Novel lipoxin-like compound having Anti-inflammatory efficacy

Abstract

The present invention relates to a novel lipoxin-like compound that inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). The novel lipoxin-like compound can be very effectively used for preventing, ameliorating or treating not only fibrosis but also cancer, autoimmune diseases, inflammation, metabolic diseases, cardiovascular diseases, or pain.

Description

Novel lipoxin-like compounds with anti-inflammatory efficacy

[0001] The present invention relates to the fields of medicine and chemistry, and to a novel lipoxin-like compound that can be used as a pharmacological component useful for treating diseases such as cancer, autoimmune diseases, inflammation, metabolic diseases, cardiovascular diseases, or pain by inhibiting the activity of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells).

[0002] Tissues consist of well-ordered cell clusters bound to an extracellular matrix and surrounded by a vascular network. Fibrosis is the abnormal accumulation of a collagen matrix resulting from injury or inflammation that alters the structure and function of various tissues. In the case of fibrosis, regardless of its location of occurrence, the excessive accumulation of fibrous connective tissue, such as a collagen matrix, replacing normal tissue accounts for most etiological factors. Progressive fibrosis in the kidneys, liver, fat, lungs, heart, bone or bone marrow, and skin is a major cause of death or suffering.

[0003] Among the aforementioned types of fibrosis, pulmonary fibrosis, which specifically occurs in the lungs, refers to a disease in which chronic inflammatory cells infiltrate the alveolar walls of the lung tissue, inducing tissue fibrosis and causing severe structural changes in the lung tissue. Once fibrosis progresses due to any cause, the lung tissue hardens and the alveolar walls thicken, reducing the oxygen supply from the blood and consequently making breathing difficult. Currently, there is no medical treatment available to completely restore lung tissue that has already undergone fibrosis; therefore, unless the condition is detected in the early stages of progression or a lung transplant is performed, patients usually die 3 to 5 years after the onset of symptoms.

[0004] Treatment methods for pulmonary fibrosis detected in the early stages include the use of steroid drugs such as steroids, azathioprine, and cyclophosphamide; antioxidants such as acetylcysteine; and growth factors such as cytokines and IFN-γ (Interferon-γ). Although there have been numerous studies and reports on treatments using steroid drugs and antioxidants since 2000, none have yet been proven to have clear efficacy; furthermore, long-term administration has been reported to cause systemic side effects or lead to the development of tolerance. Treatment through the administration of growth factors has recently garnered significant attention as a relatively fundamental approach utilizing 'interferon,' which inhibits the production of TGF-β (Transforming growth factor-β), known as a key factor in pulmonary fibrosis. Due to an approach that analyzes the causes of the disease for treatment, various forms of therapy, such as injectables or aerosols, have been reported as having superior efficacy and fewer side effects compared to treatments using steroids and antioxidants. However, since the exact cause of pulmonary fibrosis is still unknown, the therapeutic efficacy of single components like interferon may be temporary and may be effective only for a limited number of patients, thus requiring continuous research and clinical trials.

[0005] The present invention is a result derived as part of the “Discovery of Cathepsin S-Targeted Pulmonary Fibrosis Improvement Compounds” project, conducted at CHA University of Medical Science from September 1, 2021, to February 28, 2025, under the “Mid-Career Researcher Support Program” funded by the Ministry of Science and ICT of the Republic of Korea and supported by the National Research Foundation of Korea (Project No. 2710016478, Project No. 2021R1A2C2094925).

[0006] In addition, the present invention is a result derived as part of the “Development of Candidate Substances for the Treatment of Radiation Lung Disease Using Next-Generation Synthetic Lipoxin Analogs” under the “Mid-Career Researcher Support Program (Type 2)” conducted at Yonsei University from March 1, 2022, to February 28, 2025, with funding from the Ministry of Science and ICT of the Republic of Korea and support from the National Research Foundation of Korea (Project No. 2 710014834, Project No. 2022R1A2C3011611).

[0007] One objective of the present invention is to provide a novel lipoxin-like compound capable of inhibiting NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells).

[0008] Another objective of the present invention is to provide a composition for the prevention or treatment of fibrosis, cancer, autoimmune disease, inflammation, metabolic disease, cardiovascular disease, or pain, comprising a novel lipoxin-like compound capable of inhibiting NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells).

[0009] Another objective of the present invention is to provide a method for preventing or treating fibrosis, cancer, autoimmune diseases, inflammation, metabolic diseases, cardiovascular diseases, or pain using the above composition.

[0010]

[0011] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below.

[0012] Various embodiments of the present invention are described with reference to the drawings. In the following description, for a complete understanding of the present invention, various specific details, such as specific forms, compositions, and processes, are described. However, specific embodiments may be practiced without one or more of these specific details, or in combination with other known methods and forms. In other examples, known processes and manufacturing techniques are not described as specific details so as not to make the present invention unnecessary or obscure. Reference throughout this specification to one embodiment implies that a particular feature, form, composition, or characteristic described in association with the embodiment is included in one or more embodiments of the present invention. Accordingly, the circumstances of an embodiment expressed at various locations throughout this specification do not necessarily represent the same embodiment of the present invention. Additionally, a particular feature, form, composition, or characteristic may be combined in any suitable way in one or more embodiments.

[0013]

[0014] Pulmonary fibrosis, the primary cause of chronic obstructive pulmonary disease, occurs as pneumonia persists, which is an inflammatory response resulting from damage to alveolar cells and vascular endothelial cells caused by various external stimuli. Radiation-induced lung fibrosis (RILF) also occurs as a side effect after radiation therapy, which is one of the cancer treatments. However, since it is currently classified as a clinical syndrome with no clearly elucidated pathological mechanism, there is a lack of established effective methods to prevent the disease.

[0015] Currently, combination therapy with steroids and azathioprine or cyclophosphamide is used in clinical practice to treat radiation-induced lung damage. Common treatments for pulmonary fibrosis include prednisone and glucocorticosteroids for inflammation relief, colchicine and penicillamine for collagen synthesis inhibition, and antibiotic therapy; however, these treatments are accompanied by strong toxicity and side effects. Therefore, no effective drug capable of controlling pulmonary fibrosis suitable for clinical application has yet been developed.

[0016] Furthermore, tissue damage generally induces inflammation, and damaged epithelial cells transform into fibroblasts, leading to fibrosis; this necessitates suppressing fibrosis by controlling the initial inflammatory response through substances with potent anti-inflammatory effects, such as LXA4.

[0017] Meanwhile, changes in LXA4 biosynthesis have been reported in various diseases such as asthma, fibrosis, cancer, atherosclerosis, sclerosis, and interstitial fibrotic lung disease, with a decrease in LXA4 levels specifically reported in asthma mouse models and patients. In a recent report, aspirin-triggered lipoxins (ATLs) have been reported to possess antifibrotic functions in bleomycin-induced pulmonary fibrosis by inhibiting pulmonary fibrosis not only through the suppression of inflammatory cell infiltration in lung tissue but also by regulating the production of fibrosis-related cytokines.

[0018] The NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) complex regulates genes important for cell proliferation, survival, and drug resistance. In mammals, the NF-κB transcription factor family consists of five proteins: p50, p52, p65, Rel-B, and c-Rel, which associate with each other to form distinct transcriptionally active homodimeric and heterodimeric complexes. In unstimulated cells, the NF-κB complex remains inactive in the plasma by the κB repressor (IκB). Typically, when activated by signals originating from outside the cell, IκB kinase (IKK) phosphorylates IκB, which leads to the degradation of IκB and its translocation to the nucleus, as well as the release of the NF-κB complex for the activation of target genes. The nuclear translocation of the NF-κB complex is a critical step in the coupling of extracellular stimuli to the transcriptional activation of specific target genes. In other words, it is widely known that dysregulation of NF-κB signaling is associated with inflammatory diseases, autoimmune diseases, and certain cancers (Journal of Autoimmunity Volume 31, Issue 3, November 2008, Pages 245-251)

[0019]

[0020] In one embodiment of the present invention, a compound represented by the following formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0021] [Chemical Formula 1]

[0022]

[0023] In the above Chemical Formula 1, R1 is unsubstituted or substituted with C6-C1 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1-C5 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy, or C1-C2 alkoxy. 10It is an aryl or a heteroaryl of a pentagonal or decagonal ring; wherein R2 and R3 are each independently hydrogen or C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or are connected to each other to form a heterocycloalkyl of a pentagonal or hexagonal ring that is unsubstituted or substituted with C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl; wherein n is an integer from 0 to 2 or from 0 to 1, and m is an integer from 1 to 3 or from 1 to 2; and wherein is a single bond or a double bond; and R4 is a C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0024] In this specification, the terms “alkyl” or “alk” refer to linear or branched-chain alkanes (hydrocarbons) radicals comprising 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutylpentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. For example, the term “C1-C4alkyl” refers to linear or branched-chain alkanes (hydrocarbons) radicals comprising 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available attachment site.

[0025] In this specification, the term “alkoxy” means a radical formed by removing hydrogen from an alcohol, for example, C1-C5 alkoxy means an alkyl ether formed by removing hydrogen from an alcohol having 1 to 5 carbon atoms.

[0026] In this specification, the term “aryl” refers to a monocyclic or polycyclic carbon ring that is wholly or partially unsaturated and aromatic. For example, C6-C 10 An aryl refers to a monocyclic or polycyclic carbon ring that is wholly or partially unsaturated and aromatic, composed of 6 to 10 carbon atoms. For example, if it contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). "Substituted aryl" refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available attachment point.

[0027] In this specification, the terms “aromatic heterocyclic” or “heteroaryl” have the same meaning and refer to a heteroaromatic group comprising one or more heteroatoms. The heteroatoms referred to herein include oxygen, sulfur, and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be condensed to an aryl, heterocyclic group, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl is optionally substituted or unsubstituted.

[0028] In this specification, the term “cycloalkenyl” refers to an unsaturated hydrocarbon ring forming a single or multiple rings, and refers to a cyclic group comprising at least one carbon-carbon double bond in a cycloalkyl group. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc. For example, C3-C7 cycloalkenyl refers to an unsaturated hydrocarbon ring composed of an alkene unit having 3 to 7 carbon atoms, and when C3-C7 alkenyl is substituted, the number of carbon atoms of the substituent is not included. “Substituted cycloalkenyl” refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available attachment site.

[0029] In this specification, the term “cycloalkyl” or “cycloalkyl” refers to a fully saturated cyclic hydrocarbon group comprising 1 to 4 rings and 3 to 8 carbons per ring. It includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. The terms “C3-C8 cycloalkyl”, “C3-C7 cycloalkyl”, and “C3-C6 cycloalkyl” have similar meanings; for example, “C3-C7 cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. “Substituted cycloalkyl” refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available attachment site.

[0030] In this specification, the terms “heterocycle” and “heterocyclic” refer to fully saturated, or partially or fully unsaturated, comprising an aromatic (i.e., “heteroaryl”) cyclic group (e.g., a 4 to 7-membered monocyclic, a 7 to 11-membered bicyclic, or an 8 to 16-membered tricyclic ring system) having at least one heteroatom within at least one carbon atom-containing ring. Each ring of the heterocyclic group containing the heteroatom may have 1, 2, 3, or 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and / or a sulfur atom, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. (The term "heteroarylium" refers to a heteroaryl group containing a quaternary nitrogen atom and is therefore positively charged.) A heterocyclic group can be attached to any heteroatom or carbon atom of the rest of the molecule in a ring or ring system. Exemplary monocyclic and heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanil, pyrazolinyl, imidazollyl, imidazollinyl, imidazollinyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazollyl, isothiazollyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperajinil, 2-oxopiperajinil, 2-oxopyrrolodinyl, 2-oxoazefinil, azefinil, hexahydrodiazefinil, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, Includes triazolyl, tetrazolyl, tetrahydropyranil, morpholinyl, thiamofolinyl, thiamofolinyl sulfoxide, thiamofolinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, etc.The terms “substituted heterocycle” and “substituted heterocyclic” (e.g., “substituted heteroaryl”) refer to a heterocycle or heterocyclic group substituted with one or more substituents, preferably 1 to 4 substituents, at any available attachment site.

[0031] In this specification, the term “substitution” means that one or more hydrogen atoms on a specified group are substituted by a specified substituent. The specified substituent is the substituent correspondingly described above or the substituent shown in each example. Unless specifically stated otherwise, the specified substituted group may have one substituent selected from a specific group at any substitutable site of the group, and said substituent may be the same or different at each position. Cyclic substituents, such as heterocycloalkyls, may be connected to another ring, such as cycloalkyls, to form a spiro-double ring system, such as a two-ring system having one common carbon atom. Those skilled in the art should understand that the combination of substituents anticipated in this invention is a stable or chemically feasible combination. The substituents are, for example, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkinyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl(-COOH), C 1-8 Aldehyde group, C 2-10 Asil, C 2-10 Ester group, C 1-C12 Alkoxycarbonyl, amino, alkoxy, C 1-10 Sulfonyl, etc., but are not limited to these.

[0032] Unless otherwise determined, any heteroatom with an unfulfilled valence is assumed to have enough hydrogen atoms to satisfy the valence.

[0033] As used herein, the terms “combination” or “pharmaceutical combination” refer to a product produced from a mixture or combination of more than one active ingredient and comprising both fixed and non-fixed combinations of the active ingredient. The term “fixed combination” means that an active ingredient, e.g., a compound of the present invention, and one or more additional therapeutic agents are administered to a patient simultaneously in the form of a single substance or dosage. The term “non-fixed combination” means that an active ingredient, e.g., a compound of the present invention, and one or more additional therapeutic agents are administered to a patient simultaneously, jointly, or sequentially without specific time limits as individual substances, wherein such administration provides a therapeutically effective level of the active ingredient within the patient’s body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0034] As used herein, the terms “composition” or “pharmaceutical composition” refer to a mixture of at least one of the compounds of the present invention and optionally one or more other pharmaceutically acceptable chemical components, such as a carrier, stabilizer, diluent, dispersant, suspending agent, thickener and / or excipient.

[0035] As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomer coordinations that may exist for a given compound of the present invention, including geometric isomers. Substituents are understood to be capable of attaching to the chiral center of a carbon atom. The term "chiral" refers to a molecule having the characteristic of non-superimposability on its mirror image partner, whereas the term "achiral" refers to a molecule capable of superposition on its mirror image partner. Accordingly, the present invention includes enantiomers, diastereomers, or racemics of a compound. "Enantiomers" are a pair of stereoisomers that are mirror images of each other and are non-superimposable. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate racemic mixtures where appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds whose absolute coordination is unknown may be designated as (+) or (-) depending on the direction in which they rotate plane polarization at the wavelength of the sodium D line (left-handed or right-handed). The specific compounds described herein may contain one or more asymmetric centers or axes and thus produce enantiomers, diastereomers, and other stereoisomer forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0036] Salts of the compounds of the present invention having at least one salt-forming group can be prepared in a manner known to those skilled in the art. For example, salts of the compounds of the present invention having an acid group can be formed, for example, by treating the compound with a metal compound, e.g., an alkali metal salt of a suitable organic carboxylic acid, e.g., a sodium salt of 2-ethylhexanoic acid; an organic alkali metal or alkaline earth metal compound, e.g., a corresponding hydroxide, carbonate, or hydrogen carbonate, e.g., sodium hydroxide or potassium hydroxide, carbonate, or hydrogen carbonate; a corresponding calcium compound; or ammonia or a suitable organic amine, preferably in stoichiometric amounts or only a slight excess of the salt-forming agent. Acid addition salts of the compounds of the present invention are obtained in a conventional manner, for example, by treating the compound with an acid or a suitable anion exchange reagent. The internal salt of the compound of the present invention containing acid and basic salt-forming groups, for example, free carboxyl groups and free amino groups, can be formed, for example, by neutralizing a salt, such as an acid addition salt, to an isoelectric point using a weak base, for example, or by treating with an ion exchanger.

[0037] Salts can be converted into free compounds according to methods known to those skilled in the art. Metal and ammonium salts can be converted, for example, by treatment using a suitable acid, and acid addition salts can be converted, for example, by treatment using a suitable basic agent.

[0038] All of the above-mentioned process steps may be carried out under reaction conditions known to a person skilled in the art, including those specifically mentioned, in the absence or ordinarily present of a solvent or diluent (e.g., a solvent or diluent that is inert to the reagent used and dissolves it), in the absence or present of a catalyst, condensing agent or neutralizing agent, e.g., an ion exchanger depending on the nature of the reaction and / or reactants, e.g., a cation exchanger (e.g., in the form of H+), at reduced, ordinary, or elevated temperatures, e.g., in a temperature range of about -100°C to about 190°C (e.g., approximately -80°C to about 150°C, e.g., -80 to -60°C, room temperature, -20 to 40°C, or reflux temperature), under atmospheric pressure or in a sealed container, under pressure where appropriate, and / or in an inert atmosphere, e.g., under an argon or nitrogen atmosphere.

[0039] In one embodiment, the present invention relates to acetate, adipate, ascorbate, aspartate, benzoate, besylate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, bromide / hydrobromide, camphorsulfonate, camsylate, caprate, chloride / hydrochloride, chlortheophilonate, citrate, edicilate, ethanedisulfonate, fumarate, gluteptate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hypurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, maleate, maleate, malonate, mandelate, mesylate, methanesulfonate, methyl sulfate, mucate, naphthoate, It is provided in the form of napsylate, 2-napsylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, p-toluenesulfonate, trifluoroacetate, triphenate, triphenylacetate, or xinapoate salt.

[0040] The compounds of the present invention may form solvates with a pharmaceutically permissible solvent (including water), either by nature or by design; thus, the present invention is intended to encompass both solvated and nonsolved forms. The term "solvate" refers to a molecular complex of the compound of the present invention (including a pharmaceutically permissible salt thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and known to be harmless to recipients, e.g., water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0041] Any asymmetric atom (e.g., carbon, etc.) of the compound(s) of the present invention may exist in racemic or enantiomerically abundant, e.g., in (R)-, (S)-, or (R,S)- coordinations. In certain embodiments, each asymmetric atom has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess in (R)- or (S)- coordinations. Substituents on atoms having unsaturated double bonds may exist in cis-(Z)- or trans-(E)- forms, where possible.

[0042] Accordingly, as used herein, the compound of the present invention may be in the form of one of possible isomers, rotational isomers, rotationally impaired isomers, tautomers, or mixtures thereof, for example, substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antiomers), racemics, or mixtures thereof.

[0043] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, and racemics based on physicochemical differences of the constituent components, for example by chromatography and / or fractional crystallization.

[0044] Any resulting racemic mixture of the final product or intermediate can be decomposed into an optically active compound by known methods, for example, by separating its diastereomer salt obtained using an optically active acid or base and liberating the optically active acidic or basic compound. In particular, the basic moiety can therefore be used to decompose the compound of the present invention into its optically active compound by fractional crystallization of a salt formed using an optically active acid, for example, tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyly tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic product can also be decomposed by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0045] In certain embodiments, the compound is prepared as its individual stereoisomer. In other embodiments, the compound is prepared as its individual stereoisomer by reacting a racemic mixture of the compound with an optically active decomposer to form a pair of diastereomeric compounds, separating the diastereomeric compounds, and recovering the optically pure enantiomer. In certain embodiments, this is carried out using a covalent diastereomeric derivative of the enantiomer compound or using a dissociable complex (e.g., a crystalline diastereomeric salt). The diastereomeric compounds have distinct physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are easily separated by utilizing these differences. In certain embodiments, the diastereomeric compounds are separated by chromatography or by separation / decomposition techniques based on differences in solubility. Subsequently, the optically pure enantiomer is recovered along with the decomposer by any means that does not induce racemization. A more detailed description of the technique applicable to the decomposition of stereoisomers of a compound from its racemic mixture can be found in the literature [Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981].

[0046] A mixture of isomers obtainable according to the present invention can be separated into individual isomers in a manner known to those skilled in the art; diastereomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization and / or separation, for example, by silica gel-phase chromatographic separation, or for example, by reverse-phase column-phase medium-pressure liquid chromatography, and racemic mixtures can be separated, for example, by the formation of salts using optically pure salt-forming reagents, and by separation of the mixture of diastereomers thus obtainable by means of fractional crystallization or by optically active column-phase chromatography.

[0047] Depending on the choice of starting materials and procedures, specific embodiments of the compounds of the present invention exist in the form of one of the possible isomers or as a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic mixture and a diastereomer mixture, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible isomers, including racemic mixtures, diastereomer mixtures, and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthetic monomers or chiral reagents, or may be decomposed using conventional techniques. If the compound contains a double bond, the substituent may be in E or Z coordination. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have cis- or trans-coordination. All tautomeric forms are also intended to be included.

[0048] Intermediates and final products may be post-treated and / or purified according to standard methods, for example, by chromatographic methods, partitioning methods, (re)crystallization, etc. The present invention also relates to a process in which a compound obtainable as an intermediate at any step of the process is used as a starting material and the remaining process steps are performed, or a process in which the starting material is formed under reaction conditions or used in the form of a derivative, for example, in a protected form or in the form of a salt, or a form of a process in which a compound obtainable by the process according to the present invention is prepared under process conditions and further processed in situ. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention may be commercially available or may be prepared by organic synthesis methods known to those skilled in the art.

[0049] The compounds of the present invention may form salts, and this is also within the scope of the present invention. Unless otherwise determined, references to the compounds of the present invention are understood to include references to their salts. As used herein, the term "salt(s)" means acidic and / or basic salts formed from inorganic and / or organic acids and bases. Additionally, where the compounds of the present invention contain both basic moietyes, e.g., pyridine or imidazole, without limitation, and acidic moietyes, e.g., carboxylic acids, without limitation, pairions (“intramolecular salts”) may be formed and are included within the term "salt(s)" as used herein. Although other salts may be useful, for example, during the isolation or purification step during formulation, pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred. Salts of the compounds of the present invention are formed by reacting, for example, Compound I with a predetermined amount, e.g., an equal amount of acid or base, in a medium such as a medium in which the salt precipitates, or in an aqueous medium, and then freeze-drying.

[0050] Compounds of the present invention comprising a basic moiety, such as an amine or pyridine or imidazole ring without limitation, can form salts having various organic and inorganic acids. Exemplary acid addition salts include acetates (e.g., those formed from acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfate, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, and naphthalenesulfonates (e.g., 2- It includes naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., those formed from sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate, e.g. tosylate, undecanoate, etc.

[0051] Compounds of the present invention, comprising an acidic moiety, such as a carboxylic acid without limitation, can form salts having various organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts having organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydravamin (formed from N,N-bis(dehydroaviethyl)ethylenediamine), N-methyl-D-glucarmine, N-methyl-D-glycamide, t-butylamine, and salts having amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized into substances such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chloride, bromide and iodide), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chloride, bromide and iodide), aralkyl halides (e.g., benzyl and phenethyl bromide), etc.

[0052] The prodrugs and solvates of the compounds of the present invention are also considered herein. As used herein, the term "prodrug" means a compound that, when administered to a subject, undergoes chemical transformation by metabolic or chemical processes to yield the compounds of the present invention, or their salts and / or solvates. Solvents of the compounds of the present invention include, for example, hydrates.

[0053] The compounds of the present invention, and their salts or solvates, may exist in their tautomeric forms (e.g., as amides or iminoethers). All such tautomeric forms are considered herein as part of the invention.

[0054] All stereoisomers of the compound of the present invention, including enantiomers and diastereomers (e.g., those that may exist due to the presence of asymmetric carbons on various substituents), are considered within the scope of the present invention. Individual stereoisomers of the compound of the present invention may, for example, be substantially absent from other isomers (e.g., as pure or substantially pure optical isomers having specific activity), or may, for example, be mixed with any other or other selected stereoisomers as a racemic mixture. The chiral center of the present invention may have an S or R configuration as defined by the 1974 Recommendation of the International Union of Pure and Applied Chemistry (IUPAC). The racemic form may be decomposed by physical methods, e.g., fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemic mixture by any suitable method, including but not limited to crystallization following salt formation using an optically active acid, for example.

[0055] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described in said book. Additionally, general principles of organic chemistry, as well as specific functional moiety and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of said document incorporated herein by reference.

[0056] Isomer mixtures comprising any various isomer ratios may be used according to the present invention. For example, when only two isomers are combined, mixtures comprising isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all considered by the present invention. Those skilled in the art will immediately understand that similar ratios are considered for more complex isomer mixtures.

[0057] The present invention also comprises isotope-labeled compounds identical to the compounds disclosed herein, but in which one or more atoms are substantially replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number generally found in nature. Examples of isotopes that may be included in the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., individually 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O,31 P, 32 P, 35 S, 18 F, and 36 Includes Cl. Compounds of the present invention comprising the aforementioned isotopes and / or other isotopes of other atoms, or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof are within the scope of the present invention. Specific isotope-labeled compounds of the present invention, e.g. 3 H, and, 14 Those containing radioactive isotopes such as C are useful in drug and / or matrix tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly desirable due to their ease of production and detection. In addition, heavier isotopes, such as deuterium, i.e., 2 Substitution with H can provide specific therapeutic benefits resulting from better metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and thus may be desirable in some cases. Isotope-labeled compounds can generally be prepared by performing the procedures disclosed in the following reaction schemes and / or examples by substituting a non-isotope-labeled reagent with an readily available isotope-labeled reagent.

[0058] In another embodiment of the present invention, R1 is unsubstituted or substituted with a C6-C1 alkyl or C1-C3 alkoxy. 10 Provides a compound that is an aryl or a heteroaryl of a 5-membered or 10-membered ring, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0059] In another embodiment of the present invention, R2 and R3 are each independently hydrogen or C1-C3 alkyl, or are connected to each other to form a heterocycloalkyl of a pentagonal or hexagonal ring that is unsubstituted or substituted with a C1-C3 alkyl, provide an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0060] In another embodiment of the present invention, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided, wherein n is an integer from 0 to 2 and m is an integer from 1 to 2.

[0061] In another embodiment of the present invention, R4 provides a compound that is a C1-C3 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0062] In another embodiment of the present invention, the heterocycloalkyl of the pentagonal or hexagonal ring may be a saturated or unsaturated heterocycloalkyl containing one or more oxygen atoms. In another embodiment of the present invention, the heterocycloalkyl of the pentagonal or hexagonal ring may be a dioxolane or a dioxane.

[0063] In another embodiment of the present invention, a compound represented by Formula 1 is selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0064] Methyl 4-((4S,5R)-5-(hydroxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0065] (E)-methyl 4-((4S,5R)-5-(hydroxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0066] Methyl 4-((4S,5R)-5-(hydroxy(3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0067] (E)-methyl 4-((4S,5R)-5-(hydroxy(3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0068] Methyl 4-((4S,5R)-5-(hydroxy(2-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0069] Methyl 4-((4S,5R)-5-(hydroxy(naphthalene-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0070] Methyl 4-((4S,5R)-5-(hydroxy(pyridine-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0071] Methyl (5S,6S)-5,6,7-trihydroxy-7-phenylheptanoate;

[0072] Methyl (5S,6S,E)-5,6,7-trihydroxy-7-phenylhept-2-enoate;

[0073] Methyl (5S,6S)-5,6,7-trihydroxy-7-(3-methoxyphenyl)heptanoate;

[0074] Methyl (5S,6S,E)-5,6,7-trihydroxy-7-(3-methoxyphenyl)heptanoate;

[0075] Methyl (5S,6S)-5,6,7-trihydroxy-7-(2-methoxyphenyl)heptanoate;

[0076] Methyl (5S,6S)-5,6,7-trihydroxy-7-(naphthalene-2-yl)heptanoate; and

[0077] Methyl (5S,6S)-5,6,7-trihydroxy-7-(pyridine-2-yl)heptanoate.

[0078] In another embodiment of the present invention, a compound represented by Formula 1 is selected from the group consisting of compounds represented by Formulas 2 to 15 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0079] [Chemical Formula 2]

[0080]

[0081] [Chemical Formula 3]

[0082]

[0083] [Chemical Formula 4]

[0084]

[0085] [Chemical Formula 5]

[0086]

[0087] [Chemical Formula 6]

[0088]

[0089] [Chemical Formula 7]

[0090]

[0091] [Chemical Formula 8]

[0092]

[0093] [Chemical Formula 9]

[0094]

[0095] [Chemical Formula 10]

[0096]

[0097] [Chemical Formula 11]

[0098]

[0099] [Chemical Formula 12]

[0100]

[0101] [Chemical Formula 13]

[0102]

[0103] [Chemical Formula 14]

[0104]

[0105] [Chemical Formula 15]

[0106]

[0107]

[0108] In one embodiment of the present invention, a compound represented by the following formula 16, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0109] [Chemical Formula 16]

[0110]

[0111] In the above chemical formula 16, R1 is a substituted or unsubstituted pentagonal or decagonal heteroaryl ring or a substituted or unsubstituted C6-C 10 As an aryl, the above substitution is an unsubstituted or hydroxy-substituted C1-C 15 Alkoxy, -C(=O)-(C1-C 15 alkyl) or C1-C 15 It is a substitution with an alkyl group; said n is an integer from 1 to 5; said R2 and R3 are each independently hydrogen or C1-C3 alkyl, or connected to each other to form a heterocycloalkyl of a pentagonal or hexagonal ring that is unsubstituted or substituted with a C1-C3 alkyl; said R4 is a C1-C5 alkyl.

[0112] In another embodiment of the present invention, R1 is a substituted or unsubstituted pentagonal or decagonal heteroaryl ring or a substituted or unsubstituted C6-C 10 As an aryl, the above substitution is an unsubstituted or hydroxy-substituted C1-C 10 It can be an alkoxy, C1-C8 alkoxy, C1-C6 alkoxy, or C1-C4 alkoxy, and C(=O)-(C1-C 10 It may be alkyl), C(=O)-(C1-C8alkyl), C(=O)-(C1-C6alkyl) or C(=O)-(C1-C4alkyl), or C1-C 10 Provides a compound that is substituted with an alkyl, C1-C8 alkyl, C1-C6, or C1-C4 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0113] In another embodiment of the present invention, the compound, its optical isomer, or its pharmaceutically acceptable salt is provided, wherein n is an integer from 1 to 3 or an integer from 1 to 2.

[0114] In another embodiment of the present invention, R2 and R3 may each independently be hydrogen or a C1-C3 alkyl or a C1-C2 alkyl, and provide a compound that is connected to form a heterocycloalkyl of a pentagonal or hexagonal ring that is unsubstituted or substituted with a C1-C3 alkyl or a C1-C2 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0115] In another embodiment of the present invention, the heterocycloalkyl of the pentagonal or hexagonal ring may be a saturated or unsaturated heterocycloalkyl containing one or more oxygen atoms. In another embodiment of the present invention, the heterocycloalkyl of the pentagonal or hexagonal ring may be a dioxolane or a dioxane.

[0116] In another embodiment of the present invention, R4 provides a compound that is a C1-C3 alkyl or C1-C2 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0117] In another embodiment of the present invention, a compound represented by Formula 16 is selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0118] Methyl 4-((4S,5R)-5-((E)-2-(4-hexanoylquinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0119] Methyl 4-((4S,5R)-5-((E)-2-(2-hexanoylquinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0120] Methyl 4-((4S,5R)-5-((E)-2-(2-hexanoylquinoline-5-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0121] Methyl 4-((4S,5R)-5-((E)-2-(4-(1-hydroxyhexyl)quinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0122] Methyl 4-((4S,5R)-5-((E)-2-(2-(1-hydroxyhexyl)quinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0123] Methyl 4-((4S,5R)-5-((E)-2-(2-(1-hydroxyhexyl)quinoline-5-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0124] Methyl 4-((4S,5R)-5-((E)-2-(2-((2-hydroxyheptyl)oxy)naphthalene-1-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate;

[0125] (5S,6R,E)-methyl 5,6-dihydroxy-8-(2-((2-hydroxyheptyl)oxy)naphthalene-1-yl)oct-7-enoate;

[0126] (5S,6R,E)-methyl 5,6-dihydroxy-8-(4-(1-hydroxyhexyl)quinoline-3-yl)oct-7-enoate;

[0127] (5S,6R,E)-methyl 5,6-dihydroxy-8-(2-(1-hydroxyhexyl)quinoline-3-yl)oct-7-enoate; and

[0128] (5S,6R,E)-methyl 5,6-dihydroxy-8-(2-(1-hydroxyhexyl)quinoline-5-yl)oct-7-enoate.

[0129] In another embodiment of the present invention, a compound represented by Formula 16 is selected from the group consisting of compounds represented by Formulas 17 to 27, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0130] [Chemical Formula 17]

[0131]

[0132] [Chemical Formula 18]

[0133]

[0134] [Chemical Formula 19]

[0135]

[0136] [Chemical Formula 20]

[0137]

[0138] [Chemical Formula 21]

[0139]

[0140] [Chemical Formula 22]

[0141]

[0142] [Chemical Formula 23]

[0143]

[0144] [Chemical Formula 24]

[0145]

[0146] [Chemical Formula 25]

[0147]

[0148] [Chemical Formula 26]

[0149]

[0150] [Chemical Formula 27]

[0151]

[0152]

[0153] In one embodiment of the present invention, a composition for the prevention or treatment of NF-κB-related diseases is provided, comprising the aforementioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0154] In another embodiment of the present invention, a pharmaceutical composition is provided in which the NF-κB-related disease is one or more selected from the group consisting of fibrosis, cancer, immune-related disease, metabolic disease, cardiovascular disease, inflammation, or pain. The novel lipoxin-like compound provided in the present invention can effectively prevent or treat fibrosis, as well as cancer, autoimmune disease, inflammation, or pain, by effectively inhibiting NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells).

[0155] The “fibrosis” of the present invention is a disease in which the abnormal production, accumulation, and deposition of extracellular matrix by fibroblasts occurs. It may include fibrosis in any organ where an abnormal accumulation of a collagen matrix can occur due to damage or inflammation that can alter the structure and function of various tissues, and preferably, it may be fibrosis occurring in at least one organ selected from the group consisting of the kidney, liver, lung, heart, bone or bone marrow, and skin, but is not limited thereto.

[0156] In another embodiment of the present invention, the fibrosis may be at least one selected from the group consisting of pulmonary fibrosis, uterine fibrosis, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia, and preferably may be pulmonary fibrosis, but is not limited thereto.

[0157] The "pulmonary fibrosis" of the present invention refers to the development of scarred (fibrous) tissue due to the formation or development (fibrosis) of excessive fibrous connective tissue in the lungs. Specifically, pulmonary fibrosis is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissues of the lungs. Such scar tissue replaces healthy tissue and causes inflammation, and chronic inflammation can be identified as a precursor to fibrosis. Due to such damage to lung tissue, the lungs may become stiff, and the individual may have difficulty breathing on their own.

[0158] In another embodiment of the present invention, the pulmonary fibrosis may be idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis, and preferably may be idiopathic pulmonary fibrosis, but is not limited thereto.

[0159] The pulmonary fibrosis of the present invention may develop due to micro-injury to the lungs induced by the inhalation of various causes, such as fine particles (asbestos, stone dust, metal dust, particles present in cigarette smoke, silica dust, etc.). Additionally, pulmonary fibrosis may occur as a secondary effect of other diseases (autoimmune diseases, viral or bacterial infections, etc.) and may be induced by specific drugs such as cytotoxic agents (bleomycin, busulfan, and methotrexate, etc.); antibiotics (nitrofurantoin and sulfasalazine, etc.); antiarrhythmic agents (amiodarone and tocainide, etc.); anti-inflammatory drugs (gold and penicillamine, etc.); and illicit drugs (narcotics, cocaine, and heroin, etc.). In the case of idiopathic pulmonary fibrosis, it may appear due to other unknown causes other than those mentioned above.

[0160] In another embodiment of the present invention, a pharmaceutical composition is provided in which the cancer is a solid tumor.

[0161] In another embodiment of the present invention, the cancer may be at least one selected from the group consisting of gastric cancer, thyroid cancer, parathyroid cancer, ovarian cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, pro-anal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine gland cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renopelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma and pituitary adenoma, but is not limited thereto.

[0162] In another embodiment of the present invention, the immune-related disease may be at least one selected from the group consisting of autoimmune diseases, graft-versus-host disease, organ transplant rejection, asthma, atopy, and acute or chronic inflammatory diseases, but is not limited thereto.

[0163] In another embodiment of the present invention, the acute or chronic inflammatory disease may be chronic obstructive pulmonary disease (COPD), but is not limited thereto. NF-κB plays a central role in airway inflammation in asthma and chronic obstructive pulmonary disease, and NF-κB activation is stimulated by cytokine and TLR activation in various airway cell types to regulate immune regulation and the expression of inflammatory mediators (Schuliga M. NF-kappaB Signaling in Chronic Inflammatory Airway Disease.)

[0164] In another embodiment of the present invention, the autoimmune disease may be at least one selected from the group consisting of rheumatoid arthritis, systemic scleroderma, systemic lupus erythematosus, atopic dermatitis, psoriasis, alopecia areata, asthma, Crohn's disease, Behcet's disease, Sjögren's syndrome, Guillain-Barré syndrome, chronic thyroiditis, multiple sclerosis, polymyositis, ankylosing spondylitis, fibromyositis, and nodular polyarteritis, but is not limited thereto.

[0165] In another embodiment of the present invention, the pain may be inflammatory pain or neuropathic pain, but is not limited thereto.

[0166] The above pain may be inflammatory pain of peripheral nerves or muscles, blood vessels, ligaments, connective tissues, etc. Additionally, the above pain may be physical pain, psychogenic pain, hyperalgesia, headache, lower back pain, pelvic pain, myofascial pain, migraine, vascular pain, arthritis pain, diabetic pain, cancer-derived pain, visceral pain, fibromyalgia, postoperative pain, phantom limb pain, trigeminal neuralgia, diabetic neuropathy, or sciatica, but is not limited thereto.

[0167] The term "neuropathic pain" in this invention refers to a disease caused by nerve damage or abnormal nerve function, and is generally known to involve functional impairment and changes in peripheral nerves. Major symptoms include numbness in the hands and feet, reduced sensation, and burning pain in the extremities; however, various other symptoms such as sensory impairment, motor impairment, and autonomic nerve damage are also known.

[0168] In another embodiment of the present invention, the neuropathic pain may be peripheral neuropathic pain or central neuropathic pain, but is not limited thereto.

[0169] In another embodiment of the present invention, the neuropathic pain may be a condition selected from the group consisting of cold allodynia, mechanical allodynia, spontaneous pain, paresthesiasis, dysesthesiasis, hyperalgesia, hyperpathia, and combinations thereof, but is not limited thereto.

[0170] Chronic pain can be loosely divided into two categories: painful pain and neuropathic pain. Painful pain is generally characterized by tissue damage resulting from injury or disease, such as the breakdown of bone and cartilage in rheumatoid arthritis. Neuropathic pain occurs due to damage to the nerves themselves and may be the result of injury, disease, or environmental factors. The boundaries between painful pain and neuropathic pain overlap, and in such cases, patients may experience pain resulting from damage to both tissues and nerves (Gangadharan and Kuner, 2013).

[0171] In another embodiment of the present invention, a pharmaceutical composition is provided in which the metabolic disease is one or more selected from the group consisting of insulin resistance disease, obesity, type 1 and type 2 diabetes, dyslipidemia, liver disease, kidney damage, arteriosclerosis, and hypertension.

[0172] In another embodiment of the present invention, the metabolic disease may be one or more selected from the group consisting of insulin resistance disease, obesity, diabetes, dyslipidemia, liver disease, kidney damage, arteriosclerosis and hypertension, but is not limited thereto.

[0173] In the present invention, “metabolic disease” refers to a condition or disease that is closely associated with or caused by obesity, and specifically may be one or more selected from the group consisting of fatty liver, type 2 diabetes, hyperlipidemia, cardiovascular disease, and atherosclerosis. In particular, NF-κB is known to be a logical target for preventing or inhibiting the vascular disturbance properties of various harmful molecules associated with diabetes and insulin resistance, ranging from oxidized lipoproteins to AGEs, high levels of glucose, or insulin (Sandip Patel, Pharmacological Reports Volume 61, Issue 4, July–August 2009, Pages 595-603, et al.).

[0174] In this invention, “fatty liver” refers to a condition or disease in which fat accumulates in excessive amounts in liver cells due to a disorder of lipid metabolism in the liver.

[0175] In this invention, “hyperlipidemia” refers to a condition or disease in which the concentration of lipid components in the blood, particularly cholesterol and triglycerides, is higher than normal levels, and is used in a broad sense to include all conditions requiring a reduction in blood lipid concentrations.

[0176] In this specification, “arteriosclerosis” refers to a condition or disease in which blood circulation to organs and tissues in the body is reduced due to the thickening of artery walls and a decrease in elasticity, and includes the meaning of “atherosclerosis,” which refers to a condition or disease in which blood circulation is reduced as the lumen narrows due to the deposition of fat, cholesterol, and other substances on the inner walls of arteries forming plaque. Arteriosclerosis can occur in any part of the body; if it occurs in the blood vessels of the heart, it can cause coronary artery diseases such as angina pectoris and myocardial infarction; if it occurs in the brain, it can cause cerebral infarction; and if it occurs in the kidneys, it can cause renal failure.

[0177] In another embodiment of the present invention, a pharmaceutical composition is provided in which the cardiovascular disease is one or more selected from the group consisting of hypertension, arteriosclerosis, heart disease, thrombosis, angina pectoris, heart failure, myocardial infarction, atherosclerosis and arteriosclerosis, cerebrovascular disease and stroke.

[0178] Cardiovascular disease refers to abnormalities in the heart and vascular system, encompassing heart disease, diseases of central vessels such as the aorta, and diseases of peripheral vessels in lower organs and tissues. According to statistics from the World Health Organization (WHO), the number of annual deaths due to cardiovascular disease is on a steep upward trend worldwide, with particularly high growth rates reported in Asia, including Japan and Korea. This is presumed to be due to the increasing risk factors for coronary artery disease resulting from the approach to an aging society and changes in dietary habits.

[0179] Although various factors such as genetic factors, lifestyle habits, and complications of diabetes are known as major factors in the development of cardiovascular disease, from the perspective of modern medicine, it is known to be caused by increased reactive oxygen species (ROS) due to increased activity of NADPH oxidase, increased oxidative stress within blood vessels, and decreased nitric oxide due to decreased activity of endothelial type nitric oxide synthase (eNOS).

[0180] Cardiovascular disease is a term for a group of heart and blood vessel abnormalities, including but not limited to hypertension, arteriosclerosis, angina pectoris, myocardial infarction, ischemic heart disease, heart failure, complications occurring after transvascular angioplasty, cerebral infarction, cerebral hemorrhage, and stroke. In particular, it is well known that the activity of NF-κB affects cardiovascular diseases, including atherosclerosis (Jung In-kyung et al., BioWare Vol. 9 No. 7 2007).

[0181] The "prevention" of the present invention may include, without limitation, any act that can block symptoms caused by a disease, or suppress or delay such symptoms, using the composition of the present invention.

[0182] The "treatment" of the present invention may include, without limitation, any act that uses the composition of the present invention to improve or benefit from symptoms caused by a disease.

[0183] The "improvement" of the present invention may be included without limitation as long as it is any act in which symptoms caused by a disease are improved or beneficially altered using the composition of the present invention.

[0184] The pharmaceutical composition of the present invention is not limited to these, but may be formulated and used in the form of oral formulations such as powders, granules, capsules, tablets, and aqueous suspensions, as well as topical preparations, suppositories, and sterile injectable solutions, according to conventional methods. Preferably, the pharmaceutical composition may be formulated for intratracheal administration or inhalation administration; or for use as an injectable, but is not limited thereto. For the purposes of the present invention, when a disease occurs in the respiratory system, such as the lungs, it is preferable to formulate it for inhalation administration so that the active ingredient can reach the target organ in a yield suitable for prevention or treatment.

[0185] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. For oral administration, the pharmaceutically acceptable carrier may include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc. For injectables, a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a stabilizer, etc. may be mixed and used. For topical administration, a base, an excipient, a lubricant, a preservative, etc., may be used. The formulation of the pharmaceutical composition of the present invention may be prepared in various forms by mixing with the pharmaceutically acceptable carrier described above. For example, for oral administration, it may be prepared in the form of a tablet, troche, capsule, elixir, suspension, syrup, wafer, etc., and for injectables, it may be prepared in the form of a unit dosing ampoule or a multi-dose formulation. Additionally, it may be formulated into a solution, suspension, tablet, capsule, sustained-release formulation, etc.

[0186] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. Additionally, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.

[0187] The routes of administration of the pharmaceutical composition of the present invention are not limited to but include oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, or rectal. Oral or parenteral administration is preferred.

[0188] The parenteral methods of the present invention include subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intradural, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0189] The pharmaceutical composition of the present invention may vary depending on several factors including the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, route of administration, elimination rate, drug combination, and the severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may be appropriately selected by a person skilled in the art, depending on the patient's condition, body weight, degree of disease, form of medication, route of administration, and duration, and may be administered at a dose of 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several doses. The dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, coated tablet, capsule, liquid, gel, syrup, slurry, or suspension.

[0190] In one embodiment of the present invention, a functional food composition for inhibiting NF-κB is provided, comprising the aforementioned compound, its optical isomer, or a food-grade acceptable salt thereof as an active ingredient.

[0191] When the food composition of the present invention is prepared in the form of a beverage, there are no special limitations other than including the food composition in the indicated proportions, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. Specifically, as natural carbohydrates, it may include monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, conventional sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, erythritol, etc. As the flavoring agent, it may be a natural flavoring agent (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and a synthetic flavoring agent (saccharin, aspartame, etc.).

[0192] The food composition of the present invention may further include various nutritional supplements, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0193] The ingredients included in the food composition of the present invention may be used independently or in combination. Although the proportion of the additive does not constitute a core element of the present invention, it may be selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.

[0194] In the present invention, the term "individual" refers to an individual suspected of having a disease. The individual suspected of having a disease refers to mammals, including rats, livestock, etc., including humans, that have developed or may develop the disease, but any individual treatable with the composition of the present invention is included without limitation.

[0195] The above method of the present invention may include administering the active ingredient in a pharmaceutically effective amount. A suitable total daily dose may be determined by the treating physician within the scope of proper medical judgment and may be administered in one or several doses. However, for the purposes of the present invention, it is preferable to apply a specific therapeutically effective dose for a specific patient differently depending on various factors and similar factors well known in the pharmaceutical field, including the type and degree of response to be achieved, the specific composition including whether other preparations are used in some cases, the patient's age, weight, general health condition, gender and diet, time of administration, route of administration and secretion rate of the composition, duration of treatment, and drugs used together or simultaneously with the specific composition.

[0196]

[0197] The present invention relates to a novel lipoxin-like compound that inhibits NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells), which can be very effectively used for the prevention, improvement, or treatment of fibrosis as well as cancer, autoimmune diseases, metabolic diseases, cardiovascular diseases, inflammation, or pain.

[0198]

[0199] Figure 1 shows the screening results through the inhibition of NF-kB activity of 11 compounds (Group 1) newly synthesized in the present invention.

[0200] Figure 2 shows the screening results through the inhibition of NF-kB activity of 11 compounds (Group 2) newly synthesized in the present invention.

[0201] The present invention will be described in more detail below through examples. These examples are intended solely to explain the present invention more specifically, and it will be obvious to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the invention.

[0202]

[0203] [Preparation Examples and Examples of Group 1]

[0204] [Preparation Example] General Synthesis Method of Compounds - Acetonide-Protected Lipoxin Compounds (Synthesis of Acetonide-Protected Lipoxin Derivatives)

[0205] 1. Method 1

[0206]

[0207] An aryl halide compound (1.0 equiv.) was added under an argon stream to a mixture of magnesium turnings (1.1 equiv.) and anhydrous tetrahydrofuran (THF) in a round-bottom flask and stirred for 2 hours at room temperature. Another round-bottom flask containing the anhydrous tetrahydrofuran mixture with dissolved aldehyde compound (1.0 equiv.) was set to 0 °C, Grignard reagent (1.0 equiv.) was added under an argon stream, and stirred for 1 hour. Saturated NH4Cl was added to the reaction mixture at 0 °C, extracted with ethyl acetate, and the organic layer was collected and water removed with anhydrous MgSO4. After removing the organic solvent by distillation under reduced pressure, the remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:20) to obtain the compound.

[0208]

[0209] 2. Method 2

[0210]

[0211] Anhydrous tetrahydrofuran was added to a round-bottom flask containing an aryl halide compound (1.0 equiv.) under an argon stream, and n-butyllithium (2.0 M in cyclohexane, 1.0 equiv.) was added to the mixture at -78 °C and stirred for 10 minutes. Methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (1.0 equiv.) was added to the reaction mixture and stirred at room temperature for 1 hour, after which the reaction was terminated and saturated NH4Cl was added at 0 °C to adjust the pH to 7–8. The reaction mixture was extracted with ethyl acetate, the organic layer was collected, and water was removed with anhydrous MgSO4, after which the organic solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:1) to obtain the compound.

[0212]

[0213] [Preparation Example] General Synthesis Method of Compounds – Lipoxin Compound with Acetonide Group Removed (Synthesis of Lipoxin Derivative with Acetonide Group Removed)

[0214] An acetonide-protected compound (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 240 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0215]

[0216] [Preparation Example 1] Methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate, LXA-64

[0217] Using Method 1, LXA-64 (127 mg, 47.3%) was obtained as a transparent liquid diastereomer mixture using methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (200 mg, 1.27 mmol), anhydrous THF (10 mL), and phenyl magnesium bromide in THF (1 mL, 1.27 mmol in THF).

[0218] R f 0.13 (Ethyl acetate: n-hexane = 1:3);

[0219] HPLC: R T 2.66 min (purity: 95.6%);

[0220] 1H-NMR (400 MHz, DMSO-d6) δ 1.14 (s, 0.75H), 1.27 (s, 2.25H), 1.29 (s, 0.75H), 1.35 ~ 1.44 (m, 1.5H), 1.44 (s, 2.25H),1.59 ~ 1.70 (m, 2H), 1.78 ~ 1.82 (m, 0.5H), 2.26 (t,J= 7.2 Hz, 1.5H), 2.28 ~ 2.38 (m, 0.5H), 3.55 (s, 2.25H), 3.60 (s, 0.75H), 3.85 ~ 3.89 (m, 1.5H), 4.02 ~ 4.07 (m, 0.5H), 4.14 ~ 4.17 (m, 0.5H), 4.23 (t,J= 6.0 Hz, 0.75H), 4.41 (dd,J= 9.6, 5.6 Hz, 0.5H), 4.52 (t,J= 5.6 Hz, 0.75H), 5.03 (d,J= 5.2 Hz, 0.75H), 5.44 (d,J= 5.2 Hz, 0.25H), 7.22 ~ 7.26 (m, 1H), 7.29 ~ 7.38 (m, 4H);

[0221] 13 C-NMR (100 MHz, DMSO-d6) 21.6, 25.8(25.7), 27.5(28.2), 28.4(28.3), 33.0(33.2), 51.1(51.2), 71.0(70.9), 76.4(77.4), 80.9(80.1), 107.2(107.1), 127.1(127.0), 127.2(127.3), 127.9(127.8), 142.8(143.9), 173.(173.3) ppm;

[0222] HRMS-ESI (m / z) [M+H] + C 17 H 24 NaO5calcd 331.1516, found 331.1516.

[0223]

[0224] [Preparation Example 2] (E)-Methyl 4-((4S,5R)-5-(hydroxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate ((E)-Methyl 4-((4S,5R)-5-(hydroxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate, LXA-68

[0225] Using Method 1, LXA-68 (335 mg, 52.9%) was obtained as a transparent liquid diastereomer mixture using (E)-methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (500 mg, 2.19 mmol), anhydrous THF (10 mL), and phenyl magnesium bromide (1 mL, 2.19 mmol in THF).

[0226] R f 0.35 (Ethyl acetate: n-hexane = 1:3);

[0227] HPLC: R T 5.22 min (purity: 69.5%), R T 6.13 min (purity: 27.9%);

[0228] 1H-NMR (400 MHz, DMSO-d6) δ 1.16 (s, 0.75H), 1.27 (s, 2.25H), 1.32 (s, 0.75H), 1.45 (s, 2.25H), 2.43 (ddd,J= 13.6, 6.8, 3.6 Hz, 1H), 2.64 (ddd,J= 15.2, 10.0, 6.8 Hz, 1H), 3.64 (s, 2.25H), 2.67 (s, 0.75H), 4.07 ~ 4.16 (m, 1H), 4.29 ~ 4.46 (m, 1H), 4.48 (dd,J= 9.2, 4.8 Hz, 0.25H), 4.58 (dd,J= 10.0, 5.2 Hz, 0.75H), 5.17 (d,J= 5.6 Hz, 0.75H), 5.21 (d,J= 4.8 Hz, 0.25H), 5.88 (dt,J= 16.0, 1.2 Hz, 0.75H), 5.99 (dt,J= 16.0, 1.2 Hz, 0.25H), 6.85 (dt,J= 16.0, 7.2 Hz, 0.75H), 7.00 (dt,J= 16.0, 7.2 Hz, 0.25H), 7.23 ~ 7.28 (m, 1H), 7.31 ~ 7.35 (m, 2H), 7.36 ~ 7.41 (m, 2H);

[0229] 13 C-NMR (400 MHz, DMSO-d6) 25.5(25.6), 27.3(28.0), 32.5(32.6), 51.2(50.9), 70.9, 75.3(76.2), 80.6(79.9),107.6(107.7), 122.0(122.1), 127.2(127.3), 127.4(127.5), 128.0(127.9), 142.7(143.6), 146.8(147.2), 165.9(166.0) ppm.

[0230]

[0231] [Preparation Example 3] Methyl 4-((4S,5R)-5-(hydroxy(3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (LXA-66)

[0232] Using Method 1, LXA-66 (323 mg, 44.0%) was obtained as a transparent liquid diastereomer mixture using methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (500 mg, 2.17 mmol), anhydrous THF (10 mL), and (3-methoxyphenyl) magnesium bromide (2 mL, 2.17 mmol in THF).

[0233] R f 0.21 (Ethyl acetate: n-hexane = 1:3);

[0234] HPLC: R T 5.18 min (purity: 71.7%), R T 5.79 min (purity: 25.7%);

[0235] 1H-NMR (400 MHz, DMSO-d6) δ 1.15 (s, 0.75H), 1.26 (s, 2.25H), 1.30 (s, 0.75H), 1.38 ~ 1.48 (m, 1.5H), 1.43 (s, 2.25H), 1.60 ~ 1.72 (m, 2H), 1.76 ~ 1.91 (m, 0.5H), 2.27 (t,J= 7.2 Hz, 1.5H), 2.38 (t,J= 7.2 Hz, 0.5H), 3.56 (s, 2.25H), 3.60 (s, 0.75H), 3.74 (s, 3H), 3.87 ~ 3.91 (m 0.75H), 4.00 ~ 4.06 (m, 0.5H), 4.13 ~ 4.17 (m, 0.25H), 4.22 (t,J= 6.0 Hz, 0.75H), 4.44 (d,J= 5.6 Hz, 0.75H), 5.01 (s, 0.75H), 5.43 (s, 0.25H), 6.80 (dd,J= 2.0, 1.6 Hz, 0.5H), 6.82 (dd,J= 2.0, 1.6 Hz, 0.5H), 6.91 ~ 6.95 (m, 2H), 7.22 (dd,J= 8.0, 8.0 Hz, 1H);

[0236] 13 C-NMR (100 MHz, DMSO-d6) 21.6(21.7), 25.7(25.6), 27.5(28.2), 28.4(28.3), 33.0(33.2), 51.1(51.2), 54.9(55.0), 70.9(71.0), 76.4(77.4), 80.8(79.9), 107.2, 112.5(112.4), 113.0, 119.4(119.6), 128.9(128.8), 144.4(145.5), 159.0(158.9), 173.1(173.3) ppm;

[0237] HRMS-ESI (m / z) [M+Na] + C 18 H 26 NaO6calcd 361.1622, found 361.1622.

[0238]

[0239] [Preparation Example 4] (E)-Methyl 4-((4S,5R)-5-(hydroxy(3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate ((E)-Methyl 4-((4S,5R)-5-(hydroxy(3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate, LXA-70)

[0240] Using Method 1, LXA-70 (370 mg, 50.2%) was obtained as a transparent liquid diastereomer mixture using (E)-methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (500 mg, 2.19 mmol), anhydrous THF (10 mL), and (3-methoxyphenyl) magnesium bromide (2 mL, 2.19 mmol in THF).

[0241] R f 0.29 (Ethyl acetate: n-hexane = 1:3);

[0242] HPLC: R T 5.20 min (purity: 88.5%), R T 6.01 min (purity: 11.5%);

[0243] 1H-NMR (400 MHz, DMSO-d6) δ 1.17 (s, 0.75H), 1.26 (s, 2.25H), 1.32 (s, 0.75H), 1.44 (s, 2.25H), 1.99 ~ 2.47 (m, 0.75H), 2.59 ~ 2.67 (m, 1H), 2.74 ~ 2.82 (m, 0.25H), 3.64 (s, 2.25H), 3.66 (s, 0.75H), 3.75 (s, 3H), 4.08 ~ 4.14 (m, 1H), 4.30 (dd,J= 6.0, 4.8 Hz, 0.75H), 4.31 ~ 4.35 (m, 0.25H), 4.45 (dd,J= 9.2, 4.8 Hz, 0.25H), 4.56 (dd,J= 5.2, 4.8 Hz, 0.75H), 5.15 (d,J= 5.2 Hz, 0.75H), 5.58 (d,J= 4.4 Hz, 0.25H), 5.88 (dt,J= 15.6, 1.6 Hz, 0.75H), 5.99 (dt,J= 16.0, 1.6 Hz, 0.25H), 6.82 ~ 6.89 (m, 2H), 6.93 ~ 6.99 (m, 2H), 7.23 (dd,J= 8.0, 7.6 Hz, 1H);

[0244] 13 C-NMR (100 MHz, DMSO-d6) 25.5, 25.6, 25.7, 27.3, 32.5, 32.6, 51.2, 54.8, 54.9, 55.0, 70.8, 75.3, 76.2, 79.8, 80.6, 107.6, 107.7, 112.5, 112.9, 119.3, 119.6, 122.0, 122.1, 128.8, 129.0, 144.3, 145.2, 146.8, 147.2, 158.9, 159.0, 165.9, 166.0 ppm.

[0245]

[0246] [Preparation Example 5] Methyl 4-((4S,5R)-5-(hydroxy(2-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (LXA-78)

[0247] Using Method 1, LXA-78 (107 mg, 36.3%) was obtained as a transparent liquid diastereomer mixture using methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (200 mg, 0.87 mmol), anhydrous THF (8 mL), and (2-methoxyphenyl) magnesium bromide (2 mL, 0.87 mmol in THF).

[0248] R f 0.57 (Ethyl acetate: n-hexane = 1:3);

[0249] HPLC: R T 5.91 min (purity: 100.0%);

[0250] 1H-NMR (400 MHz, DMSO-d6) δ 1.24 (s, 3H), 1.43 (s, 3H), 1.33 ~ 1.48 (m, 2H), 1.65 ~ 1.72 (m, 2H), 2.28 (t,J= 7.2 Hz, 2H), 3.56 (s, 3H), 3.77 (s, 3H), 3.91 ~ 3.95 (m, 1H), 4.19 (dd,J= 6.0, 4.4 Hz, 1H), 4.76 (d,J= 6.0 Hz, 1H), 4.91 (t,J= 5.2 Hz, 1H), 5.07 (d,J= 5.2 Hz, 1H), 6.93 (ddd,J= 7.6, 7.2, 0.8 Hz, 1H), 6.94 (d,J= 8.4 Hz, 1H), 7.22 (ddd,J= 8.0, 7.6, 1.6 Hz, 1H), 7.41 (dd,J= 7.6, 1.6 Hz, 1H) ;

[0251] 13 C-NMR (100 MHz, DMSO-d6) 21.7, 25.7, 27.3, 28.2, 33.1, 51.1, 55.3, 64.1, 76.5, 79.7, 107.1, 110.4, 120.1, 128.0, 128.1, 130.8, 155.3, 173.1 ppm;

[0252] HRMS-ESI (m / z) [M+Na] + C 18 H 16 NaO6calcd 361.1622, found 361.1626.

[0253]

[0254] [Preparation Example 6] Methyl 4-((4S,5R)-5-(hydroxy(naphthalen-2-yl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butan oate (LXA-80)

[0255] Using Method 1, LXA-80 (104 mg, 33.4%) was obtained as a transparent liquid diastereomer mixture using methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (200 mg, 0.87 mmol), anhydrous THF (10 mL), and naphthalen-2-yl magnesium bromide (3 mL, 0.87 mmol in THF).

[0256] R f 0.54 (Ethyl acetate: n-hexane = 1:3);

[0257] HPLC: R T 3.47 min (purity: 69.5%), R T 3.66 min (purity: 30.5%);

[0258] 1 H-NMR (400 MHz, DMSO-d6) δ 1.13 (s, 0.9H), 1.28 (s, 2.1H), 1.29 (s, 0.9H), 1.35 ~ 1.44 (m, 1H), 1.47 (s, 2.1H), 1.61 ~ 1.74 (m, 3H), 2.25 (t,J= 7.2 Hz, 1.4H), 2.42 (dt,J= 7.2, 2.0 Hz, 0.6H), 3.49 (s, 2.1H), 3.58 (s, 0.9H), 3.89 ~ 3.94 (m, 0.7H), 4.15 ~ 4.21 (m, 0.3H), 4.34 ~ 4.38 (m, 1H), 4.60 (dd,J= 9.2, 4.4 Hz, 0.3H), 4.71 (t,J= 5.2 Hz, 0.7H), 5.19 (d,J= 5.2 Hz, 0.7H), 5.60 (d,J= 4.4 Hz, 0.3H), 7.46 ~ 7.52 (m, 2H), 7.54 ~ 7.58 (m, 1H), 7.84 ~ 7.91 (m, 4H) ;

[0259] 13 C-NMR (100 MHz, DMSO-d6) 21.6, 25.8(25.6), 27.5(28.2), 28.4(29.2), 33.0(33.3), 51.0(51.2), 71.1(60.7), 76.4(77.4), 80.8(79.9), 107.2(107.1), 125.6, 125.7, 125.8, 126.0(125.9), 127.4(127.3), 127.8(127.7), 132.3(132.4), 132.7, 140.4(141.4), 173.1(173.3) ppm;

[0260] HRMS-ESI (m / z) [M+Na] + C 21 H 26 NaO5calcd 381.1672, found 381.1677.

[0261]

[0262] [Preparation Example 7] Methyl 4-((4S,5R)-5-(hydroxy(pyridin-2-yl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (LXA-76)

[0263] Using Method 2, LXA-76 (150 mg, 15.3%) was obtained as a clear liquid using 2-bromopyridine (500 mg, 3.16 mmol), n-butyllithum 2.0 M in cyclohexane (1.58 mL, 3.16 mmol), methyl 4-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (722 mg, 3.16 mmol), and dry THF (20 mL).

[0264] R f 0.44 (Ethyl acetate: n-hexane = 1:1);

[0265] HPLC: R T 7.79 min (purity: 98.1%);

[0266] 1 H-NMR (400 MHz, DMSO-d6) δ 1.15 (s, 3H), 1.26 (s, 3H), 1.60 ~1.65 (m, 2H), 1.75 ~ 1.80 (m, 2H), 2.37 (t,J= 6.8 Hz, 2H), 3.60 (s, 3H), 4.15 ~ 4.18 (m, 1H), 4.25 (dd,J= 9.2, 5.6 Hz, 1H), 4.51 (dd,J= 9.2, 5.6 Hz, 1H), 5.49 (d,J= 5.6 Hz, 1H), 7.27 (ddd,J= 7.2, 4.8, 1.2 Hz, 1H), 7.41 (ddd,J= 8.0, 0.8, 0.8 Hz, 1H), 7.76 (ddd,J= 7.6, 7.6, 2.0 Hz, 1H), 8.50 (ddd,J= 9.2, 2.0, 0.8 Hz, 1H);

[0267] 13C-NMR (100 MHz, DMSO-d6) 21.7, 25.7, 28.0, 28.3, 33.2, 51.2, 72.2, 77.3, 79.3, 107.2, 122.2, 122.5, 136.3, 148.3, 162.0, 173.3 ppm;

[0268] HRMS-ESI (m / z) [M+Na] + C 16 H 24 NO5calcd 310.1649, found 310.1651.

[0269]

[0270] [Preparation Example 8] Methyl 4-((4S,5R)-5-(hydroxy(pyridin-2-yl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (LXA-76)

[0271] An acetonide-protected compound (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 240 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0272] That is, LXA-65 (20 mg, 46.6%) was obtained as a transparent liquid diastereomer mixture (3:1) using LXA-64 (50 mg, 0.16 mmol) prepared in Preparation Example 1 above and 1N HCl / MeOH (4 mL).

[0273] R f0.49 (MeOH : dichloromethane = 1:9);

[0274] HPLC: R T 3.09 min (purity: 18.4%), R T 3.47 min (purity: 77.2%);

[0275] 1 H-NMR (400 MHz, DMSO-d6) δ 1.23 ~ 1.32 (m, 1H), 1.48 ~ 1.55 (m, 1H), 1.58 ~ 1.75 (m, 2H), 2.27 (td,J= 6.8, 3.2 Hz, 2H), 3.20 (ddd,J= 7.6, 7.6, 3.2 Hz, 1H), 3.22 ~ 3.29 (m, 0.3H), 3.33 ~ 3.38 (m, 1H), 3.57 (s, 0.75H), 3.58 (s, 2.25H), 4.34 (d,J= 7.6 Hz, 0.75H), 4.43 (d,J= 5.2 Hz, 0.25H), 4.55 (d,J= 6.4 Hz, 1H), 4.56 (dd,J= 6.0, 2.8 Hz, 0.25H), 4.77 (dd,J= 6.0, 2.8 Hz, 0.75H), 4.96 (d,J= 6.0 Hz, 0.75H), 5.29 (d,J= 4.4 Hz, 0.25H), 7.17 ~ 7.22 (m, 1H), 7.26 ~ 7.37 (m, 4H);

[0276] 13 C-NMR (100 MHz, DMSO-d6) 20.9, 32.3(31.5), 33.5(33.6), 51.1, 70.0(71.3), 71.5(74.2), 78.0(77.0), 126.3(126.5), 126.4(127.2), 127.5(127.7), 144.4(143.3), 173.4 ppm;

[0277] HRMS-ESI (m / z) [M+HCOO] - C 15 H 21 O7calcd 313.1293, found 313.1294.

[0278]

[0279] [Preparation Example 9] Methyl(5S,6S,E)-5,6,7-trihydroxy-7-phenylhept-2-enoate (LXA-69)

[0280] An acetonide-protected compound (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 240 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0281] LXA-69 (53 mg, 60.3%) was obtained as a white semi-solid diastereomer mixture (3:1) using LXA-68 (100 mg, 0.33 mmol) prepared in Preparation Example 2 above and 1N HCl / MeOH (24 mL).

[0282] R f 0.33 (Ethyl acetate: n-hexane = 1:1);

[0283] HPLC: R T 3.70 min (purity: 95.0%);

[0284] 1H-NMR (400 MHz, DMSO-d6) δ 2.23 ~ 2.32 (m, 1H), 2.51 ~ 2.55 (m, 1H), 3.24 (ddd,J= 7.6, 7.6, 2.8 Hz, 0.75H), 3.44 ~ 3.52 (m, 0.5H), 3.54 ~ 3.59 (m, 0.75H), 4.47 (d,J= 7.6 Hz, 0.25H), 4.52 (d,J= 7.6 Hz, 0.75H), 4.81 (dd,J= 6.0, 2.4 Hz, 1H), 4.84 (d,J= 6.0 Hz, 0.25H), 4.87 (d,J= 6.0 Hz, 0.75H), 5.03 (d,J= 6.0 Hz, 0.75H), 5.32 (d,J= 4.4 Hz, 0.25H), 5.87 (dt,J= 15.6, 1.2 Hz, 1H), 6.94 ~ 7.02 (m, 1H), 7.18 ~ 7.23 (m, 1H), 7.28 ~ 7.37 (m, 4H);

[0285] 13 C-NMR (100 MHz, DMSO-d6) 36.1(35.3), 51.1, 69.6(70.5), 71.3(73.8), 77.6(76.7), 121.9, 126.4(126.6), 126.5(127.3), 127.6(127.7), 144.3, 148.1(148.2), 166.1 ppm;

[0286] HRMS-ESI (m / z) [M+Na] + C 14 H 18 NaO5calcd 289.1046, found 289.1045.

[0287]

[0288] [Preparation Example 10] Methyl (5S,6S)-5,6,7-trihydroxy-7-(3-methoxyphenyl)heptanoate (LXA-67)

[0289] An acetonide-protected compound (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 240 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0290] LXA-66 (100 mg, 0.30 mmol) prepared in Preparation Example 3 above and 2N HCl / MeOH (12 mL) were used to obtain LXA-67 (52 mg, 58.5%) as a transparent liquid diastereomer mixture (3:1).

[0291] R f 0.33 (Ethyl acetate: n-hexane = 1:1);

[0292] HPLC: R T 3.39 min (purity: 28.2%), R T 3.77 min (purity: 71.1%);

[0293] 1H-NMR (400 MHz, DMSO-d6) δ 1.23 ~ 1.33 (m, 1H), 1.48 ~ 1.56 (m, 1H), 1.57 ~ 1.67 (m, 1H), 1.69 ~ 1.76 (m, 1H), 2.28 (dtJ= 6.8, 3.6 Hz, 2H), 3.20 (dt,J= 7.2, 3.2 Hz, 0.75H), 3.30 ~ 3.40 (m, 1.25H), 3.42 (s, 3H), 3.73 (s, 3H), 4.33 (d,J= 7.6 Hz, 0.75H), 4.41 (d,J= 5.2 Hz, 0.25H), 4.51 ~ 4.56 (m, 1.25H), 4.75 (dd,J= 6.0, 2.8 Hz, 0.75H), 4.94 (d,J= 6.0 Hz, 0.75H), 5.28 (d,J= 4.4 Hz, 0.25H), 6.75 (dd,J= 2.4, 0.8 Hz, 0.5H), 6.77 (dd,J= 2.4, 0.8 Hz, 0.5H), 6.87 ~ 6.94 (m, 2H), 7.18 (dd,J= 8.0, 8.0 Hz, 0.25H), 7.20 (dd,J= 8.0, 8.0 Hz, 0.75H);

[0294] 13 C-NMR (100 MHz, DMSO-d6) 20.8(20.9), 32.3(32.5), 33.5(33.6), 51.1, 54.9, 70.0(71.2), 71.4(74.1), 78.0(77.0), 111.7(111.9), 112.2(113.3), 118.7(120.0), 128.5(128.2), 146.2(144.9), 158.9(158.6), 173.5 ppm;

[0295] HRMS-ESI (m / z) [M+Na] + C 15 H 22 NaO6calcd 321.1309, found 321.1307.

[0296]

[0297] [Preparation Example 11] Methyl(5S,6S,E)-5,6,7-trihydroxy-7-(3-methoxyphenyl)hept-2-enoate (LXA-71)

[0298] An acetonide-protected compound (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 240 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0299] LXA-71 (49 mg, 55.1%) was obtained as a white semi-solid using LXA-70 (100 mg, 0.30 mmol) prepared in Preparation Example 4 above, MeOH (2 mL), and 1N HCl / MeOH (24 mL).

[0300] R f 0.36 (Ethyl acetate: n-hexane = 1:1);

[0301] HPLC: R T 34.1 min (purity: 96.0%);

[0302] 1H-NMR (400 MHz, DMSO-d6) δ 2.23 ~ 2.31 (m, 1.5H), 2.51 ~ 2.57 (m, 0.5H) 3.23 (dt,J= 7.6, 2.4 Hz, 0.75H), 3.45 ~ 3.48 (m, 0.5H), 3.54 ~ 3.58 (m, 0.75H), 3.61 (s, 0.75H), 3.64 (s, 2.25H), 3.73 (s, 3H), 4.51 (d,J= 7.6 Hz, 0.75H), 4.62 (d,J=4.8 Hz, 0.25H), 4.76 (dd,J= 6.4, 2.4 Hz, 1H), 4.84 (d,J= 5.6 Hz, 0.25H), 4.86 (d,J= 6.4 Hz, 0.75H), 5.02 (d,J= 6.0 Hz, 0.75H), 5.32 (d,J= 4.8 Hz, 0.25H), 5.87 (dt,J= 15.6, 1.2 Hz, 1H), 6.77 (ddd,J= 8.0, 2.4, 0.8 Hz, 1H), 6.89 (d,J= 7.2 Hz, 1H), 6.93 ~ 7.02 (m, 2H), 7.21 (t, dd,J= 8.0, 7.6Hz, 1H);

[0303] 13 C-NMR (100 MHz, DMSO-d6) 36.2(35.3), 51.1, 54.9, 69.6(70.5), 71.2(73.7), 77.6(76.8), 111.8(112.1), 112.2(113.4), 118.7(120.0), 121.8, 128.6(128.2), 146.1(144.6), 148.1(148.2), 158.9, 166.1 ppm;

[0304] HRMS-ESI (m / z) [M+HCOO] - C 16 H 21 O8calcd 341.1242, found 341.1241.

[0305]

[0306] [Preparation Example 12] Methyl (5S,6S)-5,6,7-trihydroxy-7-(2-methoxyphenyl)heptanoate (LXA-79)

[0307] An acetonide-protected compound (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 240 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0308] LXA-79 (21 mg, 46.9%) was obtained as a transparent liquid diastereomer mixture using LXA-78 (50 mg, 0.15 mmol) prepared in Preparation Example 5 above and 1N HCl / MeOH (8 mL).

[0309] R f 0.28 (MeOH: Dichloromethane = 1:9);

[0310] HPLC: R T 2.54 min (purity: 18.6%), R T 2.64 min (purity: 81.4%) ;

[0311] 1H-NMR (400 MHz, DMSO-d6) δ 1.30 ~ 1.36 (m, 1H), 1.47 ~ 1.62 (m, 2H), 1.71 ~ 1.77 (m, 1H), 2.25 ~ 2.31 (m, 2H), 3.23 (dt,J= 6.4, 3.2 Hz, 0.7H), 3.35 ~ 3.40 (m, 1.5H), 3.43 ~ 3.46 (m, 0.5H), 3.55 (dt,J= 6.8, 5.2 Hz, 0.3H), 3.57 (s, 3H), 3.74 (s, 3H), 4.17 (d,J= 8.0 Hz, 0.7H), 4.28 (d,J= 4.8 Hz, 0.3H), 4.33 (d,J= 5.2 Hz, 0.3H), 4.46 (d,J= 6.4 Hz, 0.7H), 4.7 (d,J= 5.6 Hz, 0.7H), 4.91 (dd,J= 4.8, 1.6 Hz, 0.3H), 5.06 (d,J= 4.8 Hz, 0.3H), 5.12 (dd,J= 4.8, 2.8 Hz, 0.7H), 6.89 ~ 6.96 (m, 1H), 7.16 ~ 7.22 (m, 2H), 7.39 ~ 7.44 (m, 1H) ;

[0312] 13 C-NMR (100 MHz, DMSO-d6) 21.2(21.1), 29.2(31.0), 33.6(33.3), 51.1(55.4), 55.2(60.7), 65.6(68.2), 70.5(71.6), 76.3(76.5), 110.0(110.6), 119.8(120.0), 127.3(127.7), 128.1(128.2), 132.0(131.7), 155.4(156.6), 173.5 ppm;

[0313] HRMS-ESI (m / z) [M+Cl] - C 15 H 22 ClO6calcd 333.1110, found 333.1112.

[0314]

[0315] [Preparation Example 13] Methyl(5S,6S)-5,6,7-trihydroxy-7-(naphthalen-2-yl)heptanoate (LXA-81)

[0316] An acetonide-protected compound (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 240 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0317] LXA-81 (28 mg, 62.8%) was obtained as a pale yellow semi-solid diastereomer mixture using LXA-80 (50 mg, 0.14 mmol) prepared in Preparation Example 6 above and 1N HCl / MeOH (8 mL).

[0318] R f 0.34 (MeOH: Dichloromethane = 1:9);

[0319] HPLC: R T 4.05 min (purity: 6.9%), R T 4.21 min (purity: 93.1%) ;

[0320] 1H-NMR (400 MHz, DMSO-d6) δ 1.26 ~ 1.36 (m, 1H), 1.51 ~ 1.57 (m, 1H), 1.62 ~ 1.75 (m, 2H), 2.28 (dt,J= 6.8, 2.4 Hz, 2H), 3.33 ~ 3.38 (m, 0.7H), 3.42 ~ 3.46 (m, 1H), 3.49 ~ 3.53 (m, 0.3H), 3.57 (s, 3H), 4.40 (d,J= 7.2 Hz, 0.8H), 4.49 (d,J= 5.2 Hz, 0.2H), 4.62 (d,J=6.4 Hz, 0.8H), 4.74 (dd,J= 5.2 Hz, 0.2H), 4.97 (dd,J= 6.4, 3.2 Hz, 1H), 5.11 (d,J= 6.0 Hz, 0.8H), 5.44 (d,J= 4.0 Hz, 0.2H), 7.43 ~ 7.54 (m, 3H), 7.83 ~ 7.89 (m, 4H);

[0321] 13 C-NMR (100 MHz, DMSO-d6) 20.9, 32.4, 33.5, 51.1, 70.0, 71.6, 77.9, 124.6, 125.2, 125.3, 125.8, 126.9, 127.4, 127.6, 132.1, 132.7, 142.1, 173.4 ppm;

[0322] HRMS-ESI (m / z) [M+Cl] - C 18 H 22 ClO5calcd 353.1161, found 353.1164.

[0323]

[0324] [Preparation Example 14] Methyl(5S,6S)-5,6,7-trihydroxy-7-(pyridin-2-yl)heptanoate (LXA-77)

[0325] An acetonide-protected compound (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 240 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0326] LXA-77 (29 mg, 82.84%) was obtained as a clear liquid using LXA-76 (40 mg, 0.13 mmol) prepared in Preparation Example 7 above and 2N HCl / MeOH (8 mL).

[0327] R f 0.29 (Ethyl acetate : n-hexane = 1:1);

[0328] HPLC: R T 1.58 min (purity: 100.0%);

[0329] 1 H-NMR (400 MHz, DMSO-d6) δ 1.27 ~ 1.36 (m, 1H), 1.45 ~ 1.61 (m, 2H), 1.67 ~ 1.75 (m, 1H), 2.27 (t,J= 7.2 Hz, 2H), 3.29 ~ 3.33 (m, 1H), 3.57 (s, 3H), 3.60 (t,J= 6.0 Hz, 1H), 4.61 (d,J= 5.2 Hz, 1H), 4.67 (d,J= 5.6 Hz, 1H), 4.68 (t,J= 5.2 Hz, 1H), 5.39 (d,J= 5.6 Hz, 1H), 7.26 (ddd,J= 7.6, 5.2, 1.2 Hz, 1H), 7.46 (d,J= 8.0 Hz, 1H), 7.76 (ddd,J= 7.6, 7.6, 2.0 Hz, 1H), 8.47 (ddd,J= 4.8, 2.0, 1.2 Hz, 1H);

[0330] 13 C-NMR (100 MHz, DMSO-d6) 21.0, 31.7, 33.6, 51.1, 71.1, 74.5, 77.1, 122.1, 122.3, 136.2, 136.2, 147.6, 162.1, 173.4 ppm;

[0331] HRMS-ESI (m / z) [M+Na] + C 13 H 20 NO5calcd 270.1336, found 270.1336.

[0332]

[0333] [Preparation Examples 1 to 14] Novel lipoxin-like compounds

[0334] The structures of the novel exposure-like compounds synthesized in Preparation Examples 1 to 14 above are shown in Table 1 below.

[0335] LXA-64 LXA-71 LXA-65 LXA-76 LXA-66 LXA-77 LXA-67 LXA-78 LXA-68 LXA-79 LXA-69 LXA-80 LXA-70 LXA-81

[0336] [Experimental Example] NF-kB Activation Inhibitory Test

[0337] For the experiment on NF-kB activity inhibition, THP-1 Lucia™ NF-kB cells (NF-kB-Lucia reporter monocytes) were purchased from InvivoGen. The luciferase assay was designed to confirm anti-inflammatory effects by monitoring the NF-kB signaling pathway through the evaluation of the activity of Lucia luciferase secreted by these cell lines. THP-1 Lucia NF-kB cells were placed in DMEM medium containing 0.1% FBS at a rate of 1 x 10⁶ per well. 5 Dog cells were dispensed into a 96-well plate. Subsequently, 1 nM of the novelly synthesized compound from Preparation Examples 1 to 11, 1 nM of natural lipoxan A4 (native LXA4, nLXA4, cayman), and 1 μM of the positive control dexamethasone (Dex, sigma) were each pre-treated to the cells for 2 hours, after which 100 ng / ml LPS was added and the cells were cultured for 24 hours. 50 μl of QUANTI-Luc™ detection reagent (InvivoGen) was added to 20 μl of the culture medium, and the luminescence intensity was measured using a luminometer to rapidly screen only for drugs exhibiting NF-kB activity inhibitory ability. Figure 1 shows the results for 11 newly synthesized compounds in the above Preparation Examples 1 to 11, and the FC (fold change) was expressed as a comparison value by dividing the value of the sample treatment group by the value of the negative control group (LPS alone treatment group), which is the reference condition value.

[0338] As a result, as shown in Fig. 1, it was confirmed that the novel lipoxin-like compounds synthesized in Preparation Examples 1 to 14 effectively inhibit NF-kB. In addition, it was confirmed that the synthesized lipoxin A4 has biological activity and is resistant to chemical and metabolic degradation.

[0339]

[0340] [Preparation Examples and Examples of Group 2]

[0341] [Experimental Reagents and Equipment]

[0342] The compounds and reagents used in the experiment were purchased from Aldrich Chemical Co., TCI, and others. Melting points were measured using a Barnstead electrothermal melting point apparatus (Manual MEL-TEMP (Model No: 1202D)) and a capillary tube. Thin-layer chromatography was performed using coated Merck Kieselgel 60 F 254 Verification was performed using plates at UV wavelengths of 254 nm and 365 nm. Silica gel column chromatography was performed using Merck Kieselgel 60 (0.040–0.063 mm). All solvents used for chromatography were used directly without distillation unless necessary. The purity of the compounds was evaluated by HPLC (Shimadzu LC-20AD) analysis. Conditions; Column, SunFire C18 (4.6 nm × 150 nm, 5 nm); Mobile phase, 30–50% acetonitrile using conditions A (water) and B (acetonitrile), isocratic at 0–15 min; Flow rate; 1.0 mL / min; Detector, diode array detector (Shimadzu Spd-M20A). Compound purity was expressed as a percentage (%), and retention time was measured in minutes (min). NMR spectra were analyzed using a Varian AS 400 ( 1 H-NMR is 400 MHz, 13C-NMR was performed using a 100 MHz scanner, and tetramethylsilane (TMS) was used as the internal standard. Chemical shift (δ) values ​​were expressed in ppm, and coupling constant (J) values ​​in Hertz (Hz). The mass spectrum was measured using the electrospray ionization (ESI) method with an AB SCIX API 4000.

[0343]

[0344] [Preparation Example]

[0345] General synthesis methods of compounds

[0346] 1. Synthesis of lipoxin derivatives using 3-bromoquinoline

[0347] Lipoxin derivatives were synthesized using 3-bromoquinoline with the following reaction scheme.

[0348]

[0349]

[0350]

[0351]

[0352] 2. Synthesis of Lipoxin Derivatives Using 5-Bromoquinoline

[0353] Lipoxin derivatives were synthesized using 5-bromoquinoline with the following reaction scheme.

[0354]

[0355]

[0356] 3. Synthesis of Lipoxin Derivatives Using 1-Bromo-2-hydrocynaphthalene

[0357] Lipoxin derivatives were synthesized using 1-Bromo-2-hydrocynaphthalene with the following reaction scheme.

[0358]

[0359]

[0360] [Intermediate Manufacturing Example]

[0361] [Intermediate Preparation Example 1] 1-(3-Bromoquinolin-4-yl)hexan-1-one (1-(3-Bromoquinolin-4-yl)hexan-1-one, Compound 1)

[0362] To a mixture of bromoquinoline compound (1.0 equiv.) and hexanal (4.0 equiv.) dissolved in ethyl acetate in a round-bottom flask, trimethylsilyl azide (2.0 equiv.) and [bis(trifluoroacetoxy)iodo]benzene (2.0 equiv.) were added at 0 °C and stirred at room temperature (3 to 24 hours). After the reaction was complete, the mixture was cooled to 0 °C, triethylamine (5.0 equiv.) was added, and the mixture was stirred for another 15 minutes at room temperature before being extracted with ethyl acetate and water. The organic layer was collected, washed with brine, and water was removed with anhydrous MgSO4. The organic layer was then removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:20) to obtain the compound.

[0363] Specifically, compound 1 (410 mg, 27.8%) was obtained as a yellow liquid using 3-bromoquinoline (1.0 g, 4.81 mmol), hexanal (2.37 mL, 19.22 mmol), ethyl acetate (30 mL), trimethylsilyl azide (1.26 mL, 9.61 mmol), [bis(trifluoroacetoxy)iodo]benzene (4.13 g, 9.61 mmol), and triethylamine (6 mL).

[0364] R f 0.22 (Ethyl acetate: n-hexane = 1:20);

[0365] 1 H-NMR (400 MHz, DMSO-d6) δ 0.89 (t,J= 7.2 Hz, 3H), 1.30 ~ 1.40 (m, 4H), 1.73 (quint,J= 7.2 Hz, 2H), 2.99 (t,J= 7.4 Hz, 2H), 7.65 (ddd,J= 8.4, 1.6, 0.8 Hz, 1H), 7.73 (ddd,J= 8.4, 6.8, 1.2 Hz, 1H), 7.89 (ddd,J= 8.4, 6.8, 1.6 Hz, 1H), 8.12 (d,J= 8.0 Hz, 1H), 9.04 (s, 1H);

[0366] 13 C-NMR (100 MHz, DMSO-d6) 13.8, 21.9, 22.2, 30.5, 43.2, 111.4, 124.1, 124.2, 128.9, 129.6, 130.6, 145.9, 146.7, 151.6, 204.4 ppm.

[0367]

[0368] [Intermediate Preparation Example 2] 1-(3-Bromoquinolin-2-yl)hexan-1-one (1-(3-Bromoquinolin-2-yl)hexan-1-one, Compound 2)

[0369] To a mixture of bromoquinoline compound (1.0 equiv.) and hexanal (4.0 equiv.) dissolved in ethyl acetate in a round-bottom flask, trimethylsilyl azide (2.0 equiv.) and [bis(trifluoroacetoxy)iodo]benzene (2.0 equiv.) were added at 0 °C and stirred at room temperature (3 to 24 hours). After the reaction was complete, the mixture was cooled to 0 °C, triethylamine (5.0 equiv.) was added, and the mixture was stirred for another 15 minutes at room temperature before being extracted with ethyl acetate and water. The organic layer was collected, washed with brine, and water was removed with anhydrous MgSO4. The organic layer was then removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:20) to obtain the compound.

[0370] Specifically, compound 2 (370 mg, 25.1%) was obtained as a yellow liquid using 3-bromoquinoline (1.0 g, 4.81 mmol), hexanal (2.37 mL, 19.22 mmol), ethyl acetate (30 mL), trimethylsilyl azide (1.26 mL, 9.61 mmol), [bis(trifluoroacetoxy)iodo]benzene (4.13 g, 9.61 mmol), and triethylamine (6 mL).

[0371] R f 0.40 (Ethyl acetate: n-hexane = 1:20);

[0372] 1H-NMR (400 MHz, DMSO-d6) δ 0.88 (t,J= 7.0 Hz, 3H), 1.30 ~ 1.39 (m, 4H), 1.66 (quint,J= 7.2 Hz, 2H), 3.13 (t,J= 7.2 Hz, 2H), 7.76 (ddd,J= 8.0, 6.8, 1.2 Hz, 1H), 7.89 (ddd,J= 8.4, 6.8, 1.6 Hz, 1H), 8.04 (dd,J= 8.0, 1.6 Hz, 1H), 8.09 (dd,J= 8.4, 1.2 Hz, 1H), 8.90 (s, 1H);

[0373] 13 C-NMR (100 MHz, DMSO-d6) 13.8, 21.9, 22.8, 30.7, 39.8, 111.7, 127.3, 129.0, 129.1, 129.2, 131.1, 141.0, 144.7, 153.9, 202.2 ppm.

[0374]

[0375] [Intermediate Preparation Example 3] 1-(5-Bromoquinolin-2-yl)hexan-1-one (1-(5-Bromoquinolin-2-yl)hexan-1-one, Compound 9)

[0376] To a mixture of bromoquinoline compound (1.0 equiv.) and hexanal (4.0 equiv.) dissolved in ethyl acetate in a round-bottom flask, trimethylsilyl azide (2.0 equiv.) and [bis(trifluoroacetoxy)iodo]benzene (2.0 equiv.) were added at 0 °C and stirred at room temperature (3 to 24 hours). After the reaction was complete, the mixture was cooled to 0 °C, triethylamine (5.0 equiv.) was added, and the mixture was stirred for another 15 minutes at room temperature before being extracted with ethyl acetate and water. The organic layer was collected, washed with brine, and water was removed with anhydrous MgSO4. The organic layer was then removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:20) to obtain the compound.

[0377] Specifically, compound 9 (310 mg, 21.1%) was obtained as a white solid using 5-bromoquinoline (1.00 g, 4.81 mmol), hexanal (2.37 mL, 19.22 mmol), ethyl acetate (30 mL), trimethylsilyl azide (1.26 mL, 9.61 mmol), [bis(trifluoroacetoxy)iodo]benzene (4.13 g, 9.61 mmol), and triethylamine (6 mL).

[0378] R f 0.53 (Ethyl acetate: n-hexane = 1:20);

[0379] 1H-NMR (400 MHz, DMSO-d6) δ 0.89 (t,J= 7.2 Hz, 3H), 1.32 ~ 1.38 (m, 4H), 1.66 ~ 1.73 (m, 2H), 3.32 (t,J= 7.2 Hz, 2H), 7.81 (dd,J= 8.4, 7.6 Hz, 1H), 8.12 (dd,J= 7.2, 1.0 Hz, 1H), 8.18 (d,J= 8.8 Hz, 1H), 8.21 (ddd,J= 8.4, 1.0, 1.0 Hz, 1H), 8.68 (dd,J= 8.8, 1.2 Hz, 1H);

[0380] 13 C-NMR (100 MHz, DMSO-d6) 13.8, 22.0, 23.1, 30.9, 36.8, 119.3, 121.1, 128.1, 130.1, 131.1, 132.5, 136.5, 147.2, 153.2, 201.1 ppm.

[0381]

[0382] [Intermediate Preparation Example 4] 2-(((1-Bromonaphthalen-2-yl)oxy)methyl)oxirane (2-(((1-Bromonaphthalen-2-yl)oxy)methyl)oxirane, Compound 13)

[0383] Acetone (30 mL) / DMF (20 mL) was added to a round-bottom flask containing 1-Bromo-2-naphthol (3.00 g, 13.45 mmol) and K2CO3 (3.72 g, 26.90 mmol), and epichlorohydrin (2.64 mL, 33.62 mmol) was added while stirring. The reaction mixture was refluxed and stirred at 60 °C for 1 day, water was added to the reaction mixture, and after extraction with ethyl acetate, the organic layer was washed twice with saturated NaHCO3 and water. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:3) to obtain compound 13 (1.95 g, 51.94%) as a pale yellow solid.

[0384] R f 0.36 (Ethyl acetate: n-hexane = 1:3);

[0385] 1 H-NMR (400 MHz, DMSO-d6) δ 2.80 (dd,J= 5.2, 2.8 Hz, 1H), 2.88 (dd,J= 4.8, 4.4 Hz, 1H), 3.41 (td,J= 8.4, 6.4, 2.0 Hz, 1H), 4.13 (dd,J= 11.6, 6.4 Hz, 1H), 4.59 (dd,J= 11.6, 2.4 Hz, 1H), 7.46 (ddd,J= 8.0, 6.8, 1.2 Hz, 1H), 7.52 (d,J= 9.2 Hz, 1H), 7.63 (ddd,J= 8.0, 6.8, 1.2 Hz, 1H), 7.94 (d,J= 8.0 Hz, 1H), 7.99 (d,J= 9.2 Hz, 1H), 8.09 (dd,J= 8.8, 0.8 Hz, 1H);

[0386] 13C-NMR (100 MHz, DMSO-d6) 43.7, 49.8, 70.4, 107.697, 115.6, 124.5, 125.2, 128.1, 128.3, 129.3, 129.6, 132.2, 152.6 ppm.

[0387]

[0388] [Intermediate Preparation Example 5] 1-((1-bromonaphthalen-2-yl)oxy)heptan-2-ol (1-((1-Bromonaphthalen-2-yl)oxy)heptan-2-ol, Compound 14)

[0389] Tetrahydrofuran (10 mL) was added to a round-bottom flask containing Compound 13 (600 mg, 2.15 mmol) and CuI (819 mg, 4.30 mmol) under an argon stream, and butylmagnesium bromide (4 mL, 4.30 mmol) was added while stirring at 0 °C and stirred for 1 hour. Saturated NH4Cl was added to the reaction mixture at 0 °C and extracted with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:20) to obtain Compound 14 (470 mg, 64.8%) as a clear liquid.

[0390] R f 0.11 (ethyl acetate: n-hexane = 1:20);

[0391] 1H-NMR (400 MHz, DMSO-d6) δ 0.86 (t,J= 6.8 Hz, 3H), 1.24 ~ 1.51 (m, 7H), 1.62 ~ 1.69 (m, 1H), 3.84 (dt,J= 7.2, 4.8 Hz, 1H), 4.04 (dd,J= 9.6, 5.6 Hz, 1H), 4.13 (dd,J= 9.6, 5.6 Hz, 1H), 4.85 (d,J= 5.6 Hz, 1H), 7.44 (ddd,J= 8.0, 6.8, 1.2 Hz, 1H), 7.52 (d,J= 8.8 Hz, 1H), 7.62 (ddd,J= 8.4, 6.8, 1.2 Hz, 1H), 7.92 (d,J= 8.0 Hz, 1H), 7.97 (d,J= 8.8 Hz, 1H), 8.08 (dd,J= 8.8, 1.2 Hz, 1H);

[0392] 13 C-NMR (100 MHz, DMSO-d6) 13.9, 22.1, 24.5, 31.4, 33.6, 68.4, 73.8, 107.6, 115.7, 124.3, 125.2, 128.0, 128.3, 129.2, 129.4, 132.3, 153.2 ppm.

[0393]

[0394] [Preparation Example]

[0395] [Preparation Example 1] Methyl 4-((4S,5R)-5-((E)-2-(4-hexanoylquinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (Methyl 4-((4S,5R)-5-((E)-2-(4-hexanoylquinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate, Compound 3, LXA-55

[0396] Bis(benzonitrile)Pd(II) chloride (0.2 equiv.) and bis(diphenylphosphino)butane (0.3 equiv.) were added to a microwave reaction vessel containing toluene under an argon gas stream and stirred at room temperature for 30 minutes; then, 1-(bromoquinolin-2-yl)hexan-1-one compound (1.0 equiv.) and methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate (methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate) (1.5 equiv.), Na2CO3 (0.2 equiv.), water and ethanol were added, and the mixture was stirred in a microwave reactor at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. After removing moisture from the organic layer with anhydrous MgSO4, the organic solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:3) to obtain the compound.

[0397] Specifically, toluene (15 mL), bis(benzonitrile)Pd(II) chloride (75 mg, 0.20 mmol), bis(diphenylphosphino)butane (125 mg, 0.29 mmol), compound 1 (300 mg, 0.98 mmol), methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolane-4-yl)butanoate (methyl Compound 3 (295 mg, 66.4%) was obtained as a yellow liquid using 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl) butanoate) (521 mg, 1.47 mmol), EtOH (0.5 mL), Na2CO3 (125 mg, 1.18 mmol), and water (1 mL).

[0398] R f 0.52 (Ethyl acetate: n-hexane = 1:1);

[0399] HPLC: R T 5.55 min (purity: 95.7%);

[0400] 1H-NMR (400 MHz, DMSO-d6) δ 0.87 (t,J= 7.2 Hz, 3H), 1.28 ~ 1.37 (m, 4H), 1.33 (s, 3H), 1.42 ~ 1.47 (m, 2H), 1.44 (s, 3H), 1.53 ~ 1.60 (m, 1H), 1.64 ~ 1.72 (m, 3H), 2.33 (t,J= 7.4 Hz, 2H), 2.88 (t,J= 7.2 Hz, 2H), 3.54 (s, 3H), 4.23 (q,J= 6.8 Hz, 1H), 4.77 (t,J= 6.0 Hz, 1H), 6.54 (dd,J= 16.0, 6.0 Hz, 1H), 6.62 (d,J= 16.0 Hz, 1H), 7.61 (dd,J= 8.0, 1.2 Hz, 1H), 7.65 (ddd,J= 6.8, 6.8, 1.2 Hz, 1H), 7.79 (ddd,J= 6.8, 6.8, 1.6 Hz, 1H), 8.07 (d,J= 8.0 Hz, 1H), 9.22 (s, 1H);

[0401] 13 C-NMR (100 MHz, DMSO-d6) 13.7, 21.4, 21.9, 22.4, 25.5, 27.9, 29.4, 30.6, 33.0, 44.6, 51.1, 77.6, 77.9, 107.7, 122.4, 123.7, 124.4, 124.9, 128.1, 129.4, 129.8, 132.5, 143.6, 146.4, 149.0, 173.1, 207.4 ppm;

[0402] HRMS-ESI (m / z) [M+H] + C 27 H 36 NO5calcd 454.2588, found 454.2588.

[0403]

[0404] [Preparation Example 2] Methyl 4-((4S,5R)-5-((E)-2-(2-hexanoylquinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (Methyl 4-((4S,5R)-5-((E)-2-(2-hexanoylquinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate, Compound 6, LXA-58)

[0405] Bis(benzonitrile)Pd(II) chloride (0.2 equiv.) and bis(diphenylphosphino)butane (0.3 equiv.) were added to a microwave reaction vessel containing toluene under an argon gas stream and stirred at room temperature for 30 minutes; then, 1-(bromoquinolin-2-yl)hexan-1-one compound (1.0 equiv.) and methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate (methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate) (1.5 equiv.), Na2CO3 (0.2 equiv.), water and ethanol were added, and the mixture was stirred in a microwave reactor at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. After removing moisture from the organic layer with anhydrous MgSO4, the organic solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:3) to obtain the compound.

[0406] Toluene (4 mL), bis(benzonitrile)Pd(II) chloride (75 mg, 0.20 mmol), bis(diphenylphosphino)butane (125 mg, 0.29 mmol), Compound 2 (300 mg, 0.98 mmol), Methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolane-4-yl)butanoate (Methyl Compound 6 (251 mg, 56.5%) was obtained as an orange liquid using 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl) butanoate) (521 mg, 1.47 mmol), EtOH (0.5 mL), Na2CO3 (125 mg, 1.18 mmol), and water (1 mL).

[0407] R f 0.42 (Ethyl acetate: n-hexane = 1:3);

[0408] HPLC: R T 10.93 min (purity: 97.1%);

[0409] 1H-NMR (400 MHz, DMSO-d6) δ 0.88 (t,J= 7.2 Hz, 3H), 1.30 ~ 1.37 (m, 4H), 1.34 (s, 3H), 1.46 (s, 3H), 1.48 ~ 1.52 (m, 2H), 1.55 ~ 1.69 (m, 4H), 2.34 (t,J= 7.6 Hz, 2H), 3.22 (t,J= 7.2 Hz, 2H), 3.54 (s, 3H), 4.22 (dt,J= 7.6, 6.0 Hz, 1H), 4.74 (t,J= 6.4 Hz, 1H), 6.31 (dd,J= 16.0, 7.6 Hz, 1H), 7.08 (d,J= 16.0 Hz, 1H), 7.71 (ddd,J= 8.0, 7.6, 1.2 Hz, 1H), 7.81 (ddd,J= 8.4, 7.6, 1.2 Hz, 1H), 8.06 (d,J= 8.4 Hz, 2H), 8.69 (s, 1H);

[0410] 13 C-NMR (100 MHz, DMSO-d6) 13.7, 21.3, 22.0, 23.1, 25.6, 28.0, 29.3, 30.8, 33.0, 39.4, 51.1, 77.7, 78.4, 107.6, 128.0, 128.1, 128.2, 128.5, 128.6, 129.0, 130.2, 130.3, 134.6, 145.3, 153.0, 173.2, 204.0 ppm;

[0411] HRMS-ESI (m / z) [M+H] + C 27 H 36 NO5calcd 454.2588, found 454.2588.

[0412]

[0413] [Preparation Example 3] Methyl 4-((4S,5R)-5-((E)-2-(2-hexanoylquinolin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (Methyl 4-((4S,5R)-5-((E)-2-(2-hexanoylquinolin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate, Compound 10, LXA-61)

[0414] Bis(benzonitrile)Pd(II) chloride (0.2 equiv.) and bis(diphenylphosphino)butane (0.3 equiv.) were added to a microwave reaction vessel containing toluene under an argon gas stream and stirred at room temperature for 30 minutes; then, 1-(bromoquinolin-2-yl)hexan-1-one compound (1.0 equiv.) and methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate (methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate) (1.5 equiv.), Na2CO3 (0.2 equiv.), water and ethanol were added, and the mixture was stirred in a microwave reactor at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. After removing moisture from the organic layer with anhydrous MgSO4, the organic solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:3) to obtain the compound.

[0415] Toluene (4 mL), bis(benzonitrile)Pd(II) chloride (75 mg, 0.20 mmol), bis(diphenylphosphino)butane (125 mg, 0.29 mmol), Compound 9 (300 mg, 0.98 mmol), Methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolane-4-yl)butanoate (Methyl Compound 10 (153 mg, 34.4%) was obtained as a pale yellow liquid using 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl) butanoate) (521 mg, 1.47 mmol), EtOH (0.5 mL), Na2CO3 (125 mg, 1.18 mmol), and water (1 mL).

[0416] R f 0.42 (Ethyl acetate: n-hexane = 1:3);

[0417] HPLC: R T 6.45 min (purity: 99.4%);

[0418] 1H-NMR (400 MHz, DMSO-d6) δ 0.88 (t,J= 7.2 Hz, 3H), 1.31 ~ 1.37 (m, 4H), 1.35 (s, 3H), 1.47 (s, 3H), 1.48 ~ 1.22 (m, 3H), 1.65 ~ 1.72 (m, 3H), 2.33 (t,J= 7.2 Hz, 2H), 3.32 (t,J= 7.2 Hz, 2H), 3.53 (s, 3H), 4.25 (dt,J= 8.0, 6.0 Hz, 1H), 4.86 (t,J= 7.2 Hz, 1H), 6.35 (dd,J= 15.6, 7.6 Hz, 1H), 7.45 (d,J= 15.6 Hz, 1H), 7.84 (dd,J= 8.4, 7.2 Hz, 1H), 7.93 (d,J= 6.4 Hz, 1H), 8.06 (d,J= 8.8 Hz, 1H), 8.10 (d,J= 8.4 Hz, 1H), 8.76 (dd,J= 8.4, 0.8 Hz, 1H);

[0419] 13 C-NMR (100 MHz, DMSO-d6) 13.8, 21.4, 22.0, 23.2, 25.6, 28.2, 29.3, 30.9, 33.0, 36.6, 51.1, 77.6, 78.5, 107.6, 117.7, 125.9, 126.9, 127.5, 129.7, 130.2, 131.0, 133.6, 134.2, 146.7, 152.5, 173.2, 201.6 ppm;

[0420] HRMS-ESI (m / z) [M+H] + C 27 H 36 NO5calcd 454.2588, found 454.2587.

[0421]

[0422] [Preparation Example 4] Methyl 4-((4S,5R)-5-((E)-2-(4-(1-hydroxyhexyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (Compound 4, LXA-56)

[0423] A lipoxin derivative with a ketone substituent (1.0 equiv.) was dissolved in methanol in a round-bottom flask, NaBH4 (1.2 equiv.) was added, and the mixture was stirred at room temperature for 30 to 120 minutes. After the reaction was complete, the mixture was adjusted to pH 7–8 by adding saturated NH4Cl at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0424] Specifically, compound 4 (60 mg, 50.7%) was obtained as a pale yellow liquid using compound 3 (120 mg, 0.26 mmol), NaBH4 (12 mg, 0.32 mmol), and MeOH (5 mL).

[0425] R f 0.37 (Ethyl acetate: n-hexane = 1:1);

[0426] HPLC: R T 6.23 min (purity: 96.7%);

[0427] 1H-NMR (400 MHz, DMSO-d6) δ 0.80 (t,J= 6.8 Hz, 3H), 1.21 ~ 1.24 (m, 6H), 1.35 (s, 3H), 1.36 ~ 1.52 (m, 2H), 1.47 (s, 3H), 1.5 ~ 1.62 (m, 1H), 1.66 ~ 1.73 (m, 2H), 1.96 ~ 2.01 (m, 1H), 2.33 (t,J= 7.6 Hz, 2H), 3.55 (s, 3H), 4.24 (dt,J= 6.8, 6.4 Hz, 1H), 4.79 (t,J= 6.4 Hz, 1H), 5.39 ~ 5.43 (m, 1H), 5.73 (dd,J= 4.0, 4.0 Hz, 1H), 6.20 (dd,J= 16.0, 6.8 Hz, 0.5H), 6.21 (dd,J= 16.0, 6.8 Hz, 0.5H), 7.29 (d,J= 16.0 Hz, 1H), 7.56 (ddd,J= 8.4, 7.2, 1.2 Hz, 1H), 7.68 (ddd,J= 8.4, 8.0, 1.2 Hz, 1H), 7.97 (dd,J= 8.4, 1.2 Hz, 1H), 8.64 (brs, 1H), 8.91 (s, 1H);

[0428] 13 C-NMR (100 MHz, DMSO-d6) 13.7(13.8), 21.4, 22.0, 24.9, 25.5(25.6), 28.0(28.1), 29.4(29.5), 31.1, 33.0, 37.1(37.2), 51.1, 73.5, 77.6(77.7), 78.3(78.4), 107.5(107.6), 125.4, 126.0, 127.1, 127.2, 127.9, 128.5, 129.5, 130.5, 145.7(145.8), 147.6, 149.5, 173.1 ppm;

[0429] HRMS-ESI (m / z) [M+H] + C 27 H 38 NO5calcd 456.2744, found 456.2742.

[0430]

[0431] [Preparation Example 5] Methyl 4-((4S,5R)-5-((E)-2-(2-(1-hydroxyhexyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (Methyl 4-((4S,5R)-5-((E)-2-(2-(1-hydroxyhexyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate, Compound 7, LXA-59

[0432] A lipoxin derivative with a ketone substituent (1.0 equiv.) was dissolved in methanol in a round-bottom flask, NaBH4 (1.2 equiv.) was added, and the mixture was stirred at room temperature for 30 to 120 minutes. After the reaction was complete, the mixture was adjusted to pH 7–8 by adding saturated NH4Cl at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0433] Specifically, compound 7 (17 mg, 33.92%) was obtained as a pale yellow liquid using compound 6 (50 mg, 0.11 mmol), NaBH4 (5 mg, 0.13 mmol), and MeOH (5 mL).

[0434] R f 0.77 (Ethyl acetate: n-hexane = 1:1);

[0435] HPLC: R T 7.14 min (purity: 51.0%), R T 7.48 min (purity: 48.2%);

[0436] 1H-NMR (400 MHz, DMSO-d6) δ 0.82 (t,J= 6.8 Hz, 3H), 1.21 ~ 1.29 (m, 6H), 1.35 (s, 3H), 1.43 ~ 1.50 (m, 2H), 1.47 (s, 3H), 1.50 ~ 1.60 (m, 1H), 1.64 ~ 1.70 (m, 2H), 1.77 ~ 1.80 (m, 1H), 2.33 (t,J= 7.6 Hz, 2H), 3.53 (s, 3H), 4.24 (dt,J= 6.4, 6.0 Hz, 1H), 4.78 (t,J= 6.4 Hz, 1H), 4.94 (dt,J= 7.2, 5.6 Hz, 1H), 5.35 (d,J= 6.2 Hz, 1H), 6.29 (dd,J= 15.6, 7.6 Hz, 0.5H), 6.30 (dd,J= 15.6, 7.6 Hz, 0.5H), 7.18 (d,J=15.6 Hz, 0.5H), 7.21 (d,J=15.6 Hz, 0.5H), 7.57 (dd,J= 8.0, 8.0 Hz, 1H), 7.72 (ddd,J= 8.0, 8.0, 1.2 Hz, 1H), 7.96 (d,J= 7.6, Hz, 1H), 7.98 (d,J= 7.6, Hz, 1H), 8.49 (s, 1H);

[0437] 13 C-NMR (100 MHz, DMSO-d6) 13.8, 21.4, 22.0(22.1), 25.0(25.1), 25.6, 28.1, 29.3(29.4), 31.1, 33.0, 36.3(36.4), 51.1, 71.9(72.1), 77.7, 78.3(78.4), 107.5(107.6), 126.5, 127.2, 127.7(127.9), 127.8, 128.2, 128.6(128.7), 129.5, 130.2(130.3), 133.3(133.4), 145.4(145.5), 160.6(160.7), 173.1(173.2) ppm;

[0438] HRMS-ESI (m / z) [M+H] + C 27 H 38NO5calcd 456.2744, found 456.2742.

[0439]

[0440] [Preparation Example 6] Methyl 4-((4S,5R)-5-((E)-2-(2-(1-hydroxyhexyl)quinolin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (Methyl 4-((4S,5R)-5-((E)-2-(2-(1-hydroxyhexyl)quinolin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate, Compound 11, LXA-62

[0441] A lipoxin derivative with a ketone substituent (1.0 equiv.) was dissolved in methanol in a round-bottom flask, NaBH4 (1.2 equiv.) was added, and the mixture was stirred at room temperature for 30 to 120 minutes. After the reaction was complete, the mixture was adjusted to pH 7–8 by adding saturated NH4Cl at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0442] Specifically, compound 11 (56 mg, 55.87%) was obtained as a clear liquid using compound 10 (100 mg, 0.22 mmol), NaBH4 (10 mg, 0.26 mmol), and MeOH (5 mL).

[0443] R f 0.15 (Ethyl acetate: n-hexane = 1:3);

[0444] HPLC: R T 3.73 min (purity: 98.0%);

[0445] 1H-NMR (400 MHz, DMSO-d6) δ 0.83 (t,J= 7.2 Hz, 3H), 1.25 ~ 1.38 (m, 6H), 1.35 (s, 3H), 1.47 (s, 3H), 1.48 ~ 1.61 (m, 3H), 1.66 ~ 1.77 (m, 3H), 2.33 (t,J= 7.2 Hz, 2H), 3.53 (s, 3H), 4.24 (dt,J= 8.0, 6.0 Hz, 1H), 4.71 (dt,J= 7.6, 7.6 Hz, 1H), 4.84 (t,J= 7.2 Hz, 1H), 5.48 (d,J= 4.8 Hz, 1H), 5.49 (d,J= 4.8 Hz, 1H), 6.29 (dd,J= 15.6, 8.0 Hz, 1H), 7.42 (d,J= 15.6 Hz, 1H), 7.69 (d,J= 8.8 Hz, 1H), 7.70 (dd,J= 8.0, 8.0 Hz, 1H), 7.75 (dd,J= 8.4, 1.2 Hz, 1H), 7.90 (d,J= 7.6 Hz, 1H), 8.58 (d,J= 8.8 Hz, 1H);

[0446] 13 C-NMR (100 MHz, DMSO-d6) 13.9, 21.4, 22.0, 24.8, 25.6, 28.2, 29.4, 31.2, 33.0, 37.5, 51.1, 73.7, 77.6, 78.5(78.6), 107.6, 118.6, 123.2, 124.6, 128.0(128.1), 128.5, 129.2, 130.2, 132.3, 134.0, 146.7, 165.3, 173.2 ppm;

[0447] HRMS-ESI (m / z) [M+H] + C 27 H 38 NO5calcd 456.2744, found 456.2743.

[0448]

[0449] [Preparation Example 7] Methyl 4-((4S,5R)-5-((E)-2-(((2-hydroxyheptyl)oxy)naphthalen-1-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate (Methyl 4-((4S,5R)-5-((E)-2-((2-hydroxyheptyl)oxy)naphthalen-1-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate, Compound 15, LXA-47

[0450] Compound 14 (300 mg, 0.89 mmol), methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate (methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate) (473 mg, 1.33 mmol), K2CO3 (25 mg, 0.18 mmol), H2O (0.3 mL) and in a microwave reaction vessel containing toluene (3 mL) under an argon gas stream Tetrakis(triphenylphosphine)palladium(0) (30 mg, 10 wt%) was added and stirred at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. After removing moisture from the organic layer with anhydrous MgSO4, the organic solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (ethyl acetate : n-hexane = 1:6) to obtain compound 15 (152 mg, 35.2%) as a clear liquid.

[0451] R f 0.30 (Ethyl acetate: n-hexane = 1:3);

[0452] HPLC: R T 8.09 min (purity: 98.1%);

[0453] 1 H-NMR (400 MHz, DMSO-d6) δ 0.86 (t,J= 7.2 Hz, 3H), 1.23 ~ 1.32 (m, 5H), 1.35 (s, 3H), 1.44 (s, 3H), 1.46 ~ 1.54 (m, 4H), 1.58 ~ 1.63 (m, 2H), 1.68 ~ 1.74 (m, 1H), 2.33 (t,J= 7.2 Hz, 2H), 3.53 (s, 3H), 3.78 ~ 3.84 (m, 1H), 3.98 (quint,J= 4.8 Hz, 1H), 4.00 ~ 4.07 (m, 1H), 4.23 (dt,J= 7.2, 6.0 Hz, 1H), 4.77 ~ 4.82 (m, 2H), 6.28 (dd,J= 16.0, 7.6 Hz, 0.5H), 6.29 (dd,J= 16.0, 7.6 Hz, 0.5H), 7.05 (d,J= 16.0 Hz, 1H), 7.36 (dd,J= 8.0, 7.6 Hz, 1H), 7.44 (d,J= 9.2 Hz, 1H), 7.49 (ddd,J= 8.4, 7.6, 1.2 Hz, 1H), 7.85 (d,J= 9.2 Hz, 1H), 7.86 (dd,J= 8.0, 0.8 Hz, 1H), 8.08 (d,J= 8.8 Hz, 1H);

[0454] 13 C-NMR (100 MHz, DMSO-d6) 13.9, 21.5, 22.1, 24.7, 25.7, 28.2, 29.6, 31.4, 33.1, 33.7(33.8), 51.1, 68.6, 73.3, 77.6(77.7), 79.7, 107.4, 114.8, 118.3(118.4), 123.2, 123.4, 125.0(125.1), 126.6, 128.4, 128.6, 129.0, 131.9, 132.0(132.1), 154.0(154.1), 173.1 ppm;

[0455] HRMS-ESI (m / z) [M+Na] + C 29 H 40 NaO6calcd 507.2717, found 507.2716.

[0456]

[0457] [Preparation Example 8] (5S,6R,E)-Methyl 5,6-dihydroxy-8-(2-((2-hydroxyheptyl)oxy)naphthalen-1-yl)oct-7-enoate ((5S,6R,E)-Methyl 5,6-dihydroxy-8-(2-((2-hydroxyheptyl)oxy)naphthalen-1-yl)oct-7-enoate, Compound 16, LXA-48)

[0458] An acetonide-protected lipoxin derivative (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 120 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0459] Specifically, compound 16 (22 mg, 48.1%) was obtained as a clear liquid using compound 15 (50 mg, 0.10 mmol) and 1 N HCl / MeOH (8 mL).

[0460] R f 0.34 (MeOH: Dichloromethane = 1:9);

[0461] HPLC: R T 2.90 min (purity: 43.3%), R T 3.02 min (purity: 52.2%);

[0462] 1H-NMR (400 MHz, DMSO-d6) δ 0.87 (t,J= 6.8 Hz, 3H), 1.23 ~ 1.53 (m, 8H), 1.58 ~ 1.64 (m, 3H), 1.74 ~ 1.91 (m, 1H), 2.32 (t,J= 6.8 Hz, 1H), 3.42 ~ 3.46 (m, 1H), 3.57 (s, 3H), 3.77 ~ 3.83 (m, 1H), 3.95 ~ 4.02 (m, 2H), 4.06 (q,J= 5.6 Hz, 1H), 4.53 (d,J= 6.0 Hz, 0.5H), 4.57 (d,J= 6.0 Hz, 0.5H), 4.74 (d,J= 5.2 Hz, 0.5H), 4.78 (d,J= 5.2 Hz, 0.5H), 4.92 (d,J= 5.2 Hz, 1H), 6.34 (dd,J= 16.4, 6.0 Hz, 0.5H), 6.35 (dd,J= 16.4, 6.0 Hz, 0.5H), 6.91 (d,J= 16.4 Hz, 1H), 7.35 (ddd,J= 6.8, 6.8, 1.2 Hz, 1H), 7.41 (dd,J= 8.8, 1.2 Hz, 1H), 7.46 (ddd,J= 7.2, 6.8, 1.6 Hz, 1H), 7.81 (d,J= 9.2 Hz, 1H), 7.84 (d,J= 8.4 Hz, 1H), 8.14 (d,J= 8.8 Hz, 0.5H), 8.15 (d,J= 8.8 Hz, 0.5H);

[0463] 13 C-NMR (100 MHz, DMSO-d6) 13.9, 21.2, 22.0(22.1), 24.6(24.7), 31.3(31.4), 31.8(31.9), 33.2, 33.4(33.5), 51.1, 68.6(68.7), 73.5, 73.6(73.7), 75.7, 115.0(115.1), 119.9(120.0), 121.9(122.0), 123.3, 123.9, 126.3, 128.2, 128.3, 128.7(128.8), 132.0, 137.3, 153.6, 173.4 ppm;

[0464] HRMS-ESI (m / z) [M+Na] + C 26 H 36 NaO6calcd 467.2407, found 467.2402.

[0465]

[0466] [Preparation Example 9] (5S,6R,E)-Methyl 5,6-dihydroxy-8-(4-(1-hydroxyhexyl)quinolin-3-yl)oct-7-enoate ((5S,6R,E)-Methyl 5,6-dihydroxy-8-(4-(1-hydroxyhexyl)quinolin-3-yl)oct-7-enoate, Compound 5, LXA-57)

[0467] An acetonide-protected lipoxin derivative (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 120 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0468] Specifically, compound 5 (20 mg, 43.8%) was obtained as a clear liquid using compound 4 (50 mg, 0.11 mmol) and 0.5 N-HCl / MeOH (8 mL).

[0469] R f 0.08 (Ethyl acetate : n-hexane = 1:1);

[0470] HPLC: R T 2.96 min (purity: 98.0%);

[0471] 1H-NMR (400 MHz, DMSO-d6) δ 0.81 (t,J= 6.8 Hz, 3H), 1.15 ~ 1.23 (m, 5H), 1.33 ~ 1.37 (m, 1H), 1.47 ~ 1.61 (m, 3H), 1.71 ~ 1.78 (m, 2H), 1.98 ~ 2.01 (m, 1H), 2.32 (t,J= 7.6 Hz, 2H), 3.40 ~ 3.43 (m, 1H), 3.57 (s, 3H), 4.03 (dt,J= 5.2, 4.0 Hz, 1H), 4.60 (d,J= 6.0 Hz, 0.5H), 4.61 (d,J= 6.0 Hz, 0.5H), 5.02 (d,J= 5.2 Hz, 1H), 5.40 ~ 5.43 (m, 1H), 5.69 (d,J=3.6 Hz, 1H), 6.34 (dd,J= 16.0, 5.2 Hz, 0.5H), 6.35 (dd,J= 16.0, 5.2 Hz, 0.5H), 7.19 (d,J= 16.0 Hz, 1H), 7.54 (ddd,J= 8.0, 8.0, 1.2 Hz, 1H), 7.65 (ddd,J= 8.4, 8.0, 1.2 Hz, 1H), 7.96 (dd,J= 8.4, 1.2 Hz, 1H), 8.67 (d,J= 6.4 Hz, 1H), 8.90 (s, 1H);

[0472] 13 C-NMR (100 MHz, DMSO-d6) 13.8, 21.2, 22.0, 25.4(25.5), 31.1, 31.7(31.8), 33.4, 37.0(37.1), 51.1, 68.7, 73.4(73.5), 74.9(75.0), 125.0(124.8), 125.5(125.6), 125.8, 126.5, 127.8(127.9), 128.2, 129.5, 135.8, 145.2, 147.4, 149.6, 173.4 ppm;

[0473] HRMS-ESI (m / z) [M+HCOO] - C 25 H 34 NO7calcd 460.2341, found 460.2332.

[0474]

[0475] [Preparation Example 10] (5S,6R,E)-methyl 5,6-dihydroxy-8-(2-(1-hydroxyhexyl)quinolin-3-yl)oct-7-enoate ((5S,6R,E)-methyl 5,6-dihydroxy-8-(2-(1-hydroxyhexyl)quinolin-3-yl)oct-7-enoate, Compound 8, LXA-60)

[0476] An acetonide-protected lipoxin derivative (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 120 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0477] Specifically, compound 8 (19 mg, 41.6%) was obtained as a clear liquid using compound 7 (50 mg, 0.11 mmol) and 1 N-HCl / MeOH (16 mL).

[0478] R f 0.39 (MeOH: Dichloromethane = 1:9);

[0479] HPLC: R T 8.01 min (purity: 98.5%);

[0480] 1H-NMR (400 MHz, DMSO-d6) δ 0.83 (t,J= 7.2 Hz, 3H), 1.25 ~ 1.33 (m, 5H), 1.35 ~ 1.40 (m, 2H), 1.53 ~ 1.59 (m, 2H), 1.61 ~ 1.83 (m, 3H), 2.31 (t,J= 7.2 Hz, 2H), 3.40 ~ 3.43 (m, 1H), 3.57 (s, 3H), 4.02 ~ 4.05 (m, 1H), 4.61 (d,J= 5.6 Hz, 1H), 4.93 ~ 4.96 (m, 1H), 4.99 (d,J= 5.2 Hz, 0.5H), 5.00 (d,J= 5.2 Hz, 0.5H), 5.28 (d,J= 6.4 Hz, 0.5H), 5.30 (d,J= 6.4 Hz, 0.5H), 6.44 (dd,J= 16.0, 5.6 Hz, 0.5H), 6.45 (dd,J= 16.0, 5.6 Hz, 0.5H), 7.08 (dd,J= 15.2 Hz, 0.5H), 7.09 (dd,J= 15.2 Hz, 0.5H), 7.56 (ddd,J= 8.4, 8.0, 1.2 Hz, 1H), 7.70 (ddd,J= 8.4, 8.4, 1.2 Hz, 1H), 7.96 (d,J= 8.0 Hz, 1H), 7.97 (d,J= 8.0 Hz, 1H), 8.41 (s, 1H);

[0481] 13 C-NMR (100 MHz, DMSO-d6) 13.8, 21.2, 22.1, 25.0(25.1), 31.2, 31.8(31.9), 33.4, 36.2(36.3), 51.1, 71.4(71.6), 73.5, 74.8(74.9), 124.9(124.8), 126.4, 127.3, 127.7, 128.1, 129.2, 129.4(129.5), 132.6, 135.5(135.6), 145.3, 160.7, 173.4 ppm;

[0482] HRMS-ESI (m / z) [M+H] + C 24 H 34NO5calcd 416.2430, found 416.2431.

[0483]

[0484] [Preparation Example 11] (5S,6R,E)-Methyl 5,6-dihydroxy-8-(2-(1-hydroxyhexyl)quinolin-5-yl)oct-7-enoate ((5S,6R,E)-Methyl 5,6-dihydroxy-8-(2-(1-hydroxyhexyl)quinolin-5-yl)oct-7-enoate, Compound 12, LXA-63)

[0485] An acetonide-protected lipoxin derivative (1.0 equiv.) was dissolved in HCl / MeOH in a round-bottom flask and stirred at room temperature for 30 to 120 minutes. After the reaction, the mixture was adjusted to pH 7–8 by adding saturated NaHCO3 at 0 °C and extracted twice with ethyl acetate. The organic layer was collected, water was removed with anhydrous MgSO4, and the solvent was removed by distillation under reduced pressure. The remaining residue was separated and purified by silica gel column chromatography (MeOH:dichloromethane = 1:9) to obtain the compound.

[0486] Specifically, compound 12 (20 mg, 53.5%) was obtained as a transparent semi-solid using compound 11 (40 mg, 0.09 mmol) and 1 N-HCl / MeOH (8 mL).

[0487] R f 0.22 (Ethyl acetate: n-hexane = 1:1);

[0488] HPLC: R T 4.93 min (purity: 97.4%);

[0489] 1H-NMR (400 MHz, DMSO-d6) δ 0.83 (t,J= 7.2 Hz, 3H), 1.23 ~ 1.29 (m, 4H), 1.32 ~ 1.40 (m, 3H), 1.55 ~ 1.65 (m, 2H), 1.70 ~ 1.80 (m, 3H), 2.32 (t,J= 6.4 Hz, 2H), 3.40 ~ 3.45 (m, 1H), 3.57 (s, 3H), 4.06 (dt,J= 5.2, 4.4 Hz, 1H), 4.62 (d,J= 6.0 Hz, 1H), 4.71 (dt,J= 7.6, 45.2 Hz, 1H), 5.02 (d,J= 5.2 Hz, 1H), 5.48 (d,J= 4.8 Hz, 1H), 6.45 (dd,J= 15.6, 5.6 Hz, 1H), 7.30 (d,J= 15.6 Hz, 1H), 7.67 ~ 7.72 (m, 3H), 7.84 ~ 7.88 (m, 1H), 8.60 (d,J= 8.8 Hz, 1H);

[0490] 13 C-NMR (100 MHz, DMSO-d6) 13.9, 21.1, 22.1, 24.8, 31.2, 32.1, 33.4, 37.5, 51.1, 73.5, 73.8, 74.9, 118.4, 122.8, 124.6, 124.9, 127.8, 129.2, 132.5, 134.9(135.0), 135.6(135.7), 146.8, 165.1, 173.4 ppm;

[0491] HRMS-ESI (m / z) [M+H] + C 24 H 34 NO5calcd 416.2431, found 416.2428.

[0492]

[0493] [Preparation Examples 1 to 11] Novel lipoxin-like compounds (Compounds 3 to 8, 10 to 12 and 15 to 16)

[0494] The structures of the novel exposure-like compounds synthesized in Preparation Examples 1 to 11 above are shown in Table 2 below.

[0495] LXA-55(3) LXA-61(10) LXA-56(4) LXA-62(11) LXA-57(5) LXA-63(12) LXA-58(6) LXA-47(15) LXA-59(7) LXA-48(16) LXA-60(8)

[0496] [Experimental Example] NF-kB Activation Inhibitory Test

[0497] For the experiment on NF-kB activity inhibition, THP-1 Lucia™ NF-kB cells (NF-kB-Lucia reporter monocytes) were purchased from InvivoGen. The luciferase assay was designed to confirm anti-inflammatory effects by monitoring the NF-kB signaling pathway through the evaluation of the activity of Lucia luciferase secreted by these cell lines. THP-1 Lucia NF-kB cells were placed in DMEM medium containing 0.1% FBS at a rate of 1 x 10⁶ per well. 5Dog cells were dispensed into a 96-well plate. Subsequently, 1 nM of the novelly synthesized compound from Preparation Examples 1 to 11, 1 nM of natural lipoxan A4 (native LXA4, nLXA4, cayman), and 1 μM of the positive control dexamethasone (Dex, sigma) were each pre-treated to the cells for 2 hours, after which 100 ng / ml LPS was added and the cells were cultured for 24 hours. 50 μl of QUANTI-Luc™ detection reagent (InvivoGen) was added to 20 μl of the culture medium, and the luminescence intensity was measured using a luminometer to rapidly screen only for drugs exhibiting NF-kB activity inhibitory ability. Figure 2 shows the results for 11 newly synthesized compounds in Preparation Examples 1 to 11 above, and FC (fold change) was expressed as a comparison value by dividing the value of the sample treatment group by the value of the negative control group (LPS alone treatment group), which is the reference condition value.

[0498] As a result, as shown in Fig. 2, it was confirmed that the novel lipoxin-like compounds synthesized in Preparation Examples 1 to 11 effectively inhibit NF-kB. In addition, it was confirmed that the synthesized lipoxin A4 has biological activity and is resistant to chemical and metabolic degradation.

[0499]

[0500] Foregoing, specific parts of the present invention have been described in detail. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A compound represented by the following chemical formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, The above R1 is unsubstituted or substituted with a C6-C5 alkyl or C1-C5 alkoxy. 10 It is an aryl or a heteroaryl of a 5-membered or 10-membered ring; The above R2 and R3 are each independently hydrogen or C1-C5 alkyl, or are connected to each other to form a heterocycloalkyl of a pentagonal or hexagonal ring that is unsubstituted or substituted with a C1-C5 alkyl; The above n is an integer from 0 to 2, and the above m is an integer from 1 to 3; The above is a single bond or a double bond; The above R4 is a C1-C5 alkyl.

2. In Paragraph 1, The above R1 is unsubstituted or substituted with a C6-C1 alkyl or C1-C3 alkoxy. 10 Compounds that are aryl or heteroaryl of a pentagonal or decagonal ring, optical isomers thereof, or pharmaceutically acceptable salts thereof.

3. In Paragraph 1, The above R2 and R3 are each independently hydrogen or a C1-C3 alkyl, or are compounds connected to form a heterocycloalkyl of a pentagonal or hexagonal ring that is unsubstituted or substituted with a C1-C3 alkyl, optical isomers thereof, or pharmaceutically acceptable salts thereof.

4. In Paragraph 1, A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 0 to 2 and m is an integer from 1 to 2.

5. In Paragraph 1, The above R4 is a C1-C3 alkyl compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

6. In Paragraph 1, A compound represented by the above chemical formula 1 is characterized by being selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: Methyl 4-((4S,5R)-5-(hydroxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; (E)-methyl 4-((4S,5R)-5-(hydroxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-(hydroxy(3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; (E)-methyl 4-((4S,5R)-5-(hydroxy(3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-(hydroxy(2-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-(hydroxy(naphthalene-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-(hydroxy(pyridine-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl (5S,6S)-5,6,7-trihydroxy-7-phenylheptanoate; Methyl (5S,6S,E)-5,6,7-trihydroxy-7-phenylhept-2-enoate; Methyl (5S,6S)-5,6,7-trihydroxy-7-(3-methoxyphenyl)heptanoate; Methyl (5S,6S,E)-5,6,7-trihydroxy-7-(3-methoxyphenyl)heptanoate; Methyl (5S,6S)-5,6,7-trihydroxy-7-(2-methoxyphenyl)heptanoate; Methyl (5S,6S)-5,6,7-trihydroxy-7-(naphthalene-2-yl)heptanoate; and Methyl (5S,6S)-5,6,7-trihydroxy-7-(pyridine-2-yl)heptanoate.

7. A composition for the prevention or treatment of NF-κB-related diseases comprising a compound of any one of claims 1 to 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

8. In Paragraph 7, A pharmaceutical composition wherein the above NF-κB-related disease is one or more selected from the group consisting of fibrosis, cancer, immune-related disease, metabolic disease, cardiovascular disease, inflammation, or pain.

9. In Paragraph 8, A pharmaceutical composition wherein the above fibrosis is at least one selected from the group consisting of pulmonary fibrosis, uterine fibrosis, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis caused by sickle cell anemia.

10. In Paragraph 9, A pharmaceutical composition wherein the above-mentioned pulmonary fibrosis is at least one selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

11. In Paragraph 8, A pharmaceutical composition in which the above cancer is a solid tumor.

12. In Paragraph 8, A pharmaceutical composition wherein the above cancer is at least one selected from the group consisting of gastric cancer, thyroid cancer, parathyroid cancer, ovarian cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, pro-anal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine gland cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renopelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.

13. In Paragraph 8, A pharmaceutical composition wherein the immune-related disease is at least one selected from the group consisting of autoimmune diseases, graft-versus-host disease, organ transplant rejection, asthma, atopy, and acute or chronic inflammatory diseases.

14. In Paragraph 13, A pharmaceutical composition wherein the above-mentioned autoimmune disease is at least one selected from the group consisting of rheumatoid arthritis, systemic scleroderma, systemic lupus erythematosus, atopic dermatitis, psoriasis, alopecia areata, asthma, Crohn's disease, Behcet's disease, Sjögren's syndrome, Guillain-Barré syndrome, chronic thyroiditis, multiple sclerosis, polymyositis, ankylosing spondylitis, fibromyositis, and nodular polyarteritis.

15. In Paragraph 8, A pharmaceutical composition in which the above pain is inflammatory pain or neuropathic pain.

16. In Paragraph 15, A pharmaceutical composition in which the above-mentioned neuropathic pain is peripheral neuropathic pain or central neuropathic pain.

17. In Paragraph 16, A pharmaceutical composition wherein the above-mentioned neuropathic pain is a disease selected from the group consisting of cold allodynia, mechanical allodynia, spontaneous pain, paresthesiasis, dysesthesiasis, hyperalgesia, hyperpathia, and combinations thereof.

18. In Paragraph 8, A pharmaceutical composition wherein the above metabolic disease is one or more selected from the group consisting of insulin resistance disease, obesity, type 1 and type 2 diabetes, dyslipidemia, liver disease, kidney damage, arteriosclerosis, and hypertension.

19. In Paragraph 8, A pharmaceutical composition wherein the above-mentioned cardiovascular disease is one or more selected from the group consisting of hypertension, arteriosclerosis, heart disease, thrombosis, angina pectoris, heart failure, myocardial infarction, atherosclerosis and arteriosclerosis, cerebrovascular disease and stroke.

20. A functional food composition for inhibiting NF-κB comprising, as an active ingredient, a compound of any one of claims 1 to 6, an optical isomer thereof, or a food-grade acceptable salt thereof.

21. A compound represented by the following chemical formula 16, its optical isomer, or a pharmaceutically acceptable salt thereof: [Chemical Formula 16] In the above chemical formula 16, The above R1 is a substituted or unsubstituted pentagonal or decagonal heteroaryl ring or a substituted or unsubstituted C6-C 10 As an aryl, the above substitution is an unsubstituted or hydroxy-substituted C1-C 15 Alkoxy, -C(=O)-(C1-C 15 alkyl) or C1-C 15 It is a substitution with an alkyl group; The above n is an integer from 1 to 5; The above R2 and R3 are each independently hydrogen or C1-C3 alkyl, or are connected to each other to form a heterocycloalkyl of a pentagonal or hexagonal ring that is unsubstituted or substituted with a C1-C3 alkyl; The above R4 is a C1-C5 alkyl.

22. In Paragraph 21, The above R1 is a substituted or unsubstituted pentagonal or decagonal heteroaryl ring or a substituted or unsubstituted C6-C 10 As an aryl, the above substitution is an unsubstituted or hydroxy-substituted C1-C 10 Alkoxy, -C(=O)-(C1-C 10 alkyl) or C1-C 10 A compound substituted with an alkyl group, its optical isomer, or its pharmaceutically acceptable salt.

23. In Paragraph 21, The above n is an integer from 1 to 3, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

24. In Paragraph 21, The above R2 and R3 are each independently hydrogen or C1-C2 alkyl, or connected to each other to form a heterocycloalkyl of a pentagonal or hexagonal ring that is unsubstituted or substituted with a C1-C2 alkyl; a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

25. In Paragraph 21, The above R4 is a C1-C3 alkyl compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

26. In Paragraph 21, A compound represented by the above chemical formula 16 is characterized by being selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: Methyl 4-((4S,5R)-5-((E)-2-(4-hexanoylquinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-((E)-2-(2-hexanoylquinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-((E)-2-(2-hexanoylquinoline-5-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-((E)-2-(4-(1-hydroxyhexyl)quinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-((E)-2-(2-(1-hydroxyhexyl)quinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-((E)-2-(2-(1-hydroxyhexyl)quinoline-5-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; Methyl 4-((4S,5R)-5-((E)-2-(2-((2-hydroxyheptyl)oxy)naphthalene-1-yl)vinyl)-2,2-dimethyl-1,3-dioxolane-4-yl)butanoate; (5S,6R,E)-methyl 5,6-dihydroxy-8-(2-((2-hydroxyheptyl)oxy)naphthalene-1-yl)oct-7-enoate; (5S,6R,E)-methyl 5,6-dihydroxy-8-(4-(1-hydroxyhexyl)quinoline-3-yl)oct-7-enoate; (5S,6R,E)-methyl 5,6-dihydroxy-8-(2-(1-hydroxyhexyl)quinoline-3-yl)oct-7-enoate; and (5S,6R,E)-methyl 5,6-dihydroxy-8-(2-(1-hydroxyhexyl)quinoline-5-yl)oct-7-enoate.

27. A composition for the prevention or treatment of NF-κB-related diseases comprising a compound of any one of claims 21 to 26, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

28. In Paragraph 27, A pharmaceutical composition wherein the above NF-κB-related disease is one or more selected from the group consisting of fibrosis, cancer, immune-related disease, metabolic disease, cardiovascular disease, inflammation, or pain.

29. In Paragraph 28, A pharmaceutical composition wherein the above fibrosis is at least one selected from the group consisting of pulmonary fibrosis, uterine fibrosis, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis caused by sickle cell anemia.

30. In Paragraph 29, A pharmaceutical composition wherein the above-mentioned pulmonary fibrosis is at least one selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

31. In Paragraph 28, A pharmaceutical composition in which the above cancer is a solid tumor.

32. In Paragraph 28, A pharmaceutical composition wherein the above cancer is at least one selected from the group consisting of gastric cancer, thyroid cancer, parathyroid cancer, ovarian cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, pro-anal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine gland cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renopelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.

33. In Paragraph 28, A pharmaceutical composition wherein the immune-related disease is at least one selected from the group consisting of autoimmune diseases, graft-versus-host disease, organ transplant rejection, asthma, atopy, and acute or chronic inflammatory diseases.

34. In Paragraph 23, A pharmaceutical composition wherein the above-mentioned autoimmune disease is at least one selected from the group consisting of rheumatoid arthritis, systemic scleroderma, systemic lupus erythematosus, atopic dermatitis, psoriasis, alopecia areata, asthma, Crohn's disease, Behcet's disease, Sjögren's syndrome, Guillain-Barré syndrome, chronic thyroiditis, multiple sclerosis, polymyositis, ankylosing spondylitis, fibromyositis, and nodular polyarteritis.

35. In Paragraph 28, A pharmaceutical composition in which the above pain is inflammatory pain or neuropathic pain.

36. In Paragraph 25, A pharmaceutical composition in which the above-mentioned neuropathic pain is peripheral neuropathic pain or central neuropathic pain.

37. In Paragraph 26, A pharmaceutical composition wherein the above-mentioned neuropathic pain is a disease selected from the group consisting of cold allodynia, mechanical allodynia, spontaneous pain, paresthesiasis, dysesthesiasis, hyperalgesia, hyperpathia, and combinations thereof.

38. In Paragraph 28, A pharmaceutical composition wherein the above metabolic disease is one or more selected from the group consisting of insulin resistance disease, obesity, type 1 and type 2 diabetes, dyslipidemia, liver disease, kidney damage, arteriosclerosis, and hypertension.

39. In Paragraph 28, A pharmaceutical composition wherein the above-mentioned cardiovascular disease is one or more selected from the group consisting of hypertension, arteriosclerosis, heart disease, thrombosis, angina pectoris, heart failure, myocardial infarction, atherosclerosis and arteriosclerosis, cerebrovascular disease and stroke.

40. A functional food composition for inhibiting NF-κB comprising, as an active ingredient, a compound of any one of claims 21 to 26, an optical isomer thereof, or a food-grade acceptable salt thereof.

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