 투여 경로 및 기간에 따라 다르며, 환자에 따라 적절하게 조절될 수 있다. 예를 들면, 상기 유효성분은 1일 0.0001 내지 1000 mg/kg으로, 바람직하게는 0.01 내지 100 mg/kg의 용량으로 투여할 수 있으며, 상기 투여는 하루에 한번 또는 수회 나누어 투여할 수도 있다. 또한, 본 발명의 약학 조성물은 조성물 총 중량에 대하여 상기 유효성분을 0.001 내지 90 % 중량백분율로 포함할 수 있다.The dose of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of active ingredient, the route and period of administration, and may be appropriately adjusted according to the patient. For example, the active ingredient may be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 100 mg/kg, and the administration may be administered once or several times a day. In addition, the pharmaceutical composition of the present invention may include the active ingredient in a weight percentage of 0.001 to 90% based on the total weight of the composition.
본 발명의 약학 조성물은 랫트, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로, 예를 들면, 경구, 피부, 복강, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내(intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans through various routes, for example, oral, dermal, abdominal, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebral vascular (intracerebroventricular) It may be administered by injection.
이하, 본 발명을 합성예, 실시예 및 실험예를 통하여 더욱 상세히 설명한다. 그러나, 하기 합성예, 실시예 및 실험예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이에 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail through synthesis examples, examples and experimental examples. However, the following synthesis examples, examples and experimental examples are for exemplifying the present invention, but the scope of the present invention is not limited thereto.
합성예 1. 플라보노이드 화합물 합성의 전반적 공정Synthesis Example 1. Overall process of synthesizing flavonoid compounds
하기 반응식 1에 플라보노이드 유도체(5a-5p)의 합성 과정을 나타내었다. Scheme 1 below shows the synthetic process of flavonoid derivatives ( 5a-5p ).
<반응식 1><Scheme 1>
Figure PCTKR2022007713-appb-img-000005
Figure PCTKR2022007713-appb-img-000005
[시약 및 조건: (i) a. 2a-2d의 경우 아세틸 클로라이드, 피리딘, CH2Cl2, 실온, 30분 또는 2e-2f의 경우 아세틸 클로라이드, 아세트산 무수물, 110 ℃, 3시간; b. AlCl3, 120 ℃-150 ℃, 10분-3시간; (ii) 3a-3h에 대하여는 적절한 알데히드, Ba(OH)2, MeOH (또는 EtOH), 40 ℃-50 ℃, 1시간-17시간, 44%-95% 수율 또는 3i-3z에 대하여는 적절한 알데히드, 25%(w/v) NaOMe 용액, THF, 실온, 5시간-12시간, 12%-97% 수율; (iii) 4a-4x에 대하여는 I2, DMSO, 100 ℃-110 ℃, 6시간-24시간, 47%-97% 수율; (iv) 5a-5d, 5g, 5j, 및 5m에 대하여는 CH2Cl2 중 1.0 M BBr3, CH2Cl2, 50 ℃, 14 시간-18 시간, 13%-97% 수율 또는 5e-5f, 5h-5i, 5k-5l 및 5n-5p에 대하여는 1 N NaOH, MeOH, 70 ℃-80 ℃, 1시간-4시간, 49%-78% 수율.][Reagents and conditions: (i) a. Acetyl chloride, pyridine, CH 2 Cl 2 , room temperature, 30 minutes for 2a-2d or acetyl chloride, acetic anhydride, 110° C., 3 hours for 2e -2f ; b. AlCl 3 , 120 °C-150 °C, 10 minutes-3 hours; (ii) a suitable aldehyde for 3a-3h , Ba(OH) 2 , MeOH (or EtOH), 40 °C-50 °C, 1 h-17 h, 44%-95% yield or a suitable aldehyde for 3i-3z ; 25% (w/v) NaOMe solution, THF, room temperature, 5-12 hours, 12%-97% yield; (iii) I 2 , DMSO, 100 °C-110 ° C , 6h-24h for 4a- 4x , 47%-97% yield; (iv) for 5a-5d, 5g, 5j , and 5m , 1.0 M BBr 3 in CH 2 Cl 2 , CH 2 Cl 2 , 50° C., 14 hr-18 hr, 13%-97% yield or 5e-5f; 1 N NaOH, MeOH, 70 °C-80 °C, 1 h-4 h for 5h-5i, 5k-5l and 5n-5p , 49%-78% yield.]
반응식 1에는 화합물 중 페닐 링 2개 각각에 다양한 작용기가 치환된 플라보노이드 유도체의 합성 과정이 설명되어 있다. 아세토페논(acetophenone) 화합물인 2a-2c 및 2g-2i의 경우 상업적으로 입수 가능하며 출발 물질로 사용되었다. 그러나, 치환기가 2개인 화합물 2d-2f는 2단계를 거쳐 합성되었다(반응식 1 참조). 또한, 출발물질 1a를 상온에서 다이클로로메탄 중 피리딘의 존재 하에서 아세틸 클로라이드와 반응시켰다. TLC로 반응의 진행을 모니터링한 후, 반응 혼합물에 염화알루미늄을 첨가하고 150 ℃에서 후속 반응을 수행하여 화합물 2d를 얻었다. 한편, 3,4-다이플루오로페놀 (1b) 및 3,4-다이클로로페놀 (1c)을 110 ℃에서 아세트산 무수물 중 아세트산나트륨과 반응시켰다. 정제 후 아세틸화 화합물을 다이클로로메탄에 녹이고 염화알루미늄을 조금씩 첨가하여 120 ℃에서 교반하였다. TLC로 반응 진행 상황을 모니터링한 후 10% HCl로 중화하고 다이클로로메탄으로 추출하였다. 실리카겔 컬럼 크로마토그래피로 정제하여 화합물 2e 및 2f를 얻었다. 화합물 3a-3z는 화합물 2a-2i를 적절한 알데히드와 반응시키는 클레이젠-슈미트 (Claisen-Schmidt) 축합 반응을 통해 얻었으며, 3a-3h에 대하여는 메탄올(또는 에탄올) 중 수산화바륨과 40 ℃-50 ℃에서 1시간-17시간 동안, 또는 3i-3z에 대하여는 THF 중 25% (w/v) NaOMe 용액에서 0℃에서 실온까지 12시간 동안 반응시켰다. 화합물 4a-4h는 6시간-24시간 동안 110 ℃에서 DMSO 중 화합물 3a-3h를 요오드와 반응시켜 분자내 고리화(intramolecular cyclization)를 통해 47%-97% 수율로 얻었다. 화합물 5a-5d, 5g, 5j 및 5m은 화합물 4b, 4d, 4f, 4h, 4j, 4q 및 4u를 14시간 내지 20시간 동안 다이클로로메탄 중 삼브롬화붕소(boron tribromide)와 반응시켜 13% 내지 97% 수율로 수득하였다. 화합물 5e-5f, 5h-5i, 5k-5l 및 5n-5p는 화합물 4k-4l, 4o-4p, 4r-4s 및 4v-4x를 70 ℃에서 1시간-4시간 동안MeOH 중 1 N NaOH와 반응시켜 49%-78% 수율로 얻었다. Scheme 1 describes the synthesis of flavonoid derivatives in which two phenyl rings of the compound are substituted with various functional groups. The acetophenone compounds 2a-2c and 2g-2i were commercially available and used as starting materials. However, compounds 2d-2f having two substituents were synthesized in two steps (see Scheme 1). In addition, starting material 1a was reacted with acetyl chloride in the presence of pyridine in dichloromethane at room temperature. After monitoring the progress of the reaction by TLC, aluminum chloride was added to the reaction mixture and a subsequent reaction was conducted at 150° C. to obtain compound 2d . Meanwhile, 3,4-difluorophenol ( 1b ) and 3,4-dichlorophenol ( 1c ) were reacted with sodium acetate in acetic anhydride at 110 °C. After purification, the acetylated compound was dissolved in dichloromethane, aluminum chloride was added little by little, and the mixture was stirred at 120 °C. After monitoring the progress of the reaction by TLC, it was neutralized with 10% HCl and extracted with dichloromethane. Purification by silica gel column chromatography gave compounds 2e and 2f . Compounds 3a-3z were obtained via the Claisen-Schmidt condensation reaction of compounds 2a-2i with appropriate aldehydes, and for 3a-3h with barium hydroxide in methanol (or ethanol) at 40 °C-50 °C. for 1-17 hours, or for 3i-3z in a 25% (w/v) NaOMe solution in THF from 0°C to room temperature for 12 hours. Compounds 4a-4h were obtained in 47%-97% yields through intramolecular cyclization by reacting compounds 3a-3h with iodine in DMSO at 110 °C for 6-24 hours. Compounds 5a-5d, 5g, 5j and 5m were obtained by reacting compounds 4b, 4d, 4f, 4h, 4j, 4q and 4u with boron tribromide in dichloromethane for 14 to 20 hours to obtain a concentration of 13% to 97%. Obtained in % yield. Compounds 5e-5f, 5h-5i, 5k-5l and 5n-5p reacted with compounds 4k-4l, 4o-4p, 4r-4s and 4v-4x with 1 N NaOH in MeOH at 70 °C for 1-4 hours. It was obtained in 49%-78% yield.
하기 반응식 2에 아세틸 치환 플라보노이드(7)의 합성 과정을 나타내었다.The synthetic process of the acetyl-substituted flavonoid ( 7 ) is shown in Scheme 2 below.
<반응식 2><Scheme 2>
Figure PCTKR2022007713-appb-img-000006
Figure PCTKR2022007713-appb-img-000006
[시약 및 조건: (i) 아세틸 클로라이드, 다이이소프로필에틸아민, DMF, 0 ℃ 내지 실온, 15시간, 93% 수율.][Reagents and conditions: (i) acetyl chloride, diisopropylethylamine, DMF, 0 ° C to room temperature, 15 hours, 93% yield.]
반응식 2에는 A 고리의 아세틸기를 갖는 플라보노이드 유도체의 합성 과정이 나타나 있다. 5,6,7-트리히드록시플라본 (6) [Trihydroxyflavone (6)]은 상업적으로 입수 가능하며 출발 물질로 사용되었다. 5,6,7-트리히드록시플라본 (6)을 0℃ 내지 실온에서 DMF에서 염기로서 다이이소프로필에틸아민의 존재 하에 아세틸 클로라이드와 반응시켰다. TLC로 반응 진행 상황을 모니터링한 후, 이를 톨루엔으로 농축하고 실리카겔 컬럼 크로마토그래피로 정제하여 화합물 7을 93% 수율로 얻었다. Reaction Scheme 2 shows the synthetic process of flavonoid derivatives having an acetyl group of the A ring. 5,6,7-Trihydroxyflavone ( 6 ) [Trihydroxyflavone ( 6 )] was commercially available and was used as the starting material. 5,6,7-trihydroxyflavone ( 6 ) was reacted with acetyl chloride in the presence of diisopropylethylamine as base in DMF at 0°C to room temperature. After monitoring the reaction progress by TLC, it was concentrated with toluene and purified by silica gel column chromatography to obtain compound 7 in 93% yield.
합성예 2. 화합물 3a-3z 에 대한 공통 합성 과정Synthesis Example 2. Common synthetic procedure for compounds 3a-3z
메탄올(MeOH) 또는 에탄올(EtOH) 중 치환된 아세토페논 화합물(2a-2d)의 교반된 용액에 실온에서 수산화바륨(barium hydroxide, 2.0당량) 및 적절한 알데히드(1.2당량)를 첨가하였다. TLC 분석으로 완전한 전환이 확인될 때까지(일반적으로 1시간 내지 20시간) 반응 혼합물을 아르곤 하에 40 ℃ 내지 50 ℃에서 교반하고, 아세트산(1.5 mL)으로 켄칭하고, EtOAc(30 mL) 및 H2O(30 mL)로 추출하여 3a-3h을 얻었다. 다른 방법으로, THF 중 치환된 아세토페논 화합물(2e-2i)의 교반된 용액에 아르곤 하에 0℃에서 25%(w/v) 나트륨 메톡사이드 용액(1.2 당량-1.4 당량)을 첨가하였다. 20분 후, 적절한 알데하이드(1.2 당량)를 반응 혼합물에 첨가하고, TLC 분석으로 완전한 전환이 확인될 때까지(일반적으로 12시간) 실온에서 아르곤 하에 교반하였다. 혼합물을 농축하고 EtOAc, 3N HCl 용액 및 NH4Cl 용액으로 추출하였다. 유기층을 MgSO4상에서 건조시키고, 여과하고, 감압 하에서 농축시켜 3i-3z를 얻었다. 유기층을 포화 수성 NaHCO3로 세척하고, MgSO4로 건조시키고, 여과하고, 감압 하에서 농축시켰다. 조 잔류물을 실리카겔 컬럼 크로마토그래피로 정제하여 화합물 3a-3z를 얻었다.To a stirred solution of the substituted acetophenone compound ( 2a-2d ) in methanol (MeOH) or ethanol (EtOH) was added barium hydroxide (2.0 equiv.) and the appropriate aldehyde (1.2 equiv.) at room temperature. The reaction mixture was stirred under argon at 40° C. to 50° C. until complete conversion was confirmed by TLC analysis (usually 1 hour to 20 hours), quenched with acetic acid (1.5 mL), EtOAc (30 mL) and H 2 Extraction with O (30 mL) gave 3a-3h . Alternatively, to a stirred solution of the substituted acetophenone compound ( 2e-2i ) in THF was added a 25% (w/v) sodium methoxide solution (1.2 equiv-1.4 equiv) at 0°C under argon. After 20 min, the appropriate aldehyde (1.2 eq) was added to the reaction mixture and stirred at room temperature under argon until complete conversion was confirmed by TLC analysis (typically 12 hours). The mixture was concentrated and extracted with EtOAc, 3N HCl solution and NH 4 Cl solution. The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure to give 3i-3z . The organic layer was washed with saturated aqueous NaHCO 3 , dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give compounds 3a-3z .
실시예 1. (E)-1-(4-플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3a) [Example 1. (E)-1-(4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3a) [ (E)-1-(4-Fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one(E)-1-(4-Fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3a)] (3a)]
화합물 3a는 1-(4-플루오로-2-하이드록시페닐)에탄-1-온(2a; 200 mg, 1.3 mmol) [1-(4-fluoro-2-hydroxyphenyl)ethan-1-one], 벤즈알데히드(159 μL, 1.6 mmol) 및 수산화바륨(446 mg, 2.6 mmol)을 사용하여 메탄올(8.0 mL) 중에서 50 ℃에서 1시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 72% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 13.2 (s, 1H), 7.97-7.90 (m, 2H), 7.70-7.64 (m, 2H), 7.58 (d, J = 15.6 Hz, 1H), 7.48-7.43 (m, 3H), 6.71 (dd, J = 2.6 Hz and J = 10.3 Hz, 1H), 6.69-6.65 (m, 1H).Compound 3a is 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2a ; 200 mg, 1.3 mmol) [ 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ], Benzaldehyde (159 μL, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) were stirred in methanol (8.0 mL) at 50 ° C. for 1 hour, followed by the same method as described in Synthesis Example 2, yielding 72% as a yellow powder. was obtained with The crude residue was purified by column chromatography on silica gel. 1H NMR (600 MHz, CDCl 3 ) δ 13.2 (s, 1H), 7.97-7.90 (m, 2H), 7.70-7.64 (m, 2H), 7.58 (d, J = 15.6 Hz, 1H), 7.48- 7.43 (m, 3H), 6.71 (dd, J = 2.6 Hz and J = 10.3 Hz, 1H), and 6.69–6.65 (m, 1H).
실시예 2. (E)-1-(4-플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3b) [Example 2. (E)-1-(4-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3b) [ (E)-1-(4-Fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one(E)-1-(4-Fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3b)] (3b)]
화합물 3b는 1-(4-플루오로-2-하이드록시페닐)에탄-1-온(2a; 200 mg, 1.3 mmol), p-아니스알데히드(p-anisaldehyde, 190 μL, 1.6 mmol) 및 수산화바륨(445 mg, 2.6 mmol)을 사용하여 메탄올(10 mL) 중에서 50 ℃에서 17시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 44% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 13.33 (s, 1H), 7.96-7.89 (m, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 15.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.70 (dd, J = 2.5 Hz and J = 10.3 Hz, 1H), 6.68-6.63 (m, 1H), 3.87 (s, 3H).Compound 3b was 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2a ; 200 mg, 1.3 mmol), p-anisaldehyde ( p- anisaldehyde, 190 μL, 1.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was stirred in methanol (10 mL) at 50 °C for 17 hours to obtain a yellow powder in 44% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 13.33 (s, 1H), 7.96–7.89 (m, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 15.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H) ), 6.70 (dd, J = 2.5 Hz and J = 10.3 Hz, 1H), 6.68–6.63 (m, 1H), 3.87 (s, 3H).
실시예 3. (E)-1-(5-플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3c) [Example 3. (E)-1-(5-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3c) [ (E)-1-(5-Fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one(E)-1-(5-Fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3c)] (3c)]
화합물 3c는 1-(5-플루오로-2-히드록시페닐)에탄-1-온(2b; 200 mg, 1.3 mmol), 벤즈알데히드(159 μL, 1.6 mmol) 및 수산화바륨(446 mg, 2.6 mmol)을 사용하여 메탄올(8.0 mL) 중에서 50 ℃에서 1시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 12.53 (s, 1H), 7.95 (d, J = 15.4 Hz, 1H), 7.72-7.66 (m, 2H), 7.59 (dd, J = 3.0 Hz and J = 9.0 Hz, 1H), 7.55 (d, J = 15.4 Hz, 1H), 7.47-7.44 (m, 3H), 7.29-7.22 (m, 2H), 7.0 (dd, J = 4.6 Hz and J = 9.1 Hz, 1H). Compound 3c was 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one ( 2b ; 200 mg, 1.3 mmol), benzaldehyde (159 μL, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) was stirred in methanol (8.0 mL) at 50 °C for 1 hour to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 12.53 (s, 1H), 7.95 (d, J = 15.4 Hz, 1H), 7.72-7.66 (m, 2H), 7.59 (dd, J = 3.0 Hz and J = 9.0 Hz, 1H), 7.55 (d, J = 15.4 Hz, 1H), 7.47–7.44 (m, 3H), 7.29–7.22 (m, 2H), 7.0 (dd, J = 4.6 Hz and J = 9.1 Hz, 1H).
실시예 4. (E)-1-(5-플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3d) [Example 4. (E)-1-(5-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3d) [ (E)-1-(5-Fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one(E)-1-(5-Fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3d)] (3d)]
화합물 3d는 1-(4-플루오로-2-히드록시페닐)에탄-1-온 (2b; 200 mg, 1.3 mmol), p-아니스알데히드(190 μL, 2.6 mmol) 및 수산화바륨(445 mg, 2.6 mmol)을 사용하여 메탄올(10 mL) 중에서 40℃에서 4시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 76% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 12.65 (s, 1H), 7.93 (d, J = 15.3 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 2.9 Hz and J = 9.1 Hz, 1H), 7.43 (d, J = 15.3 Hz, 1H), 7.25-7.21 (m, 1H), 7.02-6.94 (m, 3H), 3.88 (s, 3H).Compound 3d was 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2b ; 200 mg, 1.3 mmol), p-anisaldehyde (190 μL, 2.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was used in methanol (10 mL) at 40° C. for 4 hours to obtain a yellow powder in 76% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 12.65 (s, 1H), 7.93 (d, J = 15.3 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 2.9 Hz and J = 9.1 Hz, 1H), 7.43 ( d, J = 15.3 Hz, 1H), 7.25–7.21 (m, 1H), 7.02–6.94 (m, 3H), 3.88 (s, 3H).
실시예 5. (E)-1-(2-플루오로-6-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3e) [Example 5. (E)-1-(2-fluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one (3e) [ (E)-1-(2-Fluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one(E)-1-(2-Fluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one (3e)] (3e)]
화합물 3e는 1-(2-플루오로-6-히드록시페닐)에탄-1-온(2c; 166 μL, 1.3 mmol), 벤즈알데히드(159 μL, 1.6 mmol) 및 수산화바륨(446 mg, 2.6 mmol)을 사용하여 메탄올(8.0 mL)중에서 50 ℃에서 3시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.94 (dd, J = 3.5 Hz and J = 16.0 Hz, 1H), 7.72-7.64 (m, 3H), 7.49-7.38 (m, 4H), 6.58 (d, J = 8.5 Hz, 1H), 6.71-6.61 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 192.49, 164.68, 163.74, 162.05, 145.72, 136.07, 135.98, 134.66, 131.00, 129.04, 128.86, 125.39, 125.28, 114.47, 106.40, 106.23. HRMS m/z calculated for C15H11FO2 [M-H]- : 241.0670; found : 241.0681.Compound 3e was 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one ( 2c ; 166 μL, 1.3 mmol), benzaldehyde (159 μL, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) was stirred in methanol (8.0 mL) at 50 °C for 3 hours to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1H NMR (600 MHz, CDCl 3 ) δ 7.94 (dd, J = 3.5 Hz and J = 16.0 Hz, 1H), 7.72-7.64 (m, 3H), 7.49-7.38 (m, 4H), 6.58 (d, J = 8.5 Hz, 1H), 6.71–6.61 (m, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 192.49, 164.68, 163.74, 162.05, 145.72, 136.07, 135.98, 134.66, 131.00, 129.04, 128.86, 125.39, 125.28, 114.47, 106.40, 106.23 HRMS m / z calculated for C 15 H 11 FO 2 [MH] - : 241.0670; found: 241.0681.
실시예 6. (E)-1-(2-플루오로-6-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3f) [Example 6. (E)-1-(2-fluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3f) [ (E)-1-(2-Fluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one(E)-1-(2-Fluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3f)] (3f)]
화합물 3f는 1-(2-플루오로-6-히드록시페닐)에탄-1-온(2c; 200 mg, 1.3 mmol), p-아니스알데히드(190 μL, 1.6 mmol) 및 수산화바륨(445 mg, 2.6 mmol)을 사용하여 메탄올(10 mL) 중에서 50 ℃에서 6시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 13.17 (s, 1H), 7.93 (dd, J = 3.4 Hz and J = 15.2 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.56 (dd, J =1.8 Hz and J = 15.4 Hz, 1H), 7.42-7.36 (m, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.3 Hz and J = 12.1 Hz, 1H), 3.87 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 192.35, 164.68, 163.72, 162.13, 162.02, 145.77, 135.75, 135.67, 130.80, 130.78, 127.45, 122.99, 122.88, 114.55, 114.53, 114.40, 110.73, 110.63, 106.34, 106.18, 55.47. HRMS m/z calculated for C16H16F1O3 [M-H]- : 271.0776; found : 271.0780.Compound 3f was 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one ( 2c ; 200 mg, 1.3 mmol), p-anisaldehyde (190 μL, 1.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was used in methanol (10 mL) at 50 °C for 6 hours to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 13.17 (s, 1H), 7.93 (dd, J = 3.4 Hz and J = 15.2 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.56 (dd, J =1.8 Hz and J = 15.4 Hz, 1H), 7.42-7.36 (m, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.3 Hz and J = 12.1 Hz, 1H), 3.87 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 192.35, 164.68, 163.72, 162.13, 162.02, 145.77, 135.75, 135.67, 130.80, 130.78, 127.45, 122.99, 122.88, 114.55, 114.53, 114.40, 110.73, 110.63 HRMS m / z calculated for C 16 H 16 F 1 O 3 [MH] - : 271.0776; found: 271.0780.
실시예 7. (E)-1-(2,4-다이플루오로-6-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3g) [Example 7. (E)-1-(2,4-difluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one (3g) [ (E)-1-(2,4-Difluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one(E)-1-(2,4-Difluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one (3g)] (3g)]
화합물 3g는 1-(2,4-다이플루오로-6-히드록시페닐)에탄-1-온(2d; 200 mg, 1.2 mmol), 벤즈알데히드(142 μL, 1.4 mmol) 및 수산화바륨(398 mg, 2.3 mmol)을 사용하여 메탄올(8.0 mL) 중에서 50 ℃에서 2시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 95% 수율로 수득하였다. 조 잔류물을 추가 정제 없이 다음 단계에 사용하였다. 1H NMR (600 MHz, CDCl3) δ 7.98 (dd, J = 3.3 Hz and J = 15.4 Hz, 1H), 7.71-7.66 (m, 2H), 7.64 (dd, J = 2.2 Hz and J = 15.4 Hz, 1H), 7.50-7.44 (m, 3H), 6.59-6.53 (m, 1H), 6.47-6.41 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 191.64, 191.60, 167.64, 166.78, 166.71, 165.09, 164.98, 163.39, 163.28, 146.20, 134.53, 131.13, 129.07, 128.88, 124.78, 124.67, 101.59, 101.43, 101.41, 96.27, 96.08, 95.90. HRMS m/z calculated for C15H10F2O2 [M-H]- : 259.0576; found : 259.0587.Compound 3g was 1-(2,4-difluoro-6-hydroxyphenyl)ethan-1-one ( 2d ; 200 mg, 1.2 mmol), benzaldehyde (142 μL, 1.4 mmol) and barium hydroxide (398 mg, 2.3 mmol) was used in methanol (8.0 mL) at 50 °C for 2 hours to obtain a yellow powder in 95% yield in the same manner as described in Synthesis Example 2. The crude residue was used in the next step without further purification. 1H NMR (600 MHz, CDCl 3 ) δ 7.98 (dd, J = 3.3 Hz and J = 15.4 Hz, 1H), 7.71-7.66 (m, 2H), 7.64 (dd, J = 2.2 Hz and J = 15.4 Hz , 1H), 7.50-7.44 (m, 3H), 6.59-6.53 (m, 1H), 6.47-6.41 (m, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 191.64, 191.60, 167.64, 166.78, 166.71, 165.09, 164.98, 163.39, 163.28, 146.20, 134.53, 131.13, 129.07, 128.88, 124.78, 124.67, 101.59, 101.43, 96.08, 96.08, 96.08. HRMS m / z calculated for C 15 H 10 F 2 O 2 [MH] - : 259.0576; found: 259.0587.
실시예 8. (E)-1-(2,4-다이플루오로-6-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3h) [Example 8. (E) -1- (2,4-difluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (3h) [ (E)-1-(2,4-Difluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one(E)-1-(2,4-Difluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3h)] (3h)]
화합물 3h는 1-(2,4-다이플루오로-6-히드록시페닐)에탄-1-온(2d; 200 mg, 1.2 mmol), p-아니스알데히드(169 μL, 1.4 mmol) 및 수산화바륨(398 mg, 2.3 mmol)을 사용하여 메탄올(8.0 mL) 중에서 50 ℃에서 3시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 85% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.94 (dd, J = 3.5 and J = 15.4 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.50 (dd, J = 1.9 Hz and J = 15.3 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.55-6.50 (m, 1H), 6.43-6.36 (m, 1H), 3.87 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 191.39, 162.23, 146.22, 130.82, 127.30, 122.29, 122.17, 114.55, 101.47, 101.34, 96.13, 95.94, 55.46. HRMS m/z calculated for C16H12F2O5 [M-H]- : 289.0682; found : 289.0696.Compound 3h was 1-(2,4-difluoro-6-hydroxyphenyl)ethan-1-one ( 2d ; 200 mg, 1.2 mmol), p-anisaldehyde (169 μL, 1.4 mmol) and barium hydroxide ( 398 mg, 2.3 mmol) was stirred in methanol (8.0 mL) at 50 °C for 3 hours to obtain a yellow powder in 85% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.94 (dd, J = 3.5 and J = 15.4 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.50 (dd, J = 1.9 Hz and J = 15.3 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.55–6.50 (m, 1H), 6.43–6.36 (m, 1H), 3.87 (s, 3H); 13 C NMR (150 MHz, DMSO-d 6 ) δ 191.39, 162.23, 146.22, 130.82, 127.30, 122.29, 122.17, 114.55, 101.47, 101.34, 96.13, 95.94, 55.46 . HRMS m / z calculated for C 16 H 12 F 2 O 5 [MH] - : 289.0682; found: 289.0696.
실시예 9. (E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3i) [Example 9. (E)-1-(4,5-difluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3i) [ (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3i)](3i)]
화합물 3i는 1-(4,5-다이플루오로-2-히드록시페닐)에타논(2e; 200 mg, 1.2 mmol), 벤즈알데히드(142 μL, 1.7 mmol) 및 나트륨 메톡사이드 용액(397.8 μL, 1.7 mmol)을 사용하여 THF(7.5 mL) 중에서 실온에서 24시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 57% 수율로 수득하였다. 조 잔류물을 n-헥산으로 재결정하여 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 15.0 Hz), 7.73 (dd, J = 9.0 Hz and J = 10.2 Hz, 1H), 7.69-7.67 (m, 2H), 7.49-7.45 (m, 4H), 6.84 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 192.02, 161.41, 156.36, 156.27, 146.61, 134.23, 131.35, 129.16, 128.83, 119.36, 116.97, 116.95, 116.85, 107.11, 106.99. HRMS m/z calculated for C15H10F2O2 [M-H]- : 259.0576; found : 259.0587.Compound 3i was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 200 mg, 1.2 mmol), benzaldehyde (142 μL, 1.7 mmol) and sodium methoxide solution (397.8 μL, 1.7 μL). mmol) in THF (7.5 mL) at room temperature for 24 hours to obtain a yellow powder in 57% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane. 1 H NMR (600 MHz, CDCl 3 ) δ 7.96 (d, J = 15.0 Hz), 7.73 (dd, J = 9.0 Hz and J = 10.2 Hz, 1H), 7.69-7.67 (m, 2H), 7.49-7.45 (m, 4H), 6.84 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 192.02, 161.41, 156.36, 156.27, 146.61, 134.23, 131.35, 129.16, 128.83, 119.36, 116.97, 116.95, 116.85, 107.11, 106.99. HRMS m / z calculated for C 15 H 10 F 2 O 2 [MH] - : 259.0576; found: 259.0587.
실시예 10. (E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3j) [Example 10. (E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (3j) [ (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3j)](3j)]
화합물 3j는 1-(4,5-다이플루오로-2-히드록시페닐)에타논(2e; 300 mg, 1.7 mmol), p-아니스알데히드(254 μL, 2.6 mmol) 및 나트륨 메톡사이드 용액(596.8 μL, 2.6 mmol)을 사용하여 THF(11 mL) 중에서 실온에서 5시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 90% 수율로 수득하였다. 조 잔류물을 n-헥산으로 재결정하여 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 15.6 Hz, 1H), 7.72 (dd, J = 8.7 Hz and J = 10.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 15.3 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H), 3.89 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 192.02, 161.41, 156.36, 156.27, 146.61, 134.23, 131.35, 129.16, 12.83, 119.36, 116.97, 116.95, 116.5, 107.11, 106.9. HRMS m/z calculated for C16H12F2O3 [M-H]- : 289.0682; found : 289.0695.Compound 3j was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 300 mg, 1.7 mmol), p-anisaldehyde (254 μL, 2.6 mmol) and sodium methoxide solution (596.8 μL, 2.6 mmol) was stirred in THF (11 mL) at room temperature for 5 hours to obtain a yellow powder in 90% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane. 1H NMR (600 MHz, CDCl 3 ) δ 7.94 (d, J = 15.6 Hz, 1H), 7.72 (dd, J = 8.7 Hz and J = 10.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H) ), 7.35 (d, J = 15.3 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H), 3.89 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 192.02, 161.41, 156.36, 156.27, 146.61, 134.23, 131.35, 129.16, 12.83, 119.36, 116.97, 116.95, 116.1, 1.107.19 HRMS m / z calculated for C 16 H 12 F 2 O 3 [MH] - : 289.0682; found: 289.0695.
실시예 11. (E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-(4-히드록시페닐)프로프-2-엔-1-온 (3k) [Example 11. (E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one (3k) [ (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (3k)](3k)]
화합물 3k는 1-(4,5-다이플루오로-2-히드록시페닐)에테논(2e; 300 mg, 1.7 mmol), 하이드록시벤즈알데하이드(173 mg, 2.6 mmol) 및 나트륨 메톡사이드 용액(398 μL, 2.6 mmol)을 사용하여 THF(7.5 mL) 중에서 실온에서 50 ℃로 24시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 12% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, MeOD) δ 8.15 (dd, J = 9.0 Hz and J =11.4 Hz, 1H), 7.92 (d, J = 15.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 15.6 Hz, 1H), 6.89-6.86 (m, 3H).Compound 3k was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethenone ( 2e ; 300 mg, 1.7 mmol), hydroxybenzaldehyde (173 mg, 2.6 mmol) and sodium methoxide solution (398 μL, 2.6 mmol) was used in THF (7.5 mL) at room temperature to 50 ° C. for 24 hours to obtain a yellow powder in 12% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1H NMR (600 MHz, MeOD) δ 8.15 (dd, J = 9.0 Hz and J =11.4 Hz, 1H), 7.92 (d, J = 15.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H) , 7.65 (d, J = 15.6 Hz, 1H), 6.89–6.86 (m, 3H).
실시예 12. (E)-메틸 3-(3-(4,5-다이플루오로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3l) [Example 12. (E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3l) [ (E)-Methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (E)-Methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3l)](3l)]
화합물 3l은 1-(4,5-다이플루오로-2-히드록시페닐)에타논(2e; 150 mg, 0.87 mmol), 메틸-3-포르밀벤조에이트(methyl-3-formylbenzoate, 171 mg, 1.3 mmol) 및 나트륨 메톡사이드 용액(298 μL, 1.3 mmol)을 사용하여 THF(5.7 mL) 중에서 실온에서 5시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 23% 수율로 수득하였다. 조 잔류물을 EtOH로 재결정하여 정제하였다. 1H NMR (600 MHz, MeOD) δ 8.44 (brs, 1H), 8.24 (t, J = 10.2 Hz, 1H), 8.10 (dd, J = 7.2 Hz and J = 16.2 Hz, 2H), 8.03-7.91 (m, 3H), 7.61 (t, J = 7.8 Hz, 1H), 6.92 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H), 3.98 (s, 3H).Compound 3l is 1- (4,5-difluoro-2-hydroxyphenyl) ethanone ( 2e ; 150 mg, 0.87 mmol), methyl-3-formylbenzoate (methyl-3-formylbenzoate, 171 mg, 1.3 mmol) and sodium methoxide solution (298 μL, 1.3 mmol) were stirred in THF (5.7 mL) at room temperature for 5 hours to obtain a yellow powder in 23% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from EtOH. 1H NMR (600 MHz, MeOD) δ 8.44 (brs, 1H), 8.24 (t, J = 10.2 Hz, 1H), 8.10 (dd, J = 7.2 Hz and J = 16.2 Hz, 2H), 8.03-7.91 ( m, 3H), 7.61 (t, J = 7.8 Hz, 1H), 6.92 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H), 3.98 (s, 3H).
실시예 13. (E)-메틸 4-(3-(4,5-다이플루오로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3m) [Example 13. (E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3m) [ (E)-Methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (E)-Methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3m)](3m)]
화합물 3m은 1-(4,5-다이플루오로-2-하이드록시페닐)에타논(2e; 350 mg, 2.0 mmol), 메틸 테레프탈알데하이드레이트(methyl terephthalaldehydate, 400 mg, 3.0 mmol) 및 나트륨 메톡사이드 용액(696 μL, 3.0 mmol)를 사용하여 THF(13 mL) 중에서 실온에서 5시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 28% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 7.8 Hz, 2H), 7.97 (d, J = 15.6 Hz, 1H), 7.76-7.73 (m, 3H), 7.56 (d, J = 15.3 Hz, 1H), 6.85 (dd, J = 6.6 Hz and J = 10.8 Hz, 1H), 3.97 (s 3H).Compound 3m is 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 350 mg, 2.0 mmol), methyl terephthalaldehydate (400 mg, 3.0 mmol) and sodium methoxide The solution (696 μL, 3.0 mmol) was stirred in THF (13 mL) at room temperature for 5 hours to obtain a yellow powder in 28% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.14 (d, J = 7.8 Hz, 2H), 7.97 (d, J = 15.6 Hz, 1H), 7.76-7.73 (m, 3H), 7.56 (d, J = 15.3 Hz, 1H), 6.85 (dd, J = 6.6 Hz and J = 10.8 Hz, 1H), 3.97 (s 3H).
실시예 14. (E)-1-(4,5-다이클로로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3n) [Example 14. (E) -1- (4,5-dichloro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one (3n) [ (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3n)](3n)]
화합물 3n은 1-(4,5-다이클로로-2-히드록시페닐)에타논(2f; 150 mg, 0.73 mmol), 벤즈알데히드(89.4 μL, 1.1 mmol) 및 나트륨 메톡사이드 용액(250 μL, 1.1 mmol)을 사용하여 THF(4.8 mL) 중에서 실온에서 5시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 73% 수율로 수득하였다. 조 잔류물을 n-헥산으로 재결정하여 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.98 (d, J = 15.6, 1H), 7.71-7.69 (m, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.48-7.46 (m, 3H), 7.18 (s, 1H).Compound 3n was 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 150 mg, 0.73 mmol), benzaldehyde (89.4 μL, 1.1 mmol) and sodium methoxide solution (250 μL, 1.1 mmol) ) was stirred in THF (4.8 mL) at room temperature for 5 hours to obtain a yellow powder in 73% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane. 1H NMR (600 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.98 (d, J = 15.6, 1H), 7.71-7.69 (m, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.48-7.46 (m, 3H), 7.18 (s, 1H).
실시예 15. (E)-1-(4,5-다이클로로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3o) [Example 15. (E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (3o) [ (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3o)](3o)]
화합물 3o는 1-(4,5-다이클로로-2-히드록시페닐)에타논(2f; 300 mg, 1.5 mmol), p- 아니스알데히드(213 μL, 2.2 mmol) 및 나트륨 메톡사이드 용액(501 μL, 2.2 mmol)을 사용하여 THF(9.6 mL) 중에서 실온에서 5시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 82% 수율로 수득하였다. 조 잔류물을 n-헥산으로 재결정하여 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.95 (d, J = 15.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 15.3 Hz, H), 7.17 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H).Compound 3o was prepared from 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 300 mg, 1.5 mmol), p-anisaldehyde (213 μL, 2.2 mmol) and sodium methoxide solution (501 μL). , 2.2 mmol) was stirred in THF (9.6 mL) at room temperature for 5 hours to obtain a yellow powder in 82% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane. 1H NMR (600 MHz, CDCl 3 ) δ 7.98 (s, 1H), 7.95 (d, J = 15.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 15.3 Hz , H), 7.17 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H).
실시예 16. (E)-1-(4,5-다이클로로-2-히드록시페닐)-3-(4-히드록시페닐)프로프-2-엔-1-온 (3p) [Example 16. (E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one (3p) [ (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (3p)](3p)]
화합물 3p는 1-(4,5-다이클로로-2-히드록시페닐)에타논(2f; 200 mg, 0.98 mmol), 하이드록시벤즈알데하이드(182 mg, 1.5 mmol) 및 나트륨 메톡사이드 용액(334 μL, 1.5 mmol)을 사용하여 THF(6.3 mL) 중에서 실온에서 70 ℃로 24시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 15% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.97 (s, 1H), 7.94 (d, J = 15.0 Hz, 1H), 7.63 (d, J = 9.0 Hz), 7.40 (d, J = 15.6 Hz, 1H), 7.17 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H).Compound 3p was prepared from 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 200 mg, 0.98 mmol), hydroxybenzaldehyde (182 mg, 1.5 mmol) and sodium methoxide solution (334 μL). , 1.5 mmol) was used in THF (6.3 mL) at room temperature to 70 ° C. for 24 hours to obtain a yellow powder in 15% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1H NMR (600 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.94 (d, J = 15.0 Hz, 1H), 7.63 (d, J = 9.0 Hz), 7.40 (d, J = 15.6 Hz, 1H) ), 7.17 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H).
실시예 17. (E)-메틸 3-(3-(4,5-다이클로로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3q) [Example 17. (E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3q) [ (E)-Methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (E)-Methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3q)](3q)]
화합물 3q는 1-(4,5-다이클로로-2-히드록시페닐)에타논(2f; 150 mg, 0.73 mmol), 메틸-3-포르밀벤조에이트(144 mg, 1.1 mmol) 및 나트륨 메톡사이드 용액(250 μL, 1.1 mmol)을 사용하여 THF(4.75 mL) 중에서 실온에서 5시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 42% 수율로 수득하였다. 조 잔류물을 EtOH로 재결정하여 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J = 15.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 15.6 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 4.00 (s, 3H).Compound 3q was 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 150 mg, 0.73 mmol), methyl-3-formylbenzoate (144 mg, 1.1 mmol) and sodium methoxide The solution (250 μL, 1.1 mmol) was stirred in THF (4.75 mL) at room temperature for 5 hours to obtain a yellow powder in 42% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from EtOH. 1H NMR (600 MHz, CDCl 3 ) δ 8.32 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J = 15.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 15.6 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 4.00 (s, 3H).
실시예 18. (E)-메틸 4-(3-(4,5-다이클로로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3r) [Example 18. (E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3r) [ (E)-Methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (E)-Methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3r)](3r)]
화합물 3r은 1-(4,5-다이클로로-2-히드록시페닐)에타논(2f; 350 mg, 1.7 mmol), 메틸 테레프탈알데하이드레이트(336 mg, 2.6 mmol) 및 나트륨 메톡사이드 용액(585 μL, 2.6 mmol)을 사용하여 THF(11 mL) 중에서 실온에서 5시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 59% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 8.01-7.97 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 15.3 Hz, 1H), 7.21 (s, 1H), 3.98 (s, 3H).Compound 3r was obtained from 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 350 mg, 1.7 mmol), methyl terephthalaldehyde (336 mg, 2.6 mmol) and sodium methoxide solution (585 μL). , 2.6 mmol) was stirred in THF (11 mL) at room temperature for 5 hours to obtain a yellow powder in 59% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1H NMR (600 MHz, CDCl 3 ) δ 8.14 (d, J = 8.4 Hz, 1H), 8.01-7.97 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 15.3 Hz, 1H), 7.21 (s, 1H), 3.98 (s, 3H).
실시예 19. (E)-1-(2-히드록시-4,5-다이메톡시페닐)-3-페닐프로프-2-엔-1-온 (3s) [Example 19. (E) -1- (2-hydroxy-4,5-dimethoxyphenyl) -3-phenylprop-2-en-1-one (3s) [ (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-phenylprop-2-en-1-one(E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-phenylprop-2-en-1-one (3s)] (3s)]
화합물 3s는 2'-히드록시-4',5'-다이메톡시아세토페논(2g; 300 mg, 1.5 mmol), 벤즈알데히드(188 μL, 1.8 mmol) 및 나트륨 메톡사이드 용액(510 μL, 2.1 mmol)을 사용하여 THF(10 mL) 중에서 실온에서 12시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 주황색 분말로서 97% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 15.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.48-7.45 (m, 3H), 7.28 (s, 1H), 6.54 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H). Compound 3s was 2'-hydroxy-4',5'-dimethoxyacetophenone ( 2 g ; 300 mg, 1.5 mmol), benzaldehyde (188 μL, 1.8 mmol) and sodium methoxide solution (510 μL, 2.1 mmol) was stirred in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 97% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1H NMR (600 MHz, CDCl 3 ) δ 7.93 (d, J = 15.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.48-7.45 (m, 3H), 7.28 (s, 1H), 6.54 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H).
실시예 20. (E)-메틸 4-(3-(2-히드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3t) [Example 20. (E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3t) [ (E)-Methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate(E)-Methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3t)] (3t)]
화합물 3t는 2'-히드록시-4',5'-다이메톡시아세토페논(2g; 1.0 g, 5.1 mmol), 메틸 테레프탈알데하이드레이트(1.0 g, 6.1 mmol) 및 나트륨 메톡사이드 용액(1.4 mL, 6.1 mmol)을 사용하여 THF(40 mL) 중에서 실온에서 12시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 50% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 15.0 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 15.6 Hz, 1H), 7.20 (s, 1H), 6.55 (s, 1H), 3.97-3.95 (m, 9H).Compound 3t was prepared by mixing 2'-hydroxy-4',5'-dimethoxyacetophenone ( 2 g ; 1.0 g, 5.1 mmol), methyl terephthalaldehyde (1.0 g, 6.1 mmol) and sodium methoxide solution (1.4 mL, 6.1 mmol) was used in THF (40 mL) at room temperature for 12 hours to obtain a yellow powder in 50% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.12 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 15.0 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 15.6 Hz, 1H), 7.20 ( s, 1H), 6.55 (s, 1H), 3.97–3.95 (m, 9H).
실시예 21. (E)-메틸 3-(3-(2-히드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3u) [Example 21. (E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3u) [ (E)-Methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (E)-Methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3u)](3u)]
화합물 3u는 2'-히드록시-4',5'-다이메톡시아세토페논(2g; 600 mg, 3.1 mmol), 메틸 3-포르밀벤조에이트(602 mg, 3.7 mmol) 및 나트륨 메톡사이드 용액(0.84 mL, 3.7 mmol)을 사용하여 THF(40 mL) 중에서 실온에서 12시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 22% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.38 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 15.6 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 15.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.96 (s, 3H). Compound 3u was prepared by 2'-hydroxy-4',5'-dimethoxyacetophenone ( 2 g ; 600 mg, 3.1 mmol), methyl 3-formylbenzoate (602 mg, 3.7 mmol) and sodium methoxide solution ( 0.84 mL, 3.7 mmol) was stirred in THF (40 mL) at room temperature for 12 hours to obtain a yellow powder in 22% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.38 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 15.6 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 15.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.96 (s, 3H).
실시예 22. (E)-1-(2-히드록시-4,5-다이메틸페닐)-3-페닐프로프-2-엔-1-온 (3v) [Example 22. (E) -1- (2-hydroxy-4,5-dimethylphenyl) -3-phenylprop-2-en-1-one (3v) [ (E)-1-(2-Hydroxy-4,5-dimethylphenyl)-3-phenylprop-2-en-1-one (E)-1-(2-Hydroxy-4,5-dimethylphenyl)-3-phenylprop-2-en-1-one (3v)](3v)]
화합물 3v는 2'-히드록시-4',5'-다이메틸아세토페논(2h; 300 mg, 1.8 mmol), 벤즈알데히드(0.22 mL, 2.2 mmol) 및 나트륨 메톡사이드 용액(0.6 mL, 2.6 mmol)를 사용하여 THF(10 mL) 중에서 실온에서 12시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 주황색 분말로서 73% 수율로 수득하였다. 조 잔류물을 에탄올로 재결정하여 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 15.0 Hz, 1H), 7.71-7.70 (m, 2H), 7.69-7.66 (m, 2H), 7.48-7.45 (m, 3H), 6.86 (s, 1H), 2.32 (s, 3H), 2.29 (s, 3H). Compound 3v was prepared by mixing 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), benzaldehyde (0.22 mL, 2.2 mmol) and sodium methoxide solution (0.6 mL, 2.6 mmol). was stirred in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 73% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from ethanol. 1 H NMR (600 MHz, CDCl 3 ) δ 7.92 (d, J = 15.0 Hz, 1H), 7.71–7.70 (m, 2H), 7.69–7.66 (m, 2H), 7.48–7.45 (m, 3H), 6.86 (s, 1H), 2.32 (s, 3H), 2.29 (s, 3H).
실시예 23. (E)-1-(2-히드록시-4,5-다이메틸페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3w) [Example 23. (E) -1- (2-hydroxy-4,5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (3w) [ (E)-1-(2-Hydroxy-4,5-dimethylphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (E)-1-(2-Hydroxy-4,5-dimethylphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3w)](3w)]
화합물 3w는 2'-히드록시-4',5'-다이메틸아세토페논(2h; 300 mg, 1.8 mmol), p-아니스알데히드(0.27 mL, 2.2 mol) 및 나트륨 메톡사이드 용액(0.6 mL, 2.6 mmol)을 사용하여 THF(10 mL) 중에서 실온에서 12시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 주황색 분말로서 95% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 15.0 Hz, 1H), 7.67-7.66 (m, 3H), 7.55 (d, J = 15.0 Hz, 1H), 6.99-6.98 (m, 2H), 6.85 (s, 1H), 3.90 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H). Compound 3w was 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), p-anisaldehyde (0.27 mL, 2.2 mol) and sodium methoxide solution (0.6 mL, 2.6 mL). mmol) in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 95% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.90 (d, J = 15.0 Hz, 1H), 7.67-7.66 (m, 3H), 7.55 (d, J = 15.0 Hz, 1H), 6.99-6.98 (m, 2H), 6.85 (s, 1H), 3.90 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H).
실시예 24. (E)-메틸 4-(3-(2-히드록시-4,5-다이메틸페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3x) [Example 24. (E)-methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (3x) [ (E)-Methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (E)-Methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (3x)](3x)]
화합물 3x는 2'-하이드록시-4',5'-다이메틸아세토페논(2h; 300 mg, 1.8 mmol), 메틸 테레프탈알데하이드레이트(361 mg, 2.2 mmol) 및 나트륨 메톡사이드 용액(0.6 mL, 2.6 mmol)을 사용하여 THF(10 mL) 중에서 실온에서 12시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 주황색 분말로서 57% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 15.6 Hz, 1H), 7.76-7.72 (m, 3H), 7.65 (s, 1H), 6.86 (s, 1H), 3.98 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H).Compound 3x was 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), methyl terephthalaldehyde (361 mg, 2.2 mmol) and sodium methoxide solution (0.6 mL, 2.6 mL). mmol) in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 57% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.12 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 15.6 Hz, 1H), 7.76-7.72 (m, 3H), 7.65 (s, 1H), 6.86 (s, 1H), 3.98 (s , 3H), 2.32 (s, 3H), 2.30 (s, 3H).
실시예 25. (E)-메틸 3-(3-(2-히드록시-4,5-다이메틸페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3y) [Example 25. (E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (3y) [ (E)-Methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (E)-Methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (3y)](3y)]
화합물 3y는 2'-히드록시-4',5'-다이메틸아세토페논(2h; 300 mg, 1.8 mmol), 메틸 3-포르밀벤조에이트(361 mg, 2.2 mmol) 및 나트륨 메톡사이드 용액(0.6 mL, 2.6 mmol)을 사용하여 THF(10 mL) 중에서 실온에서 12시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 30% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 15.6 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 7.68 (s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 6.86 (s, 1H), 4.00 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H).Compound 3y was prepared by 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), methyl 3-formylbenzoate (361 mg, 2.2 mmol) and sodium methoxide solution (0.6 mL, 2.6 mmol) was stirred in THF (10 mL) at room temperature for 12 hours to obtain a yellow powder in 30% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 15.6 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 7.68 (s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 6.86 (s, 1H), 4.00 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H) ).
실시예 26. (E)-메틸 4-(3-(2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3z) [Example 26. (E)-methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3z) [ (E)-Methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (E)-Methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3z)](3z)]
화합물 3z는 2'-하이드록시아세토페논(2i; 200 mg, 1.5 mmol), 메틸 테레프탈알데하이드레이트(289 mg, 1.8 mmol) 및 나트륨 메톡사이드 용액(0.40 mL, 1.8 mmol)을 사용하여 THF(10 mL) 중에서 실온에서 12시간 동안 교반하여 합성예 2에 기재된 것과 동일한 방법으로 황색 분말로서 67% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 2H), 7.96-7.93 (m, 2H), 7.77-7.75 (m, 3H), 7.57-7.54 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.01-6.98 (m, 1H), 3.98 (s, 3H).Compound 3z was prepared in THF (10 mL) using 2'-hydroxyacetophenone ( 2i ; 200 mg, 1.5 mmol), methyl terephthalaldehyde (289 mg, 1.8 mmol) and sodium methoxide solution (0.40 mL, 1.8 mmol). ) was stirred at room temperature for 12 hours to obtain a yellow powder in 67% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.13 (d, J = 8.4 Hz, 2H), 7.96–7.93 (m, 2H), 7.77–7.75 (m, 3H), 7.57–7.54 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H) , 7.01–6.98 (m, 1H), 3.98 (s, 3H).
합성예 3. 화합물 4a-4x 에 대한 공통 합성 과정 Synthesis Example 3. Common Synthetic Procedure for Compounds 4a - 4x
DMSO에 녹인 칼콘(chalcone) 중간체(3a-3z)의 교반 용액에 요오드(0.1당량)를 실온에서 첨가하였다. TLC 분석으로 완전한 전환이 확인될 때까지(일반적으로 6시간 내지 24시간) 반응 혼합물을 100 ℃에서 아르곤 하에 교반하고, 1.0 M 티오황산나트륨 용액(10 mL)으로 켄칭하고, EtOAc(30 mL) 및 H2O(30 mL)로 추출하였다. 유기층을 MgSO4로 건조시키고, 여과하고, 감압 하에 농축시켰다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피(n-헥산/EtOAc 또는 CH2Cl2/MeOH)로 정제하여 화합물 4a-4x를 얻었다.To a stirred solution of the chalcone intermediates ( 3a - 3z ) in DMSO was added iodine (0.1 eq.) at room temperature. The reaction mixture was stirred under argon at 100 °C until complete conversion was confirmed by TLC analysis (typically 6 to 24 hours), quenched with 1.0 M sodium thiosulfate solution (10 mL), EtOAc (30 mL) and H Extracted with 2 O (30 mL). The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (n-hexane/EtOAc or CH 2 Cl 2 /MeOH) to give compounds 4a-4x .
실시예 27. 7-플루오로-2-페닐-4H-크로멘-4-온 (4a) [Example 27. 7-fluoro-2-phenyl-4H-chromen-4-one (4a) [ 7-Fluoro-2-phenyl-4H-chromen-4-one7-Fluoro-2-phenyl-4H-chromen-4-one (4a)] (4a)]
화합물 4a는 (E)-1-(4-플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온(3a; 194 mg, 0.80 mmol) 및 요오드(20.3 mg, 0.08 mmol)을 사용하여 DMSO(6.0 mL) 중에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 90% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.26 (dd, J = 6.4 Hz and J = 8.8 Hz, 1H), 7.91 (dd, J = 1.3 Hz and J = 7.8 Hz, 2H), 7.60-7.51 (m, 3H), 7.28 (d, J = 2.2 Hz, 1H), 7.20-7.14 (m, 1H), 6.82 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 177.48, 166.60, 164.91, 163.75, 157.31, 157.23, 131.80, 131.46, 129.14, 128.30, 126.28, 120.87, 114.09, 113.94, 107.69, 104.92, 104.75. HRMS m/z calculated for C15H9FO2 [M+H]+ : 241.0660; found : 241.0654. Compound 4a was (E)-1-(4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3a ; 194 mg, 0.80 mmol) and iodine (20.3 mg, 0.08 mmol) was used in DMSO (6.0 mL) and stirred for 24 hours to obtain a white powder in 90% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.26 (dd, J = 6.4 Hz and J = 8.8 Hz, 1H), 7.91 (dd, J = 1.3 Hz and J = 7.8 Hz, 2H), 7.60-7.51 (m, 3H), 7.28 (d, J = 2.2 Hz, 1H), 7.20-7.14 (m, 1H), 6.82 (s, 1H); 13 C NMR (150 MHz, CDCL 3 ) δ 177.48, 166.60, 164.91, 163.75, 157.31, 157.23, 131.80, 131.46, 129.14, 128.30, 126.28, 120.87, 114.09, 113.94, 107.69, 104.92, 104.75. HRMS m / z calculated for C 15 H 9 FO 2 [M+H] + : 241.0660; found: 241.0654.
실시예 28. 7-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4b) [Example 28. 7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4b) [ 7-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one7-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4b)] (4b)]
화합물 4b는 (E)-1-(4-플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온(3b; 137 mg, 0.50 mmol) 및 요오드(12.7 mg, 0.05 mmol)를 사용하여 DMSO(7.0 mL) 중에서 16시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.24 (dd, J = 6.4 Hz and J = 8.8 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.24 (dd, J = 2.3 Hz and J = 9.1 Hz, 1H), 7.17-7.12 (m, 1H), 7.04 (d, J = 8.9 Hz, 2H), 6.73 (s, 1H), 3.90 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 177.45, 166.49, 164.80, 163.77, 162.57, 157.22, 128.21, 128.14, 128.01, 123.67, 120.82, 114.56, 113.88, 113.74, 106.21, 104.80, 104.64, 55.55. HRMS m/z calculated for C16H11FO3 [M+H]+ : 271.0765; found : 271.0753.Compound 4b was (E)-1-(4-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3b ; 137 mg, 0.50 mmol) And iodine (12.7 mg, 0.05 mmol) was stirred in DMSO (7.0 mL) for 16 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.24 (dd, J = 6.4 Hz and J = 8.8 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.24 (dd, J = 2.3 Hz and J = 9.1 Hz, 1H), 7.17-7.12 ( m, 1H), 7.04 (d, J = 8.9 Hz, 2H), 6.73 (s, 1H), 3.90 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 177.45, 166.49, 164.80, 163.77, 162.57, 157.22, 128.21, 128.14, 128.01, 123.67, 120.82, 114.56, 113.88, 113.74, 106.21.5, 104.88 HRMS m / z calculated for C 16 H 11 FO 3 [M+H] + : 271.0765; found: 271.0753.
실시예 29. 6-플루오로-2-페닐-4H-크로멘-4-온 (4c) [Example 29. 6-Fluoro-2-phenyl-4H-chromen-4-one (4c) [ 6-Fluoro-2-phenyl-4H-chromen-4-one6-Fluoro-2-phenyl-4H-chromen-4-one (4c)] (4c)]
화합물 4c는 (E)-1-(5-플루오로-2-하이드록시페닐)-3-페닐프로프-2-엔-1-온(3c; 304 mg, 1.3 mmol) 및 요오드(31.7 mg, 0.13 mmol)을 사용하여 DMSO(6.0 mL) 중에서 15시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 91% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 7.1 Hz, 2H), 7.88 (dd, J = 3.2 and J = 8.1 Hz, 1H), 7.61-7.58 (m, 1H), 7.57-7.52 (m, 3H), 7.46-7.41 (m, 1H), 6.83 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 177.63, 163.71, 160.44, 158.81, 152.47, 131.82, 131.54, 129.12, 126.34, 125.21, 125.16, 122.01, 121.85, 120.22, 120.16, 110.74, 110.59, 106.92. HRMS m/z calculated for C15H9FO2 [M+H]+ : 241.0660; found : 241.0648.Compound 4c was (E)-1-(5-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3c ; 304 mg, 1.3 mmol) and iodine (31.7 mg, 0.13 mmol) was used in DMSO (6.0 mL) and stirred for 15 hours to obtain a white powder in 91% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.93 (d, J = 7.1 Hz, 2H), 7.88 (dd, J = 3.2 and J = 8.1 Hz, 1H), 7.61-7.58 (m, 1H), 7.57-7.52 (m, 3H), 7.46-7.41 ( m, 1H), 6.83 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 177.63, 163.71, 160.44, 158.81, 152.47, 131.82, 131.54, 129.12, 126.34, 125.21, 125.16, 122.01, 121.85, 120.22, 120.16, 9,910.7 HRMS m / z calculated for C 15 H 9 FO 2 [M+H] + : 241.0660; found: 241.0648.
실시예 30. 6-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4d) [Example 30. 6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4d) [ 6-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one6-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4d)] (4d)]
화합물 4d는 (E)-1-(5-플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온(3d; 240 mg, 0.88 mmol) 및 요오드(22.3 mg, 0.09 mmol)를 사용하여 DMSO(10 mL) 중에서 15시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 97% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.90-7.85 (m, 3H), 7.56 (dd, J = 4.1 Hz and J = 9.1 Hz, 1H), 7.44-7.39 (m, 1H), 7.04 (d, J = 8.9 Hz, 2H), 6.74 (s, 1H), 3.90 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 177.55, 163.72, 162.58, 160.38, 158.74, 152.39, 128.07, 125.18, 123.75, 121.74, 121.57, 120.04, 119.99, 114.54, 110.72, 110.57, 105.52, 55.54. HRMS m/z calculated for C16H11FO3 [M+H]+ : 271.0765; found : 271.0751. Compound 4d was (E)-1-(5-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3d ; 240 mg, 0.88 mmol) And iodine (22.3 mg, 0.09 mmol) was stirred in DMSO (10 mL) for 15 hours to obtain a white powder in 97% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.90-7.85 (m, 3H), 7.56 (dd, J = 4.1 Hz and J = 9.1 Hz, 1H), 7.44-7.39 (m, 1H), 7.04 (d, J = 8.9 Hz, 2H), 6.74 (s , 1H), 3.90 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 177.55, 163.72, 162.58, 160.38, 158.74, 152.39, 128.07, 125.18, 123.75, 121.74, 121.57, 120.04, 119.99, 114.54, 110.5.5, 4,10.57 HRMS m / z calculated for C 16 H 11 FO 3 [M+H] + : 271.0765; found: 271.0751.
실시예 31. 5-플루오로-2-페닐-4H-크로멘-4-온 (4e) [Example 31. 5-fluoro-2-phenyl-4H-chromen-4-one (4e) [ 5-Fluoro-2-phenyl-4H-chromen-4-one5-Fluoro-2-phenyl-4H-chromen-4-one (4e)] (4e)]
화합물 4e는 (E)-1-(2-플루오로-6-히드록시페닐)-3-페닐프로프-2-엔-1-온(3e; 200 mg, 0.83 mmol) 및 요오드(21.1 mg, 0.08 mmol)을 사용하여 DMSO(5.0 mL) 중에서 20시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 86% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz, 2H), 7.66-7.61 (m, 1H), 7.58-7.51 (m, 3H), 7.39 (d, J = 8.5 Hz, 1H), 7.12-7.05 (m, 1H), 6.78 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 176.79, 162.46, 133.74, 133.67, 131.81, 131.23, 129.13, 126.27, 114.06, 114.03, 112.23, 112.09, 108.69. HRMS m/z calculated for C15H9FO2 [M+H]+ : 241.0660; found : 241.0647.Compound 4e was (E)-1-(2-fluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3e ; 200 mg, 0.83 mmol) and iodine (21.1 mg, 0.08 mmol) was used in DMSO (5.0 mL) and stirred for 20 hours to obtain a white powder in 86% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.91 (d, J = 7.8 Hz, 2H), 7.66-7.61 (m, 1H), 7.58-7.51 (m, 3H), 7.39 (d, J = 8.5 Hz, 1H), 7.12-7.05 (m, 1H) , 6.78 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 176.79, 162.46, 133.74, 133.67, 131.81, 131.23, 129.13, 126.27, 114.06, 114.03, 112.23, 112.09, 108.69. HRMS m / z calculated for C 15 H 9 FO 2 [M+H] + : 241.0660; found: 241.0647.
실시예 32. 5-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4f) [Example 32. 5-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4f) [ 5-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one5-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4f)] (4f)]
화합물 4f는 (E)-1-(2-플루오로-6-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온(3f; 380 mg, 1.40 mmol) 및 요오드(35.5 mg, 0.14 mmol)를 사용하여 DMSO(10 mL) 중에서 16시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.87-7.84 (m, 2H), 7.63-7.58 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.08-7.04 (m, 1H), 7.04-7.01 (m, 2H), 6.69 (s, 1H), 3.90 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 176.63, 162.52, 162.35, 161.47, 159.72, 157.14, 157.12, 133.50, 133.43, 127.88, 123.20, 114.48, 114.28, 114.21, 113.94, 113.91, 112.02, 111.88, 107.04, 55.50. HRMS m/z calculated for C16H11FO3 [M+H]+ : 271.0765; found : 271.0773. Compound 4f was (E)-1-(2-fluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3f ; 380 mg, 1.40 mmol) And iodine (35.5 mg, 0.14 mmol) was stirred in DMSO (10 mL) for 16 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.87-7.84 (m, 2H), 7.63-7.58 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.08-7.04 (m, 1H), 7.04-7.01 (m, 2H), 6.69 ( s, 1H), 3.90 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 176.63, 162.52, 162.35, 161.47, 159.72, 157.14, 157.12, 133.50, 133.43, 127.88, 123.20, 114.48, 114.28, 114.21, 113.94, 113.91, 112.02 HRMS m / z calculated for C 16 H 11 FO 3 [M+H] + : 271.0765; found: 271.0773.
실시예 33. 5,7-다이플루오로-2-페닐-4H-크로멘-4-온 (4g) [Example 33. 5,7-difluoro-2-phenyl-4H-chromen-4-one (4g) [ 5,7-Difluoro-2-phenyl-4H-chromen-4-one5,7-Difluoro-2-phenyl-4H-chromen-4-one (4g)] (4g)]
화합물 4g는 (E)-1-(2,4-다이플루오로-6-히드록시페닐)-3-페닐프로프-2-엔-1-온(3g; 280 mg, 0.96 mmol) 및 요오드(24.4 mg, 0.09 mmol)를 사용하여 DMSO(10 mL) 중에서 14시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 88% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 7.0 Hz, 2H), 7.59-7.51 (m, 3H), 7.10 (d, J = 8.8 Hz, 1H), 6.88-6.83 (m, 1H), 6.75 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 175.75, 165.74, 165.64, 164.05, 163.95, 162.78, 162.68, 162.56, 161.01, 160.91, 158.07, 158.03, 157.96, 157.93, 131.97, 130.78, 129.17, 126.18, 111.58, 111.53, 111.51, 108.62, 102.19, 102.03, 101.86, 101.41, 101.38, 101.25, 101.22. HRMS m/z calculated for C15H8F2O2 [M-H]- : 259.0565; found : 259.0562. Compound 4g was (E)-1-(2,4-difluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3g ; 280 mg, 0.96 mmol) and iodine ( 24.4 mg, 0.09 mmol) was stirred in DMSO (10 mL) for 14 hours to obtain a white powder in 88% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.88 (d, J = 7.0 Hz, 2H), 7.59–7.51 (m, 3H), 7.10 (d, J = 8.8 Hz, 1H), 6.88–6.83 (m, 1H), 6.75 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 175.75, 165.74, 165.64, 164.05, 163.95, 162.78, 162.68, 162.56, 161.01, 160.91, 158.07, 158.03, 157.96, 157.93, 131.97, 130.78, 129.17, 126.18, 111.58, 111.53, 111.51, 108.62, 102.19, 102.03, 101.86, 101.41, 101.38, 101.25, 101.22. HRMS m / z calculated for C 15 H 8 F 2 O 2 [MH] - : 259.0565; found: 259.0562.
실시예 34. 5,7-다이플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4h) [Example 34. 5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4h) [ 5,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one5,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4h)] (4h)]
화합물 4h는 (E)-1-(2,4-다이플루오로-6-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온(3h; 270 mg, 0.93 mmol) 및 요오드(23.6 mg, 0.09 mmol)를 사용하여 DMSO(6.0 mL) 중에서 10시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 47% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.03 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 9.4 Hz, 1H), 7.37-7.31 (m, 1H), 7.11 (d, J = 8.9 Hz, 2H), 6.88 (s, 1H), 3.85 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 175.01, 165.48, 162.88, 162.34, 128.69, 123.01, 115.14, 106.97, 102.55, 102.46, 102.43, 102.38, 102.29, 102.26, 102.21, 56.08. HRMS m/z calculated for C16H10F2O3 [M+H]+ : 289.0671; found : 289.0657. Compound 4h is (E)-1-(2,4-difluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3h ; 270 mg, 0.93 mmol) and iodine (23.6 mg, 0.09 mmol) were stirred in DMSO (6.0 mL) for 10 hours to obtain a white powder in 47% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.03 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 9.4 Hz, 1H), 7.37-7.31 (m, 1H), 7.11 (d, J = 8.9 Hz, 2H), 6.88 (s, 1H) ), 3.85 (s, 3H); 13 C NMR (150 MHz, DMSO-d 6 ) δ 175.01, 165.48, 162.88, 162.34, 128.69, 123.01, 115.14, 106.97, 102.55, 102.46, 102.43, 102.38, 102.29, 102.26, 102.21, 56.08. HRMS m / z calculated for C 16 H 10 F 2 O 3 [M+H] + : 289.0671; found: 289.0657.
실시예 35. 6,7-다이플루오로-2-페닐-4H-크로멘-4-온 (4i) [Example 35. 6,7-difluoro-2-phenyl-4H-chromen-4-one (4i) [ 6,7-Difluoro-2-phenyl-4H-chromen-4-one 6,7-Difluoro-2-phenyl-4H-chromen-4-one (4i)](4i)]
화합물 4i는 (E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온(3i; 100 mg, 0.38 mmol) 및 요오드(106.6 mg, 0.42 mmol)를 사용하여 DMSO(5.6 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 89% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.02 (t, J = 9.3 Hz, 1H), 7.90 (d, J = 6.6 Hz, 2H), 7.58-7.55 (m, 3H), 7.43 (dd, J = 6.6 Hz and J = 9.6 Hz, 1H), 6.82 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 176.68, 164.06, 154.93, 154.82, 153.21, 153.11, 152.49, 152.42, 149.49, 149.40, 147.83, 147.74, 131.98, 131.21, 129.18, 126.27, 120.97, 120.95, 113.14, 113.13, 113.02, 113.01, 107.30, 107.15, 107.09. HRMS m/z calculated for C15H8F2O2 [M-H]- : 259.0565; found : 259.0564. Compound 4i is (E)-1-(4,5-difluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3i ; 100 mg, 0.38 mmol) and iodine ( 106.6 mg, 0.42 mmol) was stirred in DMSO (5.6 mL) at 100° C. for 24 hours to obtain a white powder in 89% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1H NMR (600 MHz, CDCl 3 ) δ 8.02 (t, J = 9.3 Hz, 1H), 7.90 (d, J = 6.6 Hz, 2H), 7.58-7.55 (m, 3H), 7.43 (dd, J = 6.6 Hz and J = 9.6 Hz, 1H), 6.82 (s, 1H); 13 C NMR (150 MHz, CDCL 3 ) Δ 176.68, 164.06, 154.93, 154.82, 153.21, 153.11, 152.49, 152.42, 149.49, 149.40, 147.83, 147.74, 131.98, 131.21, 129.18 , 113.02, 113.01, 107.30, 107.15, 107.09. HRMS m/z calculated for C 15 H 8 F 2 O 2 [MH] - : 259.0565; found: 259.0564.
실시예 36. 6,7-다이플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4j) [Example 36. 6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4j) [ 6,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one 6,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4j)](4j)]
화합물 4j는 (E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온(3j; 100 mg, 0.38 mmol) 및 요오드(107 mg, 0.42 mmol)를 사용하여 DMSO(5.6 mL) 중에서100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 89% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.03-8.00 (m, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.41 (dd, J = 6.0 Hz and J = 9.6 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.74 (s, 1H), 3.93 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 176.05, 163.81, 162.85, 152.69, 128.80, 123.28, 121.12, 115.13, 112.65, 112.52, 108.87, 108.73, 105.39, 56.07. HRMS m/z calculated for C16H10F2O3 [M+H]+ : 289.0671; found : 289.0656.Compound 4j is (E)-1-(4,5-difluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3j ; 100 mg, 0.38 mmol) and iodine (107 mg, 0.42 mmol) were stirred in DMSO (5.6 mL) at 100 ° C. for 24 hours to obtain a white powder in 89% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.03-8.00 (m, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.41 (dd, J = 6.0 Hz and J = 9.6 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.74 (s, 1H), 3.93 (s, 3H); 13 C NMR (150 MHz, DMSO-d 6 ) δ 176.05, 163.81, 162.85, 152.69, 128.80, 123.28, 121.12, 115.13, 112.65, 112.52, 108.87, 108.73, 105.39, 56.07. HRMS m / z calculated for C 16 H 10 F 2 O 3 [M+H] + : 289.0671; found: 289.0656.
실시예 37. 메틸 3-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조에이트 (4k) [Example 37. Methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate (4k) [ Methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate Methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate (4k)](4k)]
화합물 4k는 (E)-메틸 3-(3-(4,5-다이플루오로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3l; 100 mg, 0.31 mmol) 및 요오드(87.5 mg, 0.35 mmol)를 사용하여 DMSO(4.6 mL) 중에서 100 ℃에서 16시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.57 (s, 1H), 8.23 (d, J = 9.6 Hz, 1H), 8.07 (d, J = 7.8Hz, 1H), 8.03-7.99 (m, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.47 (dd, J = 6.6 Hz and J = 10.2 Hz, 1H), 6.86 (s, 1H), 4.00 (s, 3H).Compound 4k is (E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3l ; 100 mg , 0.31 mmol) and iodine (87.5 mg, 0.35 mmol) were stirred in DMSO (4.6 mL) at 100 ° C. for 16 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.23 (d, J = 9.6 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.03-7.99 (m, 1H), 7.64 (t, J = 8.1 Hz, 1H) ), 7.47 (dd, J = 6.6 Hz and J = 10.2 Hz, 1H), 6.86 (s, 1H), 4.00 (s, 3H).
실시예 38. 메틸 4-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조에이트 (4l) [Example 38. Methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate (4l) [ Methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate Methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate (4l)](4l)]
화합물 4l은 (E)-메틸 4-(3-(4,5-다이플루오로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3m; 100 mg, 0.31 mmol) 및 요오드(87.5 mg, 0.35 mmol)를 사용하여 DMSO(4.6 mL) 중에서 100 ℃에서 16시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 88% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 2H), 8.02 (t, J = 9.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 6.0 Hz and J = 10.2 Hz, 1H), 6.87 (s, 1H), 3.99 (s, 3H).Compound 4l is (E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3m ; 100 mg , 0.31 mmol) and iodine (87.5 mg, 0.35 mmol) were stirred in DMSO (4.6 mL) at 100 ° C. for 16 hours to obtain a white powder in 88% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.21 (d, J = 8.4 Hz, 2H), 8.02 (t, J = 9.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 6.0 Hz and J = 10.2 Hz, 1H), 6.87 (s, 1H), 3.99 (s, 3H).
실시예 39. 6,7-다이클로로-2-페닐-4H-크로멘-4-온 (4m) [Example 39. 6,7-dichloro-2-phenyl-4H-chromen-4-one (4m) [ 6,7-Dichloro-2-phenyl-4H-chromen-4-one 6,7-Dichloro-2-phenyl-4H-chromen-4-one (4m)](4m)]
화합물 4m은 (E)-1-(4,5-다이클로로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온(3n; 100 mg, 0.34 mmol) 및 요오드(95 mg, 0.37 mmol)를 사용하여 DMSO(5.0 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 67% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.76 (s, 1H), 7.59-7.54 (m, 3H), 6.83 (s, 1H).Compound 4m is (E)-1-(4,5-dichloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3n ; 100 mg, 0.34 mmol) and iodine (95 mg, 0.37 mmol) was stirred in DMSO (5.0 mL) at 100 °C for 24 hours to obtain a white powder in 67% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.32 (s, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.76 (s, 1H), 7.59–7.54 (m, 3H), 6.83 (s, 1H).
실시예 40. 6,7-다이클로로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4n) [Example 40. 6,7-dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one (4n) [ 6,7-Dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one 6,7-Dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one (4n)](4n)]
화합물 4n은 (E)-1-(4,5-다이클로로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온(3o; 100 mg, 0.34 mmol) 및 요오드(95 mg, 0.37 mmol)를 사용하여 DMSO(5.0 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 67% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.14 (s, 1H), 8.10 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 7.05 (s, 1H), 3.88 (s, 3H).Compound 4n was (E)-1-(4,5-dichloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3o ; 100 mg, 0.34 mmol) and iodine (95 mg, 0.37 mmol) in DMSO (5.0 mL) and stirred at 100 °C for 24 hours to obtain a white powder in 67% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.29 (s, 1H), 8.14 (s, 1H), 8.10 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 7.05 (s, 1H), 3.88 (s, 3H) ).
실시예 41. 메틸 3-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조에이트 (4o) [Example 41. Methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate (4o) [ Methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate Methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate (4o)](4o)]
화합물 4o는 (E)-메틸 3-(3-(4,5-다이클로로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3q; 100 mg, 0.29 mmol) 및 요오드(79.5 mg, 0.31 mmol)를 사용하여 DMSO(4.2 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 96% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.58 (s, 1H), 8.31 (s, 1H), 8.25 (t, J = 8.1 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 6.88 (s, 1H), 4.01 (s, 3H).Compound 4o is (E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3q ; 100 mg; 0.29 mmol) and iodine (79.5 mg, 0.31 mmol) were stirred in DMSO (4.2 mL) at 100 ° C. for 24 hours to obtain a white powder in 96% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.58 (s, 1H), 8.31 (s, 1H), 8.25 (t, J = 8.1 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 6.88 (s, 1H), 4.01 (s, 3H).
실시예 42. 메틸 4-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조에이트 (4p) [Example 42. Methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate (4p) [ Methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate Methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate (4p)](4p)]
화합물 4p는 (E)-메틸 4-(3-(4,5-다이클로로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3r; 100 mg, 0.29 mmol) 및 요오드(79.5 mg, 0.31 mmol)를 사용하여 DMSO(4.2 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 96% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 8.21 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 7.78 (s, 1H), 6.88 (s, 1H), 3.99 (s, 3H).Compound 4p is (E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3r ; 100 mg, 0.29 mmol) and iodine (79.5 mg, 0.31 mmol) were stirred in DMSO (4.2 mL) at 100 ° C. for 24 hours to obtain a white powder in 96% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.32 (s, 1H), 8.21 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 7.78 (s, 1H), 6.88 (s, 1H), 3.99 (s, 3H) ).
실시예 43. 6,7-다이메톡시-2-페닐-4H-크로멘-4-온 (4q) [Example 43. 6,7-dimethoxy-2-phenyl-4H-chromen-4-one (4q) [ 6,7-Dimethoxy-2-phenyl-4H-chromen-4-one6,7-Dimethoxy-2-phenyl-4H-chromen-4-one (4q)] (4q)]
화합물 4q는 (E)-1-(2-히드록시-4,5-다이메톡시페닐)-3-페닐프로프-2-엔-1-온(3s; 200 mg, 0.70 mmol) 및 요오드(196 mg, 0.77 mmol)를 사용하여 DMSO(10 mL) 중에서 110 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 76% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.94-7.93 (m, 2H), 7.60 (s, 1H), 7.55-7.54 (m, 3H), 7.03 (s, 1H), 6.82 (s, 1H), 4.05 (s, 3H), 4.02 (s, 3H). Compound 4q was (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-phenylprop-2-en-1-one ( 3s ; 200 mg, 0.70 mmol) and iodine ( 196 mg, 0.77 mmol) was stirred in DMSO (10 mL) at 110 ° C. for 24 hours to obtain a white powder in 76% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.94-7.93 (m, 2H), 7.60 (s, 1H), 7.55-7.54 (m, 3H), 7.03 (s, 1H), 6.82 (s, 1H), 4.05 (s, 3H), 4.02 (s, 3H).
실시예 44. 메틸 4-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (4r) [Example 44. Methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4r) [ Methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoateMethyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4r)] (4r)]
화합물 4r은 (E)-메틸 4-(3-(2-히드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3t; 200 mg, 0.58 mmol) 및 요오드(178 mg, 0.70 mmol)를 사용하여 DMSO(5.0 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 갈색 분말로서 62% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 9.0 Hz, 2H), 7.58 (s, 1H), 7.04 (s, 1H), 4.05 (s, 3H), 4.02 (s, 3H), 3.99 (s, 3H). Compound 4r is (E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3t ; 200 mg , 0.58 mmol) and iodine (178 mg, 0.70 mmol) in DMSO (5.0 mL) and stirred at 100 ° C. for 24 hours to obtain a brown powder in 62% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.19 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 9.0 Hz, 2H), 7.58 (s, 1H), 7.04 (s, 1H), 4.05 (s, 3H), 4.02 (s, 3H) ), 3.99 (s, 3H).
실시예 45. 메틸 3-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (4s) [Example 45. Methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4s) [ Methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoateMethyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4s)] (4s)]
화합물 4s는 (E)-메틸 3-(3-(2-히드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3u; 100 mg, 0.29 mmol) 및 요오드(89 mg, 0.35 mmol)를 사용하여 DMSO(3.0 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 갈색 분말로서 71% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.62 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.07 (s, 1H), 6.86 (s, 1H), 4.06 (s, 3H), 4.01 (s, 6H).Compound 4s was (E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3u ; 100 mg , 0.29 mmol) and iodine (89 mg, 0.35 mmol) in DMSO (3.0 mL) and stirred at 100 ° C. for 24 hours to obtain a brown powder in 71% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.07 (s, 1H), 6.86 (s, 1H), 4.06 (s, 3H), 4.01 (s, 6H).
실시예 46. 6,7-다이메틸-2-페닐-4H-크로멘-4-온 (4t) [Example 46. 6,7-dimethyl-2-phenyl-4H-chromen-4-one (4t) [ 6,7-Dimethyl-2-phenyl-4H-chromen-4-one6,7-Dimethyl-2-phenyl-4H-chromen-4-one (4t)] (4t)]
화합물 4t는 (E)-1-(2-히드록시-4,5-다이메틸페닐)-3-페닐프로프-2-엔-1-온(3v; 100 mg, 0.40 mmol) 및 요오드(121 mg, 0.48 mmol)를 사용하여 DMSO(3.0 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 상아색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.95-7.94 (m, 2H), 7.56-7.53 (m, 3H), 7.39 (s, 1H), 6.82 (s, 1H), 2.44 (s, 3H), 2.40 (s, 3H). Compound 4t was prepared from (E)-1-(2-hydroxy-4,5-dimethylphenyl)-3-phenylprop-2-en-1-one ( 3v ; 100 mg, 0.40 mmol) and iodine (121 mg). . The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.95-7.94 (m, 2H), 7.56-7.53 (m, 3H), 7.39 (s, 1H), 6.82 (s, 1H), 2.44 (s, 3H), 2.40 (s, 3H).
실시예 47. 2-(4-메톡시페닐)-6,7-다이메틸-4H-크로멘-4-온 (4u) [Example 47. 2-(4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (4u) [ 2-(4-Methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one 2-(4-Methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (4u)](4u)]
화합물 4u는 (E)-1-(2-히드록시-4,5-다이메틸페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온(3w; 200 mg, 0.71 mmol) 및 요오드(216 mg, 0.85 mmol)를 사용하여 DMSO(5.0 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 7.95 (s, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.33 (s, 1H), 7.03-7.01 (m, 2H), 6.70 (s, 1H), 3.89 (s, 3H), 2.41 (s, 3H), 2.36 (s, 3H).Compound 4u was (E)-1-(2-hydroxy-4,5-dimethylphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3w ; 200 mg, 0.71 mmol ) and iodine (216 mg, 0.85 mmol) were stirred in DMSO (5.0 mL) at 100 ° C. for 24 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 7.95 (s, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.33 (s, 1H), 7.03-7.01 (m, 2H), 6.70 (s, 1H), 3.89 (s, 3H), 2.41 (s, 3H), 2.36 (s, 3H).
실시예 48. 메틸 4-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조에이트 (4v) [Example 48. Methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate (4v) [ Methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate Methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate (4v)](4v)]
화합물 4v는 (E)-메틸 4-(3-(2-히드록시-4,5-다이메틸페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3x; 200 mg, 0.64 mmol) 및 요오드(196 mg, 0.77 mmol)를 사용하여 DMSO(5.0 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.37 (s, 1H), 6.84 (s, 1H), 3.98 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H).Compound 4v was (E)-methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3x ; 200 mg, 0.64 mmol) and iodine (196 mg, 0.77 mmol) in DMSO (5.0 mL) and stirred at 100 °C for 24 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.18 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.37 (s, 1H), 6.84 (s, 1H), 3.98 (s, 3H) ), 2.43 (s, 3H), 2.38 (s, 3H).
실시예 49. 메틸 3-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조에이트 (4w) [Example 49. Methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate (4w) [ Methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate Methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate (4w)](4w)]
화합물 4w는 (E)-메틸 3-(3-(2-히드록시-4,5-다이메틸페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3y; 120 mg, 0.39 mmol) 및 요오드(118 mg, 0.46 mmol)를 사용하여 DMSO(3.0 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, CDCl3) δ 8.63 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.43 (s, 1H), 6.87 (s, 1H), 4.02 (s, 3H), 2.45 (s, 3H), 2.41 (s, 3H).Compound 4w was (E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3y ; 120 mg, 0.39 mmol) and iodine (118 mg, 0.46 mmol) in DMSO (3.0 mL) and stirred at 100 °C for 24 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.43 (s, 1H), 6.87 (s, 1H), 4.02 (s, 3H), 2.45 (s, 3H), 2.41 (s, 3H).
실시예 50. 메틸 4-(4-옥소-4H-크로멘-2-일)벤조에이트 (4x) [Example 50. Methyl 4-(4-oxo-4H-chromen-2-yl)benzoate (4x) [ Methyl 4-(4-oxo-4H-chromen-2-yl)benzoate Methyl 4-(4-oxo-4H-chromen-2-yl)benzoate (4x)](4x)]
화합물 4x는 (E)-메틸 4-(3-(2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트(3z; 200 mg, 0.71 mmol) 및 요오드(198 mg, 0.78 mmol)를 사용하여 DMSO(10 mL) 중에서 100 ℃에서 24시간 동안 교반하여 합성예 3에 기재된 것과 동일한 방법으로 백색 분말로서 79% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, MeOD) δ 8.17-8.13 (m, 5H), 7.86-7.83 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 6.99 (s, 1H), 3.96 (s, 3H).Compound 4x was (E)-methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3z ; 200 mg, 0.71 mmol) and iodine (198 mg, 0.78 mmol) was stirred in DMSO (10 mL) at 100 °C for 24 hours to obtain a white powder in 79% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, MeOD) δ 8.17-8.13 (m, 5H), 7.86-7.83 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 6.99 (s, 1H), 3.96 (s, 3H).
합성예 4. 화합물 5a-5d, 5g, 5j 및 5m에 대한 공통 합성 과정Synthesis Example 4. Common synthetic procedure for compounds 5a-5d, 5g, 5j and 5m
다이클로로메탄 중 고리화된 화합물(4b, 4d, 4f, 4h, 4j, 4q 및 4u)의 교반된 용액에 다이클로로메탄 중 1.0 M BBr3(5.0 당량-12 당량)를 0 ℃에서 첨가하였다. TLC 분석으로 완전한 전환이 확인될 때까지(일반적으로 14시간 내지 20 시간), 반응 혼합물을 50 ℃에서 아르곤 하에 교반하고, 얼음물 및 진한 다이클로로메탄으로 켄칭하였다. 그 다음, EtOAc(30 mL) 및 H2O(30 mL)로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피(CH2Cl2/MeOH 또는 n-헥산/EtOAc)로 정제하거나 에테르 또는 n-헥산과 같은 유기 용매로 세척하여 화합물 5a-5d, 5g, 5j 및 5m을 얻었다.To stirred solutions of cyclized compounds ( 4b, 4d, 4f, 4h, 4j, 4q and 4u ) in dichloromethane was added 1.0 M BBr 3 (5.0 equiv-12 equiv) in dichloromethane at 0 °C. The reaction mixture was stirred at 50° C. under argon and quenched with ice water and conc. dichloromethane until complete conversion was confirmed by TLC analysis (usually 14 to 20 hours). It was then extracted with EtOAc (30 mL) and H 2 O (30 mL). The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH or n-hexane/EtOAc) or washed with an organic solvent such as ether or n-hexane to give compounds 5a-5d, 5g, 5j and 5m . got it
합성예 5. 화합물 5e-5f, 5h-5i, 5k-5l 및 5n-5p에 대한 공통 합성 과정Synthesis Example 5. Common Synthesis Procedure for Compounds 5e-5f, 5h-5i, 5k-5l and 5n-5p
메탄올 중 고리화된 화합물(4k-4l, 4o-4p, 4r-4s 및 4v-4x)의 교반된 용액에 실온에서 1 N NaOH(2.0 당량-4.0 당량)를 첨가하였다. TLC 분석으로 완전한 전환이 확인될 때까지(일반적으로 1시간-4시간) 반응 혼합물을 70 ℃-80 ℃에서 교반하였다. 그 다음, EtOAc(30 mL) 및 H2O(30 mL)로 추출하였다. 조 잔류물을 실리카겔 상의 컬럼 크로마토그래피(CH2Cl2/MeOH)로 정제하거나 에테르와 같은 유기 용매로 세척하여 화합물 5e-5f, 5h-5i, 5k-5l 및 5n-5p를 얻었다.To a stirred solution of the cyclized compounds ( 4k-4l, 4o-4p, 4r-4s and 4v-4x ) in methanol was added 1 N NaOH (2.0 equiv-4.0 equiv) at room temperature. The reaction mixture was stirred at 70 °C-80 °C until complete conversion was confirmed by TLC analysis (generally 1 h - 4 h). It was then extracted with EtOAc (30 mL) and H 2 O (30 mL). The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH) or washed with an organic solvent such as ether to give compounds 5e-5f, 5h-5i, 5k-5l and 5n-5p .
실시예 51. 7-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5a) [Example 51. 7-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5a) [ 7-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one7-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5a)] (5a)]
화합물 5a는 7-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온(4b; 76 mg, 0.28 mmol) 및 삼브롬화붕소(3.4 mL, 3.4 mmol)를 사용하여 다이클로로메탄(30 mL) 중에서 50 ℃에서 18시간 동안 교반하여 합성예 4에 기재된 것과 동일한 방법으로 갈색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.07 (dd, J = 6.5 Hz and J = 8.8 Hz, 1H), 7.97-7.92 (m, 2H), 7.69 (dd, J = 2.4 Hz and J = 9.6 Hz, 1H), 7.37-7.32 (m, 1H), 6.95-6.90 (m, 2H), 6.86 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 176.54, 166.18, 164.51, 163.87, 161.56, 157.15, 157.06, 128.86, 128.03, 127.96, 121.75, 120.94, 116.43, 114.36, 114.20, 105.79, 105.62, 105.24. HRMS m/z calculated for C15H9FO3 [M+H]+ : 257.0609; found : 257.0616.Compound 5a was distilled using 7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4b ; 76 mg, 0.28 mmol) and boron tribromide (3.4 mL, 3.4 mmol). It was stirred in chloromethane (30 mL) at 50 °C for 18 hours to obtain a brown powder in quantitative yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 8.07 (dd, J = 6.5 Hz and J = 8.8 Hz, 1H), 7.97-7.92 (m, 2H), 7.69 (dd, J = 2.4 Hz and J = 9.6 Hz, 1H), 7.37-7.32 (m, 1H), 6.95-6.90 (m, 2H), 6.86 (s, 1H); 13 C NMR (150 MHz, DMSO-d 6 ) δ 176.54, 166.18, 164.51, 163.87, 161.56, 157.15, 157.06, 128.86, 128.03, 127.96, 121.75, 120.94, 116.43, 114.36, 114.20, 114.20, 2,240.5.7 HRMS m / z calculated for C 15 H 9 FO 3 [M+H] + : 257.0609; found: 257.0616.
실시예 52. 6-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5b) [Example 52. 6-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5b) [ 6-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one6-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5b)] (5b)]
화합물 5b는 6-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온(4d; 100 mg, 0.37 mmol) 및 삼브롬화붕소(4.4 mL, 4.4 mmol)를 사용하여 다이클로로메탄(15 mL) 중에서 11시간 동안 교반하여 합성예 4에 기재된 것과 동일한 방법으로 황색 분말로서 97% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, MeOD) δ 7.96-7.89 (m, 2H), 7.81-7.74 (m, 2H), 7.63-7.55 (m, 1H), 6.98-6.93 (m, 2H), 6.81 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 176.79, 164.00, 160.19, 158.62, 152.49, 128.98, 124.97, 122.56, 122.39, 121.65, 121.59, 116.47, 109.94, 109.79, 104.59. HRMS m/z calculated for C15H9FO3 [M-H]- : 257.0609; found : 257.0599. Compound 5b was distilled using 6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4d ; 100 mg, 0.37 mmol) and boron tribromide (4.4 mL, 4.4 mmol). After stirring in chloromethane (15 mL) for 11 hours, it was obtained as a yellow powder in 97% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, MeOD) δ 7.96-7.89 (m, 2H), 7.81-7.74 (m, 2H), 7.63-7.55 (m, 1H), 6.98-6.93 (m, 2H), 6.81 (s, 1H); 13 C NMR (150 MHz, DMSO-d 6 ) δ 176.79, 164.00, 160.19, 158.62, 152.49, 128.98, 124.97, 122.56, 122.39, 121.65, 121.59, 116.47, 109.94, 109.79, 104.59. HRMS m / z calculated for C 15 H 9 FO 3 [MH] - : 257.0609; found: 257.0599.
실시예 53. 5-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5c) [Example 53. 5-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5c) [ 5-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one5-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5c)] (5c)]
화합물 5c는 5-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온(4f; 100 mg, 0.37 mmol) 및 삼브롬화붕소(4.4 mL, 4.4 mmol)를 사용하여 다이클로로메탄(30 mL) 중에서 50 ℃에서 18시간 동안 교반하여 합성예 4에 기재된 것과 동일한 방법으로 백색 분말로서 96% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, DMSO-d6) δ 10.31 (brs, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.81-7.73 (m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.3 Hz and J = 10.7 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 175.81, 162.53, 161.56, 160.89, 159.16, 157.13, 134.81, 134.74, 128.84, 121.47, 116.44, 115.03, 115.01, 113.99, 113.92, 112.54, 112.41, 106.28. HRMS m/z calculated for C15H9FO3 [M+H]+ : 257.0609; found : 257.0618. Compound 5c was distilled using 5-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4f ; 100 mg, 0.37 mmol) and boron tribromide (4.4 mL, 4.4 mmol). It was stirred in chloromethane (30 mL) at 50 °C for 18 hours to obtain a white powder in 96% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.31 (brs, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.81-7.73 (m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.3 Hz and J = 10.7 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H); 13 C NMR (150 MHz, DMSO-d 6 ) δ 175.81, 162.53, 161.56, 160.89, 159.16, 157.13, 134.81, 134.74, 128.84, 121.47, 116.44, 115.03, 115.01, 113.99, 113.92, 113.2.6, 112.5 HRMS m / z calculated for C 15 H 9 FO 3 [M+H] + : 257.0609; found: 257.0618.
실시예 54. 5,7-다이플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5d) [Example 54. 5,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5d) [ 5,7-Difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one5,7-Difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5d)] (5d)]
화합물 5d는 5,7-다이플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온(4h; 100 mg, 0.35 mmol) 및 삼브롬화붕소(4.2 mL, 4.2 mmol)를 사용하여 다이클로로메탄(30 mL) 중에서 50 ℃에서 14시간 동안 교반하여 합성예 4에 기재된 것과 동일한 방법으로 백색 분말로서 94% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, DMSO-d6) δ 10.34 (brs, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 9.0 Hz, 1H), 7.35-7.28 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.78 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 175.07, 162.66, 161.77, 157.95, 128.84, 121.08, 116.47, 111.49, 106.15, 102.38, 49.07. HRMS m/z calculated for C15H8F2O3 [M+H]+ : 275.0515; found : 275.0524.Compound 5d was prepared by combining 5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4h ; 100 mg, 0.35 mmol) and boron tribromide (4.2 mL, 4.2 mmol). was stirred in dichloromethane (30 mL) at 50 °C for 14 hours to obtain a white powder in 94% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.34 (brs, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 9.0 Hz, 1H), 7.35-7.28 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H) ), 6.78 (s, 1H); 13 C NMR (150 MHz, DMSO-d 6 ) δ 175.07, 162.66, 161.77, 157.95, 128.84, 121.08, 116.47, 111.49, 106.15, 102.38, 49.07 . HRMS m / z calculated for C 15 H 8 F 2 O 3 [M+H] + : 275.0515; found: 275.0524.
실시예 55. 3-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조산 (5e) [Example 55. 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5e) [ 3-(6,7-Difluoro-4-oxo-4H-chromen-2-yl)benzoic acid3-(6,7-Difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5e)] (5e)]
화합물 5e는 메틸 3-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조에이트(4k; 50 mg, 0.16 mmol) 및 MeOH(3.0 mL) 중 1 N NaOH(3.9 mL, 0.40 mmol)를 사용하여 70 ℃에서 2시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, MeOD) δ 8.66 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 10.2 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 6.6 Hz, 1H), 6.93 (s, 1H). HRMS m/z calculated for C16H8F2O4 [M-H]- : 301.0318; found : 301.0298. Compound 5e was prepared from methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4k ; 50 mg, 0.16 mmol) and 1 N NaOH in MeOH (3.0 mL) ( 3.9 mL, 0.40 mmol) was stirred at 70 °C for 2 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, MeOD) δ 8.66 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 10.2 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 6.6 Hz, 1H), 6.93 (s, 1H). HRMS m / z calculated for C 16 H 8 F 2 O 4 [MH] - : 301.0318; found: 301.0298.
실시예 56. 4-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조산 (5f) [Example 56. 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5f) [ 4-(6,7-Difluoro-4-oxo-4H-chromen-2-yl)benzoic acid4-(6,7-Difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5f)] (5f)]
화합물 5f는 메틸 4-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조에이트(4l; 88 mg, 0.28 mmol) 및 MeOH(1.8 mL) 중 1 N NaOH(0.55 mL, 0.56 mmol)을 사용하여, 80 ℃에서 1시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.14 (d, J = 7.8 Hz, 2H), 8.07 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 11.4 Hz, 1H), 7.67 (d, J = 6.6 Hz, 1H), 7.06 (s, 1H).Compound 5f was prepared from methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4l ; 88 mg, 0.28 mmol) and 1 N NaOH in MeOH (1.8 mL) ( 0.55 mL, 0.56 mmol) was used and stirred at 80° C. for 1 hour to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.14 (d, J = 7.8 Hz, 2H), 8.07 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 11.4 Hz, 1H), 7.67 (d, J = 6.6 Hz, 1H), 7.06 ( s, 1H).
실시예 57. 6,7-다이플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5g) [Example 57. 6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5 g) [ 6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5g)] (5g)]
화합물 5g는 6,7-다이플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온(4j; 65 mg, 0.23 mmol) 및 삼브롬화붕소(0.6 mL, 3.8 mmol)를 사용하여 다이클로로메탄(2.6 mL) 중에서 60 ℃에서 24시간 동안 교반하여 합성예 4에 기재된 것과 동일한 방법으로 백색 분말로서 13% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, MeOD) δ 7.96 (t, J = 9.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.73 (dd, J = 6.6 Hz and J = 10.2 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.80 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 175.93, 164.19, 161.69, 152.52, 128.92, 121.59, 121.09, 116.45, 112.60, 112.47, 108.76, 108.61, 104.72. HRMS m/z calculated for C15H8F2O3 [M+H]+ : 275.0515; found : 275.0527.Compound 5g was prepared by combining 6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4j ; 65 mg, 0.23 mmol) and boron tribromide (0.6 mL, 3.8 mmol). was stirred in dichloromethane (2.6 mL) at 60 °C for 24 hours to obtain a white powder in 13% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, MeOD) δ 7.96 (t, J = 9.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.73 (dd, J = 6.6 Hz and J = 10.2 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.80 (s, 1H); 13 C NMR (150 MHz, DMSO-d 6 ) δ 175.93, 164.19, 161.69, 152.52, 128.92, 121.59, 121.09, 116.45, 112.60, 112.47, 108.76, 108.61, 104.72. HRMS m / z calculated for C 15 H 8 F 2 O 3 [M+H] + : 275.0515; found: 275.0527.
실시예 58. 3-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조산 (5h) [Example 58. 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid (5h) [ 3-(6,7-Dichloro-4-oxo-4H-chromen-2-yl)benzoic acid3-(6,7-Dichloro-4-oxo-4H-chromen-2-yl)benzoic acid (5h)] (5h)]
화합물 5h는 메틸 3-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조에이트(4o; 100mg, 0.29 mmol) 및 MeOH(2.0 mL) 중 1 N NaOH(0.57 mL, 0.57 mmol)를 사용하여 80 ℃에서 1시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.60 (t, J = 1.5 Hz, 1H), 8.41 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.18-8.17 (m, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H).Compound 5h was obtained from methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4o ; 100 mg, 0.29 mmol) and 1 N NaOH (0.57 mL in MeOH (2.0 mL)). , 0.57 mmol) was stirred at 80 °C for 1 hour to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.60 (t, J = 1.5 Hz, 1H), 8.41 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.18-8.17 (m, 2H), 7.74 (t, J = 7.8 Hz, 1H) ), 7.20 (s, 1H).
실시예 59. 4-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조산 (5i) [Example 59. 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid (5i) [ 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid (5i)](5i)]
화합물 5i는 메틸 4-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조에이트(4p; 150 mg, 0.43 mmol) 및 MeOH(10 mL) 중 1 N NaOH(0.86 mL, 0.86 mmol)를 사용하여 70 ℃에서 2시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, MeOD) δ 8.12-8.11 (m, 2H), 8.10 (s, 1H), 8.06-8.05 (m, 2H), 7.92 (s, 1H), 7.10 (s, 1H).Compound 5i was prepared from methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4p ; 150 mg, 0.43 mmol) and 1 N NaOH (0.86 mL, 0.86 mmol) was stirred at 70 °C for 2 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, MeOD) δ 8.12-8.11 (m, 2H), 8.10 (s, 1H), 8.06-8.05 (m, 2H), 7.92 (s, 1H), 7.10 (s, 1H).
실시예 60. 6,7-다이히드록시-2-페닐-4H-크로멘-4-온 (5j) [Example 60. 6,7-dihydroxy-2-phenyl-4H-chromen-4-one (5j) [ 6,7-Dihydroxy-2-phenyl-4H-chromen-4-one6,7-Dihydroxy-2-phenyl-4H-chromen-4-one (5j)] (5j)]
화합물 5j는 6,7-다이메톡시-2-페닐-4H-크로멘-4-온(4q; 93 mg, 0.33 mmol) 및 삼브롬화붕소(3.3 mL, 3.3 mmol)를 사용하여 다이클로로메탄(5.0 mL) 중에서 50 ℃에서 15시간 동안 교반하여 합성예 4에 기재된 것과 동일한 방법으로 상아색 분말로서 52% 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, MeOD) δ 7.96-7.94 (m, 2H), 7.56-7.51 (m, 3H), 7.41 (s, 1H), 7.03 (s, 1H), 6.76 (s, 1H).Compound 5j was prepared using 6,7-dimethoxy-2-phenyl-4H-chromen-4-one ( 4q ; 93 mg, 0.33 mmol) and boron tribromide (3.3 mL, 3.3 mmol) in dichloromethane ( 5.0 mL) was stirred at 50 °C for 15 hours to obtain an ivory-colored powder in 52% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, MeOD) δ 7.96-7.94 (m, 2H), 7.56-7.51 (m, 3H), 7.41 (s, 1H), 7.03 (s, 1H), 6.76 (s, 1H).
실시예 61. 4-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조산 (5k) [Example 61. 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid (5k) [ 4-(6,7-Dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid4-(6,7-Dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid (5k)] (5k)]
화합물 5k는 메틸 4-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트(4r; 100 mg, 0.29 mmol) 및 메탄올(5.0 mL) 중 1 N NaOH(0.60 mL, 0.59 mmol)를 사용하여 70 ℃에서 2시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 상아색 분말로서 54% 수율로 수득하였다. 조 잔류물을 에테르 및 물로 세척하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.22 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 9.0 Hz, 2H), 7.44 (s, 1H), 7.39 (s, 1H), 7.08 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H).Compound 5k was prepared from methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4r ; 100 mg, 0.29 mmol) and 1 N NaOH in methanol (5.0 mL) ( 0.60 mL, 0.59 mmol) was used and stirred at 70° C. for 2 hours to obtain an ivory-colored powder in 54% yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.22 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 9.0 Hz, 2H), 7.44 (s, 1H), 7.39 (s, 1H), 7.08 (s, 1H), 3.96 (s, 3H) ), 3.89 (s, 3H).
실시예 62. 3-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조산 (5l) [Example 62. 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid (5l) [ 3-(6,7-Dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid3-(6,7-Dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid (5l)] (5l)]
화합물 5l은 메틸 3-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트(4s; 100 mg, 0.29 mmol) 및 메탄올(5.0 mL) 중 1 N NaOH(0.60 mL, 0.59 mmol)를 사용하여 70 ℃에서 2시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 황색 분말로서 78% 수율로 수득하였다. 조 잔류물을 에테르 및 물로 세척하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.72-7.70 (m, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.39 (s, 1H), 3.97 (s, 3H), 3.89 (s, 3H).Compound 5l was obtained from methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4s ; 100 mg, 0.29 mmol) and 1 N NaOH (5.0 mL) in methanol. 0.60 mL, 0.59 mmol) was used and stirred at 70° C. for 2 hours to obtain a yellow powder in 78% yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.72-7.70 (m, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.39 (s, 1H), 3.97 (s, 3H), 3.89 (s, 3H).
실시예 63. 2-(4-히드록시페닐)-6,7-다이메틸-4H-크로멘-4-온 (5m) [Example 63. 2-(4-hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one (5m) [ 2-(4-Hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one2-(4-Hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one (5m)] (5m)]
화합물 5m은 2-(4-메톡시페닐)-6,7-다이메틸-4H-크로멘-4-온(4u; 85 mg, 0.29 mmol) 및 삼브롬화붕소(4.5 mL, 4.4 mmol)를 사용하여 다이클로로메탄(5.0 mL) 중에서 실온에서 6시간 동안 교반하여 합성예 4에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 1H NMR (600 MHz, DMSO-d6) δ 7.93 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), 7.55 (s, 1H), 6.93 (d, J = 9.0 Hz, 2H), 6.79 (s, 1H), 2.39 (s, 3H), 2.34 (s, 3H). Compound 5m was prepared using 2-(4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 4u ; 85 mg, 0.29 mmol) and boron tribromide (4.5 mL, 4.4 mmol). was stirred in dichloromethane (5.0 mL) at room temperature for 6 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.93 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), 7.55 (s, 1H), 6.93 (d, J = 9.0 Hz, 2H), 6.79 (s, 1H), 2.39 (s, 3H) ), 2.34 (s, 3H).
실시예 64. 4-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조산 (5n) [Example 64. 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5n) [ 4-(6,7-Dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid 4-(6,7-Dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5n)](5n)]
화합물 5n은 메틸 4-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조에이트(4v; 70 mg, 0.23 mmol) 및 메탄올(5.0 mL) 중 1 N NaOH(0.68 mL, 0.68 mmol)를 사용하여 70 ℃에서 3시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 황색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 에테르 및 물로 세척하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.20 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.63 (s, 1H), 7.08 (s, 1H), 2.41 (s, 3H), 2.40 (s, 3H). Compound 5n was obtained from methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4v ; 70 mg, 0.23 mmol) and 1 N NaOH (0.68 mL) in methanol (5.0 mL). mL, 0.68 mmol) was stirred at 70 °C for 3 hours to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.20 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.63 (s, 1H), 7.08 (s, 1H), 2.41 (s, 3H) ), 2.40 (s, 3H).
실시예 65. 3-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조산 (5o) [Example 65. 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5o) [ 3-(6,7-Dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid 3-(6,7-Dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5o)](5o)]
화합물 5o는 메틸 3-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조에이트(4w; 109 mg, 0.35 mmol) 및 메탄올(5.0 mL) 중 1 N NaOH(1.1 mL, 1.1 mmol)를 사용하여 70 ℃에서 2시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 백색 분말로서 정량적 수율로 수득하였다. 조 잔류물을 에테르 및 물로 세척하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.41 (d, J = 9.0 Hz, 1H), 8.32-8.31 (m, 1H), 8.16-8.15 (m, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 2.40 (s, 3H), 2.35 (s, 3H). Compound 5o was obtained from methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4w ; 109 mg, 0.35 mmol) and 1 N NaOH (1.1 mL, 1.1 mmol) was stirred at 70 °C for 2 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.41 (d, J = 9.0 Hz, 1H), 8.32-8.31 (m, 1H), 8.16-8.15 (m, 1H), 7.12 (s, 1H), 7.02 (s, 1H) , 2.40 (s, 3H), 2.35 (s, 3H).
실시예 66. 4-(4-옥소-4H-크로멘-2-일)벤조산 (5p) [Example 66. 4-(4-oxo-4H-chromen-2-yl)benzoic acid (5p) [ 4-(4-Oxo-4H-chromen-2-yl)benzoic acid 4-(4-Oxo-4H-chromen-2-yl)benzoic acid (5p)](5p)]
화합물 5p는 메틸 4-(4-옥소-4H-크로멘-2-일)벤조에이트(4x; 100 mg, 0.36 mmol) 메탄올(5.0 mL) 중 1 N NaOH(0.70 mL, 0.71 mmol)를 사용하여 70 ℃에서 1시간 동안 교반하여 합성예 5에 기재된 것과 동일한 방법으로 백색 분말로서 49% 수율로 수득하였다. 조 잔류물을 에테르 및 물로 세척하였다. 1H NMR (600 MHz, DMSO-d6) δ 8.14 (d, J = 7.8 Hz, 2H), 8.08-8.05 (m, 3H), 7.88-7.85 (m, 1H), 7.84-7.82 (m, 1H), 7.54-7.52 (m, 1H), 7.10 (s, 1H).Compound 5p was prepared using methyl 4-(4-oxo-4H-chromen-2-yl)benzoate ( 4x ; 100 mg, 0.36 mmol) using 1 N NaOH (0.70 mL, 0.71 mmol) in methanol (5.0 mL). It was stirred at 70° C. for 1 hour and obtained as a white powder in 49% yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.14 (d, J = 7.8 Hz, 2H), 8.08–8.05 (m, 3H), 7.88–7.85 (m, 1H), 7.84–7.82 (m, 1H), 7.54–7.52 (m, 1H), 7.10 ( s, 1H).
실시예 67. 4-옥소-2-페닐-4H-크로멘-5,6,7-트리일 트리아세테이트 (7) [Example 67. 4-oxo-2-phenyl-4H-chromen-5,6,7-triyl triacetate (7) [ 4-Oxo-2-phenyl-4H-chromene-5,6,7-triyl triacetate4-Oxo-2-phenyl-4H-chromene-5,6,7-triyl triacetate (7)] (7)]
DMF(5.0 mL) 중 바이칼레인(baicalein, 6)(300 mg, 1.1 mmol)의 교반된 용액에 아르곤 하에 실온에서 다이이소프로필에틸아민(1.2 mL, 6.6 mmol)을 첨가하였다. 20분 후, 아세틸 클로라이드(0.5 mL, 6.6 mmol)를 0 ℃에서 반응 혼합물에 적가한 다음 실온에서 15시간 동안 교반하였다. 반응 혼합물을 톨루엔으로 농축하였다. 조 잔류물을 실리카겔 상 컬럼 크로마토그래피로 정제하였다. 화합물 7을 옅은 오렌지색 분말로 93% 수율로 수득하였다. 1H NMR (600 MHz, CDCl3) δ 7.89-7.87 (m, 2H), 7.59-7.53 (m, 4H), 6.68 (s, 1H), 2.47 (s, 3H), 2.38-2.37 (m, 6H).To a stirred solution of baicalein ( 6 ) (300 mg, 1.1 mmol) in DMF (5.0 mL) at room temperature under argon was added diisopropylethylamine (1.2 mL, 6.6 mmol). After 20 minutes, acetyl chloride (0.5 mL, 6.6 mmol) was added dropwise to the reaction mixture at 0 °C and then stirred at room temperature for 15 hours. The reaction mixture was concentrated with toluene. The crude residue was purified by column chromatography on silica gel. Compound 7 was obtained as a pale orange powder in 93% yield. 1 H NMR (600 MHz, CDCl 3 ) δ 7.89–7.87 (m, 2H), 7.59–7.53 (m, 4H), 6.68 (s, 1H), 2.47 (s, 3H), 2.38–2.37 (m, 6H).
실험예 1. 화합물의 안정성 평가: 안정성 시험 (Stability Test)Experimental Example 1. Evaluation of compound stability: Stability Test
바이칼레인(Baicalein)의 용액 중에서의 안정성을 확인하기 위하여, 시간 변화에 따른 1H 1D NMR 스펙트럼을 PBS 조건에서 관측하였다. 상온 (25 ℃)에서 2-26시간 동안 1D NMR의 신호 강도(signal intensity)를 비교함으로써, 바이칼레인의 구조적인 변화에 따른 NMR 신호의 변화를 관측할 수 있었으며, 강도(intensity) 변화에 의해 관측된 바이칼레인의 반감기 (half life, T1/2)는 약 22 시간 정도였다. 7.9 ppm 위치의 H2’, H6’ 신호가 시간에 따라 줄어들고, 7.8 ppm 근처에서 새로운 위치의 H2’, H6’ 신호가 정량적으로 나타남을 관측할 수 있었다. 또한 6.5 ppm 근처의 H8 신호가 시간에 따라 줄어들고, 새로운 위치의 H8 신호가 정량적으로 나타남을 관측할 수 있었다 (도 1 참조). 이러한 신호 변화를 분석할 때, 바이칼레인은 바이칼레인 퀴논 (Baicalein quinone)으로 산화(oxidation)에 의한 구조 변형을 갖는 것을 예상할 수 있다 (도 2 참조).In order to confirm the stability of baicalein in a solution, 1H 1D NMR spectrum over time was observed under PBS conditions. By comparing the signal intensity of 1D NMR at room temperature (25 ℃) for 2-26 hours, it was possible to observe the change in NMR signal according to the structural change of baicalein, which was observed by the change in intensity The half life (T 1/2 ) of baicalein was about 22 hours. It was observed that the H2' and H6' signals at the 7.9 ppm position decreased with time, and the H2' and H6' signals at the new position around 7.8 ppm appeared quantitatively. In addition, it was observed that the H8 signal near 6.5 ppm was reduced over time, and the H8 signal at a new position appeared quantitatively (see FIG. 1). When analyzing these signal changes, it can be expected that baicalein has a structural transformation due to oxidation to baicalein quinone (see FIG. 2).
반면에 화합물 5e는 퀴논 (quinone)으로 산화될 수 없도록 6번 및 7번 위치의 히드록실(hydroxyl) 기 대신에 불소 (fluorine) 기로 치환하였으므로 용액 중에서 산화에 의한 구조 변형을 받지 않고, 그 결과 26시간 까지도 1D NMR 신호의 변화가 관측되지 않고, 동일한 구조를 유지하는 것을 확인할 수 있었다 (도 3 참조).On the other hand, compound 5e was substituted with fluorine groups instead of hydroxyl groups at positions 6 and 7 so that it could not be oxidized to quinone, so it did not undergo structural transformation by oxidation in solution, and as a result, 26 It was confirmed that no change in the 1D NMR signal was observed even with time, and the same structure was maintained (see FIG. 3).
실험예 2. 화합물의 시험관내 (Experimental Example 2. Compound in vitro ( in vitroin vitro ) 활성 평가 결과 ) active evaluation result
도 4에 TSLP와 TSLP 수용체 (TSLPR) 결합의 억제를 측정하는 ELISA실험 방법을 개략적으로 나타내었다.4 schematically shows an ELISA test method for measuring inhibition of TSLP and TSLP receptor (TSLPR) binding.
2.1. 코팅(Coating)2.1. Coating
100 nM의 TSLP 수용체 (TSLPR) 사람 재조합 단백질을 1X 코팅 완충용액(Biolegend)으로 제조한 후 멀티채널 피펫 (Multichannel pipette, Gilson)을 사용하여 96 well microplate (Corning)에 넣고 4 ℃에서 12시간 이상 코팅하였다.After preparing 100 nM of TSLP receptor (TSLPR) human recombinant protein in 1X coating buffer (Biolegend), put it into a 96 well microplate (Corning) using a multichannel pipette (Multichannel pipette, Gilson), and coat for more than 12 hours at 4℃. did
2.2. 블로킹 (Blocking)2.2. Blocking
PBST (1X PBS (Welgene), 1% Tween 20 (sigma))로 3회 세척한 후 1% BSA (Bovogen) 블로킹 완충용액으로 실온에서 1시간 반응시켰다.After washing three times with PBST (1X PBS (Welgene), 1% Tween 20 (sigma)), it was reacted with 1% BSA (Bovogen) blocking buffer at room temperature for 1 hour.
2.3. 바인딩 (Binding)2.3. Binding
100 nM의 TSLP 야생형(wildtype) 사람 재조합 단백질과 10 μM 또는 100 μM의 실시예 화합물들이 각각 포함된 시료를 제조하여 동일 부피로 넣은 후 실온에서 2시간 이상 반응시켰다.Samples containing 100 nM of TSLP wildtype human recombinant protein and 10 μM or 100 μM of each of the example compounds were prepared, put into the same volume, and reacted at room temperature for 2 hours or longer.
2.4. 검출2.4. detection
PBST (1X PBS (Welgene), 1% Tween 20 (sigma))로 3회 세척한 후, Anti-TSLP(Abcam) 항체를 1:7500로 희석하여 실온에서 1시간 이상 반응시켰다.After washing three times with PBST (1X PBS (Welgene), 1% Tween 20 (sigma)), the anti-TSLP (Abcam) antibody was diluted 1:7500 and reacted at room temperature for 1 hour or longer.
PBST (1X PBS (Welgene), 0.05% Tween 20 (sigma))로 3회 세척한 후, Anti-rabbit IgG, HRP-linked Antibody(Cell signaling) 항체를 1:1000로 희석하여 실온에서 1시간 이상 반응시켰다.After washing three times with PBST (1X PBS (Welgene), 0.05% Tween 20 (sigma)), anti-rabbit IgG and HRP-linked Antibody (Cell signaling) antibodies were diluted 1:1000 and reacted at room temperature for more than 1 hour. made it
2.5. 반응2.5. reaction
PBST (1X PBS (Welgene), 1% Tween 20 (sigma))로 3회 세척한 후, TMB 기질액 (substrate solution, Thermo)을 넣고 5분 이상 반응시켰다. 1 N HCl (Samchun)를 넣어 반응을 정지한 후 Microplate reader(Tecan, Spark®)기로 5초간 오비탈 쉐이킹 (orbital shaking)한 후 450 nm에서 흡광값을 구하였다.After washing three times with PBST (1X PBS (Welgene), 1% Tween 20 (sigma)), TMB substrate solution (Thermo) was added and reacted for 5 minutes or more. After stopping the reaction by adding 1 N HCl (Samchun), orbital shaking was performed for 5 seconds using a Microplate reader (Tecan, Spark ® ), and the absorbance value was obtained at 450 nm.
2.6. 분석법2.6. assay
Microplate reader와 연동된 프로그램에서 도출되어 나온 결과값을 엑셀 프로그램을 이용해 분석하였다. 3회수행 (triplicate)을 통해 나온 3개의 값의 평균을 구하여 비히클 (vehicle) 값을 100%로 환산하여 결합율(binding) %를 구하거나 비히클 값을 100%로 환산하여 TSLP-TSLPR binding %를 구하였다. 100%에서 TSLP-TSLPR binding %를 빼어 각 화합물의 결합율 (%) 값을 구하고 3회수행 (triplicate)의 오차범위도 구해 화합물 억제율 그래프를 도출 시 반영하였다.The result values derived from the program linked with the microplate reader were analyzed using the Excel program. The average of the three values obtained through triplicate is obtained and the vehicle value is converted to 100% to obtain the binding % or the vehicle value is converted to 100% to obtain the TSLP-TSLPR binding % saved The binding rate (%) value of each compound was obtained by subtracting the TSLP-TSLPR binding % from 100%, and the error range of triplicate was also obtained, which was reflected when deriving the compound inhibition rate graph.
2.7. 결과2.7. result
TSLP와 TSLP 수용체 (TSLPR) 결합의 억제율(inhibition %) 결과를 하기 표 1 내지 표 2에 나타내었다.The results of inhibition % of TSLP and TSLP receptor (TSLPR) binding are shown in Tables 1 and 2 below.
실시예Example 화합물 번호compound number ELISA(Inhibition %)ELISA (Inhibition %) ELISA
IC50(μM)ELISA
IC 50 (μM)
10 μM10 µM 100 μM100 µM 300 μM300 µM
99 3i3i 1313 1111 -- --
1010 3j3j 1919 2222 -- --
1111 3k3k 3434 5050 -- --
1212 3l3l 2020 2020 -- --
1313 3m3m 1313 2121 -- --
1414 3n3n 1515 2929 -- --
1515 3o 3o 2222 4949 -- --
1616 3p3p 3535 7878 -- --
1717 3q3q 1414 3737 -- --
1818 3r3r 2121 3737 -- --
1919 3s 3s 44 77 -- --
2020 3t3t 3636 7070 -- --
2121 3u3u 88 1010 -- --
2222 3v3v 1One -6-6 -- --
2424 3x 3x 33 77 -- --
2525 3y 3y 66 2323 -- --
3535 4i 4i 44 5454 -- --
3636 4j4j 3939 8787 -- --
3939 4m4m 3333 3939 -- --
4040 4n4n 4747 7979 -- --
4343 4q4q 99 4343 -- --
4646 4t4t 2020 4646 -- --
실시예Example 화합물 번호compound number ELISA(Inhibition %)ELISA (Inhibition %) ELISA
IC50(μM)ELISA
IC 50 (μM)
10 μM10 µM 100 μM100 µM 300 μM300 µM
5555 5e5e 1515 1515 -- --
5656 5f 5f 2626 5959 -- --
5757 5g5g 3030 5454 -- --
5858 5h5h 4242 4949 -- --
5959 5i5i 1717 8585 -- --
6060 5j5j 5353 7676
6161 5k5k 1515 4040 -- --
6262 5l5l 1111 3838 -- --
6363 5m5m 4444 7171 -- --
6464 5n5n 1414 2424 -- --
6666 5p5p 3737 3232
6767 77 4848 7171 -- 1.91.9
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. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims (13)

  1. 하기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염:A fluorine-substituted flavonoid derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
    <화학식 Ⅰ><Formula Ⅰ>
    Figure PCTKR2022007713-appb-img-000007
    Figure PCTKR2022007713-appb-img-000007
    상기 식에서, In the above formula,
    Ra 및 Rb는 수소이거나 서로 연결되어 단일결합을 형성하고,R a and R b are hydrogen or linked to each other to form a single bond,
    X 및 Y는 독립적으로 수소, C1-C4 직쇄 또는 분지쇄 알킬, C1-C4 알콕시, 할로겐, 히드록시, 또는 OCO-알킬이고,X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, or OCO-alkyl;
    Z는 수소, 할로겐, 또는 OCO-알킬이고,Z is hydrogen, halogen, or OCO-alkyl;
    R1은 수소, C1-C4 알콕시, 히드록시, 또는 COO-Rc이고,R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
    R2는 수소 또는 COO-Rc이고,R 2 is hydrogen or COO-R c ;
    상기 Rc는 수소, 또는 C1-C4 직쇄 또는 분지쇄 알킬이다.R c is hydrogen or C 1 -C 4 straight or branched chain alkyl.
  2. 제1항에 있어서, 하기 화학식 Ⅰa로 표시되는 것을 특징으로 하는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염:The fluorine-substituted flavonoid derivative compound according to claim 1, characterized by being represented by the following formula (Ia), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
    <화학식 Ⅰa><Formula Ia>
    Figure PCTKR2022007713-appb-img-000008
    Figure PCTKR2022007713-appb-img-000008
    상기 식에서,In the above formula,
    X 및 Y는 독립적으로 수소, C1-C4 직쇄 또는 분지쇄 알킬, C1-C4 알콕시, 또는 할로겐이고,X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, or halogen;
    Z는 수소 또는 할로겐이고,Z is hydrogen or halogen;
    R1은 수소, C1-C4 알콕시, 히드록시, 또는 COO-Rc이고,R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
    R2는 수소 또는 COO-Rc이고,R 2 is hydrogen or COO-R c ;
    상기 Rc는 C1-C4 직쇄 또는 분지쇄 알킬이다.R c is C 1 -C 4 straight or branched chain alkyl.
  3. 제1항에 있어서, 하기 화학식 Ⅰb로 표시되는 것을 특징으로 하는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염:The fluorine-substituted flavonoid derivative compound according to claim 1, characterized by being represented by the following formula (Ib), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
    <화학식 Ⅰb><Formula Ib>
    Figure PCTKR2022007713-appb-img-000009
    Figure PCTKR2022007713-appb-img-000009
    상기 식에서,In the above formula,
    X 및 Y는 독립적으로 수소, C1-C4 직쇄 또는 분지쇄 알킬, C1-C4 알콕시, 할로겐, 히드록시, 또는 OCO-알킬이고,X and Y are independently hydrogen, C 1 -C 4 straight or branched chain alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, or OCO-alkyl;
    Z는 수소, 할로겐, 또는 OCO-알킬이고,Z is hydrogen, halogen, or OCO-alkyl;
    R1은 수소, C1-C4 알콕시, 히드록시, 또는 COO-Rc이고,R 1 is hydrogen, C 1 -C 4 alkoxy, hydroxy, or COO-R c ;
    R2는 수소 또는 COO-Rc이고,R 2 is hydrogen or COO-R c ;
    상기 Rc는 수소, 또는 C1-C4 직쇄 또는 분지쇄 알킬이다.R c is hydrogen or C 1 -C 4 straight or branched chain alkyl.
  4. 제1항에 있어서, 상기 X 및 Y가 독립적으로 수소, 메틸, 메톡시, F, Cl, 히드록시, 또는 아세테이트인 것을 특징으로 하는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.The fluorine-substituted flavonoid derivative compound according to claim 1, wherein X and Y are independently hydrogen, methyl, methoxy, F, Cl, hydroxy, or acetate, a hydrate thereof, a solvate thereof, or a pharmaceutical thereof. an acceptable salt.
  5. 제1항에 있어서, 상기 Z가 수소, F, 또는 아세테이트인 것을 특징으로 하는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.The fluorine-substituted flavonoid derivative compound according to claim 1, wherein Z is hydrogen, F, or acetate, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서, 상기 R1이 수소, 메톡시, 히드록시, 카르복실, 또는 메틸 카르복실레이트인 것을 특징으로 하는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.The fluorine-substituted flavonoid derivative compound according to claim 1, wherein R 1 is hydrogen, methoxy, hydroxy, carboxyl, or methyl carboxylate, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable compound thereof. salt possible.
  7. 제1항에 있어서, 상기 R2가 수소, 카르복실, 또는 메틸 카르복실레이트인 것을 특징으로 하는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.The fluorine-substituted flavonoid derivative compound according to claim 1, wherein R 2 is hydrogen, carboxyl, or methyl carboxylate, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  8. 제1항에 있어서, 상기 화학식 Ⅰ로 표시되는 불소-치환 플라보노이드 유도체 화합물이 하기 화합물로 구성되는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염:The fluorine-substituted flavonoid derivative compound according to claim 1, wherein the fluorine-substituted flavonoid derivative compound represented by Formula 1 is any one selected from the group consisting of the following compounds, a hydrate thereof, a solvate thereof, or a fluorine-substituted flavonoid derivative compound thereof. Pharmaceutically acceptable salts:
    (E)-1-(4-플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3a),(E) -1- (4-fluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3a );
    (E)-1-(4-플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3b),(E) -1- (4-fluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3b ),
    (E)-1-(5-플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3c),(E) -1- (5-fluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3c ),
    (E)-1-(5-플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3d),(E)-1-(5-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3d );
    (E)-1-(2-플루오로-6-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3e),(E) -1- (2-fluoro-6-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3e );
    (E)-1-(2-플루오로-6-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3f),(E) -1- (2-fluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3f ),
    (E)-1-(2,4-다이플루오로-6-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3g),(E) -1- (2,4-difluoro-6-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3g ),
    (E)-1-(2,4-다이플루오로-6-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3h),(E) -1- (2,4-difluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3h ),
    (E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3i),(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3i ),
    (E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3j),(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3j ),
    (E)-1-(4,5-다이플루오로-2-히드록시페닐)-3-(4-히드록시페닐)프로프-2-엔-1-온 (3k),(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one ( 3k ),
    (E)-메틸 3-(3-(4,5-다이플루오로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3l),(E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3l ),
    (E)-메틸 4-(3-(4,5-다이플루오로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3m),(E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3m );
    (E)-1-(4,5-다이클로로-2-히드록시페닐)-3-페닐프로프-2-엔-1-온 (3n),(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3n ),
    (E)-1-(4,5-다이클로로-2-히드록시페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3o),(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3o ),
    (E)-1-(4,5-다이클로로-2-히드록시페닐)-3-(4-히드록시페닐)프로프-2-엔-1-온 (3p),(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one ( 3p ),
    (E)-메틸 3-(3-(4,5-다이클로로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3q),(E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3q );
    (E)-메틸 4-(3-(4,5-다이클로로-2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3r),(E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3r );
    (E)-1-(2-히드록시-4,5-다이메톡시페닐)-3-페닐프로프-2-엔-1-온 (3s),(E) -1- (2-hydroxy-4,5-dimethoxyphenyl) -3-phenylprop-2-en-1-one ( 3s ),
    (E)-메틸 4-(3-(2-히드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3t),(E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3t ),
    (E)-메틸 3-(3-(2-히드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3u),(E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3u );
    (E)-1-(2-히드록시-4,5-다이메틸페닐)-3-페닐프로프-2-엔-1-온 (3v),(E) -1- (2-hydroxy-4,5-dimethylphenyl) -3-phenylprop-2-en-1-one ( 3v ),
    (E)-1-(2-히드록시-4,5-다이메틸페닐)-3-(4-메톡시페닐)프로프-2-엔-1-온 (3w),(E) -1- (2-hydroxy-4,5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3w ),
    (E)-메틸 4-(3-(2-히드록시-4,5-다이메틸페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3x),(E)-methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3x );
    (E)-메틸 3-(3-(2-히드록시-4,5-다이메틸페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3y),(E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3y );
    (E)-메틸 4-(3-(2-히드록시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (3z),(E)-methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3z );
    7-플루오로-2-페닐-4H-크로멘-4-온 (4a),7-fluoro-2-phenyl-4H-chromen-4-one ( 4a );
    7-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4b),7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4b );
    6-플루오로-2-페닐-4H-크로멘-4-온 (4c),6-fluoro-2-phenyl-4H-chromen-4-one ( 4c );
    6-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4d),6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4d );
    5-플루오로-2-페닐-4H-크로멘-4-온 (4e),5-fluoro-2-phenyl-4H-chromen-4-one ( 4e );
    5-플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4f),5-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4f );
    5,7-다이플루오로-2-페닐-4H-크로멘-4-온 (4g),5,7-difluoro-2-phenyl-4H-chromen-4-one ( 4g );
    5,7-다이플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4h),5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4h );
    6,7-다이플루오로-2-페닐-4H-크로멘-4-온 (4i),6,7-difluoro-2-phenyl-4H-chromen-4-one ( 4i );
    6,7-다이플루오로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4j),6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4j );
    메틸 3-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조에이트 (4k),methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4k );
    메틸 4-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조에이트 (4l),methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4l );
    6,7-다이클로로-2-페닐-4H-크로멘-4-온 (4m),6,7-dichloro-2-phenyl-4H-chromen-4-one ( 4m );
    6,7-다이클로로-2-(4-메톡시페닐)-4H-크로멘-4-온 (4n),6,7-dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4n );
    메틸 3-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조에이트 (4o),methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4o );
    메틸 4-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조에이트 (4p),methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4p );
    6,7-다이메톡시-2-페닐-4H-크로멘-4-온 (4q),6,7-dimethoxy-2-phenyl-4H-chromen-4-one ( 4q );
    메틸 4-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (4r),methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4r );
    메틸 3-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (4s),methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4s );
    6,7-다이메틸-2-페닐-4H-크로멘-4-온 (4t),6,7-dimethyl-2-phenyl-4H-chromen-4-one ( 4t );
    2-(4-메톡시페닐)-6,7-다이메틸-4H-크로멘-4-온 (4u),2-(4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 4u );
    메틸 4-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조에이트 (4v),methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4v );
    메틸 3-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조에이트 (4w),methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4w );
    메틸 4-(4-옥소-4H-크로멘-2-일)벤조에이트 (4x),methyl 4-(4-oxo-4H-chromen-2-yl)benzoate ( 4x );
    7-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5a),7-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5a );
    6-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5b),6-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5b );
    5-플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5c),5-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5c );
    5,7-다이플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5d),5,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5d );
    3-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조산 (5e),3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5e );
    4-(6,7-다이플루오로-4-옥소-4H-크로멘-2-일)벤조산 (5f),4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5f );
    6,7-다이플루오로-2-(4-히드록시페닐)-4H-크로멘-4-온 (5g),6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5g ),
    3-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조산 (5h),3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5h );
    4-(6,7-다이클로로-4-옥소-4H-크로멘-2-일)벤조산 (5i),4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5i );
    6,7-다이히드록시-2-페닐-4H-크로멘-4-온 (5j),6,7-dihydroxy-2-phenyl-4H-chromen-4-one ( 5j );
    4-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조산 (5k),4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 5k );
    3-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조산 (5l),3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 5l ),
    2-(4-히드록시페닐)-6,7-다이메틸-4H-크로멘-4-온 (5m),2-(4-hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 5m );
    4-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조산 (5n),4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid ( 5n );
    3-(6,7-다이메틸-4-옥소-4H-크로멘-2-일)벤조산 (5o),3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid ( 5o );
    4-(4-옥소-4H-크로멘-2-일)벤조산 (5p) 및4-(4-oxo-4H-chromen-2-yl)benzoic acid ( 5p ) and
    4-옥소-2-페닐-4H-크로멘-5,6,7-트리일 트리아세테이트 (7).4-oxo-2-phenyl-4H-chromene-5,6,7-triyl triacetate ( 7 ).
  9. 제1항 내지 제8항 중 어느 한 항의 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 TSLP (thymic stromal lymphoprotein) 관련 질환의 예방 또는 치료용 약학적 조성물.Prevention or treatment of thymic stromal lymphoprotein (TSLP)-related diseases comprising the fluorine-substituted flavonoid derivative compound of any one of claims 1 to 8, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient pharmaceutical composition for use.
  10. 제1항 내지 제8항 중 어느 한 항의 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알러지성 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating allergic diseases, comprising the fluorine-substituted flavonoid derivative compound according to any one of claims 1 to 8, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  11. 제1항 내지 제8항 중 어느 한 항의 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 천식, 알레르기 비염, 만성 부비동염, 알레르기성 접촉성 피부염, 아토피 피부염, 만성 자발성 두드러기 및 아나필락시스로 이루어진 군으로부터 선택된 1 이상의 알러지성 질환; 그레이브스병, 쇼그렌 증후군, 면역성 혈소판 감소증, 자가면역성 용혈성 빈혈, 염증성 장질환 및 원발성 담즙성 담관염으로 이루어진 군으로부터 선택된 1 이상의 자가면역질환; 및 만성 폐쇄성 폐질환으로 이루어진 군으로부터 선택된 1 이상의 질환의 예방 또는 치료용 약학적 조성물.Asthma, allergic rhinitis, chronic sinusitis, allergic contact comprising the fluorine-substituted flavonoid derivative compound according to any one of claims 1 to 8, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. at least one allergic disease selected from the group consisting of sexual dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from the group consisting of Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
  12. 제1항 내지 제8항 중 어느 한 항의 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염과, 약제학적으로 허용가능한 첨가제를 포함하는 것을 특징으로 하는 약학적 조성물.A pharmaceutical composition comprising the fluorine-substituted flavonoid derivative compound of any one of claims 1 to 8, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. .
  13. 제1항 내지 제8항 중 어느 한 항의 불소-치환 플라보노이드 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 포함하는 알러지성 질환의 증상 개선용 식품 조성물.A food composition for improving the symptoms of an allergic disease, comprising the fluorine-substituted flavonoid derivative compound according to any one of claims 1 to 8, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
PCT/KR2022/007713 2021-06-01 2022-05-31 Novel fluorine-substituted flavonoid derivative, and pharmaceutical composition for preventing or treating allergic diseases, comprising same WO2022255765A1 (en)

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