Novel compound and use thereof

Abstract

The present invention relates to a novel compound and use thereof. The novel compound of the present invention was confirmed as having excellent anti-inflammatory efficacy, and thus inflammatory diseases such as inflammatory bowel disease can be effectively treated using a composition comprising the compound.

Description

Novel compounds and their uses

[0001] The present invention relates to a novel compound and its use.

[0002] Inflammatory bowel disease (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), was underdiagnosed in the past and the number of patients was undervalued. However, with the recent increase in medical accessibility and increased interest in health, hidden patients are being diagnosed, and the market size is rapidly growing.

[0003] Humira from AbbVie, which is currently the most widely used in clinical practice, is known to bind to TNF-alpha and suppress inflammatory responses. However, the high price, intravenous administration problems, and drug non-responsiveness, which are limitations of antibody treatment, are emerging as major problems, emphasizing the need for the development of new small molecule new drugs.

[0004] Against this backdrop, the present invention was completed by confirming the remarkably excellent anti-inflammatory efficacy and inflammatory bowel disease treatment / improvement efficacy of a novel compound and a composition containing the same.

[0005] One aspect provides a compound represented by chemical formula 57, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0006] Another aspect provides a compound represented by chemical formula 60, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0007] Another aspect provides a pharmaceutical composition for preventing or treating inflammatory diseases, comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0008] Another aspect provides a method for preventing or treating an inflammatory disease, comprising administering to a subject the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a composition comprising the same.

[0009] Another aspect provides a food composition for preventing or improving inflammatory diseases, comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0010] Another aspect provides a feed composition for preventing or improving inflammatory diseases, comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0011] Another aspect provides an anti-inflammatory composition comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0012] Another aspect provides an antioxidant composition comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0013] Another aspect provides a use of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof for treating, preventing, or ameliorating an inflammatory disease.

[0014] Another aspect provides an anti-inflammatory or antioxidant use of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0015] Another aspect provides the use of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof in the manufacture of a medicament for preventing or treating an inflammatory disease.

[0016] Another aspect provides the use of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof in the manufacture of a medicament for anti-inflammatory or antioxidant action.

[0017] To provide a compound represented by the following chemical formula 57, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:

[0018] [Chemical Formula 57]

[0019]

[0020] In the above chemical formula 57,

[0021] Ring W is selected from the group consisting of a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 cycloalkenyl, a substituted or unsubstituted C6-C14 aryl group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group,

[0022] One or more R 1 are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR 5 R 6, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group;

[0023] R 2 and R 3 Each independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Acyl group, substituted or unsubstituted C1-C10 Alkyl ester group, substituted or unsubstituted C7-C10 aryl ester group, , , and selected from the group consisting of glycosyl groups;

[0024] The above R 4 is hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR5 R 6 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group;

[0025] X is a vinylene group (-CH=CH-) n , -(CH2) n -, or -[CH=CH-(CH2) n ]- and,

[0026] R 5 , R 6 and R 7 Each independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 It is an alkyl group,

[0027] One or more R 8 are each independently selected from the group consisting of a C1-C5 alkyl group, a C3-C7 cycloalkyl group, a C1-C5 alkenyl group, a C1-C5 alkynyl group, a C1-C4 alkyloxy group, a nitro group (-NO2), a cyanide group (-CN), -F, -Cl, -Br, -I, and hydrogen,

[0028] l is an integer in the range 0 to 5,

[0029] m is 0 or 1,

[0030] n is an integer in the range 1 to 10,

[0031] q is an integer in the range 0 to 5,

[0032] r is an integer in the range 1 to 4,

[0033] s is an integer from 1 to 5.

[0034] In one embodiment, the glycosyl group may be selected from the group consisting of a 4-O-β-D-galactopyranosyl group, a 4-O-α-L-arabinosyl group, a 4-O-β-D-glucopyranosyl group, a 4-O-β-D-gyrosyl group, a 6'-O-methyl-4-O-β-D-glucopyranosyl, a 6'-O-methyl-4-O-β-D-galactopyranosyl, a 4-O-β-D-fucopyranosyl, a 6'-O-benzyl-4-O-β-D-glucopyranosyl, or a 6'-O-benzyl-4-O-β-D-galactopyranosyl.

[0035] The definitions of substituted substituents used in chemical formulas in this specification are as follows.

[0036] The term "alkyl" as used in chemical formulas refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon group. Non-limiting examples of such "alkyl" groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, and the like.

[0037] The term "halogen" as used in chemical formulas includes fluorine, bromine, chlorine, iodine, etc.

[0038] The term "halogen-substituted alkyl group (haloalkyl)" as used in chemical formulas refers to an alkyl group substituted with one or more halo groups, including, but not limited to, polyhaloalkyl containing monohaloalkyl, dihaloalkyl, or perhaloalkyl. Monohaloalkyl refers to an alkyl group having one iodine, bromine, chlorine, or fluorine, while dihaloalkyl and polyhaloalkyl refer to an alkyl group having two or more identical or different halo atoms.

[0039] The term "alkoxy" as used in chemical formulas refers to alkyl-O-, wherein the alkyl is as described above. Non-limiting examples of the alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclohexyloxy, and the like.

[0040] The term "alkenyl" as used in chemical formulas refers to a branched or unbranched hydrocarbon having at least one carbon-carbon double bond. Non-limiting examples of alkenyls include vinyl, allyl, butenyl, isopropenyl, and isobutenyl.

[0041] The term "alkynyl" as used in chemical formulas refers to a branched or unbranched hydrocarbon having at least one carbon-carbon triple bond. Non-limiting examples of such alkynyls include ethynyl, butynyl, isobutynyl, and isopropynyl.

[0042] The term "cycloalkyl" as used in chemical formulas refers to an alkyl group that forms a ring, as described above. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In addition, "cycloalkenyl" refers to an alkenyl group that forms a ring, as described above.

[0043] The term "heterocycloalkyl" as used in chemical formulas refers to a cyclic hydrocarbon that contains one or more heteroatoms selected from N, O, P or S as a reducing group and is entirely saturated. In addition, "heterocycloalkenyl" refers to a cyclic hydrocarbon that contains one or more heteroatoms selected from N, O, P or S as a reducing group and has at least one double bond.

[0044] The term "aryl" as used in chemical formulas, alone or in combination, refers to an aromatic hydrocarbon group containing one or more rings. The term "aryl" also includes groups in which an aromatic ring is fused to one or more cycloalkyl rings. Non-limiting examples of "aryl" include phenyl, naphthyl, and tetrahydronaphthyl.

[0045] The term "arylalkyl" as used in chemical formulas refers to an alkyl substituted with an aryl. Examples of arylalkyl include benzyl or phenyl-CH2CH2-. Additionally, "aryloxy" refers to O-aryl, and examples of aryloxy include phenoxy.

[0046] The term "heteroaryl" as used in chemical formulas refers to a monocyclic or bicyclic organic compound containing one or more heteroatoms selected from N, O, P or S, with the remaining ring atoms being carbon. The heteroaryl group may contain, for example, 1-5 heteroatoms and 3-12 ring members. The S or N may be oxidized to have various oxidation states.

[0047] The term "heteroarylalkyl" as used in chemical formulas means an alkyl substituted with a heteroaryl. Additionally, the term "heteroaryloxy" means an -O-heteroaryl moiety.

[0048] The term "amino group" as used in chemical formulas refers to a nitrogen atom covalently bonded to at least one carbon or heteroatom. Amino groups include, for example, -NH2 and substituted moieties. The term "amino group" may include alkylamino groups in which the nitrogen is bonded to at least one additional alkyl group, arylamino groups in which the nitrogen is bonded to at least one or more independently selected aryl groups, and diarylamino groups.

[0049] The '*' used in chemical formulas represents a bonding site with a neighboring atom.

[0050] The term "substituted" or "substituted" as used herein means a group in which one or more hydrogen atoms are replaced by one or more non-hydrogen atoms, provided that valence requirements are satisfied and a chemically stable compound results from the substitution. As used herein, all substituents should be interpreted as being either substituted or unsubstituted, unless explicitly stated as "unsubstituted."

[0051] For example, the 'substitution' in 'substituted' used in the alkyl group, haloalkyl group, alkoxy group, alkylamino group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group and heteroaryl group used above means a C1-C10 alkyl group (e.g., CF3, CHF2, CH2F, CCl3, etc.) in which one or more hydrogen atoms are substituted with halogen, halogen, alkoxy group, hydroxy group, nitro group, cyano group, amino group, amide group, sulfonamide group, ketone group, ester group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group, arylalkyl, aryloxy, heteroaryl group, It may mean substituted with heteroarylalkyl, heteroaryloxy, etc.

[0052] In one embodiment, the substitution in the 'substituted' above is one or more R a may be substituted with one or more of the R a are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, and substituted or unsubstituted C1-C10 It may be selected from the group consisting of alkoxy groups.

[0053] The term "pharmaceutically acceptable salt" as used herein refers to a salt that can be used pharmaceutically among salts, which are substances in which cations and anions are bound by electrostatic attraction, and can typically be a metal salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. For example, the metal salt can be an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt, etc.; the salt with an organic base can be a salt with triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.; the salt with an inorganic acid can be a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; salts with basic amino acids include salts with arginine, lysine, ornithine, etc.; salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Particularly preferred salts include, when the compound has an acidic functional group therein, inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.), and organic salts such as ammonium salts; and, when the compound has a basic functional group therein, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

[0054] The term "isomer" as used herein refers to a compound or salt thereof that has the same chemical formula or molecular formula but is optically or sterically different. Specifically, the isomer may include at least one selected from the group consisting of enantiomers, stereoisomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, racemates, and pharmaceutically acceptable salts thereof.

[0055] The term "solvate" as used herein refers to a compound solvated in an organic or inorganic solvent. The solvate may be, for example, a hydrate.

[0056] In one embodiment, the ring W may be a substituted or unsubstituted C3-C8 cycloalkyl group, and the C3-C8 cycloalkyl group may be, for example, a cyclopropanyl group, a cyclobutanyl group, a cyclopentanyl group, a cyclohexanyl group, a cycloheptanyl group, or a cyclooctanyl group.

[0057] In one embodiment, the ring W may be a substituted or unsubstituted C3-C8 cycloalkenyl group, and the C3-C8 cycloalkenyl group may be, for example, a cyclopropenyl group, a cyclobut-1-enyl group, a cyclopenta-1,3-dienyl group, a cyclohexenyl group, a cyclohexa-1,3-dienyl group, a cycloheptenyl group, a cyclohepta-1,3-dienyl group, a cyclohepta-1,3,5-trienyl group, a cyclooctenyl group, a cycloocta-1,3-dienyl group, or a cycloocta-1,3,5-trienyl group.

[0058] In one embodiment, the ring W may be a substituted or unsubstituted C6-C14 aryl group, and the C6-C14 aryl group may be, for example, a benzene group, a naphthalene group, an anthracene group, or a phenanthrene group.

[0059] In one embodiment, the ring W may be a substituted or unsubstituted 3- to 12-membered heteroaryl group, and the 3- to 12-membered heteroaryl group may be a pyrrole group, an indole group, a furan group, a benzofuran group, a thiophene group, a benzothiophene group, a pyridine group, a quinoline group, an isoquinoline group, a pyrimidine group, a pyrazine group, a quinazoline group, a quinoxaline group, an acridine group, a phenantridine group, a phenazine group, an imidazole group, a benzoimidazole group, an oxazole group, an isoxazole group, or a benzoisoxazole group.

[0060] In the chemical formula 57, the compound may be an integer ranging from 0 to 5, specifically, an integer ranging from 0 to 5, 0 to 4, 0 to 3, 0 to 2, 0 to 1, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.

[0061] In the above compound, in the above chemical formula 57, W may include at least one selected from the group consisting of groups represented by the following chemical formulas 58-1 to 58-5:

[0062] .

[0063] In the above chemical formulas 58-1 to 58-5, one or more R 1 are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR 5 R6 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group;

[0064] l is an integer in the range 0 to 5.

[0065] In one embodiment, in the chemical formulas 58-1 to 58-5, at least one R 1 are each independently hydrogen, halogen, substituted or unsubstituted C1-C5 Alkyl group, substituted or unsubstituted C1-C5 haloalkyl group, substituted or unsubstituted C1-C5 It can be selected from the group consisting of an alkoxy group, a hydroxy group, a cyano group, a formyl group, and a nitro group.

[0066] The compound may include at least one selected from the group consisting of groups represented by the following chemical formulas 59-1 to 59-5, in the chemical formula 57, and may specifically include chemical formula 59-4:

[0067] .

[0068] In the above chemical formulas 59-1 to 59-5, one or more R 1 (Specifically, R 1 , R 1` , and R 1`` One or more of them) are each independently hydrogen, substituted or unsubstituted C1-C5 Alkyl group, substituted or unsubstituted C1-C5 haloalkyl group, substituted or unsubstituted C1-C5 Selected from the group consisting of an alkoxy group, a hydroxy group, a cyano group, a formyl group, and a nitro group.

[0069] In one embodiment, in the chemical formula 59-4, R 1 and R 1` may be independently selected from the group consisting of a substituted or unsubstituted methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and hydrogen, and specifically, the R 1 and R 1` can each independently be a methyl group or an isopropyl group, and more specifically R 1 Silver isopropyl group, R 1` is a methyl group; or R 1 is a methyl group, R 1` may be an isopropyl group.

[0070] In one embodiment, in the chemical formula 59-5, R 1 and R 1` are each independently selected from the group consisting of a substituted or unsubstituted methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and hydrogen, and R 1`` may be a hydroxyl group, specifically R 1 and R 1` is a methyl group and R 1`` may be a hydroxy group.

[0071] In one embodiment, in the chemical formula 57, R 2 and R 3 are each independently hydrogen, substituted or unsubstituted C1-C5 Alkyl group and substituted or unsubstituted C1-C5 It may be selected from the group consisting of acyl groups, and specifically may be hydrogen, a methyl group, or an acetyl group.

[0072] In one embodiment, in the chemical formula 57, R 4 It may be selected from the group consisting of hydrogen, a formyl group, a substituted or unsubstituted C1-C10 alkyl group (specifically, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, or a heptyl group, etc.), a formyl group, and a substituted or unsubstituted C3-C10 aryl group.

[0073] In one embodiment, in the chemical formula 57, m may be 0 or 1, and X is a vinylene group (-CH=CH-) or -(CH2) n - (n can be an integer in the range 1 to 3).

[0074] In one embodiment, the compound may include one or more compounds selected from the group consisting of compounds 1 to 56 described in Tables 1 to 6. Specifically, compounds 1 to 56 may be represented by chemical formulas 1 to 56, respectively, and the chemical formulas of compounds 1 to 56 are described below.

[0075]

[0076]

[0077]

[0078]

[0079] .

[0080] The compound of the above chemical formula 57 can be prepared according to the following reaction scheme 1 or reaction scheme 2:

[0081] [Reaction Formula 1]

[0082]

[0083] [Reaction Formula 2]

[0084]

[0085] In the above reaction formulas 1 and 2,

[0086] L is a leaving group such as Cl, Br, I, or Tosyl group (-SO2C6H4CH3), Mesyl group (-SO2CH3), etc.

[0087] B is a boron compound used in the Suzuki Carbon-Carbon Coupling Reaction, such as a boronic acid (-B(OH)2) group, a boronic ester (-B(OR6)2) group, and a potassium trifluoroborate (-BF3K) group.

[0088] W, R 1 , R 2 , R 3 , R 4 , X, l, and m are as defined in chemical formula 57.

[0089] In one embodiment, in the Suzuki carbon-carbon bonding reaction of the above reaction formulas 1 and 2, the catalyst used may be a palladium catalyst.

[0090] In one embodiment, in the Suzuki carbon-carbon bond reaction of the above reaction formulas 1 and 2, the palladium catalyst used may be 0.01 to 0.2 equivalents with respect to the boron compound.

[0091] In one embodiment, in the Suzuki carbon-carbon bonding reaction of the above reaction formulas 1 and 2, the inorganic salt used may be at least one selected from the group consisting of potassium carbonate (K2CO3), sodium carbonate (Na2CO3), and cesium carbonate (Cs2CO3).

[0092] In one embodiment, in the Suzuki carbon-carbon bond reaction of the above reaction formulas 1 and 2, the amount of the inorganic salt used may be 1.0 to 3.0 equivalents with respect to the boron compound.

[0093] In one embodiment, in the Suzuki carbon-carbon bonding reaction of the above reaction formulas 1 and 2, the solvent used is not particularly limited, but is preferably a single solvent such as 1,4-dioxane, 1,2-dimethoxyethane, methanol (MeOH), ethanol, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), distilled water (H2O), or a mixed solvent of an organic solvent and distilled water.

[0094] In one embodiment, R in the compound 2 and R 3 The deprotection reaction of a compound having a methoxy group (-OMe) can be carried out in anhydrous dichloromethane (CH2Cl2) solvent using 2.0 to 6.0 equivalents of boron tribromide (BBr3).

[0095] The compound of the above chemical formula 57 can be prepared according to the following reaction scheme 3:

[0096] [Reaction Formula 3]

[0097] .

[0098] Another aspect provides a compound represented by the following chemical formula 60, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The same parts as described above also apply to the above compounds and the like:

[0099] [Chemical Formula 60]

[0100]

[0101] In the above chemical formula 60,

[0102] One or more rings W are each independently a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C3-C8 cycloalkenyl group, a substituted or unsubstituted C6-C14 aryl group, or a substituted or unsubstituted 3- to 12-membered heteroaryl group,

[0103] One or more R 1 are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR 5 R 6 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group;

[0104] R 2 and R 3 Each independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Acyl group, substituted or unsubstituted C1-C10 Alkyl ester group, substituted or unsubstituted C7-C10 aryl ester group, , , and selected from the group consisting of glycosyl groups;

[0105] One or more R 4 are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR 5 R 6 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group;

[0106] One or more Xs are each independently a vinylene group (-CH=CH-) n , -(CH2) n -, or -[CH=CH-(CH2) n ]- and,

[0107] R 5 , R 6 and R 7 Each independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 It is an alkyl group,

[0108] One or more R 8 are each independently selected from the group consisting of a C1-C5 alkyl group, a C3-C7 cycloalkyl group, a C1-C5 alkenyl group, a C1-C5 alkynyl group, a C1-C4 alkyloxy group, a nitro group (-NO2), a cyanide group (-CN), -F, -Cl, -Br, -I, and hydrogen,

[0109] Linker is , , , , and is selected from the group consisting of,

[0110] l is an integer in the range 0 to 5, each independently,

[0111] m is independently 0 or 1,

[0112] n is an integer in the range 1 to 10,

[0113] q is an integer in the range 0 to 5,

[0114] r is an integer in the range 1 to 4,

[0115] s is an integer from 1 to 5.

[0116] In the above chemical formula 60, ring W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, l, m, n, q, r and s are as defined in chemical formula 57.

[0117] In the above chemical formula 60, '-O-Linker-O-' including Linker may be in a form including ether, ester, carbonate, carbamate or thiocarbamate.

[0118] In one embodiment, the compound of the chemical formula 60 may be a dimer of the compound of the chemical formula 57, and specifically, may be a heterodimer or homodimer.

[0119]

[0120] Another aspect provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The same parts as described above also apply to the composition.

[0121] The compound included in the above composition may be represented by the chemical formula 57 or chemical formula 60 described above. In addition, the compound of chemical formula 60 may be a dimer of the compound of chemical formula 57, and specifically, may be a heterodimer or homodimer.

[0122] The term "inflammatory diseases" in this specification refers to a general term for diseases in which inflammation is the main lesion. The inflammatory diseases may include at least one selected from the group consisting of autoimmune diseases, systemic lupus erythematosus, multiple sclerosis, Sjogren's syndrome, asthma, conjunctivitis, iritis, scleritis, uveitis, periodontitis, dermatitis, arthritis, degenerative arthritis, inflammatory bowel disease, ankylosing spondylitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastritis, nephritis, pancreatitis, hepatitis, tendonitis, and tenosynovitis, and may specifically include inflammatory bowel disease.

[0123] The term "inflammatory bowel disease (IBD)" as used herein refers to an inflammatory disease caused by an inflammatory substance that occurs in the digestive tract. The inflammatory bowel disease may include at least one selected from the group consisting of ulcerative colitis, ulcerative duodenitis, Crohn's disease, irritable bowel syndrome, intestinal Behcet's disease, ischemic colitis, leaky gut syndrome, collagenous colitis, lymphocytic colitis, diversionary colitis, simple ulcer, and radiation enteritis.

[0124] The term “treatment” in this specification means any action that improves or beneficially changes the symptoms of an inflammatory disease by administering the composition of the present invention.

[0125] The term “prevention” in this specification means any action by which the possibility of the onset of an inflammatory disease is suppressed or delayed by administration of the composition of the present invention.

[0126] The compound, its isomer, its pharmaceutically acceptable salt, its solvate or a composition comprising the same may have anti-inflammatory efficacy, antioxidant efficacy and / or efficacy in promoting tight junctions of intestinal epithelial cells.

[0127] In one embodiment, the composition may have an anti-inflammatory effect and may suppress the expression and / or activity of inflammatory cytokines or inflammatory factors. Specifically, the inflammatory cytokines or inflammatory factors may include at least one selected from the group consisting of NO (Nitric oxide), IL-1β (Interleukin 1 beta), TNF-a (Tumor Necrosis Factor-alpha), iNOS (inducible Nitric Oxide Synthase), and COX-2 (cyclooxygenase-2).

[0128] In one embodiment, the inflammatory cytokine or inflammatory factor may include an inflammatory signaling substance, an inflammatory signaling pathway factor, and / or a MAPK signaling pathway factor. The inflammatory signaling substance, an inflammatory signaling pathway factor, and / or a MAPK signaling pathway factor may include at least one selected from the group consisting of IKK, IkB, NF-Kb(p65), ERK, JNK, and p38. Accordingly, the composition may inhibit one or more phosphorylated forms (activated forms) selected from the group consisting of IKK, IkB, NF-Kb(p65), ERK, JNK, and p38, and / or inhibit the expression level of the phosphorylated forms.

[0129] In one embodiment, the composition may have antioxidant properties, and specifically, may inhibit the production and / or expression of reactive oxygen species (ROS), and more specifically, may inhibit the production and / or expression of reactive oxygen species caused by endogenous factors and / or exogenous factors. In addition, the composition may inhibit the expression and / or activity of factors related to the inhibition or removal of reactive oxygen species, and specifically, may enhance the expression level and / or activity level of NRF2 (Nuclear factor erythroid 2-related factor 2).

[0130] In one embodiment, the composition may have an effect of maintaining and / or promoting tight junctions of intestinal epithelial cells, and specifically may induce the survival rate, activity, and proliferation of intestinal epithelial cells, and / or promote the expression and / or activity of tight junction-related factors. The intestinal epithelial cell tight junction-related factors may include at least one selected from the group consisting of ZO-1 and Occludin.

[0131] The compound, its isomer, its pharmaceutically acceptable salt, its solvate or a composition comprising the same may be capable of normalizing damage to intestinal tissue caused by inflammatory bowel disease, and specifically may be capable of normalizing intestinal (colon) length, mucosal structure of intestinal tissue, intestinal gland structure, smooth muscle layer, submucosal and / or muscle invasion.

[0132] The pharmaceutical composition may include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" may refer to a carrier or diluent that does not stimulate a living organism and does not inhibit the biological activity or properties of the injected compound. Here, "pharmaceutically acceptable" means that the carrier does not inhibit the activity of the active ingredient and does not exhibit toxicity exceeding the adaptability of the subject of application (prescription). Any carrier commonly used in the art and pharmaceutically acceptable for the pharmaceutical composition may be used. Non-limiting examples of the above carriers include lactose, dextrose, maltodextrin, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, glycerol, ethanol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. These may be used alone or in combination of two or more. The pharmaceutical composition may be prepared as an oral formulation or a parenteral formulation according to the route of administration by a conventional method known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient. The above pharmaceutical composition can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions, each according to a conventional method.

[0133] When formulating the above pharmaceutical composition, it may be prepared using a diluent or excipient such as a generally used filler, bulking agent, binder, wetting agent, disintegrant, or surfactant, but may not be limited thereto.

[0134] When the above pharmaceutical composition is manufactured into an oral dosage form, it can be manufactured into a dosage form such as powder, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, wafers, etc., using a suitable carrier according to a method known in the art. At this time, examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, xylitol, etc.; starches such as corn starch, potato starch, and wheat starch; celluloses such as cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyols, and vegetable oils. In case of formulation, the formulation may include diluents and / or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants, as needed.

[0135] When the above pharmaceutical composition is prepared as a parenteral dosage form, it can be formulated in the form of injections, transdermal administration, nasal inhalation, and suppositories using a suitable carrier according to a method known in the art. When formulated as an injection, suitable carriers include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof, and preferably, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, sterile water for injection, and isotonic solutions such as 5% dextrose can be used. When formulated as a transdermal dosage form, it can be formulated in the form of ointments, creams, lotions, gels, external solutions, pastes, liniments, aerosols, etc. In the case of nasal inhalation, it can be formulated in the form of an aerosol spray using a suitable propellant such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, or carbon dioxide, and in the case of formulating it as a suppository, the base can be witepsol, tween 61, polyethylene glycol, cacao butter, laurin butter, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sorbitan fatty acid ester, etc.

[0136] The pharmaceutical composition may be administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention, and the effective dosage level may be determined according to factors including the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the excretion rate, the treatment period, drugs used in combination or simultaneously with the composition of the present invention used, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered alone or in combination with a known ingredient known to exhibit a therapeutic effect. It is important to take all of the above factors into consideration and administer an amount that can achieve the maximum effect with the minimum amount without side effects.

[0137] The dosage of the pharmaceutical composition may be determined by a person skilled in the art in consideration of the intended use, the degree of toxicity of the disease, the patient's age, weight, sex, medical history, or the type of substance used as the active ingredient. For example, the pharmaceutical composition of the present invention may be administered at about 0.1 ng to about 1,000 mg / kg, preferably 1 ng to about 100 mg / kg, per adult, and the frequency of administration of the composition of the present disclosure is not particularly limited thereto, but may be administered once a day or administered in divided doses several times. The dosage or frequency of administration does not limit the scope of the present disclosure in any way.

[0138]

[0139] Another aspect provides a method for treating or preventing an inflammatory disease, comprising administering to a subject a pharmaceutical composition for preventing or treating the inflammatory disease. The same principles as described above apply to the method.

[0140] The term "subject" as used herein may include, without limitation, mammals, birds, reptiles, farmed fish, etc., including dogs, cats, rats, livestock, humans, etc., that have developed or are at risk of developing or developing an inflammatory disease, and the subject may exclude humans.

[0141] The pharmaceutical composition may be administered in single or multiple doses in a pharmaceutically effective amount. The composition may be formulated and administered in the form of a liquid, powder, aerosol, injection, infusion (Ringel), capsule, pill, tablet, suppository, or patch. The pharmaceutical composition may be administered via any conventional route as long as it can reach the target tissue.

[0142] The pharmaceutical composition may be administered, but is not particularly limited thereto, via routes such as intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, transdermal patch administration, oral administration, intranasal administration, intrapulmonary administration, and rectal administration, depending on the intended purpose. However, when administered orally, it may be administered in an unformulated form, and since the active ingredient of the pharmaceutical composition may be denatured or decomposed by gastric acid, the oral composition may be administered orally in a form that coats the active agent or is formulated to protect it from decomposition in the stomach, or in the form of an oral patch. In addition, the composition may be administered by any device that allows the active ingredient to move to the target cell.

[0143]

[0144] Another aspect provides a food composition for preventing or improving inflammatory diseases, comprising a compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The same portions described above also apply to the composition.

[0145] The compound included in the above composition may be represented by the chemical formula 57 or chemical formula 60 described above. In addition, the compound of chemical formula 60 may be a dimer of the compound of chemical formula 57, and specifically, may be a heterodimer or homodimer.

[0146] The term "food" in this specification includes meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, health functional foods, and health foods, and includes all foods in the conventional sense.

[0147] The above food can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly added in the art during the manufacturing process. In addition, the formulation of the food can be manufactured without limitation as long as it is a formulation recognized as a food. The food composition can be manufactured in various forms of formulations, and unlike general drugs, it has the advantage of not having side effects that may occur when taking drugs for a long time because it uses food as a raw material, and is highly portable, so the food composition of the present invention can be consumed as a supplement to enhance the efficacy of preventing or improving inflammatory diseases.

[0148] The above food composition may be a health functional food composition.

[0149] The term "health functional food" in this specification refers to a food manufactured and processed using raw materials or ingredients with functionality useful to the human body as defined in Act No. 6727 on Health Functional Foods, and "functionality" refers to obtaining a useful effect for health purposes, such as regulating nutrients or physiological effects for the structure and function of the human body.

[0150] The above health food refers to a food that has a more active health maintenance or promotion effect than general food, and health supplement food refers to a food for the purpose of health supplementation. In some cases, the terms health functional food, health food, and health supplement may be used interchangeably. Specifically, the above health functional food refers to a food that is made by adding a composition to food materials such as beverages, teas, spices, gum, and confectionery, or by manufacturing it in the form of capsules, powder, suspension, etc., and means that when consumed, it brings about a specific health effect. However, unlike general drugs, it has the advantage of not having the side effects that can occur with long-term use of drugs because it is made from food.

[0151] The above food composition can be used very usefully because it can be consumed on a daily basis and is expected to be highly effective in improving or preventing inflammatory diseases.

[0152] The food composition may further comprise a physiologically acceptable carrier, and the type of the carrier is not particularly limited, and any carrier commonly used in the art may be used. Specifically, the food composition may comprise additional ingredients commonly used in food compositions to improve odor, taste, sight, etc. For example, the food composition may comprise vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, etc. In addition, the food composition may comprise minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr). In addition, the food composition may comprise amino acids such as lysine, tryptophan, cysteine, and valine.

[0153] In addition, the food composition may include food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), bactericides (bleaching powder and high-purity bleaching powder, sodium hypochlorite, etc.), antioxidants (butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.), colorants (tar colorants, etc.), color developers (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG, monosodium glutamate, etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), leavening agents (alum, D-potassium hydrogen tartrate, etc.), reinforcing agents, emulsifiers, thickeners (glucose fillers), film-forming agents, gum-forming agents, foam suppressants, solvents, and improvers. The above additives can be selected according to the type of food and used in an appropriate amount.

[0154] The above food composition can be added as is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method. The amount of the active ingredient mixed can be appropriately determined depending on its purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing a food or beverage, the food composition of the present invention can be added to the food or beverage in an amount of 50 parts by weight or less, specifically 20 parts by weight or less. However, when consumed for a long period of time for health and hygiene purposes, the content below the above range can be included, and since there is no problem in terms of safety, the active ingredient can also be used in an amount above the above range.

[0155] As an example of the food composition, the above-mentioned food composition may be used as a health beverage composition, and in this case, various flavoring agents or natural carbohydrates may be contained as additional ingredients, as in a conventional beverage. The above-mentioned natural carbohydrates may be monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugar alcohols such as xylitol, sorbitol, and erythritol. The sweetener may be a natural sweetener such as thaumatin and stevia extract; or a synthetic sweetener such as saccharin and aspartame. The proportion of the natural carbohydrate may be generally about 0.01 to 0.04 g, specifically about 0.02 to 0.03 g, per 100 mL of the health beverage composition of the present invention.

[0156] In addition to the above, the health beverage composition may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, or carbonating agents. In addition, it may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, or vegetable drinks. These ingredients may be used independently or in combination. The proportion of these additives is not particularly important, but is typically selected within the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the health beverage composition of the present invention.

[0157] The food composition may contain various weight % of the compound of the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, as long as the food composition can exhibit an efficacy in preventing or improving inflammatory diseases, and specifically, the food composition may contain the compound in an amount of 0.00001 to 100 wt % or 0.01 to 80 wt % relative to the total weight of the food composition, but is not limited thereto.

[0158]

[0159] Another aspect provides a feed composition for preventing or improving inflammatory diseases, comprising a compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The same portions described above also apply to the composition.

[0160] The compound included in the above composition may be represented by the chemical formula 57 or chemical formula 60 described above. In addition, the compound of chemical formula 60 may be a dimer of the compound of chemical formula 57, and specifically, may be a heterodimer or homodimer.

[0161] The term "feed" in this specification may mean any natural or artificial diet, meal, etc. or a component of said meal, intended for or suitable for eating, ingesting and digesting by an animal.

[0162] The type of the above feed is not particularly limited, and feed commonly used in the relevant technical field can be used. Non-limiting examples of the above feed include plant-based feed such as grains, roots, food processing by-products, algae, fiber, pharmaceutical by-products, oils, starches, meal, or grain by-products; and animal-based feed such as proteins, inorganic substances, oils, minerals, oils, single-cell proteins, zooplankton, or food. These may be used alone or in combination of two or more types.

[0163] The feed composition may further include known additives that can be added to the formulation to improve or prevent inflammatory diseases. The feed composition may be in the form of a highly concentrated solution, powder, or granules. The feed composition may further include any protein-containing organic grain meal commonly used to meet the dietary needs of animals. The feed composition may be used by immersion, spraying, or mixing into animal feed.

[0164] The above feed composition may additionally contain substances that have various effects, such as nutrient supplementation and weight loss prevention, increased digestibility and availability of fiber in feed, improved milk quality, prevention of reproductive disorders and improved conception rate, and prevention of summer heat stress. For example, the feed composition may additionally contain mineral preparations such as sodium bicarbonate, bentonite, magnesium oxide, and complex minerals; trace mineral preparations such as zinc, copper, cobalt, and selenium; vitamins such as carotene, vitamin E, vitamins A, D, and E, nicotinic acid, and vitamin B complex; protected amino acids such as methionine and lysate; protected fatty acids such as fatty acid calcium salts; probiotics (lactic acid bacteria), yeast cultures, and mold fermentations; and yeast agents.

[0165] The above feed composition can be applied to a number of animal diets, including mammals and poultry, i.e., feed and drinking water.

[0166] The above feed composition may include all of a substance added to the feed (i.e., a feed additive), a feed raw material, or the feed itself to be fed to the individual.

[0167]

[0168] Another aspect provides an anti-inflammatory composition comprising a compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The same aspects described above also apply to the composition.

[0169] The compound included in the above composition may be represented by the chemical formula 57 or chemical formula 60 described above. In addition, the compound of chemical formula 60 may be a dimer of the compound of chemical formula 57, and specifically, may be a heterodimer or homodimer.

[0170] The above anti-inflammatory composition may be a pharmaceutical composition, a food composition, a feed composition, a cosmetic composition, and / or a composition for external application to the skin.

[0171] The formulation of the above cosmetic composition is not particularly limited, and may have any one formulation selected from among skin products, lotions, essences, creams, packs, foundations, patches, hair tonics, micro needle patches, and makeup bases, but may not be limited thereto.

[0172] The above cosmetic composition may contain optionally selected substances according to the formulation or intended use of the cosmetic, but may not be limited thereto. For example, purified water, oil, surfactants, moisturizers, higher alcohols, thickeners, chelating agents, pigments, fatty acids, antioxidants, preservatives, waxes, pH regulators, fragrances, etc. may be added, but may not be limited thereto.

[0173] When the formulation of the above cosmetic composition is a paste, cream or gel, it may include, but is not limited to, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide as a carrier component.

[0174] When the formulation of the above cosmetic composition is a powder or spray, it may include lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder as a carrier component, and in particular, when it is a spray, it may additionally include a propellant such as chlorofluorohydrocarbon, propane / butane or dimethyl ether, but may not be limited thereto.

[0175] When the formulation of the above cosmetic composition is a solution or emulsion, it may include a solvent, a solubilizer or an emulsifier as a carrier component, and may include, but is not limited to, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.

[0176] When the formulation of the above cosmetic composition is a suspension, it may include, but is not limited to, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth as a carrier component.

[0177] When the formulation of the above cosmetic composition is a surfactant-containing cleansing, the carrier component may include, but is not limited to, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester.

[0178]

[0179] Another aspect provides a method for inducing anti-inflammation, comprising administering the anti-inflammatory composition to a subject. The same principles as described above apply to the method.

[0180]

[0181] Another aspect provides an antioxidant composition comprising a compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The same aspects described above also apply to the composition.

[0182] The compound included in the above composition may be represented by the chemical formula 57 or chemical formula 60 described above. In addition, the compound of chemical formula 60 may be a dimer of the compound of chemical formula 57, and specifically, may be a heterodimer or homodimer.

[0183] The above antioxidant composition may be a pharmaceutical composition, a food composition, a feed composition, a cosmetic composition, and / or a composition for external application to the skin.

[0184] The term “antioxidant” in this specification may mean any action that prevents oxidation, and may specifically mean reducing oxidative stress by antioxidant activity.

[0185] Therefore, the above antioxidant composition may be a composition for preventing, improving, or treating a disease caused by oxidative stress.

[0186] The diseases caused by the above oxidative stress are not limited in type as long as the causal relationship between oxidative stress and the disease is known, and may include, for example, inflammatory diseases, sepsis, cancer, aging, skin aging, sarcopenia, autoimmune diseases, lung diseases (e.g., asthma, chronic bronchitis), kidney diseases (e.g., nephritis, chronic heart failure), joint diseases (e.g., rheumatism, arthritis), brain diseases (e.g., Alzheimer's, Parkinson's disease, memory loss, depression, stroke), eye diseases (e.g., cataracts, retinal diseases), cardiovascular diseases (e.g., arteriosclerosis, hypertension, ischemia, cardiomyopathy, cardiac arrest), fetal abnormalities (e.g., preeclampsia, intrauterine growth retardation), neurodegenerative diseases, etc.

[0187]

[0188] Another aspect provides a method for inducing antioxidant activity, comprising administering the antioxidant composition to a subject. The same principles as described above apply to the method.

[0189]

[0190] Another aspect provides a use of the compound, its isomer, its pharmaceutically acceptable salt, or its solvate for treating, preventing, or ameliorating inflammatory diseases. The same portions described above also apply to the above use.

[0191]

[0192] Another aspect provides an anti-inflammatory or antioxidant use of the compound, its isomer, its pharmaceutically acceptable salt, or its solvate. The same principles as described above apply to the above use.

[0193]

[0194] Another aspect provides the use of the compound, its isomer, its pharmaceutically acceptable salt, or its solvate in the manufacture of a medicament for preventing or treating inflammatory diseases. The same principles as described above apply to the above-described use.

[0195]

[0196] Another aspect provides the use of the compound, its isomers, its pharmaceutically acceptable salts, or its solvates in the manufacture of anti-inflammatory or antioxidant medicaments. The same principles as described above apply to the above-described uses.

[0197] It has been confirmed that the novel compound of the present invention has excellent anti-inflammatory efficacy, and thus, inflammatory diseases such as inflammatory bowel disease can be effectively treated using a composition containing the compound.

[0198] Figure 1 is a diagram showing the results of evaluating the anti-inflammatory activity of cannabis-derived compounds.

[0199] Figure 2 is a drawing showing the results of evaluating the anti-inflammatory activity of NCB-D1 and its derivative compounds.

[0200] Figure 3 is a diagram showing the results of evaluating the inhibitory efficacy of the NCB-D1 compound on macrophage key cytokines.

[0201] Figure 4 is a drawing showing the results of evaluating the inhibitory effect of the NCB-D1 compound on inflammation-related factors (iNOS and COX-2).

[0202] Figures 5 and 6 are drawings showing the results of evaluating the antioxidant efficacy of the NCB-D1 compound.

[0203] Figure 7 is a diagram showing the results of evaluating the NFR2 increasing efficacy of the NCB-D1 compound.

[0204] Figure 8 is a diagram showing the results of evaluating the NF-kB signaling pathway inhibition efficacy of the NCB-D1 compound.

[0205] Figure 9 is a drawing showing the results of evaluating the tight bond recovery efficacy of the NCB-D1 compound.

[0206] Figure 10 is a drawing showing the results of evaluating the therapeutic efficacy of the NCB-D1 compound for inflammatory bowel disease under in vivo conditions.

[0207] The present invention will be described in more detail through the following examples. However, these examples are provided for illustrative purposes only and the scope of the present invention is not limited to these examples.

[0208] Meanwhile, the natural compounds derived from medical cannabis (Hemp) used in the examples of this specification were separated and manufactured from cannabis extracts based on the Seoul Regional Food and Drug Administration's Narcotics (Cannabis) Academic Researcher's Permit (No. 1564, No. 1979, No. 2083).

[0209]

[0210] Example 1: Evaluation and screening of anti-inflammatory activity of cannabinoid compounds derived from medical cannabis (hemp)

[0211] To evaluate the anti-inflammatory activity of cannabis-derived compounds, the following experiments were performed.

[0212] Specifically, 321.06 g of dried medical cannabis was placed in a 5 L Erlenmeyer flask with 3.2 L of ethanol (EtOH), and ultrasonicated for 1 hour at 40% power (200 W) of the device using an ultrasonic extractor (Sonics, VC505), followed by extraction for 24 hours at room temperature. This process was repeated twice. The extracted mixture was filtered through a filter paper, and the obtained extract was evaporated and concentrated under reduced pressure to obtain 28.6 g of an extract containing cannabinoids. Among them, 1 g of the extract was dissolved in 10 mL of ethanol (EtOH) and then heated at 150°C, 300 W, and 2450 MHz for 1 hour using a microwave irradiator (model number 908005) manufactured by CEM, USA. Thereafter, various types of cannabinoid compounds were extracted from the processed product processed by microwave.

[0213] To evaluate the anti-inflammatory activity of the above compounds, the inhibition ability of nitric oxide (NO), one of the representative substances that induces inflammation such as vasodilation and tissue damage in vivo, was analyzed. For this purpose, 5x10 RAW264.7 cells were cultured. 4 The cells were seeded in 96-well plates and, after 24 hours, co-treated with LPS (1 μg / ml) and each compound at 25 μM, and further cultured for 24 hours. The supernatant was then obtained and reacted 1:1 with Griess reagent. After 20 minutes, the OD value was measured at a wavelength of 550 nm to evaluate the NO production inhibition ability according to the treatment of cannabis-derived compounds. As a control group, quercetin, a compound known to inhibit macrophages, was used at a concentration of 25 μM.

[0214] Next, a cell viability assay was performed to determine the cytotoxicity of cannabis-derived compounds against macrophages (normal immune cells). For this purpose, RAW264.7 cells were seeded in a 96-well plate at a density of 5 x 10 per well. 4 After seeding each well and culturing for one day, the culture medium was removed, and 25 uM of a cannabis-derived compound was treated, followed by 24-hour incubation to perform the MTT assay. MTT dye was added to the plate at a concentration of 5 mg / ml, incubated for 4 hours, the medium was removed, and dimethyl sulfoxide was added to each well to dissolve the dye for 20 minutes. The degree of cell viability was analyzed by measuring the absorbance at a wavelength of 490 nm.

[0215] First, the activity and toxicity of 27 cannabis-derived compounds were analyzed, and it was confirmed that most compounds did not exhibit toxicity toward normal cells at a concentration of 25 μM. Furthermore, materials 2, 4, 15, 16, 22, and 26 inhibited NO production by more than 50% at a concentration of 25 μM. Among the above materials, material 26 was ultimately selected considering its excellent NO activity, low toxicity, and synthetic potential.

[0216] It was confirmed that the above material No. 26 is a novel compound having the structural formula of Chemical Formula 30 below, and in this specification, the compound is named 'NCB-D1'.

[0217] [Chemical Formula 30]

[0218]

[0219]

[0220] Example 2: Synthesis of NCB-D1 compound and its derivative library

[0221] To construct a library of NCB-D1, a novel compound discovered in Example 1, and its derivatives and to synthesize them, the following experiments were performed.

[0222]

[0223] 2-1: Suzuki's reaction

[0224] To synthesize the above library compounds, the Suzuki carbon-carbon bond reaction of the following reaction scheme 1 or reaction scheme 2 was performed under a palladium catalyst.

[0225] [Reaction Formula 1]

[0226]

[0227] [Reaction Formula 2]

[0228]

[0229] Specifically, in order to perform the Suzuki reaction using the compound of Reaction Scheme 1 or 2, first, the boronic acid or boron ester compound of Compound A or Compound D and the halogen compound B or Compound C are prepared in equal equivalents. The prepared boron compound A or Compound D and the halogen compound B or Compound C are dissolved in a 10-20% aqueous 1,2-dioxane solvent using 5-10 mol% of a tetrakis(triphenylphosphine)palladium(0), Pd(PPH3)4] catalyst and 3.0-3.5 equivalents of calcium carbonate (K2CO3), and then reacted in a microwave at 80-120°C for 0.5-1.5 hours. After confirming the completion of the reaction, extraction with salt water and ethyl acetate (EtOAc) is performed and purified through a silica gel column to obtain compounds represented by chemical formula 57. The synthetic process and H-NMR results of the compounds obtained through the Suzuki reaction are as follows.

[0230]

[0231] [NCB-P1] 2,6-Dimethoxy-2'-methyl-4-pentyl-5'-(prop-1-en-2-yl)-1,1'-biphenyl

[0232] [Chemical Formula 1]

[0233]

[0234] According to reaction scheme 2 of Example 2-1, 175 mg of NCB-P1 compound was obtained through Suzuki reaction and column purification using 2-bromo-1-methyl-4-(prop-1-en-2-yl)benzene (150 mg, 0.71 mmol) and 2,6-dimethoxy-4-pentylphenyl)boronic acid (180 mg, 0.71 mmol).

[0235] 1 H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 8.02, 2.06 Hz, 1H), 7.27 (d, J = 2.06 Hz, 1H), 7.22 (d, J = 8.02 Hz, 1H), 6.48 (s, 2H), 5.36 (s, 1H), 5.01 (s, 1H), 3.71 (s, 6H), 2.66 (t, J = 7.8 Hz, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 1.77-1.63 (m, 2H), 1.48-1.36 (m, 4H), 0.95 (t, J = 6.9 Hz, 3H).

[0236]

[0237] [NCB-P3] 2,6-Dimethoxy-2'-methyl-4-pentyl-1,1'-biphenyl

[0238] [Chemical Formula 3]

[0239]

[0240] According to reaction scheme 2 of Example 2-1, 132 mg of NCB-P3 compound was obtained through Suzuki reaction and column purification using 1-bromo-2-methylbenzene (130 mg, 0.76 mmol) and (2,6-dimethoxy-4-pentylphenyl)boronic acid (192 mg, 0.76 mmol).

[0241] 1 H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 3H), 7.18-7.14 (m, 1H), 6.49 (s, 2H), 3.72 (s, 6H), 2.67 (t, J = 7.7 Hz, 2H), 2.10 (s, 3H), 1.83-1.68 (m, 2H), 1.48-1.36 (m, 4H), 0.96 (t, J = 6.8 Hz, 3H).

[0242]

[0243] [NCB-P4] 2,6-Dimethoxy-3'-methyl-4-pentyl-1,1'-biphenyl

[0244] [Chemical Formula 4]

[0245]

[0246] According to reaction scheme 2 of Example 2-1, 154 mg of NCB-P4 compound was obtained through Suzuki reaction and column purification using 1-bromo-3-methylbenzene (155 mg, 0.91 mmol) and (2,6-dimethoxy-4-pentylphenyl)boronic acid (228 mg, 0.76 mmol).

[0247] 1H NMR (400 MHz, CDCl3) δ 7.46-7.33 (m, 1H), 7.33-7.26 (m, 1H), 7.19-7.08 (m, 2H), 6.48 (s, 2H), 3.73 (s, 6H), 2.64 (t, J = 7.8 Hz, 2H), 2.38 (s, 3H), 1.77-1.63 (m, 2H), 1.46-1.35 (m, 4H), 0.93 (t, J = 6.8 Hz, 3H).

[0248]

[0249] [NCB-P5] 2,6-Dimethoxy-4-pentyl-3'-(trifluoromethyl)-1,1'-biphenyl

[0250] [Chemical Formula 5]

[0251]

[0252] According to reaction scheme 1 of Example 2-1, 113 mg of NCB-P5 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (144 mg, 0.5 mmol) and 3-(trifluoromethyl)phenylboronic acid (95 mg, 0.5 mmol).

[0253] 1 H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.58-7.52 (m, 2H), 7.52-7.46 (m, 1H), 6.50 (s, 2H), 3.75 (s, 6H), 2.65 (t, J = 7.6 Hz, 2H), 1.77-1.63 (m, 2H), 1.47-1.33 (m, 4H), 0.95 (t, J = 6.8 Hz, 3H).

[0254]

[0255] [NCB-P6] 2,2',6-Trimethoxy-4-pentyl-1,1'-biphenyl

[0256] [Chemical Formula 6]

[0257]

[0258] According to reaction scheme 1 of Example 2-1, 98 mg of NCB-P6 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (128 mg, 0.45 mmol) and 2-methoxyphenylboronic acid (68 mg, 0.45 mmol).

[0259] 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.45 (s, 2H), 3.82 (s, 3H), 3.74 (s, 6H), 2.64 (t, J = 7.2 Hz, 2H), 1.77-1.63 (m, 2H), 1.47-1.33 (m, 4H), 0.94 (t, J = 6.8 Hz, 3H).

[0260]

[0261] [NCB-P7] 2,3',6-Trimethoxy-4-pentyl-1,1'-biphenyl

[0262] [Chemical Formula 7]

[0263]

[0264] According to reaction scheme 1 of Example 2-1, 103 mg of NCB-P7 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (115 mg, 0.40 mmol) and 3-methoxyphenylboronic acid (61 mg, 0.40 mmol).

[0265] 1 H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.6 Hz, 1H), 6.96-6.91 (m, 2H), 6.87 (dd, J = 7.6, 2.8 Hz, 1H), 6.49 (s, 2H), 3.82 (s, 3H), 3.74 (s, 6H), 2.65 (t, J = 7.6 Hz, 2H), 1.73-1.66 (m, 2H), 1.44-1.35 (m, 4H), 0.94 (t, J = 6.8 Hz, 3H).

[0266]

[0267] [NCB-P8] 2,6-Dimethoxy-2',5'-dimethyl-4-pentyl-1,1'-biphenyl

[0268] [Chemical Formula 8]

[0269]

[0270] According to reaction scheme 2 of Example 2-1, 158 mg of NCB-P8 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,4-dimethylbenzene (111 mg, 0.60 mmol) and (2,6-dimethoxy-4-pentylphenyl)boronic acid (151 mg, 0.6 mmol).

[0271] 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 7.2 Hz, 1H), 7.05 (dd, J = 7.6, 1.6 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 6.47 (s, 2H), 3.71 (s, 6H), 2.65 (t, J = 7.6 Hz, 2H), 2.33 (s, 3H), 2.03 (s, 3H), 1.73-1.65 (m, 2H), 1.42-1.37 (m, 4H), 0.94 (t, J = 6.8 Hz, 3H).

[0272]

[0273] [NCB-P9] 2,6-Dimethoxy-4-pentyl-1,1'-biphenyl

[0274] [Chemical Formula 9]

[0275]

[0276] According to reaction scheme 1 of Example 2-1, 93 mg of NCB-P9 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (115 mg, 0.4 mmol) and phenylboronic acid (49 mg, 0.4 mmol).

[0277] 1 H NMR (400 MHz, CDCl3) δ 7.43-7.27 (m, 5H), 6.50 (s, 2H), 3.73 (s, 6H), 2.64 (t, J = 7.8 Hz, 2H), 1.77-1.63 (m, 2H), 1.43-1.35 (m, 4H), 0.94 (t, J = 6.8 Hz, 3H).

[0278]

[0279] [NCB-P10] 4'-(tert-Butyl)-2,6-dimethoxy-4-pentyl-1,1'-biphenyl

[0280] [Chemical Formula 10]

[0281]

[0282] According to reaction scheme 1 of Example 2-1, 103 mg of NCB-P10 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (115 mg, 0.4 mmol) and 4-(tert-butylphenyl)boronic acid (71 mg, 0.4 mmol).

[0283] 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.7, 2.1 Hz, 2H), 7.29 (d, J = 8.7, 2.1 Hz, 2H), 6.48 (s, 2H), 3.73 (s, 6H), 2.63 (t, J = 7.8 Hz, 2H), 1.77-1.63 (m, 2H), 1.42-1.36 (m, 4H), 1.35 (s, 9H), 0.93 (t, J = 6.8 Hz, 3H).

[0284]

[0285] [NCB-P11] 2,6-Dimethoxy-4-pentyl-4'-(trifluoromethyl)-1,1'-biphenyl

[0286] [Chemical Formula 11]

[0287]

[0288] According to reaction scheme 1 of Example 2-1, 114 mg of NCB-P11 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (115 mg, 0.4 mmol) and 4-(trifluoromethyl)phenylboronic acid (76 mg, 0.4 mmol).

[0289] 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 6.50 (s, 2H), 3.75 (s, 6H), 2.66 (t, J = 7.7 Hz, 2H), 1.77-1.63 (m, 2H), 1.44-1.35 (m, 4H), 0.95 (t, J = 6.1 Hz, 3H).

[0290]

[0291] [NCB-P12] 2,4',6-Trimethoxy-3',5'-dimethyl-4-pentyl-1,1'-biphenyl

[0292] [Chemical Formula 12]

[0293]

[0294] According to reaction scheme 1 of Example 2-1, 125 mg of NCB-P12 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (144 mg, 0.5 mmol) and 4-methoxy-3,5-dimethylphenylboronic acid (90 mg, 0.5 mmol).

[0295] 1 H NMR (400 MHz, CDCl3) δ 7.01 (s, 2H), 6.48 (s, 2H), 3.78 (s, 3H), 3.76 (s, 6H), 2.64 (t, J = 7.8 Hz, 2H), 2.32 (s, 6H), 1.77-1.63 (m, 2H), 1.40-1.35 (m, 4H), 0.95 (t, J = 6.8 Hz, 3H).

[0296]

[0297] [NCB-P13] 2,3',4',6-Tetramethoxy-4-phenyl-1,1'-biphenyl

[0298] [Chemical Formula 13]

[0299]

[0300] According to reaction scheme 1 of Example 2-1, 98 mg of NCB-P13 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (115 mg, 0.4 mmol) and 3,4-dimethoxyphenylboronic acid (73 mg, 0.4 mmol).

[0301] 1 H NMR (400 MHz, CDCl3) δ 6.92 (s, 2H), 6.90 (s, 1H), 6.49 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.75 (s, 6H), 2.64 (t, J = 7.9 Hz, 2H), 1.77-1.63 (m, 2H), 1.43-1.35 (m, 4H), 0.94 (t, J = 6.8 Hz, 3H).

[0302]

[0303] [NCB-P14] 2,3',5',6-Tetramethoxy-4-phenyl-1,1'-biphenyl

[0304] [Chemical Formula 14]

[0305]

[0306] According to reaction scheme 1 of Example 2-1, 85 mg of NCB-P14 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (115 mg, 0.4 mmol) and 3,5-dimethoxyphenylboronic acid (73 mg, 0.4 mmol).

[0307] 1H NMR (400 MHz, CDCl3) δ 6.51 (d, J = 2.4 Hz, 2H), 6.48 (s, 2H), 6.44 (t, J = 2.4 Hz, 1H), 3.79 (s, 6H), 3.74 (s, 6H), 2.63 (t, J = 7.6 Hz, 2H), 1.72-1.64 (m, 2H), 1.41-1.36 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H).

[0308]

[0309] [NCB-P15] 2-(2,6-Dimethoxy-4-pentylphenyl)pyridine

[0310] [Chemical Formula 15]

[0311]

[0312] According to reaction scheme 1 of Example 2-1, 63 mg of NCB-P15 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (172 mg, 0.6 mmol) and 2-pyridinylboronic acid (74 mg, 0.6 mmol).

[0313] 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 4.8 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 6.4 Hz, 1H), 6.47 (s, 2H), 3.72 (s, 6H), 2.63 (t, J = 7.6 Hz, 2H), 1.70-1.63 (m, 2H), 1.40-1.30 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H).

[0314]

[0315] [NCB-P16] 4-(2,6-Dimethoxy-4-pentylphenyl)pyridine

[0316] [Chemical Formula 16]

[0317]

[0318] According to reaction scheme 1 of Example 2-1, 86 mg of NCB-P16 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (201 mg, 0.7 mmol) and 4-pyridinylboronic acid (86 mg, 0.7 mmol).

[0319] 1 H NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 4.4, 1.6 Hz, 2H), 7.31 (dd, J = 4.4, 1.6 Hz, 2H), 6.48 (s, 2H), 3.74 (s, 6H), 2.64 (t, J = 7.6 Hz, 2H), 1.71-1.64 (m, 2H), 1.41-1.33 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H).

[0320]

[0321] [NCB-P17] 3-(2,6-Dimethoxy-4-pentylphenyl)quinoline

[0322] [Chemical Formula 17]

[0323]

[0324] According to reaction scheme 1 of Example 2-1, 90.5 mg of NCB-P17 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (144 mg, 0.5 mmol) and 3-quinolinylboronic acid (87 mg, 0.5 mmol).

[0325] 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.16 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.1 Hz, 1H), 7.52 (t, J) = 6.7 Hz, 1H), 6.56 (s, 2H), 3.76 (s, 6H), 2.67 (t, J = 7.7 Hz, 2H), 1.77-1.63 (m, 2H), 1.42-1.36 (m, 4H), 0.95 (t, J = 6.8 Hz, 3H).

[0326]

[0327] [NCB-P18] 2-(2,6-Dimethoxy-4-pentylphenyl)thiophene

[0328] [Chemical Formula 18]

[0329]

[0330] According to reaction scheme 1 of Example 2-1, 59 mg of NCB-P18 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (244 mg, 0.85 mmol) and 2-thiophenylboronic acid (109 mg, 0.85 mmol).

[0331] 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.45 (t, J = 1.6 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.46 (s, 2H), 3.84 (s, 6H), 2.61 (t, J = 7.7 Hz, 2H), 1.77-1.63 (m, 2H), 1.43-1.30 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H).

[0332]

[0333] [NCB-P19] 2',6'-Dimethoxy-4'-pentyl-[1,1'-biphenyl]-3-carbonitrile

[0334] [Chemical Formula 19]

[0335]

[0336] According to reaction scheme 1 of Example 2-1, 84 mg of NCB-P19 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (115 mg, 0.4 mmol) and 3-cyanophenylboronic acid (59 mg, 0.4 mmol).

[0337] 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.61-7.54 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 6.48 (s, 2H), 3.74 (s, 6H), 2.63 (t, J = 7.6 Hz, 2H), 1.77-1.63 (m, 2H), 1.45-1.31 (m, 4H), 0.95 (t, J = 6.8 Hz, 3H).

[0338]

[0339] [NCB-P20] 2',6'-Dimethoxy-4'-pentyl-[1,1'-biphenyl]-3-carboaldehyde

[0340] [Chemical Formula 20]

[0341]

[0342] According to reaction scheme 1 of Example 2-1, 111 mg of NCB-P20 compound was obtained through Suzuki reaction and column purification using (E)-2-bromo-1,3-dimethoxy-5-(pent-1-en-1-yl)benzene (185 mg, 0.65 mmol) and 3-formylphenylboronic acid (97.5 mg, 0.65 mmol).

[0343] 1 H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.58-7.51 (m, 1H), 6.65 (s, 2H), 6.42 (d, J = 15.6 Hz, 1H), 6.33-6.27 (m, 1H), 3.76 (s, 6H), 2.23 (q, J = 7.2 Hz, 2H), 1.59-1.46 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).

[0344]

[0345] [NCB-P21] 2,6-Dimethoxy-4'-nitro-4-pentyl-1,1'-biphenyl

[0346] [Chemical Formula 21]

[0347]

[0348] According to reaction scheme 1 of Example 2-1, 96 mg of NCB-P21 compound was obtained through Suzuki reaction and column purification using 2-bromo-1,3-dimethoxy-5-pentylbenzene (115 mg, 0.4 mmol) and 4-nitrophenylboronic acid (67 mg, 0.4 mmol).

[0349] 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 9.2 Hz, 2H), 7.52 (d, J = 9.2 Hz, 2H), 6.49 (s, 2H), 3.74 (s, 6H), 2.65 (t, J = 7.6 Hz, 2H), 1.77-1.63 (m, 2H), 1.42-1.31(m, 4H), 0.95 (t, J = 6.8 Hz, 3H).

[0350]

[0351] [NCB-P22] (E / Z)-4-(hept-1-en-1-yl)-2,6-dimethoxy-1,1'-biphenyl NMRE&Zform Mixture

[0352] [Chemical Formula 22]

[0353]

[0354] For the Wittig olefin reaction, hexyl triphenyl phosphonium bromide (150 mg, 0.35 mmol) was dissolved in 20 mL of anhydrous THF, and 0 o After lowering to C, BuLi (1.6 M, 0.22 mL) was slowly added dropwise to prepare ylide. After 1 hour, 2,6-dimethoxy-[1,1'-biphenyl]-4-carboaldehyde (NCB-P23) (61 mg, 0.25 mmol) dissolved in 5 mL of anhydrous THF was added dropwise. After completion of the reaction, extraction was performed with water and EtOAc, and after removal of the solvent and column purification, 58 mg of E&Z mixed NCB-P22 compound was obtained.

[0355] 1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 10H,E / Z-mix), 6.67 (s, 2H,E-form), 6.60 (s, 2H,Z-form), 6.45 (d, J = 11.6 Hz, 1H,Z-form), 6.42 (d, J = 13.2 Hz), 6.35-6.27 (dt, J = 8.0, 3.2 Hz, 1H,E-form), 5.78-5.71 (dt, J = 5.8, 3.6 Hz, 1H,E-form), 3.76 (s, 6H,E-form), 3.75 (s, 6H,Z-form), 2.43 (q, J = 6.4 Hz, 2H,Z-form), 2.26 (q, J = 7.2 Hz, 2H,E-form), 1.73-1.53 ​​(m, 4H,E / Z-mix), 1.44-1.32 (m, 8H,E / Z-mix), 0.95 (t, J = 6.8 Hz, 3H,E-form), 0.93 ((t, J = 6.8 Hz, 3H,Z-form).

[0356]

[0357] [NCB-P23] 2,6-Dimethoxy-[1,1'-biphenyl]-4-carboaldehyde

[0358] [Chemical Formula 23]

[0359]

[0360] According to reaction scheme 1 of Example 2-1, 161 mg of NCB-P23 compound was obtained through Suzuki reaction and column purification using 4-bromo-3,5-dimethoxybenzaldehyde (208 mg, 0.85 mmol) and phenylboronic acid (104 mg, 0.85 mmol).

[0361] 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 7.47-7.41 (m, 2H), 7.40-7.32 (m, 3H), 7.18 (s, 2H), 3.82 (s, 6H).

[0362]

[0363] [NCB-P24] (E)-2,6-Dimethoxy-4-styryl-1,1'-biphenyl

[0364] [Chemical Formula 24]

[0365]

[0366] For the Wittig olefin reaction, benzyl triphenyl phosphonium bromide (117 mg, 0.30 mmol) was dissolved in 15 mL of anhydrous THF, and 0 o After lowering to C, BuLi (1.6 M, 0.20 mL) was slowly added dropwise to prepare a yilde. After 1 hour, 2,6-dimethoxy-[1,1'-biphenyl]-4-carboaldehyde (NCB-P23) (61 mg, 0.25 mmol) dissolved in 5 mL of anhydrous THF was added dropwise. After completion of the reaction, extraction was performed with water and EtOAc, and after removal of the solvent, 66 mg of an E&Z mixture was obtained. Afterwards, 26 mg of an E-Form NCB-P24 compound was obtained through column purification.

[0367] 1 H NMR (400 MHz, CDCl3) δ 7.47-7.26 (m, 9H), 7.24-7.18 (m, 1H), 6.68 (d, J = 12.0 Hz, 1H), 6.59 (d, J = 12.0 Hz, 1H), 6.54 (s, 2H), 3.52 (s, 6H).

[0368]

[0369] [NCB-P25] (Z)-2,6-Dimethoxy-4-styryl-1,1'-biphenyl

[0370] [Chemical Formula 25]

[0371]

[0372] From 66 mg of the E&Z mixture obtained through the above Wittig olefin reaction, 12 mg of the NCB-P25 compound of Z-Form was obtained through column purification.

[0373] 1 H NMR (400 MHz, CDCl3) δ 7.58-7.53 (m, 2H), 7.45-7.35 (m, 6H), 7.35-7.26 (m, 2H), 7.14 (s, 2H), 6.82 (s, 2H), 3.80 (s, 6H).

[0374]

[0375] [NCB-P26] 2,6-Dimethoxy-4-phenethyl-1,1'-biphenyl

[0376] [Chemical Formula 26]

[0377]

[0378] For olefin hydrogenation, 15 mg of a mixture of (E / Z)-2,6-dimethoxy-4-styryl-1,1'-biphenyl was dissolved in 10 mL of methanol, 5 mg of Pd / C was added, and the mixture was reacted at room temperature for 10 hours using a hydrogen balloon to obtain 14 mg of a NCB-P26 compound.

[0379] 1 H NMR (400 MHz, CDCl3) δ 7.45-7.27 (m, 8H), 7.28-7.21 (m, 2H) 6.48 (s, 2H), 3.71 (s, 6H), 3.05 (m, 4H).

[0380]

[0381] [NCB-P27] 4-Heptyl-[1,1'-biphenyl]-2,6-diol

[0382] [Chemical Formula 27]

[0383]

[0384] For olefin hydrogenation, 18 mg of a mixture of (E / Z)-4-(hept-1-en-1-yl)-2,6-dimethoxy-1,1'-biphenyl (NCB-P22) was dissolved in 10 mL of methanol, 5 mg of Pd / C was added, and the mixture was reacted at room temperature for 10 hours using a hydrogen balloon to obtain 15 mg of a NCB-P27 compound.

[0385] 1 H NMR (400 MHz, CDCl3) δ 7.43-7.33 (m, 4H), 7.32-7.27 (m, 1H), 6.49 (s, 2H), 3.73 (s, 6H), 2.64 (t, J = 7.6 Hz, 2H), 1.77-1.63 (m, 2H), 1.46-1.25 (m, 8H), 0.91 (t, J = 6.8 Hz, 3H).

[0386]

[0387] [NCB-P28] 5'-Isopropyl-2,6-dimethoxy-2'-methyl-4-pentyl-1,1'-biphenyl

[0388] [Chemical Formula 28]

[0389]

[0390] For olefin hydrogenation, 54 mg of 2,6-dimethoxy-2'-methyl-4-pentyl-5'-(prop-1-en-2-yl)-1,1'-biphenyl (NCB-P1) compound was dissolved in 35 mL of methanol, 20 mg of Pd / C was added, and the mixture was reacted at room temperature for 10 hours using a hydrogen balloon to obtain 52 mg of NCB-P28 compound.

[0391] 1 H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 7.6 Hz, 1H), 7.11 (dd, J = 7.6, 2.0 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.48 (s, 2H), 3.71 (s, 6H), 2.89 (sept, J = 6.8 Hz, 1H), 2.65 (t, J = 7.6 Hz, 2H), 2.06 (s, 3H), 1.74-1.66 (m, 2H), 1.44-1.35 (m, 4H), 1.25 (d, J = 6.8 Hz, 6H), 0.94 (t, J = 6.8 Hz, 3H).

[0392]

[0393] Next, the derivative compound protected with the alkyl ether group synthesized above was purified by using anhydrous tetrahydrofuran (THF) solvent at -78 ℃, 3.0 to 5.0 equivalents of boron tribromide (BBr3) are added, and the reaction is allowed to proceed at room temperature for 1 to 3 hours to complete the deprotection reaction. The following derivative compound having a biphenyl-2,6-diol structure can be prepared by Prep. LC purification.

[0394]

[0395] [NCB-D1, Material No. 26] 5'-Isopropyl-2'-methyl-4-pentyl-[1,1'-biphenyl]-2,6-diol

[0396] [Chemical Formula 30]

[0397]

[0398] A deprotection reaction was performed using NCB-P28 compound (34 mg, 0.1 mmol) and BBr3, and 27 mg of NCB-D1 (C26) compound of chemical formula 30 was obtained by Prep. LC purification.

[0399] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 6.44 (s, 2H), 4.57 (bs, -OH, 2H), 2.91 (sept, J = 6.8) Hz, 1H), 2.56 (t, J = 7.6 Hz, 2H), 2.13 (s, 3H), 1.70-1.60 (m, 2H), 1.41-1.33 (m, 4H), 1.25 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 6.8 Hz, 3H).

[0400]

[0401] [NCB-D3] 2'-Methyl-4-pentyl-[1,1'-biphenyl]-2,6-diol

[0402] [Chemical Formula 32]

[0403]

[0404] As described above, a deprotection reaction was performed using NCB-P3 compound (30 mg, 0.1 mmol) and BBr3, and 23 mg of NCB-D3 compound was obtained through Prep. LC purification.

[0405] 1 H NMR (400 MHz, CDCl3) δ 7.40-7.29 (m, 3H), 7.26-7.24 (m, 1H), 6.42 (s, 2H), 4.61 (s, -OH, 2H), 2.54 (t, J = 7.6 Hz, 2H), 2.15 (s, 3H), 1.67-1.58 (m, 2H), 1.38-1.31 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0406]

[0407] [NCB-D4] 3'-Methyl-4-pentyl-[1,1'-biphenyl]-2,6-diol

[0408] [Chemical Formula 33]

[0409]

[0410] As described above, a deprotection reaction was performed using NCB-P4 compound (35 mg, 0.12 mmol) and BBr3, and 25 mg of NCB-D4 compound was obtained by Prep. LC purification.

[0411] 1 H NMR (400 MHz, CDCl3) δ 7.44 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 7.6 Hz, 2H), 6.42 (s, 2H), 4.75 (bs, -OH, 2H), 2.54 (t, J = 7.6 Hz, 2H), 2.42 (s, 3H), 1.67-1.60 (m, 2H), 1.43-1.30 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0412]

[0413] [NCB-D5] 4-Pentyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-2,6-diol

[0414] [Chemical Formula 34]

[0415]

[0416] As described above, a deprotection reaction was performed using NCB-P5 compound (35 mg, 0.1 mmol) and BBr3, and 26 mg of NCB-D5 compound was obtained through Prep. LC purification.

[0417] 1H NMR (400 MHz, CDCl3) δ 7.74-7.55 (m, 4H), 6.40 (s, 2H), 4.75 (bs, -OH, 2H), 2.54 (t, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.42-1.27 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0418]

[0419] [NCB-D6] 4-Pentyl-[1,1'-biphenyl]-2,2',6-triol

[0420] [Chemical Formula 35]

[0421]

[0422] As described above, a deprotection reaction was performed using NCB-P6 compound (31 mg, 0.10 mmol) and BBr3, and 11 mg of NCB-D6 compound was obtained through Prep. LC purification.

[0423] 1 H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.14 (dd, J = 7.6, 1.6 Hz, 1H), 7.07-6.99 (m, 2H) 6.52 (s, 2H), 5.53 (bs, -OH, 1H), 4.90 (bs, -OH, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.67-1.60 (m, 2H), 1.36-1.33 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H).

[0424]

[0425] [NCB-D7] 4-Pentyl-[1,1'-biphenyl]-2,3',6-triol

[0426] [Chemical Formula 36]

[0427]

[0428] As described above, a deprotection reaction was performed using NCB-P7 compound (35 mg, 0.11 mmol) and BBr3, and 21 mg of NCB-D7 compound was obtained by Prep. LC purification.

[0429] 1 H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.43 (s, 2H), 5.32 (bs, -OH, 1H), 4.91 (bs, -OH, 2H), 2.53 (t, J = 7.6 Hz, 2H), 1.66-1.59 (m, 2H), 1.38-1.31 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0430]

[0431] [NCB-D8] 2',5'-Dimethyl-4-pentyl-[1,1'-biphenyl]-2,6-diol

[0432] [Chemical Formula 37]

[0433]

[0434] As described above, a deprotection reaction was performed using NCB-P8 compound (30 mg, 0.1 mmol) and BBr3, and 23 mg of NCB-D8 compound was obtained through Prep. LC purification.

[0435] 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.0 Hz, 1H), 7.16 (dd, 7.6, 1.6 Hz, 1H) 7.09 (d, J = 1.6 Hz, 1H), 6.43 (s, 2H), 4.64 (s, -OH, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.35 (s, 3H), 2.11 (s, 3H), 1.68-1.61 (m, 2H), 1.39-1.33 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H).

[0436]

[0437] [NCB-D9] 4-Pentyl-[1,1'-biphenyl]-2,6-diol

[0438] [Chemical Formula 38]

[0439]

[0440] As described above, a deprotection reaction was performed using NCB-P9 compound (33 mg, 0.12 mmol) and BBr3, and 25 mg of NCB-D9 compound was obtained by Prep. LC purification.

[0441] 1 H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 6.44 (s, 2H), 4.84 (s, -OH, 2H), 2.55 (t, J = 7.6 Hz, 2H), 1.67-1.60 (m, 2H), 1.39-1.32 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H).

[0442]

[0443] [NCB-D10] 4'-(tert-Butyl)-4-pentyl-[1,1'-biphenyl]-2,6-diol

[0444] [Chemical Formula 39]

[0445]

[0446] As described above, a deprotection reaction was performed using NCB-P10 compound (35 mg, 0.1 mmol) and BBr3, and 22 mg of NCB-D10 compound was obtained by Prep. LC purification.

[0447] 1 H NMR (400 MHz, CDCl3) δ 7.57 (dt, J = 8.0, 2.0 Hz, 2H), 7.34 (td, J = 8.0, 2.0 Hz, 2H), 6.44 (s, 2H), 4.83 (s, -OH, 2H), 2.54 (t, J = 7.6) Hz, 2H), 1.67-1.60 (m, 2H), 1.41-1.31 (m, 13H), 0.91 (t, J = 7.2 Hz, 3H).

[0448]

[0449] [NCB-D11] 4-Pentyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-2,6-diol

[0450] [Chemical Formula 40]

[0451]

[0452] As described above, a deprotection reaction was performed using NCB-P11 compound (30 mg, 0.85 mmol) and BBr3, and 17 mg of NCB-D11 compound was obtained by Prep. LC purification.

[0453] 1H NMR (400 MHz, CDCl3) δ 7.78 (t, J = 8.4 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.42 (s, 2H), 4.74 (bs, -OH, 2H), 2.54 (t, J = 7.6 Hz, 2H), 1.69-1.52 (m, 2H), 1.41-1.29 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0454]

[0455] [NCB-D12] 3',5'-Dimethyl-4-pentyl-[1,1'-biphenyl]-2,4',6-triol

[0456] [Chemical Formula 41]

[0457]

[0458] As described above, a deprotection reaction was performed using NCB-P12 compound (35 mg, 0.1 mmol) and BBr3, and 21 mg of NCB-D12 compound was obtained by Prep. LC purification.

[0459] 1 H NMR (400 MHz, CDCl3) δ 7.01 (s, 2H), 6.41 (s, 2H), 4.86 (s, -OH, 2H), 4.86 (s, -OH, 1H), 2.53 (t, J = 7.6 Hz, 2H), 2.29 (s, 6H), 1.66-1.59 (m, 2H), 1.37-1.31 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H).

[0460]

[0461] [NCB-D13] 4-Pentyl-[1,1'-biphenyl]-2,3',4',6-tetraol

[0462] [Chemical Formula 42]

[0463]

[0464] As described above, a deprotection reaction was performed using NCB-P13 compound (38 mg, 0.11 mmol) and BBr3, and 18 mg of NCB-D13 compound was obtained by Prep. LC purification.

[0465] 1 H NMR (400 MHz, CDCl3) δ 7.22 (m, 1H), 6.87 (s, 1H), 6.65 (m, 1H), 6.50 (s, 2H), 4.91 (s, -OH, 2H), 4.80 (bs, -OH, 2H), 2.54 (t, J = 7.6 Hz, 2H), 1.66-1.57 (m, 2H), 1.36-1.30 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0466]

[0467] [NCB-D14] 4-Pentyl-[1,1'-biphenyl]-2,3',5',6-tetraol

[0468] [Chemical Formula 43]

[0469]

[0470] As described above, a deprotection reaction was performed using NCB-P14 compound (35 mg, 0.10 mmol) and BBr3, and 20 mg of NCB-D14 compound was obtained by Prep. LC purification.

[0471] 1 H NMR (400 MHz, CDCl3) δ 6.71 (d, J = 2.4 Hz, 2H), 6.46 (s, 2H), 6.35 (t, J = 2.4 Hz, 1H), 5.43 (bs, -OH, 1H), 4.93 (bs, -OH, 2H), 2.53 (t, J = 7.6 Hz, 2H), 1.64-1.55 (m, 2H), 1.33-1.28 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H).

[0472]

[0473] [NCB-D15] 5-Pentyl-2-(pyridin-2-yl)benzene-1,3-diol

[0474] [Chemical Formula 44]

[0475]

[0476] As described above, a deprotection reaction was performed using NCB-P15 compound (33 mg, 0.12 mmol) and BBr3, and 15 mg of NCB-D15 compound was obtained by Prep. LC purification.

[0477] 1 H NMR (400 MHz, CDCl3) δ 10.45 (bs, -OH, 2H), 8.53 (d, J = 8.4 Hz, 1H), 8.48 (dt, J = 4.8, 1.6 Hz, 1H), 7.80 (td, J = 7.6, 1.6 Hz, 1H), 7.19 (dd, J = 7.6, 4.8 Hz, 1H), 6.33 (s, 2H), 2.48 (t, J = 7.6 Hz, 2H), 1.63-1.56 (m, 2H), 1.35-1.25 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H).

[0478]

[0479] [NCB-D16] 5-Pentyl-2-(pyridin-4-yl)benzene-1,3-diol

[0480] [Chemical Formula 45]

[0481]

[0482] As described above, a deprotection reaction was performed using NCB-P16 compound (35 mg, 0.12 mmol) and BBr3, and 19 mg of NCB-D16 compound was obtained by Prep. LC purification.

[0483] 1 H NMR (400 MHz, CDCl3) δ 8.33 (dt, J = 8.8, 2.4 Hz, 2H), 7.62 (dt, J = 8.8, 2.4 Hz, 2H), 6.51 (s, 1H), 5.77 (s, 1H), 4.94 (s, -OH, 2H), 2.70 (t, J = 7.6 Hz, 2H), 1.68-1.60 (m, 2H), 1.44-1.33 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H).

[0484]

[0485] [NCB-D17] 5-Pentyl-2-(quinolin-3-yl)benzene-1,3-diol

[0486] [Chemical Formula 46]

[0487]

[0488] As described above, a deprotection reaction was performed using NCB-P17 compound (40 mg, 0.13 mmol) and BBr3, and 24 mg of NCB-D17 compound was obtained by Prep. LC purification.

[0489] 1 H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 2H), 7.80-7.37 (m, 4H), 6.28 (s, 2H), 2.48 (t, J = 7.6 Hz, 2H), 1.65-1.58 (m, 2H), 1.42-1.26 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H).

[0490]

[0491] [NCB-D18] 5-Pentyl-2-(thiophen-2-yl)benzene-1,3-diol

[0492] [Chemical Formula 47]

[0493]

[0494] As described above, a deprotection reaction was performed using NCB-P18 compound (40 mg, 0.14 mmol) and BBr3, and 22 mg of NCB-D18 compound was obtained by Prep. LC purification.

[0495] 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.40 (t, J = 1.6 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.36 (s, 2H), 5.31 (s, -OH, 2H), 2.68 (t, J = 7.6) Hz, 2H), 1.65-1.57 (m, 2H), 1.43-1.32 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H).

[0496]

[0497] [NCB-D19] 2',6'-Dihydroxy-4'-pentyl-[1,1'-biphenyl]-3-carbonitrile

[0498] [Chemical Formula 48]

[0499]

[0500] As described above, a deprotection reaction was performed using NCB-P19 compound (38 mg, 0.12 mmol) and BBr3, and 22 mg of NCB-D19 compound was obtained by Prep. LC purification.

[0501] 1H NMR (400 MHz, CDCl3) δ 7.72 (t, J = 1.6 Hz, 1H), 7.68 (dt, J = 8.0, 1.6 Hz, 1H), 7.62 (dt, J = 8.0, 1.6 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 6.37 (s, 2H), 5.32 (bs, -OH, 2H), 2.51 (t, J = 7.6 Hz, 2H), 1.65-1.57 (m, 2H), 1.37-1.30 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0502]

[0503] [NCB-D20] (E)-2',6'-Dihydroxy-4'-(pent-1-en-1-yl)-[1,1'-biphenyl]-3-carboaldehyde

[0504] [Chemical Formula 49]

[0505]

[0506] As described above, a deprotection reaction was performed using NCB-P20 compound (28 mg, 0.09 mmol) and BBr3, and 18 mg of NCB-D20 compound was obtained through Prep. LC purification.

[0507] 1 H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.88 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59-7.53 (m, 1H), 6.46 (d, J = 16 Hz, 1H), 6.38 (s, 2H), 6.33-6.27 (m, 1H), 2.48 (t, J = 7.6 Hz, 2H), 1.66-1.58 (m, 2H), 1.38-1.31 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0508]

[0509] [NCB-D21] 4'-Nitro-4-pentyl-[1,1'-biphenyl]-2,6-diol

[0510] [Chemical Formula 50]

[0511]

[0512] As described above, a deprotection reaction was performed using NCB-P21 compound (35 mg, 0.11 mmol) and BBr3, and 18 mg of NCB-D21 compound was obtained by Prep. LC purification.

[0513] 1 H NMR (400 MHz, Methanol-d4) δ 9.25 (s, -OH, 1H), 9.17 (s, -OH, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.08 (t, J = 7.2 Hz, 1H), 7.91 (t, J = 7.2 Hz, 1 H), 6.39 (s, 2H), 2.53 (t, J = 7.6 Hz, 2H), 1.67-1.60 (m, 2H), 1.40-1.31 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H).

[0514]

[0515] [NCB-D22] (E / Z)-4-(Hept-1-en-1-yl)-[1,1'-biphenyl]-2,6-diol

[0516] [Chemical Formula 51]

[0517]

[0518] As described above, a deprotection reaction was performed using NCB-P22 compound (37 mg, 0.12 mmol) and BBr3, and 25 mg of NCB-D22 (E / Z = 2:1 mixture) compound was obtained by Prep. LC purification.

[0519] 1 H NMR (400 MHz, CDCl3) δ 7.59-7.39 (m, 7.5H,E / Z-mix), 6.60 (s, 2H,E-form), 6.54 (s, 1H,Z-form), 6.33-6.20 (m, 2.5H,E / Z-mix), 5.68 (dt, J = 12.0, 6.8 Hz, 0.5H,Z-form), 4.56 (s, 1H,Z-form), 4.85 (s, 2H,E-form), 2.39 (q, J = 7.2 Hz, 1H,Z-form), 2.21 (q, J = 7.2 Hz, 2H,E-form), 1.51-1.44 (m, 3H, E / Z-mix), 1.38-1.28 (m, 6H,E / Z-mix), 0.94-0.87 (m, 4.5H,E / Z-mix)

[0520]

[0521] [NCB-D23] 2,6-Dihydroxy-[1,1'-biphenyl]-4-carboaldehyde

[0522] [Chemical Formula 52]

[0523]

[0524] As described above, a deprotection reaction was performed using NCB-P23 compound (30 mg, 0.12 mmol) and BBr3, and 16 mg of NCB-D23 compound was obtained by Prep. LC purification.

[0525] 1 H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.52-7.47 (m, 2H), 7.42-7.33 (m, 3H), 7.08 (s, 2H), 4.88 (s, -OH, 2H).

[0526]

[0527] [NCB-D24] (E)-4-Styryl-[1,1'-biphenyl]-2,6-diol

[0528] [Chemical Formula 53]

[0529]

[0530] As described above, a deprotection reaction was performed using NCB-P24 compound (35 mg, 0.11 mmol) and BBr3, and 24 mg of NCB-D24 (E-form) compound was obtained by Prep. LC purification.

[0531] 1 H NMR (400 MHz, CDCl3) δ 7.60 (t, J = 8.0 Hz, 2H), 7.52 (t, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 16.4 Hz, 1H), 7.03 (d, J = 16.4 Hz, 1H), 6.79 (s, 2H), 4.91 (br, -OH, 2H).

[0532]

[0533] [NCB-D25] (Z)-4-Styryl-[1,1'-biphenyl]-2,6-diol

[0534] [Chemical Formula 54]

[0535]

[0536] As described above, a deprotection reaction was performed using NCB-P25 compound (31 mg, 0.1 mmol) and BBr3, and 21 mg of NCB-D25 (Z-form) compound was obtained by Prep. LC purification.

[0537] 1H NMR (400 MHz, CDCl3) δ 7.55-7.50 (m, 2H), 7.47-7.33 (m, 6H), 7.30-7.22 (m, 2H), 7.03 (s, 2H), 6.63 (s, 2H), 4.96 (s, -OH, 2H).

[0538]

[0539] [NCB-D26] 4-Phenethyl-[1,1'-biphenyl]-2,6-diol

[0540] [Chemical Formula 55]

[0541]

[0542] As described above, a deprotection reaction was performed using NCB-P26 compound (33 mg, 0.1 mmol) and BBr3, and 23 mg of NCB-D26 compound was obtained by Prep. LC purification.

[0543] 1 H NMR (400 MHz, CDCl3) δ 7.57 (t, J = 7.2 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.26-7.20 (m, 3H), 6.48 (s, 2H), 4.82 (s, -OH, 2H), 2.98-2.93 (m, 2H), 2.89-2.85 (m, 2H).

[0544]

[0545] [NCB-D27] 4-Heptyl-[1,1'-biphenyl]-2,6-diol

[0546] [Chemical Formula 56]

[0547]

[0548] As described above, a deprotection reaction was performed using NCB-P27 compound (35 mg, 0.11 mmol) and BBr3, and 24 mg of NCB-D27 compound was obtained by Prep. LC purification.

[0549] 1 H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 7.6 Hz, 2H), 7.46 (tt, J = 7.6, 1.2 Hz, 1H), 7.42-7.40 (m, 2H), 6.44 (s, 2H), 4.84 (s, -OH, 2H), 2.55 (t, J = 7.6 Hz, 2H), 1.70-1.60 (m, 2H), 1.38-1.25 (m, 8H), 0.90 (t, J = 7.2 Hz, 3H).

[0550]

[0551] 2-2: Synthesis using cannabidiol

[0552] In order to further synthesize compounds represented by the above chemical formula 57, the reaction of the following reaction formula 3 was performed.

[0553] [Reaction Formula 3]

[0554]

[0555]

[0556] [NCB-P2] [3-acetyloxy-2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylphenyl] acetate)

[0557] [Chemical Formula 2]

[0558]

[0559] Cannabidiol (157 mg, 0.5 mmol) isolated from cannabis was reacted with 2.5–3.0 equivalents of acetic anhydride (Ac2O) and 2.5–3.0 equivalents of pyridine in anhydrous dichloromethane (CH2Cl2) for 3 hours. The reaction was quenched with a saturated aqueous solution of NH4Cl, extracted three times with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The mixture was purified by column chromatography to obtain 166 mg of the NCB-P2 compound.

[0560] 1 H NMR (400 MHz, CDCl3) δ 6.71 (s, 2H), 5.20 (s, 1H), 4.55 (s, 1H), 4.45 (s, 1H), 3.51 (m, 1H), 2.65 (td, J = 10.9, 2.3 Hz, 1H), 2.55 (t, J = 7.3 Hz, 2H), 2.30-2.10 (m, 6H), 2.08-1.98 (m, 1H), 1.83-1.68 (m, 2H), 1.67 (s, 3H), 1.58 (s, 6H), 1.37-1.23 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H).

[0561]

[0562] [NCB-P29] 2'-isopropyl-5'-methyl-4-pentyl-[1,1'-biphenyl]-2,6-diyl diacetate

[0563] [Chemical Formula 29]

[0564]

[0565] NCB-P2 compound (100 mg, 0.25 mmol) was dissolved in toluene with 2.0 to 2.5 equivalents of iodine (I2), and sufficiently reacted at 110°C for 3 hours. After quenching the reaction with an aqueous Na2S2O3 solution, the extracted organic layer was dried over anhydrous Na2SO4, and the solvent was concentrated under reduced pressure. After column purification, 46 mg of NCB-P29 compound was obtained.

[0566] 1 H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 8.0, 2.0 Hz, 1H), 6.88 (s, 2H), 6.81 (d, J = 2.4 Hz, 1H), 2.65 (t, J = 7.6 Hz, 2H), 2.62 (sept, J = 6.8 Hz, 1H), 2.27 (s, 3H), 1.88 (s, 6H), 1.67 (m, 2H), 1.40-1.32 (m, 4H), 1.10 (d, J = 7.2 Hz, 6H), 0.92 (t, J = 7.2 Hz, 3H).

[0567]

[0568] [NCB-D2] 2'-isopropyl-5'-methyl-4-pentyl-[1,1'-biphenyl]-2,6-diol

[0569] [Chemical Formula 31]

[0570]

[0571] The NCB-P29 compound (35 mg, 0.09 mmol) was purified by column chromatography after removing the acetate protecting group using potassium carbonate and methanol, to obtain 22 mg of the NCB-D2 compound.

[0572] 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.43 (s, 2H), 4.56 (bs, -OH, 2H), 2.76 (sept, J = 6.8 Hz, 1H), 2.56 (t, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.70-1.60 (m, 2H), 1.43-1.30 (m, 4H), 1.12 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 6.8 Hz, 3H).

[0573]

[0574] 2-3: Construction of a library of NCB-D1 compounds and their derivatives and evaluation of their anti-inflammatory activity.

[0575] Information on the compounds synthesized through the reactions described in Examples 2-1 and 2-2 above is described in Tables 1 to 6 below.

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582] Next, to evaluate the anti-inflammatory activity and cytotoxicity of the compounds included in the library, NO production assay and cell viability inhibition assay in macrophages were performed as described in Example 1.

[0583] As a result, it was confirmed that the library compounds exhibited excellent anti-inflammatory activity by suppressing NO production without exhibiting cytotoxicity. In addition, it was confirmed that NCB-D1 among the library compounds exhibited remarkably excellent anti-inflammatory activity (Fig. 2).

[0584]

[0585] Example 3: Evaluation of anti-inflammatory activity of NCB-D1 compound

[0586] To evaluate the anti-inflammatory activity of the NCB-D1 compound as an example of the library compound constructed in Example 2, the following experiment was performed.

[0587]

[0588] 3-1: Evaluation of IL-1B and TNF-a expression inhibition ability

[0589] Specifically, 50,000 RAW264.7 cells were seeded and cultured for 24 hours, then simultaneously treated with 1 ug / ml LPS and NCB-D1 compound at a concentration of 25 uM. After another 24-hour culture, the mRNA expression of anti-inflammatory markers IL-1B and TNF-α was analyzed by qPCR. To this end, all cells were harvested, RNA was extracted, and qRT-PCR was performed, which was corrected for the mRNA expression of the GAPDH gene. Meanwhile, dexamethasone (DEX), a steroid agent actually used in clinical practice, was applied at a concentration of 25 uM as a control. Meanwhile, IL-1b is one of the representative cytokines secreted by macrophages and has a meaning beyond a simple cytokine. IL-1b travels to the hypothalamus through the blood vessels, generates heat, and induces contraction of epithelial cells in the intestinal wall, which plays a role in destroying the intestinal wall, which is the first barrier against microorganisms, thereby inducing an inflammatory response and spreading functions. Therefore, when IL-1b is suppressed, multiple effects such as improvement of fever, barrier protection, and inhibition of inflammation spread can be achieved simultaneously.

[0590] The above experimental results confirmed that the NCB-D1 compound exhibited superior IL-1b expression inhibition ability compared to dexamethasone at the same concentration (Fig. 3). In addition, in the case of TNF-α, a cytokine secreted by macrophages and acting on them in an autocrine manner, it was confirmed that the NCB-D1 compound exhibited an inhibition efficiency similar to that of dexamethasone at the same concentration (Fig. 3).

[0591]

[0592] 3-2: Evaluation of iNOS and COX-2 expression inhibition ability

[0593] Next, RAW264.7 cells were cultured at 1.2x10 6 Each cell was seeded in a 6-well plate and cultured for 24 hours. Then, 1ug / ml LPS and NCB-D1 compound were simultaneously treated at concentrations of 10 and 25uM. After 24 hours, cells were harvested, proteins were extracted, and Western blotting was performed to analyze the expression levels of iNOS and COX-2, which are inflammation-related factors.

[0594] Specifically, nitric oxide (NO) is an inflammatory factor produced by macrophages that dilates blood vessels and, as a reactive oxygen species, causes the breakdown of epithelial cell adhesion. Although the level of NO production was measured in the above-mentioned experimental results, it is necessary to analyze whether this is due to the inhibition of the enzymatic activity of iNOS (inducible nitric oxide synthase) or the inhibition of the expression of the protein itself. As a result of the above experiment, it was confirmed that the NCB-D1 compound showed superior inhibition even at a concentration of 10 uM compared to Dex, and almost inhibited expression at 25 uM (Fig. 4).

[0595] Next, the expression level of COX-2, an enzyme that produces prostaglandins and induces pain and fever in disease situations, was analyzed using Western blotting. Since the most widely used drugs for chronic inflammatory diseases are also COX2 inhibitors such as diclofenac, COX2 is one of the important analysis indicators that can experience rapid effects in the development of new drugs for chronic diseases. The results of the above experiment confirmed that the NCB-D1 compound suppressed the expression level of COX2 protein better than Dex at a concentration of 25uM (Fig. 4).

[0596]

[0597] Example 4: Evaluation of antioxidant activity of NCB-D1 compound

[0598] In order to evaluate the antioxidant activity of the NCB-D1 compound as an example of the library compound constructed in Example 2 above, the following experiment was performed.

[0599] Specifically, to evaluate antioxidant activity, the ability to inhibit reactive oxygen species (ROS) production was examined, and fluorescence spectroscopy using 2',7'-dichlorofluorescein diacetate (H2DCFDA) was used. To evaluate the ROS-reducing effect of the NCB-D1 compound, 1X10 5RAW264.7 cells were seeded in 12 wells and cultured for 24 hours. After treatment with LPS and NCB-D1 at a concentration of 1 μg / ml, the cells were cultured for an additional 24 hours. Afterwards, the cells were stained with 50 μM H2DCFDA for 1 hour at 37 °C and washed with PBS. DCF-positive cells were imaged and analyzed using a fluorescence microscope, and the fluorescence intensity was quantified using ImageJ. In addition, after performing the same experiment as described above, the cells were harvested and the expression level of Nuclear factor erythroid 2-related factor 2 (NRF2), a key factor involved in the removal of reactive oxygen species, was analyzed by Western blotting.

[0600] Meanwhile, reactive oxygen species are largely generated in the tissue environment by exogenous factors such as ultraviolet rays, radiation, pollutants, smoking, and drinking, and by endogenous factors in which various cells in the body generate reactive oxygen species upon stimulation. In the case of endogenous reactive oxygen species, a large amount is produced, representatively, in macrophages. Macrophages mainly produce reactive oxygen species such as hydrogen peroxide, nitric oxide, nitric oxide, and hydroxyl radicals, and reactive oxygen species such as hydroxyl radicals can cause structural damage to cells, resulting in serious damage such as barrier collapse. Therefore, in this example, we aimed to analyze whether treatment with the NCB-D1 compound could suppress the production of such endogenous and exogenous reactive oxygen species.

[0601] First, the results of the endogenous reactive oxygen species inhibition assay showed that the NCB-D1 compound strongly inhibited the production of reactive oxygen species at a concentration of 10 μM or higher, which was superior to that of Dex at 25 μM (Fig. 5). In addition, it was confirmed that reactive oxygen species accumulated within the cells when treated externally with H2O2, an exogenous reactive oxygen species, at a concentration of 200 μM for 5 hours, and it was confirmed that the NCB-D1 compound exhibited a strong hydrogen peroxide inhibition ability in a concentration-dependent manner (Fig. 6).

[0602] Meanwhile, when cells are exposed to reactive oxygen species, they respond by producing substances such as glutathione, which can function as enzymes or reducing agents that can remove them. The most key factor in responding to these reactive oxygen species is well known to be Nuclear factor erythroid 2-related factor 2 (NRF2). Accordingly, it was confirmed that treatment with the NCB-D1 compound significantly increased the protein expression level of NRF2, indicating that the NCB-D1 compound is effective in improving tissue damage caused by chronic reactive oxygen species production (Figure 7).

[0603]

[0604] Example 5: Evaluation of the inhibitory efficacy of the NCB-D1 compound in inflammation-related signaling

[0605] In order to evaluate the inflammation-related signal transduction inhibitory efficacy of the NCB-D1 compound as an example of the library compound constructed in Example 2 above, the following experiment was performed.

[0606] Meanwhile, most immune cells are activated by receptor stimulation by cytokines, chemokines, and growth factors, and macrophages also express various inflammatory factor receptors. In particular, macrophages, which are part of the innate immune system, express pattern recognition receptors (PPRs), which recognize microorganisms and initiate signaling responses. Furthermore, NF-kB (p65) signaling molecules are essential for all inflammation-related signals, and are activated by the IkB activation cascade caused by the activation of IKK.

[0607] Accordingly, in the above example, the TLR4 receptor activation conditions were simulated in vitro through LPS treatment, and the level of inhibition of the activity of the downstream signaling pathway by treatment with the NCB-D1 compound was analyzed using Western blotting.

[0608] As a result of the above experiment, it was confirmed that the expression levels of the phosphorylated forms (activated forms) of IKK, IkB, and NF-kB were suppressed by treatment with the NCB-D1 compound, and the expression levels of the phosphorylated forms (activated forms) of ERK, JNK, and p38, which are MAPK signaling pathway factors, were also suppressed (Fig. 8), indicating that the NCB-D1 compound can effectively suppress the inflammation-related signaling pathway.

[0609]

[0610] Example 6: Evaluation of the efficacy of NCB-D1 compound in promoting tight junctions in intestinal epithelial cells.

[0611] In order to evaluate the efficacy of the NCB-D1 compound, as an example of the library compound constructed in Example 2 above, in promoting intestinal epithelial cell tight junction, the following experiment was performed.

[0612] Meanwhile, in the case of inflammatory bowel disease, intestinal epithelial cells are often not sufficiently recovered by suppressing immune cells alone, and are continuously exposed to antigens including microorganisms. Therefore, improving the survival rate of intestinal epithelial cells and restoring their structural function is very important for improving the overall inflammatory bowel disease.

[0613] Accordingly, in the above example, Caco2 cell line, a human intestinal epithelial cell line, was treated with ITI (Interferon-γ, IL-1β, and TNF-α - each 20 ng / ml) that induces the breakdown of tight junctions between intestinal epithelial cells for 48 hours, and the survival rate of intestinal epithelial cells according to the treatment with the NCB-D1 compound was analyzed. In addition, the expression levels of ZO-1 and Occludin, which are key factors for maintaining the tight junctions of intestinal epithelial cells, were analyzed using qRT-PCR.

[0614] As a result of the above experiment, it was confirmed that the survival rate of intestinal epithelial cells decreased by ITI treatment was significantly increased by treatment with the NCB-D1 compound, and that the expression level of the tight junction factor of intestinal epithelial cells was also significantly increased (Fig. 9).

[0615]

[0616] Example 7: In vivo efficacy evaluation of NCB-D1 compound

[0617] In order to evaluate the activity of the NCB-D1 compound as an example of the library compound constructed in Example 2 above at the in vivo level, the following experiment was performed.

[0618] Specifically, inflammatory bowel disease was induced in 7-week-old male C57BL / 6 mice by administering 2.5% (w / v) dextran sulfate sodium (DSS), which is most commonly used to induce intestinal epithelial damage, for 5 days. From day 1, the NCB-D1 compound was administered via intraperitoneal injection once daily at a concentration of 5 mg / kg or 10 mg / kg, and as a positive control, 100 mg / kg of 5-ASA (5-aminosalicylic acid), a drug actually used in inflammatory bowel disease, was administered orally. The administration was performed for 7 days, and the body weights of the mice were measured daily. In addition, the mice were sacrificed on the 10th day from the DSS intake, and subsequent experiments (measurement of intestinal length and histoimmunochemical staining) were performed. Each group included 5 mice, and the experiment was performed with a total of 25 mice.

[0619] As a result of the above experiment, in the group administered 5 mg / kg of the NCB-D1 compound, body weight and intestinal length were recovered similarly to the group administered 5-ASA, and in the group administered 10 mg / kg of the NCB-D1 compound, body weight and intestinal length were confirmed to be significantly improved compared to the group administered 5-ASA. In addition, as a result of analyzing the intestinal tissue through HE histoimmunochemical staining, it was confirmed that the group administered the NCB-D1 compound showed significantly better histological normalization in the mucosal structure, intestinal gland structure, submucosal membrane, and smooth muscle layer compared to the group administered 5-ASA (Fig. 10).

[0620]

[0621] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

A compound represented by the following chemical formula 57, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof: [Chemical Formula 57] In the above chemical formula 57, Ring W is selected from the group consisting of a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C3-C8 cycloalkenyl group, a substituted or unsubstituted C6-C14 aryl group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group, One or more R 1 are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR 5 R 6 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group; R 2 and R 3 Each independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Acyl group, substituted or unsubstituted C1-C10 Alkyl ester group, substituted or unsubstituted C7-C10 aryl ester group, , , and selected from the group consisting of glycosyl groups; The above R 4 is hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR 5 R 6 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group; X is a vinylene group (-CH=CH-) n , -(CH2) n -, or -[CH=CH-(CH2) n ]- and, R 5 , R 6 and R 7 Each independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 It is an alkyl group, One or more R 8 are each independently selected from the group consisting of a C1-C5 alkyl group, a C3-C7 cycloalkyl group, a C1-C5 alkenyl group, a C1-C5 alkynyl group, a C1-C4 alkyloxy group, a nitro group (-NO2), a cyanide group (-CN), -F, -Cl, -Br, -I, and hydrogen, l is an integer in the range 0 to 5, m is 0 or 1, n is an integer in the range 1 to 10, q is an integer in the range 0 to 5, r is an integer in the range 1 to 4, s is an integer from 1 to 5. In claim 1, W is a compound comprising at least one selected from the group consisting of groups represented by the following chemical formulae 58-1 to 58-5, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof: In the above chemical formulas 58-1 to 58-5, One or more R 1 are each independently hydrogen, halogen, substituted or unsubstituted C1-C5 Alkyl group, substituted or unsubstituted C1-C5 haloalkyl group, substituted or unsubstituted C1-C5 Selected from the group consisting of an alkoxy group, a hydroxy group, a cyano group, a formyl group, and a nitro group, l is an integer in the range 0 to 5. In claim 1, W comprises at least one selected from the group consisting of groups represented by the following chemical formulae 59-1 to 59-5, a compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof: In the above chemical formulas 59-1 to 59-5, One or more R 1 (Specifically, R 1 , R 1` and R 1`` One or more of) are each independently hydrogen, halogen, substituted or unsubstituted C1-C5 Alkyl group, substituted or unsubstituted C1-C5 haloalkyl group, substituted or unsubstituted C1-C5 Selected from the group consisting of an alkoxy group, a hydroxy group, a cyano group, a formyl group, and a nitro group. In claim 1, W is a compound represented by the following chemical formula 59-4, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof: The above R 1 and R 1` is independently selected from the group consisting of a substituted or unsubstituted methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and hydrogen. In claim 1, the R 2 and R 3 are each independently hydrogen, substituted or unsubstituted C1-C5 A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of an alkyl group and a substituted or unsubstituted C1-C5 acyl group. In claim 1, the R 4 A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from the group consisting of hydrogen, a formyl group, a substituted or unsubstituted C1-C10 alkyl group, a formyl group, and a substituted or unsubstituted C3-C10 aryl group. A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound comprises at least one compound selected from the group consisting of compounds 1 to 56 described in Tables 1 to 6 of the specification, in claim 1. In claim 1, the substitution is one or more R a may be substituted with one or more of R a are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, and substituted or unsubstituted C1-C10 A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of an alkoxy group. A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, according to claim 1, having anti-inflammatory, antioxidant, and / or tight junction promoting effects. A compound represented by the following chemical formula 60, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof: [Chemical Formula 60] In the above chemical formula 60, One or more rings W are each independently a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C3-C8 cycloalkenyl group, a substituted or unsubstituted C6-C14 aryl group, or a substituted or unsubstituted 3- to 12-membered heteroaryl group, One or more R 1 are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR 5 R 6 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group; R 2 and R 3 Each independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Acyl group, substituted or unsubstituted C1-C10 Alkyl ester group, substituted or unsubstituted C7-C10 aryl ester group, , , and selected from the group consisting of glycosyl groups; One or more R 4 are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, -OH, cyano group, nitro group, amino group, amidino group, formyl group, substituted or unsubstituted C1-C10 Alkyl group, substituted or unsubstituted C1-C10 haloalkyl group, substituted or unsubstituted C2-C10 Alkenyl group, substituted or unsubstituted C2-C10 Alkynyl group, substituted or unsubstituted C1-C10 Alkoxy group, -NR 5 R 6 , -NH(C=O)R 5 , -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NR 5 R 6 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3- to 12-membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, a substituted or unsubstituted C3-C12 arylalkyl group, a substituted or unsubstituted C3-C12 aryloxy group, a substituted or unsubstituted C3-C12 arylthio group, and a substituted or unsubstituted 3- to 12-membered heteroaryl group; One or more Xs are each independently a vinylene group (-CH=CH-) n , -(CH2) n -, or -[CH=CH-(CH2) n ]- and, R 5 , R 6 and R 7 Each independently represents hydrogen, deuterium, substituted or unsubstituted C1-C10 It is an alkyl group, One or more R 8 are each independently selected from the group consisting of a C1-C5 alkyl group, a C3-C7 cycloalkyl group, a C1-C5 alkenyl group, a C1-C5 alkynyl group, a C1-C4 alkyloxy group, a nitro group (-NO2), a cyanide group (-CN), -F, -Cl, -Br, -I, and hydrogen, Linker is , , , and is selected from the group consisting of, l is an integer in the range 0 to 5, each independently, m is independently 0 or 1, n is an integer in the range 1 to 10, q is an integer in the range 0 to 5, r is an integer in the range 1 to 4, s is an integer from 1 to 5. A pharmaceutical composition for preventing or treating inflammatory diseases, comprising a compound according to any one of claims 1 to 10, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. A composition according to claim 11, wherein the inflammatory disease comprises at least one selected from the group consisting of autoimmune disease, systemic lupus erythematosus, multiple sclerosis, Sjogren's syndrome, asthma, conjunctivitis, iritis, scleritis, uveitis, periodontitis, dermatitis, arthritis, degenerative arthritis, inflammatory bowel disease, ankylosing spondylitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastritis, nephritis, pancreatitis, hepatitis, tendonitis, and tenosynovitis. A composition according to claim 12, wherein the inflammatory bowel disease (IBD) comprises at least one selected from the group consisting of ulcerative colitis, ulcerative duodenitis, Crohn's disease, irritable bowel syndrome, intestinal Behcet's disease, ischemic colitis, leaky gut syndrome, collagenous colitis, lymphocytic colitis, diversionary colitis, simple ulcer, and radiation enteritis. A composition according to claim 11, wherein the composition has anti-inflammatory, antioxidant and / or dense bonding promoting effects. A composition according to claim 11, wherein the composition suppresses the expression and / or activity of an inflammatory cytokine or inflammatory factor. A composition according to claim 11, wherein the composition inhibits the production and / or expression of reactive oxygen species (ROS). A composition according to claim 11, wherein the composition increases the expression and / or activity of a tight junction factor of intestinal epithelial cells. A food composition for preventing or improving inflammatory diseases, comprising a compound according to any one of claims 1 to 10, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. A feed composition for preventing or improving inflammatory diseases, comprising a compound according to any one of claims 1 to 10, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. An anti-inflammatory composition comprising a compound of any one of claims 1 to 10, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. An antioxidant composition comprising a compound according to any one of claims 1 to 10, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

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