Anticancer agent

Abstract

To provide an anticancer agent capable of specifically inhibiting the proliferation of cancer cells against breast cancer, lung cancer, skin cancer and / or colon cancer, especially lung cancer and breast cancer having high morbidity and mortality.SOLUTION: The anticancer agent is represented by the following chemical formula (1) (wherein R1 to R5 are alkyl groups, alkoxy groups, mercapto groups, alkylthioether groups, halogeno groups, amino groups, mono / di-alkyl groups, partial / per-halogenoalkyl groups, aromatic ring groups, heterocyclic groups, or hydrogen atoms; R6 is alkyl groups, alkoxy groups, alkylthioether groups, halogeno groups, hydroxyl groups, amino groups, mono / di-alkyl groups, aromatic ring groups, heterocyclic groups, or hydrogen atoms; R7 is hydrogen atoms, halogeno groups, or azido groups; R8 is hydrogen atoms or alkyl groups; and X is hydroxyl groups, alkoxy groups, mercapto groups, alkylthioether groups, halogeno groups, amino groups, mono / di-alkyl groups, or hydrogen atoms), Or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an anticancer agent used in the treatment of various cancers and sarcomas, particularly breast cancer and lung cancer. [Background technology]

[0002] For over 20 years, cancer has been the leading cause of death among Japanese people. Among the various types of cancer and sarcoma, lung cancer and breast cancer, which are malignant tumors, have been increasing in both mortality and incidence every year. Looking at the primary tumor site, lung cancer is the second most common disease and the leading cause of death for both men and women, while breast cancer is the most common disease for women.

[0003] Cancer treatments include surgical therapies that are highly invasive for patients, such as removing cancer tumors and metastatic sites, chemotherapy that uses anticancer drugs to suppress the progression and proliferation of cancer cells, molecular targeted therapy using immune checkpoint inhibitors that block the binding of PD-1 and PD-L1 and activate T cells that have been suppressed by PD-L1, endocrine therapy (hormone therapy) that suppresses the secretion and function of male hormones, and radiation therapy that uses X-rays, electron beams, proton beams, heavy particle beams, alpha-alpha rays, beta-beta rays, gamma-gamma rays, and neutron beams to damage cancer cells by cutting their DNA. Treatments are administered in combination as needed.

[0004] Among these, various anticancer drugs used in chemotherapy are in practical use, and they contain compounds that prevent the proliferation and progression of rapidly dividing and proliferating cancer cells, leading to their death. While conventional anticancer drugs have the powerful effect of directly inhibiting the division and proliferation of cancer cells, they also act on and damage normal cells in the body, especially those that divide and proliferate rapidly, such as normal cells in the gastrointestinal mucosa, bone marrow, oral mucosa, and hair, resulting in serious side effects such as nausea and vomiting, weakened immune system, decreased white blood cells, bone marrow suppression, stomatitis, hair loss, and numbness.

[0005] Not only anticancer drugs but also various other pharmaceuticals are known to have been developed by using physiologically active natural products derived from natural sources, such as plant chemicals extracted from tropical rainforest plants and marine plants, as key compounds to derive various analogues to enhance activity and improve safety.

[0006] Waltherione A, represented by chemical formula (I), is a quinolone alkaloid isolated from the mallow plant Walthria douradinha (Non-Patent Document 1), and has a very unique structure in which oxabicyclo[3.2.1]octane is fused to the 5- and 6-positions of a 4-quinolone. Waltherione A has been reported to have antifungal activity (Non-Patent Document 2), anti-HIV activity (Non-Patent Document 3), and nematicidal activity (Non-Patent Document 4). [ka]

[0007] The quinolones to which Waltherion A belongs have been primarily researched and developed as antibiotics, but in recent years, research into their use as anticancer agents has been progressing (Non-Patent Document 5). Pharmaceutical compounds with a privileged quinolone skeleton have a structure in which the substituents are on the same plane. However, in the case of Waltherion A, there are sp 3 There are no known examples of carbon-rich quinolones being used as anticancer agents.

[0008] The inventors focused on naturally occurring physiologically active substances and searched for compounds that specifically inhibit the growth of specific cancer cells, rather than inhibiting the growth of various cancer cells, thereby reducing damage to normal cells. They discovered that waltherion A has anti-cancer effects that are relatively useful against specific cancer cells. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] SCSM, Hoelzel et al., Phytochem, 66, p 1163-1167 (2005) [Non-patent document 2] A.Emile et al., Phyrother.Res., 21, p398-400 (2007) [Non-patent document 3] RC Jadulco et al., J.Nat.Prod., 77, p183-187 (2014) [Non-patent document 3] JYJang et al., J. Agric.FoodChem., 63 p68-74 (2015) [Non-patent document 5] F.Gao, et al., J.Med.Chem., 165, p59-79 (2019) Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention has been made to solve the above-mentioned problems, and aims to provide an anticancer agent that can inhibit the proliferation of cancer cells such as breast cancer, lung cancer, skin cancer, and / or colon cancer, and in particular can specifically inhibit the proliferation of specific cancer cells, particularly lung cancer and breast cancer, which have high morbidity and mortality rates.

[0011] The present inventors have discovered that not only can valserione A and its derivatives inhibit the proliferation of certain cancer cells, but that valserione A derivatives having particular substituents can specifically inhibit the proliferation of lung cancer and breast cancer cells, thereby completing the present invention. [Means for solving the problem]

[0012] The anticancer agent devised to achieve the above object is represented by the following chemical formula (1): [ka] (In chemical formula (1), R 1 ~R5 is a linear, hydroxyl group, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkoxy group having 1 to 6 carbon atoms, a mercapto group, a linear, branched, or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, an amino group, a monoalkyl group or dialkyl group having a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic partial halogeno or per halogenoalkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, or a hydrogen atom; R 6 represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, a linear, branched or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an amino group, a monoalkyl group or dialkyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, or a hydrogen atom; R 7 represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, a linear, branched or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an amino group, a monoalkyl group or dialkyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, a hydrogen atom, a halogeno group, or an azide group; R 8 is a hydrogen atom or a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, X is a hydroxyl group, a linear, branched, or cyclic alkoxy group having 1 to 6 carbon atoms, a mercapto group, a linear, branched, or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, an amino group, a monoalkyl or dialkyl group having a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, or a hydrogen atom. or a pharmaceutically acceptable salt thereof.

[0013] The anti-cancer agent is preferably a therapeutic agent for breast cancer, lung cancer, skin cancer, and / or colon cancer.

[0014] This anticancer agent is characterized in that the 4-quinolone derivative is represented by the following chemical formula (2): [ka] (In chemical formula (2), R 4 is a halogeno group, or a linear, branched, or cyclic partial halogeno or per halogeno alkyl group having 1 to 6 carbon atoms. and is therefore specific to breast cancer and / or lung cancer.

[0015] This anticancer agent is characterized in that the 4-quinolone derivative represented by chemical formula (2) exhibits IC 50 The concentration is less than 3 μM.

[0016] The anticancer agent may contain, for example, an excipient, a dispersant, a filler, a carrier, and / or a solvent. [Effects of the Invention]

[0017] The anticancer agent of the present invention contains, as an active ingredient, a waltherion A analogue, which is a 4-quinolone derivative represented by chemical formula (1), or a pharmaceutically acceptable salt thereof, and thus inhibits the proliferation of cancer cells, making it effective in treating various cancers. Such an anticancer agent is particularly effective as a therapeutic agent for breast cancer, lung cancer, skin cancer, and / or colon cancer, particularly breast cancer and lung cancer, and is therefore useful in treating these diseases, which have high morbidity and mortality rates.

[0018] In particular, by containing a 4-quinolone derivative represented by chemical formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient, it exhibits a particularly high inhibitory effect on cancer cell proliferation against breast cancer cell lines and / or lung cancer cell lines, and therefore has high cancer specificity, which results in less damage to normal cells and contributes to reducing or mitigating side effects, thereby not only improving quality of life (QOL) but also enabling effective and efficient cancer treatment. DETAILED DESCRIPTION OF THE INVENTION

[0019] Hereinafter, embodiments for carrying out the present invention will be described in detail, but the scope of the present invention is not limited to these embodiments.

[0020] The anticancer agent of the present invention is represented by the following chemical formula (1): [ka] or a pharmaceutically acceptable salt thereof.

[0021] In this chemical formula (1), R 1 ~R 5 may be the same or different and may have a substituent, and each independently represents a linear, hydroxyl group, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkoxy group having 1 to 6 carbon atoms, a mercapto group, a linear, branched, or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, an amino group, a monoalkyl group or dialkyl group having a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic partial halogeno or per halogenoalkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, or a hydrogen atom.

[0022] R 6 is, for example, a hydrogen atom or an optionally substituted, straight-chain, branched-chain or cyclic alkyl group having 1 to 6 carbon atoms.

[0023] R 7 is, for example, an optionally substituted group, such as a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkoxy group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an amino group, a monoalkyl group or dialkyl group having a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, or a hydrogen atom, a halogeno group, or an azide group.

[0024] R 8 may have a substituent, and is, for example, a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkoxy group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkylthioether group having 1 to 6 carbon atoms, a monoalkyl or dialkyl group having a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, or a halogeno group, a hydroxyl group, an amino group, or a hydrogen atom.

[0025] X may have a substituent, and is, for example, a linear, branched, or cyclic alkoxy group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkylthioether group having 1 to 6 carbon atoms, a monoalkyl or dialkyl group having a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a mercapto group, a halogeno group, an amino group, or a hydrogen atom.

[0026] Examples of the alkyl group having 1 to 6 carbon atoms, the alkyl group in the alkoxy group, the alkyl group in the alkylthioether group, and the alkyl group in the monoalkyl group or dialkyl group include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, tert-pentyl, cyclopentyl, n-hexyl, isohexyl, neohexyl, tert-hexyl, and cyclohexyl. The same applies to the alkyl group in the partial halogeno or perhalogenoalkyl group having 1 to 6 carbon atoms.

[0027] The halogeno group in these halogeno groups, partial halogeno or perhalogenoalkyl groups includes a fluoro group, a chloro group, a bromo group and an iodo group, with a fluoro group being preferred.

[0028] Examples of the aromatic ring group include monocyclic and condensed hydrocarbon aromatic ring groups. Specific examples of the aromatic ring of the monocyclic hydrocarbon aromatic ring group include a benzene ring, and examples of the aromatic ring of the condensed hydrocarbon aromatic ring group include naphthalene, anthracene, phenanthrene, and azulene.

[0029] Examples of the heterocyclic ring of the non-aromatic heterocyclic group include pyrrolidine, dioxolane, pyrazolidine, piperidine, 1,4-dioxane, morpholine, piperazine, and 1,3,5-trithiane.

[0030] The aromatic heterocyclic group may be a monocyclic or condensed aromatic heterocyclic group.Specific examples of the heterocyclic ring of the monocyclic aromatic heterocyclic group include thiophene, furan, pyrrole, pyrazole, imidazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiazole, isothiazole, oxazole, isoxazole, and furazan.Specific examples of the heterocyclic ring of the condensed aromatic heterocyclic group include thianaphthene, benzothiophene, benzofuran, isobenzofuran, indole, isoindole, indolizine, indazole, benzimidazole, benzothiazole, purine, quinoline, isoquinoline, cinnoline, quinoxaline, phthalazine, naphthyridine, quinazoline, and cinnoline.

[0031] These groups may be unsubstituted, but may have a substituent as necessary. Examples of the substituent include a linear, branched, and / or cyclic alkyl group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms; a linear, branched, and / or cyclic alkyloxy group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms; an aryl group having 6 to 20 carbon atoms, preferably 6 to 14 carbon atoms, such as a phenyl group, a naphthyl group, an anthracenyl group, or a phenanthryl group; a heteroaryl group having 2 to 20 carbon atoms, which is a 5- or 6-membered ring or a condensed ring thereof, such as a thiophene ring, a furan ring, a pyrrole ring, or a pyridine ring; an aralkyl group having 7 to 20 carbon atoms, such as a benzyl group or a phenethyl group; an aralkyloxy group having 7 to 20 carbon atoms, such as a benzyl group or a phenethyloxy group; an alkylthio group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, which has a linear, branched, and / or cyclic alkyl; an aralkylthio group having 7 to 20 carbon atoms; a hydroxyl group; an amino group; Examples of the alkyl group include an alkyl group having 1 to 20 carbon atoms, an ammonium salt, a mono- or di-alkylamino group substituted with an alkyl having 1 to 20 carbon atoms, a mercapto group, a carboxyl group or a salt thereof, an acyl group having 2 to 20 carbon atoms, an ester group having an alkyl having 1 to 20 carbon atoms, a thioester group having an alkyl having 1 to 20 carbon atoms, an amide group, a mono- or di-alkylamide group substituted with a linear, branched, and / or cyclic alkyl having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, a halogeno group, a nitro group, and a nitrile group; a sulfonic acid group or a salt thereof; sulfinic acid or a salt thereof or an ester thereof substituted with a linear, branched, and / or cyclic alkyl having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms; sulfenic acid or a salt thereof or an ester thereof substituted with a similar alkyl having 1 to 20 carbon atoms; and phosphoric acid or a salt thereof or an ester thereof substituted with a similar alkyl having 1 to 20 carbon atoms.

[0032] Such a 4-quinolone derivative represented by chemical formula (1) or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent for breast cancer, lung cancer, skin cancer, and / or colon cancer.

[0033] The synthesis of the 4-quinolone derivative represented by chemical formula (1) will be explained using Waltherion A as an example, with reference to the outline of chemical reaction formula (A). However, 4-quinolone derivatives other than Waltherion A can also be synthesized in the same manner by using reagents with different substituents.

[0034] [ka]

[0035] Starting from commercially available benzosuberone (10), the aromatic ring was nitrated with a nitrating agent, followed by bromination at the benzyl position with a brominating agent to give the nitrobromo derivative (11) (Wohl-Ziegler bromination reaction). The bromo group was then dehydrobrominated with a debrominating agent to give the olefin (12). The carbonyl group was then asymmetrically reduced using a hydrogen transfer catalyst to give the alcohol (13) with >95% ee.

[0036] To construct oxabicyclo[3.2.1]octane, an anti-epoxy alcohol (16) is required, in which the hydroxyl group and the cyclic epoxy group are on the opposite side of the seven-membered ring. However, direct epoxidation of the alcohol (13) preferentially gives the syn-epoxy alcohol (16'), in which the hydroxyl group and the cyclic epoxy group are on the same side of the seven-membered ring, starting from the hydroxyl group. Therefore, the hydroxyl group of the alcohol (13) was protected with various protecting groups, such as tert-butyldimethylsilyl (TBS), acetyl, pivaloyl, or trifluoroacetyl (14a to 14d, respectively), and the olefin group was oxidized to an epoxy ring with a peracid (e.g., m-chloroperbenzoic acid: mCPBA) to produce the desired anti-isomer (16, 15a to 15d, respectively) and the undesired syn-isomer (16', 15'a to 15'd, respectively). As is clear from Table 1, when the trifluoroacetyl-protected form (14d) was oxidized, the epoxidation proceeded stereoselectively with a diastereomeric ratio (anti:syn) of 12:1, resulting in the desired anti-isomer (15d). Although the details of the stereospecificity are not entirely clear, it is presumed that the strong electron-withdrawing effect of the trifluoroacetyl group promotes the approach of the peracid from the less sterically hindered side.

[0037] [Table 1]

[0038] Next, the oxabicyclo[3,2,1]octane skeleton was constructed. The trifluoroacetyl group of the anti-form (15d) was deprotected to give the epoxy alcohol (16), which was then treated with base to cleave the epoxy ring with the hydroxyl group, yielding the desired oxabicyclo (17) and its undesired regioisomer (18) in a ratio of approximately 1:1. On the other hand, acid treatment to cleave the epoxy ring with the hydroxyl group favored the desired oxabicyclo (17) and its undesired regioisomer (18) in a ratio of approximately 3:1.

[0039] Next, the newly generated hydroxyl group in the oxabicyclo compound (17) with the desired configuration is protected with a protecting group (e.g., TBS) and its nitro group is reduced to give the oxabicycloamine compound (20). This is then treated with an iodinating agent followed by a brominating agent to give the oxabicyclobromoiodo compound (21). This is then deiodinated with a deiodinating agent (e.g., turbo-Grignard reagent) and then diacetylated at the 2-position with an acetylating agent to give the oxabicycloimide compound (22). This is then subjected to a Fries-like intramolecular rearrangement using a strong base (e.g., butyllithium) to give the key intermediate, the aceto-oxabicycloamide compound (23).

[0040] The quinolone skeleton is constructed by an intramolecular aldol reaction between the acetyl group on the nitrogen and the acetyl group on the aromatic ring under basic conditions (e.g., sodium bis(trimethylsilyl)amide NaHMDS, sodium hydroxide, sodium butoxide, potassium butoxide, preferably potassium butoxide), to give the desired 4-quinolone (24) and the undesired 2-quinolone (25). The protecting group of the hydroxyl group of the oxabicyclo[3,2,1]octane skeleton of the desired 4-quinolone (24) is deprotected, and then oxidized to give the oxo-4-quinolone (26). This is then converted to an oxo-3-bromo-4-quinolone with a brominating agent, and the bromo group is replaced with a methoxy group to give the oxo-3-methoxy-4-quinolone (27). This is then reacted in situ with phenyllithiums (e.g., anisole lithium) for nucleophilic addition (1,2 addition) to the carbonyl, resulting in a stereoselective asymmetric total synthesis of Waltherione A (I).

[0041] In addition, in chemical formula (1), 4-quinolone derivatives other than Waltherion A (I) can be obtained by replacing the reagent used to synthesize Waltherion A (I) with a reagent having the desired substituent.

[0042] In vitro breast cancer cell lines for which these 4-quinolone derivatives and their salts are effective include MCF-7, MDA-MB-231 (a triple-negative breast cancer cell line lacking excessive expression of the estrogen receptor (ER), progesterone receptor (PgR), and epidermal growth factor receptor 2 (HER2) proteins), BT-549, T-47D, and MDA-MB-468. In vitro lung cancer cell lines include A549 / ATCC, EKVX, NCI-H23, NCI-H460, and NCI-H522. In vitro skin cancer (melanoma) cell lines include LOX IMVI, MALME-3M, M14, MDA-MB435, SK-MEL-5, and UACC-257. Examples of colon cancer cell lines in vitro include COLO205, HCC-2988, HCT-116, HCT-15, HT29, KM12, and SW-620.

[0043] Among these 4-quinolone derivatives, the following chemical formula (2) [ka] (In chemical formula (2), R 4 is a halogeno group, or a linear, branched, or cyclic partial halogeno or perhalogeno alkyl group having 1 to 6 carbon atoms) is specific to breast cancer and / or lung cancer, and in an in vitro system, has an IC value 7 to several tens to several hundreds times higher against breast cancer and / or lung cancer cell lines than against other cancer cell lines. 50 The 50% inhibitory concentration (50%) was low, indicating strong cytotoxicity to cancer cell lines.

[0044] Among the 4-quinolone derivatives represented by chemical formula (2), R 4 The compounds with chloro, fluoro, or trifluoromethyl groups have been shown to have specific IC 50 It has strong specificity with a few μM of activity, and exhibits stronger activity than waltherion A (compound 1).

[0045] In this anticancer agent, the 4-quinolone derivative represented by chemical formula (1) or chemical formula (2) may be free and have no counter ion, or may be a pharmaceutically acceptable salt, specifically, an alkali metal salt or an alkaline earth metal salt, or an organic acid salt such as hydrochloride, sulfate, nitrate, acetate, citrate, tartrate, methanesulfonate, or toluenesulfonate, or a salt with an amino acid.

[0046] This anticancer agent contains a 4-quinolone derivative represented by chemical formula (1) or chemical formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient with anticancer activity, and inhibits the proliferation of cancer cells or kills them, and is used as a preventive agent, therapeutic agent, recurrence prevention agent, and relapse prevention agent for various cancers, particularly breast cancer, lung cancer, skin cancer, and / or colon cancer. In particular, when this anticancer agent contains a 4-quinolone derivative represented by chemical formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient with anticancer activity, it can be used as a preventive agent, therapeutic agent, recurrence prevention agent, and relapse prevention agent specific to breast cancer and / or lung cancer.

[0047] This anticancer agent may contain other ingredients as long as it contains the 4-quinolone derivative represented by chemical formula (1) or (2) or a pharmaceutically acceptable salt thereof as an active ingredient with anticancer activity, and is formulated, if necessary, by mixing it with non-toxic, inert, pharmaceutically acceptable excipients, such as solid, semi-solid, or liquid diluents, dispersants, fillers, and carriers. Furthermore, stabilizers, preservatives, pH adjusters, binders, disintegrants, surfactants, lubricants, flow enhancers, flavoring agents, colorants, fragrance preservatives, vehicles, physiological saline, and other medicinal agents may be contained as additives.

[0048] Examples of the anticancer agent include elixirs, capsules, granules, pills, ointments, suspensions, liquids, enteric-coated formulations, emulsions, plasters, suppositories, powders, tablets, syrups, injections, troches, ointments, poultices, liniments, lemonades, and lotions. The agent may be dissolved or suspended in a liquid medium, or dispersed in a solid medium.

[0049] This anticancer agent may be administered orally, by intravenous injection or drip infusion, or may be applied to the skin or attached to the skin for transdermal absorption.

[0050] This anticancer agent contains, as a pharmaceutical formulation, 0.001 to 99% by mass of the 4-quinolone derivative represented by chemical formula (1) or chemical formula (2) or a pharmaceutically acceptable salt thereof, and preferably contains 0.001 to 100 mg / kg of the patient's body weight.

[0051] The dosage of this anticancer agent is selected appropriately depending on the efficacy of the active ingredient, which is a 4-quinolone derivative represented by chemical formula (1) or chemical formula (2) or a pharmaceutically acceptable salt thereof, the form and route of administration, the stage of cancer progression, the patient's body type, weight, and age, and the type and amount of other therapeutic agents used in combination. The agent may be administered daily, 1 to 5 times a day, or intermittently every 1 to 14 days or every 2 to 6 weeks.

[0052] The efficacy and mechanism of action of this anticancer drug is explained as follows: It exhibits a remarkable antitumor effect against cancer cells, such as those of breast cancer, lung cancer, skin cancer, and / or colon cancer, by suppressing the proliferation of cancer cells and inducing apoptosis in cancer cells, causing their death. Although the mechanism of action is not entirely clear, it is presumed to inhibit DNA synthesis and cell division in cancer cells, or to cause DNA damage in cancer cells. [Example]

[0053] Examples to which the present invention is applied and comparative examples to which the present invention is not applied will be described in detail.

[0054] (General conditions for synthesis examples) All reagents were purchased commercially and used without further purification unless otherwise noted. All reactions requiring heating were performed using an oil bath. Crude materials were purified by column chromatography on silica gel 60N (average particle size 63–210 μm, Kanto Chemical Co., Ltd.). NMR spectra were measured using JEOL JMN-ECA600 and JMN-ECS400 spectrometers. Tetramethylsilane was used as the internal standard, and chemical shifts are reported as δ values. High-resolution mass spectrometry (HRMS) data were obtained using a JEOL JMS-700 MStation mass spectrometer (quadrupole). Optical rotations were measured using a JASCO P-2200 digital polarimeter. Melting points were measured using an AS ONE ATM-02. Analytical TLC was performed on precoated silica gel 60F254 and RP-18F254 plates (0.25 mm thick; Merck). For preparative liquid chromatography (HPLC), a GL Science Recycling System InertSustain C18 column (average particle size 5 μm, 20×250 mm) was used.

[0055] (Synthesis Example 1: Synthesis of Waltherion A) Waltherion A was synthesized as follows, with reference to the detailed reaction formula shown below in chemical reaction formula (B). [ka]

[0056] [Synthesis of 9-bromo-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (11)] Benzosuberone was nitrated with nitric acid in the presence of sulfuric acid using a known method to give nitrobenzosuberone in 62% yield. Azoisobutyronitrile (AIBN: 177 mg, 1.05 mmol) and N-bromosuccinimide (NBS: 811 mg, 4.55 mmol) were added to a solution of this nitrobenzosuberone (718 mg, 3.50 mmol) in CCl4 (35 mL) at room temperature, and the mixture was refluxed with stirring at 100 °C for 4 h. The reaction mixture was then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography eluting with hexane-ethyl acetate (EtOAc) (9:1) to give the nitrobromo-form (11) (885 mg, 3.11 mmol) as a white amorphous solid in 89% yield. The following results of the physicochemical evaluation support the structure of the nitrobromo compound (11). 1 H NMR (400 MHz, CDCl3): δ 8.44 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.2, 2.3 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 5.55 (dd, J = 6.2, 2.8 Hz, 1H), 3.26-3.19 (m,1H), 2.82-2.75 (m,1H), 2.57-2.48 (m, 1H), 2.38-2.24 (m, 2H), 2.12-2.03 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 202.4, 147.9, 146.0, 140.9, 131.1, 126.0, 124.5, 51.4, 41.9, 33.8, 21.4. HRMS (FAB) m / z: [M+H] + Calcd for C 11 H 11 BrNO3283.9922; Found 283.9915.

[0057] [Synthesis of 3-nitro-6,7-dihydro-5H-benzo[7]annulen-5-one (12)] To a solution of the nitrobromo derivative 11 (1980 mg, 6.97 mmol) in DMF (20 mL) was added 2,4,6-collidine (0.900 mL, 6.97 mmol) at room temperature. The mixture was stirred at 100 °C for 2 h. The reaction mixture was then cooled to 0 °C, quenched with 1N HCl, and stirred for 10 min until a solid precipitated. After filtration, the precipitate was dissolved in CHCl, and 1N HCl was added. The resulting mixture was extracted with CHCl. ​​The combined organic layers were washed with saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (9:1) to give the olefin derivative 12 (1010 mg, 4.99 mmol) as a white amorphous solid in 72% yield. The following results of the physicochemical evaluation support the structure of the olefin (12). 1 H NMR (400 MHz, CDCl3): δ 8.76 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.2, 2.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 11.9 Hz, 1H), 6.47-6.42 (m, 1H), 3.02-2.96 (m, 2H), 2.63-2.58 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 199.5, 146.4, 141.4, 138.2, 137.5, 133.0, 129.9, 126.6, 125.1, 41.5, 24.5. HRMS (FAB) m / z: [M+H] + Calcd for C 11 H 10 NO3204.0661; Found 204.0653.

[0058] [Synthesis of (S)-3-nitro-6,7-dihydro-5H-benzo[7]annulen-5-ol (13)] According to Hashiguchi, S. et al., J. Am. Chem. Soc., 117, p. 7562 (1995), olefin (12) (443 mg, 2.18 mmol), RuCl[(S,S)-Tsdpen](mesitylene) (62.0 mg, 0.0974 mmol), and HCOONa (450 mg, 6.62 mmol) were dissolved in anhydrous MeOH (19 mL) at 0 °C under an argon atmosphere. After stirring at room temperature for 3 h, the reaction mixture was quenched with water and extracted with CHCl. ​​The combined organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (4:1) to give the alcohol (13) (418 mg, 2.04 mmol) as a white amorphous solid in 93% yield and optical yield >95% ee (the S-configuration was determined by a modified Mosher method using optically active MTPA). The following results of the physicochemical evaluation support the structure of the alcohol (13). 1 H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 8.3, 2.4 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 12.4 Hz, 1H), 6.19-6.15 (m, 1H), 4.92-4.91 (m, 1H), 2.58-2.55 (m, 2H), 2.24-2.15 (m, 2H), 2.04 (d, J = 5.2 Hz, 1H). 13 C NMR (150 MHz, CDCl3):δ 146.4, 144.2, 140.2, 137.1, 131.7, 128.1, 122.2, 120.8, 72.2, 35.4, 28.0. HRMS (FAB) m / z: [M+H] + Calcd for C 11 H 12 NO3206.0817; Found 206.0812. [α] D25 -422.4 (c 0.1, MeOH).

[0059] [(S)-3-nitro-6,7-dihydro-5H-benzo[7]annulen-5-yl 2,2,2-trifluoroacetate (14d)] To a solution of alcohol 13 (514 mg, 2.50 mmol) in CHCl (8 mL), triethylamine (EtN: 0.500 mL, 3.76 mmol) and trifluoroacetic acid (TFAA: 0.500 mL, 3.76 mmol) were added at −30 °C, and the mixture was stirred at the same temperature for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO. The reaction mixture was extracted with CHCl. ​​The combined organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (3:1) to give trifluoroacetyl-protected 14d (647 mg, 2.15 mmol) as a colorless oil in 86% yield. The following results of the physicochemical evaluation support the structure of the trifluoroacetyl-protected compound (14d). 1 H NMR (600 MHz, CDCl3): δ 8.25 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 12.2 Hz, 1H), 6.24-6.20 (m, 1H), 6.13 (d, J = 8.4 Hz, 1H), 2.70-2.63 (m, 1H), 2.62-2.55 (m, 1H), 2.46-2.40 (m, 1H), 2.30-2.25 (m, 1H). 13C NMR (150 MHz, CDCl3): δ 156.7 (q, J = 43.0 Hz), 146.2, 141.2, 137.2, 137.1, 132.6, 127.8, 123.8, 122.6, 114.6 (q, J = 285.7 Hz), 78.0, 31.2, 27.2. HRMS (FAB) m / z: [M+H] + Calcd for C 13 H 11 F3NO4302.0640; Found 302.0619. [α] D 25 -163.6 (c 1.47, CHCl3).

[0060] [Synthesis of (1aS,4S,8bR)-6-nitro-1a,3,4,8b-tetrahydro-2H-benzo[3,4]cyclohepta[1,2-b]oxiren-4-yl 2,2,2-trfluoroacetate (15d)] To a solution of trifluoroacetyl-protected 14d (625 mg, 2.08 mmol) in CHCl (10 mL), m-chloroperbenzoic acid (mCPBA, approximately 30% water content: 769 mg, 3.11 mmol) was added at 0 °C, and the reaction mixture was stirred at the same temperature for 28 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO at 0 °C and stirred for 10 min. Saturated aqueous NaSO was added to the reaction mixture at the same temperature and stirred for 10 min. The resulting reaction mixture was extracted with CHCl, and the combined organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (4:1) to afford a diastereomeric mixture of anti (15d) and syn (15'd; see Table 1) (491 mg, 1.55 mmol) in 74% yield as a colorless oil. The diastereomeric ratio of 15d:15'd (anti:syn) is 1 Determined to be 12:1 by 1 H NMR. The following results of physicochemical evaluation of the major diastereomer, anti (15d), support its structure. 1 H NMR (400 MHz, CDCl3): δ 8.28 (dd, J = 8.4, 2.3 Hz, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 6.33 (t, J = 4.3 Hz, 1H), 4.06 (d, J = 4.3 Hz, 1H), 3.54-3.51 (m, 1H), 2.36-2.32 (m, 1H), 2.27-2.23 (m, 2H), 1.47-1.40 (m, 1H). 13 C NMR (150 MHz, CDCl3): δ 156.3 (q, J = 42.6 Hz), 147.9, 142.1, 135.7, 133.0, 124.5, 123.5, 114.5 (q, J = 286.1 Hz), 78.3, 54.8, 54.4, 28.0, 24.7. HRMS (FAB) m / z: [M+H] + Calcd for C 13 H 11 F3NO5318.0589; Found 318.0566.

[0061] [(1aS,4S,8bR)-6-nitro-1a,3,4,8b-tetrahydro-2H-benzo[3,4]cyclohepta[1,2-b]oxiren-4-ol (16) and Synthesis of (1aR,4S,8bS)-6-nitro-1a,3,4,8b-tetrahydro-2H-benzo[3,4]cyclohepta[1,2-b]oxiren-4-ol (16')] To a solution of the diastereomeric mixture of trifluoroacetate esters anti (15d) and syn (15d') (480 mg, 1.51 mmol) in anhydrous MeOH (5.0 mL) was added pyridine (0.0122 mL, 0.151 mmol) at room temperature, and the reaction mixture was stirred at the same temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (2:1) to give anti-epoxy alcohol (16) (284 mg, 1.28 mmol) and its diastereomeric syn-epoxy alcohol (16') (17.3 mg, 0.0782 mmol) as white amorphous solids in 85% and 5%, respectively. The minor diastereomeric by-product syn-epoxy alcohol (16') was also isolated at this stage. The following results of physicochemical evaluation of the desired epoxy alcohol (16) and the undesired diastereoepoxy alcohol (16') support their structures. Desired anti-epoxy alcohol (16): 1 H NMR (600 MHz, CDCl3): δ 8.20 (d, J = 2.3 Hz, 1H), 8.15 (dd, J = 8.4, 2.4 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 5.31-5.29 (m, 1H), 4.05 (d, J = 4.4 Hz, 1H), 3.52-3.50 (m, 1H), 2.29-2.24 (m, 1H), 2.18 (d, J = 3.9 Hz, 1H), 2.15- 2.10 (m, 1H), 2.02-1.97 (m, 1H), 1.66-1.60 (m, 1H). 13 C NMR (150 MHz, CDCl3): δ 147.7, 143.1, 141.5, 132.2, 122.7, 122.0, 71.3, 56.5, 55.4, 31.0, 24.3. HRMS (FAB) m / z: [M+H] + Calcd for C 11 H12 NO4222.0766; Found 222.0769. [α] D 25 -15.1 (c 0.1, MeOH). Unexpected diastereo - syn - epoxy alcohol (16'): 1 H NMR (600 MHz, CDCl3): δ 8.35 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 2.4, 8.3 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 5.17 - 5.15 (m, 1H), 4.05 (d, J = 4.2 Hz, 1H), 3.49 - 3.47 (m, 1H), 2.34 - 2.26 (m, 2H), 1.79 - 1.73 (m, 1H), 1.52 - 1.45 (m, 1H). 13 C NMR (150 MHz, CDCl3): δ 148.4, 143.6, 139.4, 131.7, 122.7, 120.8, 70.2, 55.2, 54.7, 30.9, 25.4. HRMS (FAB) m / z: [M + H] + Calcd for C 11 H 12 NO4222.0766; Found 222.0765. [α] D 25 -13.4 (c 0.70, MeOH).

[0062] Synthesis of [(5S,8R,9R)-3-nitro-6,7,8,9-tetrahydro-5H-5,8-epoxybenzo[7]annulen-9-ol (17) and (5S,6S,9S)-2-nitro-6,7,8,9-tetrahydro-5H-5,9-epoxybenzo[7]annulen-6-ol (18)] To a solution of epoxy alcohol 16 (100 mg, 0.452 mmol) in dioxane (1 mL), trifluoroacetic acid (TFA: 0.00870 mL, 0.1 mmol) was added at 50 °C, and the reaction mixture was stirred at the same temperature for 9 h. The reaction mixture was quenched with saturated aqueous NaHCO and extracted with CHCl. ​​The combined organic layers were washed with saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (2:1) to afford the desired oxabicyclo 17 (73.8 mg, 0.334 mmol) and its undesired regioisomer 18 (27.0 mg, 0.122 mmol) as white amorphous solids in 73% and 26%, respectively. The following results of physicochemical evaluation of the desired oxabicyclic compound (17) and its undesired regioisomer (18) support their structures. The desired oxabicyclo (17): 1 H NMR (600 MHz, CDCl3): δ 8.12 (dd, J = 8.5, 2.3 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 5.24 (t, J = 5.8 Hz, 1H), 5.14 (d, J = 6.0 Hz, 1H), 4.68-4.65 (m, 1H), 2.27-2.21 (m, 1H), 2.17-2.11 (m, 2H), 2.09-2.03 (m, 1H), 1.91-1.87 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 147.1, 143.2, 142.2, 128.8, 122.8, 118.5, 77.4, 77.1, 69.6, 34.6, 21.7. HRMS (FAB) m / z: [M+H] + Calculated for C 11 H 12 NO4222.0766; Found 222.0769. [α] D 25-54.6 (c 0.1, MeOH). The position of the opposite sex (18): 1 H NMR (600 MHz, CDCl3): δ 8.21 (dd, 1H, J = 2.0, 8.1 Hz), 8.06 (d, 1H, J = 1.7 Hz), 7.47 (d, 1H, J = 8.0 Hz), 5.25 (d, 1H, J = 2.8 Hz), 5.07 (d, 1H, J = 4.3 Hz), 4.14-4.10 (m, 1H), 2.13-2.08 (m, 1H), 1.90-1.86 (m, 1H), 1.63-1.60 (m, 1H). 0.78-0.71 (m, 1H). 13 C NMR (150 MHz, CDCl3) δ: 148.3, 147.6, 145.0, 123.6, 122.7, 115.5, 81.3, 78.3, 65.9, 27.1, 26.1. HRMS (FAB) m / z: [M+H] + Calcd for C 11 H 12 NO4222.0766; Found 222.0772. [α] D 25 -162.2 (c 1.0, MeOH)

[0063] [tert-butyldimethyl{[(5S,8R,9R)-3-nitro-6,7,8,9-tetrahydro-5H-5,8-epoxybenzo[7]annulen-9-yl]oxy}silane(19)] To a solution of oxabicyclo (17) (63.6 mg, 0.288 mmol) in CHCl (1.0 mL), 2,6-lutidine (0.067 mL, 0.578 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf: 0.099 mL, 0.431 mmol) were added at 0 °C, and the reaction mixture was stirred at room temperature for 1.5 h. After completion of the reaction, aqueous NHCl was added to the reaction mixture, which was then extracted with CHCl. ​​The combined organic layers were washed with saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (40:1) to afford the TBS-protected oxabicyclo (19) (83.8 mg, 0.250 mmol) as a white amorphous solid in 87% yield. The following results of the physicochemical evaluation support the structure of the TBS-protected oxabicyclo compound (19). 1 H NMR (400 MHz, CDCl3): δ 8.09 (dd, J = 8.6, 2.4 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 5.14 (d, J = 5.5 Hz, 1H), 5.11 (d, J = 5.8 Hz, 1H), 4.57-4.54 (m, 1H), 2.27-2.15 (m, 2H), 2.00-1.94 (m, 1H), 1.90-1.83 (m, 1H), 0.96 (s, 9H), 0.25 (s, 3H), 0.18 (s, 3H). 13 C NMR (150 MHz, CD3OD): δ 148.2, 145.3, 143.5, 130.0, 123.3, 119.4, 78.8, 78.2, 71.4, 35.6, 26.2, 22.5, 18.9, -4.1, -4.8. HRMS (FAB) m / z: [M+H] + Calcd for C 17 H 25 NO4Si 336.1631; Found 336.1634. [α] D25 -74.9 (c 0.1, MeOH).

[0064] [Synthesis of (5S,8R,9R)-9-[(tert-butyldimethylsilyl)oxy]-6,7,8,9-tetrahydro-5H-5,8-epoxybenzo[7]annulen-3-amine (20)] To a solution of the TBS-protected oxabicyclo amine 19 (280 mg, 0.834 mmol) in 80% EtOH (5 mL) was added NH4Cl (170 mg, 3.18 mmol) and iron powder (226 mg, 4.05 mmol) at room temperature, and the reaction mixture was stirred at 75 °C for 1.5 h. The suspension was filtered through a Celite membrane, washed with CHCl2, and the filtrate was concentrated. The resulting aqueous layer was extracted with CHCl2, and the combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (2:1) to afford the oxabicyclo amine 20 (240 mg, 0.786 mmol) as a white amorphous solid in 94% yield. The following results of the physicochemical evaluation support the structure of the oxabicycloamine compound (20). 1 H NMR (400 MHz, CDCl3): δ 7.12 (d, J = 8.6 Hz, 1H), 6.56 (dd, J = 8.6, 2.4 Hz, 1H), 6.27 (d, J = 2.4 Hz, 1H), 5.09 (d, J = 5.5 Hz, 1H), 4.88 (d, J = 5.8 Hz, 1H), 4.49-4.45 (m, 1H), 3.59 (s, 2H), 2.31-2.23 (m, 1H), 2.14-2.04 (m, 1H), 1.89-1.81 (m, 2H), 0.94 (s, 9H), 0.20 (s, 3H), 0.14 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 145.2, 141.5, 128.7, 126.3, 114.4, 109.5, 78.1, 77.7, 70.0, 34.6, 26.0, 21.6, 18.2, -4.0, -4.5. HRMS (FAB) m / z: [M+H] + Calcd for C 17 H 28 NO2Si 306.1889; Found 306.1885. [α] D 25 -15.9 (c 0.1, MeOH).

[0065] [Synthesis of (5S,8R,9R)-9-[(tert-butyldimethylsilyl)oxy]-2-iodo-6,7,8,9-tetrahydro-5H-5,8-epoxybenzo[7]-annulen-3-amine] To a solution of oxabicycloamine (20) (868 mg, 2.84 mmol) in anhydrous acetonitrile (MeCN: 7 mL) and CHCl (5 mL) was added TFA (0.0440 mL, 0.568 mmol) at −30 °C, and N-iodosuccinimide (NCS: 641 mg, 2.85 mmol) was added in portions over 1 h. After stirring at the same temperature for 1 h, the reaction mixture was quenched with saturated aqueous NaSO and extracted with CHCl. ​​The combined organic layer was washed with saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (15:1) to afford the oxabicycloiodo (943 mg, 2.19 mmol) as a white amorphous solid in 77% yield. The following results of the physicochemical evaluation support the structure of the oxabicycloiodo derivative. 11H NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.33 (s, 1H), 5.05 (d, J = 5.6 Hz, 1H), 4.86 (d, J = 6.0 Hz, 1H), 4.47 - 4.43 (m, 1H), 4.02 (s, 2H), 2.28 - 2.20 (m, 1H), 2.14 - 2.04 (m, 1H), 1.91 - 1.78 (m, 2H), 0.95 (s, 9H), 0.21 (s, 3H), 0.14 (s, 3H). 13 13C NMR (100 MHz, CDCl3): δ 145.5, 142.1, 138.4, 128.3, 109.0, 82.6, 78.0, 77.3, 69.6, 34.6, 26.0, 21.5, 18.2, -4.1, -4.5. HRMS (FAB) m / z: [M+H] + Calcd for C 17 H 27 INO2Si 432.0856; Found 432.0859. [α] D 25 +21.1 (c 1.0, MeOH).

[0066] [Synthesis of (5S,8R,9R)-4-bromo-9-[(tert-butyldimethylsilyl)oxy]-2-iodo-6,7,8,9-tetrahydro-5H-5,8-epoxybenzo[7]annulen-3-amine (21)] To a solution of this oxabicycloiodo derivative (220 mg, 0.509 mmol) in CHCl (3 mL), N-bromosuccinimide (NBS: 91.0 mg, 0.511 mmol) was added portionwise over 1 h at −30 °C and stirred for 1 h. After stirring for an additional 30 min at 0 °C, the reaction mixture was quenched with saturated aqueous NaSO and extracted with CHCl. ​​The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-toluene (40:1) to afford the oxabicyclobromoiodo derivative (21) (230 mg, 0.451 mmol) as a colorless oil in 89% yield. The following results of the physicochemical evaluation support the structure of the oxabicyclobromoiodo derivative (21). 1 H NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 5.22 (d, J = 6.0 Hz, 1H), 5.04 (d, J = 5.5 Hz, 1H), 4.57 (s, 2H), 4.47-4.43 (m, 1H), 2.22-2.05 (m, 2H), 1.94-1.83 (m, 2H), 0.94 (s, 9H), 0.22 (s, 3H), 0.14 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ: 142.7, 140.6, 137.4, 129.3, 103.8, 81.2, 77.9, 77.8, 69.0, 33.1, 25.9, 21.5, 18.2, -4.0, -4.5. HRMS (FAB) m / z: [M+H] + Calcd for C 17 H 26 BrINO2Si 509.9961; Found 509.9993. [α] D 25 -25.0 (c 1.06, MeOH).

[0067] [Synthesis of (5S,8R,9R)-4-bromo-9-[(tert-butyldimethylsilyl)oxy]-6,7,8,9-tetrahydro-5H-5,8-epoxybenzo[7]-annulen-3-amine] To a solution of this oxabicyclobromoiodo derivative (21) (1350 mg, 2.64 mmol) in anhydrous tetrahydrofuran (THF: 25 mL), a 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in THF (i-PrMgCl·LiCl: 12 mL, 15.8 mmol) was added dropwise over 10 min at 0 °C under an argon atmosphere, and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CHCl2. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (15:1) to give the oxabicyclobromo derivative (661 mg, 2.32 mmol) as a white amorphous solid in 88% yield. The following results of the physicochemical evaluation support the structure of the oxabicyclobromo compound. 1 H NMR (400 MHz, CDCl3): δ 7.09 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.29 (d, J = 6.0 Hz, 1H), 5.09 (d, J = 5.0 Hz, 1H), 4.51-4.46 (m, 1H), 4.06 (s, 2H), 2.26-2.10 (m, 2H), 1.94-1.85 (m, 2H), 0.93 (s, 9H), 0.20 (s, 3H), 0.14 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 142.8, 140.0, 127.8, 127.4, 114.6, 105.9, 77.9, 77.8, 69.4, 33.0, 25.9, 21.6, 18.2, -4.0, -4.6. HRMS (FAB) m / z: [M] + Calcd for C17 H 26 BrNO2Si 383.0916; Found 383.0903. [α] D 25 -51.0 (c 0.82, MeOH).

[0068] [Synthesis of N-acetyl-N-{(5S,8R,9R)-4-bromo-9-[(tert-butyldimethylsilyl)oxy]-6,7,8,9-tetrahydro-5H-5,8-epoxy-benzo[7]annulen-3-yl}acetamide (22)] To a solution of this bromo oxabicycloimide (895 mg, 2.33 mmol) in anhydrous CHCl (20 mL) was added 4-dimethylaminopyridine (DMAP: 257 mg, 1.51 mmol), pyridine (0.560 mL, 6.99 mmol), and acetic anhydride (AcO: 0.71 mL, 6.99 mmol) at room temperature. After refluxing for 21 h, the reaction mixture was quenched with saturated aqueous NHCl and extracted with CHCl. ​​The combined organic layers were washed with saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (15:1) to afford the oxabicycloimide (22) (993 mg, 2.12 mmol) as a colorless oil in 91% yield. The following results of the physicochemical evaluation support the structure of the oxabicycloimide compound (22). 1 H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 5.34 (d, J = 6.0 Hz, 1H), 5.14 (d, J = 5.0 Hz, 1H), 4.56-4.52 (m, 1H), 2.36 (s, 3H), 2.28-2.13 (m, 5H), 2.04-1.86 (m, 2H), 0.95 (s, 9H), 0.23 (s, 3H), 0.18 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 172.4, 141.7, 140.0, 137.2, 129.0, 128.2, 120.1, 77.8, 77.7, 69.7, 33.5, 26.9, 26.5, 25.9, 21.7, 18.2, -4.0, -4.6. HRMS (FAB) m / z: [M+H] + Calcd for C 21 H 31 BrNO4Si 468.1206; Found 468.1212. [α] D 25 -53.1 (c 0.72, MeOH).

[0069] [Synthesis of N-{(5S,8R,9R)-4-acetyl-9-[(tert-butyldimethylsilyl)oxy]-6,7,8,9-tetrahydro-5H-5,8-epoxybenzo[7]-annulen-3-yl}acetamide (23)] To a solution of oxabicycloimide 22 (230 mg, 0.492 mmol) in anhydrous THF (5.5 mL), a 1.6 M n-butyllithium solution in hexane (n-BuLi: 1.8 mL, 2.95 mmol) was added dropwise over 2 min at −78 °C under an argon atmosphere and stirred at the same temperature for 2.5 h to undergo Fries-like intramolecular rearrangement. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (3:2) to give aceto-oxabicycloamide 23 (131 mg, 0.336 mmol) as a white solid in 68% yield. The following results of the physicochemical evaluation support the structure of the aceto-oxabicycloamide compound (23). 11H NMR (600 MHz, CDCl3): δ 7.86 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 5.10 (d, J = 5.4 Hz, 1H), 5.05 (d, J = 6.6 Hz, 1H), 4.53 - 4.50 (m, 1H), 2.51 (s, 3H), 2.32 - 2.27 (m, 1H), 2.23 - 2.11 (m, 4H), 1.97 - 1.91 (m, 2H), 0.94 (s, 9H), 0.22 (s, 3H), 0.16 (s, 3H). 13 13C NMR (150 MHz, CDCl3): δ 205.4, 169.0, 137.6, 134.0, 132.1, 130.4, 129.7, 123.9, 78.0, 75.1, 70.0, 34.9, 32.9, 25.9, 24.4, 21.6, 18.2, -4.0, -4.6. HRMS (FAB) m / z: [M+H] + Calcd for C 21 H 32 NO4Si 390.2101; Found 390.2071. [α] D 25 -19.0 (c 0.79, MeOH).

[0070] [(7R,8R,11S)-7-[(tert-butyldimethylsilyl)oxy]-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxy-cyclohepta[f]quinolin-1-one (24) and (7R,8R,11S)-7-[(tert-butyldimethylsilyl)oxy]-1-methyl-4,7,8,9,10,11-hexahydro-3H-8,11-epoxy-cyclohepta[f]quinolin-3-one (25) Synthesis] To a solution of aceto-oxabicycloamide 23 (69.1 mg, 0.177 mmol) in anhydrous dioxane (1.5 mL) was added potassium tert-butoxide (t-BuOK: 67.4 mg, 0.532 mmol), and the reaction mixture was stirred at 100 °C for 1.5 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (1:3) and acetone-EtOAc (1:1) to afford the desired 4-quinolone 24 (47.4 mg, 0.128 mmol) and the undesired 2-quinolone 25 (4.7 mg, 0.013 mmol) as white amorphous solids in 72% and 7%, respectively. The following results of physicochemical evaluation of the desired 4-quinolone (24) and the undesired 2-quinolone (25) support their structures. Desired 4-quinolone (24): 1 H NMR (600 MHz, CDCl3): δ 11.32 (brs, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 6.3 Hz, 1H), 6.05 (d, J = 1.0 Hz, 1H), 5.24 (d, J = 5.5 Hz, 1H), 4.56-4.53 (m, 1H), 2.35-2.24 (m, 5H), 2.13-2.07 (m, 1H), 1.93-1.88 (m, 1H), 0.94 (s, 9H), 0.24 (s, 3H), 0.17 (s, 3H). (However, NOESY showed NOE between the NH group of the 4-quinolone structure and the 2-position methyl group.) 1313C NMR (150 MHz, CDCl3): δ 180.7, 148.8, 141.8, 140.6, 131.5, 131.3, 119.6, 117.2, 110.7, 77.1, 76.1, 70.5, 34.4, 26.0, 21.5, 19.8, 18.2, -3.9, -4.6. HRMS (FAB) m / z: calc for C 21 H 30 NO3Si, [M+H] + , 372.1995; Found 372.1996. [α]D25 -144.3 (c 0.27, MeOH). Unexpected 2 - quinolone derivative (25): 1 1H NMR (400 MHz, CDCl3): δ 11.86 (s, 1H), 7.51 (d, 1H, J = 8.5 Hz), 7.31 (d, 1H, J = 8.5 Hz), 6.54 (s, 1H), 5.94 (d, 1H, J = 6.1 Hz), 5.20 (d, 1H, J = 5.6 Hz), 4.58 - 4.54 (m, 1H), 2.67 (s, 3H), 2.40 - 2.30 (m, 2H), 2.12 - 2.06 (m, 1H), 2.00 - 1.93 (m, 1H), 0.94 (s, 9H), 0.25 (s, 3H), 0.17 (s, 3H). 13 13C NMR (150 MHz, CDCl3): δ 163.2, 149.3, 138.9, 138.7, 131.3, 130.6, 123.5, 116.9, 115.8, 77.5, 75.6, 70.3, 35.0, 26.4, 25.9, 21.5, 18.2, -3.9, -4.7. HRMS (FAB) m / z: [M+H] + Calcd for C 21 H 30 NO3Si 372.1995; Found 372.1978. [α] D 25-97.4 (c 0.60, MeOH).

[0071] [Synthesis of (7R,8R,11S)-7-hydroxy-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one] To a solution of this 4-quinolone (24) (82.0 mg, 0.221 mmol) in anhydrous THF (3 mL) was added a solution of 1 M tetrabutylammonium fluoride (1 M TBAF: 0.04 mL, 0.401 mmol) in THF. The reaction mixture was stirred at room temperature for 65 hours, and then MeOH was added to the mixture. The reaction solution was filtered through a Celite membrane, washed with MeOH, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with acetone-EtOAc (1:1) to give hydroxy-4-quinolone (26) (50.8 mg, 0.197 mmol) as a white amorphous solid in 89% yield. The following results of the physicochemical evaluation support the structure of the hydroxy-4-quinolone compound. 1 H NMR (600 MHz, CD3OD): δ 7.72 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 6.6 Hz, 1H), 6.06 (s, 1H), 5.13 (d, J = 5.4 Hz, 1H), 4.56-4.53 (m, 1H), 2.38 (s, 3H), 2.31-2.20 (m, 2H), 2.01-1.90 (m, 2H). 13 C NMR (150 MHz, CD3OD): δ 182.2, 151.2, 142.4, 141.8, 132.5, 132.4, 120.2, 118.0, 111.2, 78.4, 77.2, 70.3, 35.2, 22.1, 19.3. HRMS (FAB) m / z: [M+H] + Calcd for C 15 H 16NO3258.1130; Found 258.1142. [α] D 25 -145.3 (c 0.5, MeOH).

[0072] [Synthesis of (8R,11S)-3-methyl-8,9,10,11-tetrahydro-1H-8,11-epoxycyclohepta[f]quinoline-1,7(4H)-dione (26)] To a solution of this hydroxy-4-quinolone (313 mg, 1.23 mmol) in dimethyl sulfoxide (DMSO: 5 mL) was added 2-iodoxybenzoic acid (IBX: 554 mg, 1.96 mmol) at room temperature, and the reaction mixture was stirred at the same temperature for 5 hours. Saturated aqueous NaHCO3 was added to the reaction mixture, and the mixture was extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with acetone-EtOAc (1:1) to afford oxo-4-quinolone (26) (274 mg, 1.07 mmol) as a white amorphous solid in 88% yield. The following results of the physicochemical evaluation support the structure of the oxo-4-quinolone compound (26). 1 H NMR (400 MHz, DMSO-d6): δ 11.78 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 6.4 Hz, 1H), 5.94 (s, 1H), 4.63 (dd, J = 7.1, 1.4 Hz, 1H), 2.38-2.24 (m, 5H), 1.83-1.76 (m, 1H), 1.66-1.55 (m, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 194.2, 178.7, 150.0, 149.5, 144.5, 128.3, 122.3, 118.7, 117.6, 111.5, 79.8, 74.6, 29.7, 23.5, 19.0. HRMS (FAB) m / z: [M+H] + Calcd for C 15 H 14 NO3256.0974; Found 256.0986. [α] D 25 -26.1 (c 0.25, MeOH).

[0073] [Synthesis of (8R,11S)-2-bromo-3-methyl-8,9,10,11-tetrahydro-1H-8,11-epoxycyclohepta[f]quinoline-1,7(4H)-dione] To a solution of oxo-4-quinolone (26) (74.5 mg, 0.292 mmol) in DMF (3 mL) was added NBS (52.7 mg, 0.296 mmol) in three portions at room temperature, and the reaction mixture was stirred at the same temperature for 3 hours. Toluene was added to the reaction mixture, and the mixture was concentrated. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (1:3) to afford the bromo-4-quinolone (71.8 mg, 0.214 mmol) as a white amorphous solid in 74% yield. The following results of the physicochemical evaluation support the structure of the oxo-3-bromo-4-quinolone compound. 1 H NMR (600 MHz, DMSO-d6): δ 8.06 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 6.74 (d, J = 6.6 Hz, 1H), 4.69 (d, J = 7.8 Hz, 1H), 2.55 (s, 3H), 2.43-2.33 (m, 2H), 1.91-1.83 (m, 1H), 1.70-1.64 (m, 1H). 13 C NMR (150 MHz, DMSO-d6): δ 194.0, 172.4, 150.0, 149.0, 143.0, 128.5, 123.0, 118.0, 117.2, 109.0, 79.8, 74.9, 29.7, 23.5, 21.3. HRMS (FAB) m / z: [M+H] + Calcd for C 15 H 13 BrNO3334.0079; Found 334.0091. [α] D 25 -37.6 (c 0.187, MeOH).

[0074] [Synthesis of (8R,11S)-2-methoxy-3-methyl-8,9,10,11-tetrahydro-1H-8,11-epoxycyclohepta[f]quinoline-1,7(4H)-dione (27)] Anhydrous MeOH (2.1 ml) and n-BuLi (1.0 ml, 1.62 mmol) were mixed in a round-bottom flask and pre-stirred at room temperature for 5 minutes. This suspension was added to a solution of oxo-3-bromo-4-quinolone (54.4 mg, 0.162 mmol) and CuI (29.5 mg, 0.406 mmol) in anhydrous DMF (5.3 ml). The reaction mixture was stirred at room temperature for 5 minutes and then at 120°C for 9 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexane-EtOAc (1:3) and acetone-EtOAc (1:1) to afford oxo-3-methoxy-4-quinolone 27 (38.3 mg, 0.134 mmol) in 82% yield as a white amorphous solid. The following results of the physicochemical evaluation support the structure of the oxo-3-methoxy-4-quinolone (27). 1H NMR (600 MHz, CDCl3): δ 11.95 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 4.80 (dd, J = 8.7, 1.4 Hz, 1H), 3.81 (s, 3H), 2.59–2.52 (m, 4H), 2.49–2.43 (m, 1H), 2.14–2.10 (m, 1H), 1.83–1.78 (m, 1H). 13 C NMR (150 MHz, CDCl3): δ 195.2, 174.8, 151.1, 143.2, 142.9, 142.5, 128.8, 123.3, 120.4, 118.0, 80.9, 75.9, 60.1, 30.0,00. 24.4, HRMS (FAB) m / z: [M+H] + Calcd for C 16 H 16 NO4286.1079; Found 286.1058. [α] D 25 -95.6 (c 0.35, MeOH).

[0075] [Waltherione A :character A(I)] To a solution of 2-bromoanisole (0.0300 mL, 0.247 mmol) in anhydrous THF (1.0 mL) was added dropwise t-BuLi (1.6 M, 0.2 mL, 0.320 mmol) in hexane at −78 °C. The reaction mixture was stirred at the same temperature for 2 h. To the reaction mixture was added a solution of oxo-3-methoxy-4-quinolone (27) (4.7 mg, 0.016 mmol) in anhydrous THF (1.0 mL). The reaction mixture was stirred for 10 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane-EtOAc (1:3) and acetone-EtOAc (1:1) to give waltherion A (I) (5.2 mg, 0.013 mmol) as a white amorphous solid in 80% yield. The following results of the physicochemical evaluation support the structure of waltherion A(I). 1 H NMR (400 MHz, CDCl3): δ 8.84 (brs, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.24-7.21 (m, 1H), 6.97 (dd, J = 0.95, 8.3 Hz, 1H), 6.75 (td, J = 1.0, 7.6 Hz, 1H), 6.73 (dd, J = 1.4, 8.2 Hz, 1H), 6.40 (dd, J = 1.7, 7.7 Hz, 1H), 5.09 (s, 1H), 4.69 (dd, J = 2.0, 8.0 Hz, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 2.43 (s, 3H), 2.46-2.35 (m, 2H), 2.11-2.08 (m, 1H), 2.05-2.00 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 174.8, 156.3, 142.5, 141.8, 139.9, 138.7, 134.6, 132.5, 131.8, 130.9, 128.6, 120.7, 120.0, 116.6, 110.9, 80.1, 78.2, 75.7, 59.9, 55.5, 34.1, 22.3, 14.9. HRMS (FAB) m / z: [M+H] + Calcd for C 23 H 24 NO5394.1654; Found 394.1647. [α] D 25 -69.3 (c 0.1, MeOH)

[0076] Isolation Example 2: Isolation of 5'-Methoxy-waltherion A (31) When waltherion A (I) was isolated, 5'-methoxy-waltherion A (31) was also isolated and used.

[0077] (Synthesis Example 3: Synthesis of (7R,8R,11S)-7-hydroxy-2-methoxy-7-(3-methoxyphenyl)-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:2'-demethoxy-3'-methoxy-waltherion A (32)) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that instead of the reaction of 2-lithioanisole obtained from 2-bromoanisole and t-BuLi with oxo-4-quinolone (26), a Grignard reagent of 3-bromoanisole was used. A round-bottom flask was charged with magnesium turnings (158 mg, 6.51 mmol) and iodine (38.8 mg, 0.153 mmol), backfilled with argon, and anhydrous THF (5.7 mL) was added. 3-Bromoanisole (0.8 mL, 6.37 mmol), which had been anhydrous under reduced pressure, was then added to the flask, and the reaction mixture was stirred at room temperature for 30 minutes. The resulting 1 M Grignard reagent was added dropwise to a solution of oxo-3-methoxy-4-quinolone 27 (4.7 mg, 0.0165 mmol) in anhydrous THF (1 mL) at 0°C, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was cooled to 0°C, quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:H2O=2:3) to give 2'-demethoxy-3'-methoxy-waltherion A (32) as a white solid (1.2 mg) in 18% yield. The following results of its physicochemical evaluation support the structure of 2'-demethoxy-3'-methoxy-waltherion A (32). 1 H NMR (600 MHz, CD3OD) δ: 7.43 (1H, d, J = 8.7 Hz), 7.36 (d, J = 8.7 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.9-6.92 (m, 1H), 6.84-6.87 (m, 1H), 6.77 (ddd, J = 0.92, 2.8, 8.2 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 4.38 (dd, J = 2.1, 8.0 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 2.41-2.48 (m, 4H), 2.28-2,38 (m, 1H), 1.99-2.09 (m, 2H). 13C NMR (150 MHz, CD3OD) δ: 176.0, 160.7, 151.5, 143.6, 143.1, 142.2, 134.3, 132.9, 129.5, 120.9, 118.2, 114.3, 113.1, 84.0, 77.4, 77.1, 60.3, 55.6, 34.7, 23.7, 14.3. HRMS (FAB) m / z: Calcd for C 23 H 24 NO5, [M+H] + , 394.1654; found 394.1574 [α] D 25 = +20.2 (c 0.0857, MeOH)

[0078] Synthesis Example 4: Synthesis of (7R,8R,11S)-7-hydroxy-2-methoxy-7-(4-methoxyphenyl)-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:2'-demethoxy-4'-methoxy-waltherion A (33) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that a Grignard reagent of 4-bromoanisole was used instead of the reaction mixture of 2-bromoanisole and t-BuLi used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)]. A round-bottom flask was charged with magnesium turnings (76.6 mg, 3.15 mmol) and iodine (55.1 mmol, 0.217 mmol), backfilled with argon, and anhydrous THF (2.8 mL) was added. 4-Bromoanisole (0.4 mL, 3.21 mmol), which had been anhydrous under reduced pressure, was then added to the flask, and the reaction mixture was stirred at room temperature for 1 h. The resulting 1 M Grignard reagent was added dropwise to a solution of oxo-3-methoxy-4-quinolone 27 (4.7 mg, 0.0165 mmol) in anhydrous THF (1 mL) at 0 °C, and the mixture was stirred at room temperature for 22 h. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:H2O=2:3) to give 2'-demethoxy-4'-methoxy-waltherion A (33) as a white solid (1.9 mg) in 29% yield. The following results of its physicochemical evaluation support the structure of 2'-demethoxy-4'-methoxy-waltherion A (33). 1 H NMR (600 MHz, CD3OD) δ: 7.57 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.23-7.26 (m, 1H) 7.10 (d, J = 8.2 Hz, 1H), 6.71-6.74 (m, 1H), 6.67 (d, J = 6.5 Hz, 1H), 6.30 (dd, J = 7.9, 2.4 Hz, 1H), 4.58 (s, 1H), 4.00 (s, 3H), 3.81 (s, 3H), 2.47 (s, 3H), 2.22-2,35 (m, 2H), 1.99-2,05 (m, 2H). 13 C NMR (150 MHz, CD3OD) δ: 195.2, 174.8, 151.1, 143.2, 142.9, 142.5, 128.8, 123.3, 120.4, 118.0, 80.9, 75.9, 60.1, 30.0, 24.4, 14.8. HRMS (FAB) m / z: Calcd for C 23 H 24 NO5, [M+H] + , 394.1654; found 394.1590 [α] D 25 = -69.3 (c 0.1, MeOH)

[0079] Synthesis Example 5: Synthesis of (7S,8R,11S)-7-(5-amino-2-methoxyphenyl)-7-hydroxy-2-methoxy-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one: 5'-amino-waltherion A (34) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that a synthetic intermediate was prepared using N,N'-dibenzyl-3-bromo-4-methoxyaniline instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], and then the benzyl group of the synthetic intermediate was deprotected. To a solution of N,N'-dibenzyl-3-bromo-4-methoxyaniline (136 mg, 0.355 mmol) in anhydrous THF (2.0 mL), t-BuLi solution (1.6 M in hexane, 0.4 mL, 0.640 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 50 min. A solution of oxo-3-methoxy-4-quinolone (27) (9.1 mg, 0.0319 mmol) in anhydrous THF (1 mL) was added via syringe, and the mixture was stirred for an additional 7 h. The mixture was then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluting with hexane-EtOAc (1:3) and acetone-EtOAc (1:1) to give a white solid (14.5 mg) of the synthetic intermediate (5'-NBu2 derivative) in which the amino group at the 5' position of 5'-amino-waltherion A was protected with a benzyl group in 77% yield. The following results of the physicochemical evaluation support the structure of the synthetic intermediate (5'-NBu2 derivative) in which the amino group at the 5' position of 5'-amino-walserion A is protected with a benzyl group. 1 H NMR (600 MHz, CDCl3) δ: 8.08 (brs, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.14-7.18 (m, 6H), 6.99-7.00 (m, 4H), 6.87 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.53 (dd, J = 3.2, 8.9 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 5.71 (d, J = 3.2 Hz, 1H), 5.12 (s, 1H), 4.62 (dd, J = 1.8, 8.0 Hz, 1H), 4.40 (d, J = 16.9 Hz, 2H), 4.29 (d, J = 16.9 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 2.46 (s, 3H), 2.29-2.37 (m, 2H), 1.93-2.03 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ: 174.8, 148.5, 143.0, 142.1, 141.9, 139.0, 138.8, 135.0, 132.3, 130.8, 128.4, 126.6, 126.6, 119.9, 118.6, 116.8, 112.3, 111.8, 80.2, 78.5, 75.6, 59.9, 55.9, 55.7, 34.2, 22.4, 14.8. HRMS (FAB) m / z: Calcd for C 37 H 37 N2O5, [M+H] + , 589.2702; found 589.2612 [α] D 25 = -19.0 (c 0.090, MeOH). To a solution of the above synthetic intermediate (5'-NBu2 derivative) (3.4 mg, 0.00578 mmol) in anhydrous EtOAc (2.0 mL) was added 5% Pd-C (3.5 mg). The mixture was hydrogenated under a hydrogen gas atmosphere at room temperature for 17 hours with stirring. The solution was filtered through a Celite membrane, extracted with methanol, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 1:2) to give 5'-amino-waltherion A (34) as a white solid (1.2 mg) in 51% yield. The following results of its physicochemical evaluation support the structure of 5'-amino-waltherion A (34). 1 H NMR (600 MHz, CDCl3) δ: 9.22 (brs, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 6.0 Hz, 1H), 6.56 (dd, J = 2.8, 8.6 Hz, 1H), 5.78 (d, J = 2.8 Hz, 1H), 5.24 (s, 1H), 4.66 (dd, J = 1.8, 8.0 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.29 (s, 2H), 2.35-2.44 (m, 5H), 1.99-2.10 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ: 174.9, 150.0, 142.6, 142.0, 139.7, 139.2, 138.7, 135.7, 132.5, 130.8, 120.2, 120.1, 116.8, 115.2, 112.1, 80.4, 78.3, 75.8, 60.0, 55.9, 34.2, 22.5, 14.9. HRMS (FAB) m / z: Calcd for C 23 H 25 N2O5, [M+H] + , 409.1673; found 409.1706 [α] D25 = -63.8 (c 0.10, MeOH)

[0080] (Synthesis Example 6: Synthesis of (7S,8R,11S)-7-hydroxy-7-(5-hydroxy-2-methoxyphenyl)-2-methoxy-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one: 5'-hydroxy-waltherion A (35)) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that a synthetic intermediate was prepared using (3-bromo-4-methoxyphenoxy)-t-butyldimethylsilane instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], and then the TBS group of the synthetic intermediate was deprotected. To a solution of (3-bromo-4-methoxyphenoxy)-t-butyldimethylsilane (116 mg, 0.364 mmol) in anhydrous THF (2.0 mL), t-BuLi solution (1.6 M in hexane, 0.38 mL, 0.617 mmol) was added dropwise via syringe at -78 °C, and the reaction mixture was stirred at the same temperature for 50 min. A solution of oxo-3-methoxy-4-quinolone (27) (8.8 mg, 0.0308 mmol) in anhydrous THF (2.0 mL) was added and stirred for an additional 8 h. The mixture was then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 2:1) and isolated as a synthetic intermediate. To a solution of this synthetic intermediate in anhydrous THF (2 mL) was added a solution of tetra-n-butylammonium fluoride (TBAF) in THF (1 M, 0.05 mL, 0.05 mmol). The mixture was stirred at room temperature for 13 hours, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 1:2) to give 5'-hydroxy-waltherion A (35) as a white solid (3.9 mg) in 33% yield. The following results of its physicochemical evaluation support the structure of 5'-hydroxy-waltherion A (35). 1 H NMR (600 MHz, DMSO-d6) δ: 11.49 (brs, 1H), 8.64 (brs, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.56-6.59 (m, 2H), 5.68 (d, J = 3.0 Hz, 1H), 5.23 (s, 1H), 4.56 (dd, J = 1.8, 8.0 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 2.35 (s, 3H), 2.22-2.27 (m, 1H), 2.07-2.13 (m, 1H), 1.85-1.91 (m, 1H), 1.78-1.82 (m, 1H). 13 C NMR (150 MHz, DMSO-d6) δ: 173.2, 150.1, 149.5, 140.9, 140.7, 140.2, 138.6, 135.7, 131.8, 130.6, 119.2, 118.8, 116.8, 113.9, 112.5, 79.2, 76.9, 74.4, 58.8, 56.0, 34.1, 22.0, 14.0. HRMS (FAB) m / z: Calcd for C 23 H 24 NO6, [M+H] +, 410.1604; found 410.1583 [α] D 25 = -63.0 (c 0.03, MeOH : Acetone = 1 : 1)

[0081] (Synthesis Example 7: Synthesis of (7S,8R,11S)-7-(5-chloro-2-methoxyphenyl)-7-hydroxy-2-methoxy-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one: 5'-chloro-waltherion A (36)) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that 2-bromo-4-chloroanisole was used instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], as follows. To a solution of 2-bromo-4-chloroanisole (0.04 mL, 0.294 mmol) in anhydrous THF (1.0 mL), t-BuLi solution (1.6 M in hexane, 0.24 mL, 0.384 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 1 h. Then, a solution of oxo-3-methoxy-4-quinolone 27 (5.4 mg, 0.0189 mmol) in anhydrous THF (1 mL) was added dropwise via syringe. The mixture was stirred at room temperature for 8 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 2:3) to give 5'-chlorowaltherion A (36) as a white solid (6.5 mg) in 80% yield. The following results of its physicochemical evaluation support the structure of 5'-chloro-waltherion A (36). 1H NMR (600 MHz, CD3OD) δ: 7.57 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 2.7, 8.8 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 6.68 (d, J = 6.4 Hz, 1H), 6.24 (d, J = 2.7 Hz, 1H), 4.74 (dd, J = 2.2, 8.0 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 2.47 (s, 3H), 2.37-2.42 (m, 1H), 2.26-2.33 (m, 1H), 2.00-2.05 (m, 2H). 13 C NMR (150 MHz, CD3OD) δ: 176.0, 157.0, 143.7, 143.2, 142.6, 140.5, 137.6, 133.3, 132.4, 131.8, 129.5, 126.3, 120.9, 118.3, 114.0, 81.0, 78.9, 77.0, 60.3, 56.5, 35.2, 23.1, 14.3. HRMS (FAB) m / z: Calculated for C 23 H 23 ClNO5, [M+H] + , 428.1265; found 428.1229 [α] D 25 = -47.3 (c 0.11, MeOH)

[0082] (Synthesis Example 8: (7S, 8R, 11S)-7-(5-fluoro-2-methoxyphenyl)-7-hydroxy-2-methoxy-3-methyl-4,7,8 ,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:5'-フルオロ-ワルセリオンA(37)のSynthesis) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that 2-bromo-4-fluoroanisole was used instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], as follows. To a solution of 2-bromo-4-fluoroanisole (0.10 mL, 0.771 mmol) in anhydrous THF (5.0 mL), t-BuLi solution (1.6 M in hexane, 0.96 mL, 1.54 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 1 h. Then, a solution of oxo-3-methoxy-4-quinolone (27) (22.0 mg, 0.0771 mmol) in anhydrous THF (2.0 mL) was added dropwise via syringe. The mixture was stirred at room temperature for 6 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 2:3) to give 5'-fluoro-waltherion A (37) as a white solid (25.4 mg) in 80% yield. The following results of its physicochemical evaluation support the structure of 5'-fluoro-waltherion A (37). 1 H NMR (600 MHz, CD3OD) δ: 7.58 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 4.4, 9.0 Hz, 1H), 6.95-6.99 (m, 1H), 6.68 (d, J = 6.4 Hz, 1H), 6.00 (dd, J = 3.2, 9.9 Hz, 1H), 4.74 (dd, J = 2.2, 8.0 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 2.47 (s, 3H), 2.43-2.36 (m, 1H), 2.26-2.33 (m, 1H), 2.00-2.05 (m, 2H). 13C NMR (150 MHz, CD3OD) δ: 176.0, 157.7 (d, J = 237.33 Hz), 154.4 (d, J = 1.8 Hz), 143.7, 137.6 (d, J = 5.8 Hz), 143.2, 142.6, 140.5, 133.3, 131.9, 120.9, 119.4 (d, J = 25.3 Hz), 118.2, 115.5 (d, J = 23.1 Hz),113.5 (d, J = 8.3 Hz), 113.5, 81.1, 78.8, 77.0, 60.3, 56.6, 35.2, 23.1, 14.3. HRMS (FAB) m / z: Calcd for C 23 H 23 FNO5, [M+H] + , 412.1560; found 412.1432 [α] D 25 = -126.5 (c 0.236, MeOH)

[0083] (Synthesis Example 9: Synthesis of (7S,8R,11S)-7-hydroxy-2-methoxy-7-[2-methoxy-5-(trifluoromethyl)phenyl]-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:5'-trifluoromethyl-waltherion A (38)) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that 2-bromo-4-(trifluoromethyl)anisole was used instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], as follows. To a solution of 2-bromo-4-(trifluoromethyl)anisole (0.050 mL, 0.321 mmol) in anhydrous THF (2.0 mL), t-BuLi solution (1.6 M in hexane, 0.38 mL, 0.617 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 50 min. A solution of oxo-3-methoxy-4-quinolone 27 (8.8 mg, 0.0308 mmol) in anhydrous THF (1.0 mL) was then added dropwise. The mixture was stirred at room temperature for 7 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 2:3) to give 5'-trifluoro-waltherion A (38) as a white solid (10.5 mg) in 74% yield. The following results of its physicochemical evaluation support the structure of 5'-trifluoromethyl-waltherion A (38). 1 H NMR (600 MHz, CDCl3) δ: 10.65 (brs, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.48-7.50 (m, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 6.4 Hz, 1H), 6.65 (d, J = 2.2 Hz, 1H), 4.81 (s, 1H), 4.70 (dd, J = 2.1, 8.0 Hz, 1H), 4.04 (s, 3H), 3.81 (s, 3H), 2.32-2.46 (m, 5H), 2.10-2.14 (m, 1H), 1.99-2.04 (m, 1H). 13C NMR (150 MHz, CDCl3) δ: 174.8, 158.8 (d, J = 1.1 Hz), 142.5, 142.1, 139.4, 135.6, 132.0, 129.8, 129.0 (m), 126.2 (distorted q, J = 3.6 Hz), 125.1, 123.1 (distorted t, J = 34.9 Hz), 120.2, 117.6, 111.1, 79.8, 78.2, 76.0, 60.0, 56.1, 34.2, 22.4, 14.8. HRMS (FAB) m / z: Calcd for C 24 H 23 F3NO5, [M+H] + , 462.1528; found 462.1448 [α] D 25 = -151.5 (c 0.350, MeOH)

[0084] (Synthesis Example 10: Synthesis of (7S,8R,11S)-7-(2-fluoro-6-methoxyphenyl)-7-hydroxy-2-methoxy-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one: 6'-fluoro-waltherion A (39)) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that 2-bromo-3-fluoroanisole was used instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], as follows. To a solution of 2-bromo-3-fluoroanisole (59.6 mg, 0.291 mmol) in anhydrous THF (2.0 mL), t-BuLi solution (1.6 M in hexane, 0.36 mL, 0.582 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 50 min. A solution of oxo-3-methoxy-4-quinolone (27) (8.3 mg, 0.0291 mmol) in anhydrous THF (1.0 mL) was then added dropwise. The mixture was stirred at room temperature for 7 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 2:3) to give 6'-fluoro-waltherion A (39) as a white solid (5.1 mg) in 43% yield. The following results of its physicochemical evaluation support the structure of 6'-fluoro-waltherion A (39). 1 H NMR (600 MHz, CDCl3) δ: 10.64 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 6.4 Hz, 1H), 6.69 (dd, J = 2.4, 10.5 Hz, 1H), 6.44 (td, J = 2.4, 8.6 Hz, 1H), 6.34-6.37 (m, 1H), 4.85 (s, 3H), 4.65 (dd, J = 2.0, 8.0 Hz, 1H), 3.98 (s, 3H), 3.80 (s, 3H), 2.30-2.46 (m, 4H), 2.30-2.37 (m, 1H), 2.08-2.12 (m, 2H), 1.97-2.03 (m, 2H). 13C NMR (150 MHz, CDCl3) δ: 174.7, 162.9 (d, J = 246.0 Hz), 157.3 (d, J = 9.8 Hz), 142.2, 142.06, 141.96, 141.5, 139.3, 133.3, 132.9 (d, J = 10.1 Hz), 132.2, 130.6 (d, J = 11.2 Hz), 120.1, 117.5, 107.0 (d, J = 20.6 Hz), 99.5 (d, J = 26.0 Hz), 80.2, 78.0, 75.8, 59.9, 56.0, 34.3, 22.4, 14.7. HRMS (FAB) m / z: Calcd for C 23 H 23 FNO5, [M+H] + , 412.1560; found 412.1560 [α] D 25 = -98.4 (c 0.450, MeOH)

[0085] (Synthesis Example 11: Synthesis of (7S,8R,11S)-7-(4-fluoro-2-methoxyphenyl)-7-hydroxy-2-methoxy-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one: 4'-fluoro-waltherion A (40)) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that 2-bromo-5-fluoroanisole was used instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], as follows. To a solution of 2-bromo-5-fluoroanisole (0.04 mL, 0.314 mmol) in anhydrous THF (2.0 mL), t-BuLi solution (1.6 M in hexane, 0.38 mL, 0.617 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 50 min. Then, a solution of oxo-3-methoxy-4-quinolone (27) (8.8 mg, 0.0308 mmol) in anhydrous THF (1.0 mL) was added dropwise via syringe. The mixture was stirred at room temperature for 7 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 2:3) to give 4'-fluoro-waltherion A (40) as a white solid (9.0 mg) in 70% yield. The following results of its physicochemical evaluation support the structure of 4'-fluoro-waltherion A (40). 1 H NMR (600 MHz, CDCl3) δ: 9.30 (brs, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.18 (td, J = 5.8, 8.4 Hz, 1H), 6.75-6.78 (m, 2H), 6.51 (ddd, J = 1.0, 8.4, 11.3 Hz, 1H), 5.35 (s, 1H), 4.69 (dd, J = 1.8, 8.2 Hz, 1H), 4.00 (s, 3H), 3.83 (s, 3H), 2.35-2.43 (m, 5H), 2.12-2.18 (m, 1H), 1.96-2.03 (m, 1H). 13C NMR (150 MHz, CDCl3) δ: 174.9, 160.8 (d, J = 249.3 Hz), 157.7 (d, J = 6.5 Hz), 141.8, 140.7, 140.1, 138.7, 132.1 (d, J = 4.7 Hz), 131.4 (d, J = 2.5 Hz), 129.1 (d, J = 11.9 Hz), 122.7 (d, J = 11.2 Hz), 120.4, 116.5, 110.8 (d, J = 26.4 Hz), 107.2 (d, J = 2.5 Hz), 81.2, 76.3, 75.9 (d, J = 3.2 Hz), 59.9, 56.5, 34.4, 22.4, 14.9. HRMS (FAB) m / z: Calcd for C 23 H 23 FNO5, [M+H] + , 412.1560; found 412.1563 [α] D 25 = -113.2 (c 0.255, MeOH)

[0086] Synthesis Example 12: Synthesis of (7S,8R,11S)-7-(3-fluoro-2-methoxyphenyl)-7-hydroxy-2-methoxy-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:3'-fluoro-waltherion A (41) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that 2-bromo-6-fluoroanisole was used instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], as follows. To a solution of 2-bromo-6-fluoroanisole (0.038 mL, 0.298 mmol) in anhydrous THF (2.0 mL), t-BuLi solution (1.6 M in hexane, 0.37 mL, 0.596 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 50 min. A solution of oxo-3-methoxy-4-quinolone 27 (8.5 mg, 0.0298 mmol) in anhydrous THF (1.0 mL) was then added dropwise. The mixture was stirred at room temperature for 8 h, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 2:3) to give 3'-fluoro-waltherion A (41) as a white solid (7.4 mg) in 65% yield. The following results of its physicochemical evaluation support the structure of 3'-fluoro-waltherion A (41). 1 H NMR (600 MHz, CDCl3) δ: 10.31 (brs, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.97-7.00 (m, 1H), 6.83 (d, J = 6.4 Hz, 1H), 6.74-6.77 (m, 1H), 6.21-6.22 (m, 1H), 5.03 (s, 1H), 4.54 (dd, J = 2.0, 8.0 Hz, 1H), 4.16 (d, J = 2.8 Hz, 3H), 3.82 (s, 3H), 2.42-2.46 (m, 4H), 2.33-2.39 (m, 1H), 2.09-2.13 (m, 1H), 2.01-2.07 (m, 1H). 13C NMR (150 MHz, CDCl3) δ: 174.8, 155.0 (d, J = 247.1 Hz), 144.9 (d, J = 10.1 Hz), 142.0 (d, J = 9.0 Hz), 141.1, 140.5, 139.2, 132.2, 130.7, 127.2 (d, J = 2.2 Hz), 122.7 (d, J = 8.3 Hz), 120.1, 117.4, 116.4 (d, J = 19.9 Hz), 116.3, 81.5, 78.4 (d, J = 2.2 Hz), 75.9, 61.8, 60.0, 34.2, 22.5, 14.8. HRMS (FAB) m / z: Calcd for C 23 H 23 FNO5, [M+H] + , 412.1560; found 412.1563 [α] D 25 = -112.2 (c 0.370, MeOH)

[0087] Synthesis Example 13: Synthesis of (7S,8R,11S)-7-hydroxy-7-(2-methoxyphenyl)-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:3-demethoxy-waltherion A (42) The reaction was carried out in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that instead of the reaction of 2-lithioanisole obtained from 2-bromoanisole and t-BuLi with oxo-4-quinolone (26), a Grignard reagent of 2-bromoanisole was used. A round-bottom flask was charged with magnesium turnings (159 mg, 6.55 mmol) and iodine (38.7 mg, 0.152 mmol), and the flask was filled with argon. Anhydrous THF (5.7 mL) was added. 2-Bromoanisole (0.8 mL, 6.50 mmol), which had been anhydrous under reduced pressure, was then added to the flask, and the reaction mixture was stirred at room temperature for 1 hour. The resulting 1 M Grignard reagent was added dropwise to a solution of oxo-4-quinolone 26 (11.6 mg, 0.0454 mmol) in anhydrous THF (1.5 mL) at 0 °C, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:H2O=2:3) to give 3-demethoxy-waltherion A (42) as a white solid (11.0 mg) in 66% yield. The following results of its physicochemical evaluation support the structure of 3-demethoxy-waltherion A (42). 1 H NMR (600 MHz, CD3OD) δ: 7.61 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.23-7.26 (m, 1H), 7.10 (dd, J = 0.86, 8.3 Hz, 1H), 6.73 (td, J = 1.03, 7.53 Hz, 1H), 6.61 (d, J = 6.5 Hz, 1H), 6.31 (dd, J = 1.68, 7.7 Hz, 1H), 6.12 (d, J = 0.43 Hz, 1H), 4.00 (s, 3H), 2.38-2.44 (m, 4H), 2.23-2,31 (m, 1H), 1.97-2.04 (m, 1H). 13C NMR (150 MHz, CD3OD) δ: 158.2, 151.2, 142.5, 142.3, 135.5, 134.3, 133.2, 132.7, 130.0, 121.2, 119.8, 118.2, 112.4, 111.6, 81.3, 79.1, 76.9, 56.0, 35.2, 23.1, 19.3. HRMS (FAB) m / z: Calcd for C 22 H 22 NO4, [M+H] + , 364.1665; found 394.1549 [α] D 25 = -90.3 (c 0.16, MeOH)

[0088] Synthesis Example 14: Synthesis of (7S,8R,11S)-2-bromo-7-hydroxy-7-(2-methoxyphenyl)-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:3-demethoxy-3-bromo-waltherion A (43) 3-Demethoxy-waltherion A (42) obtained in Synthesis Example 13 was reacted with N-bromosuccinimide (NBS) as follows. N-Bromosuccinimide (NBS) (1.5 mg, 0.00843 mmol) was added to a solution of 3-demethoxy-waltherion A (42) (3.1 mg, 0.00853 mmol) in CHCl (1 mL) at room temperature. The mixture was stirred at room temperature for 3.5 h, then quenched with saturated aqueous NaSO and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 1:1) to give 3-demethoxy-3-bromo-waltherion A (43) as a white solid (2.8 mg) in 74% yield. The following results of its physicochemical evaluation support the structure of 3-demethoxy-3-bromo-waltherion A (43). 1 H NMR (400 MHz, CD3OD) δ: 7.65 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.27-7.23 (m, 1H), 7.10 (dd, J = 0.9, 8.3 Hz, 1H), 6.73 (td, J = 1.0, 7.5 Hz, 1H), 6.57 (d, J = 6.5 Hz, 1H), 6.30 (dd, J = 1.7, 7.7 Hz, 1H), 4.75 (dd, J = 2.2, 8.0 Hz, 1H), 4.00 (s, 3H), 2.64 (s, 3H), 2.38-2.48 (m, 1H), 2.25-2.34 (m, 1H), 1.98-2,06 (m, 2H). 13 C NMR (150 MHz, CD3OD) δ: 175.7, 158.2, 150.0, 142.5, 140.9, 135.5, 134.6, 134.0, 132.7, 130.0, 121.2, 118.5, 118.1, 112.4, 109.4, 81.3, 79.1, 77.0, 56.0, 35.2, 23.0, 21.5. HRMS (FAB) m / z: Calculated for C 22 H 21 BrNO4, [M+H] + , 442.0654; found 442.0592 [α] D 25 = -91.7 (c 0.16, MeOH)

[0089] (Synthesis Example 15: (7S,8R,11S)-2-chloro-7-hydroxy-7-(2-methoxyphenyl)-3-methyl-4,7,8,9,10,1 1-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:Synthesis of 3-デメトキシ-3-クロロ-ワルセリオンA(44) 3-Demethoxy-waltherion A (42) obtained in Synthesis Example 13 was reacted with N-chlorosuccinimide (NCS) as follows. N-chlorosuccinimide (NCS) (1.6 mg, 0.0120 mmol) was added to a solution of 3-demethoxy-waltherion A (42) (2.5 mg, 0.00688 mmol) in CHCl (2 mL) at room temperature. The mixture was stirred at room temperature for 24 h, then quenched with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous NaHCO, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 1:1) to give 3-demethoxy-3-chloro-waltherion A (44) as a white solid (2.6 mg) in 95% yield. The following results of its physicochemical evaluation support the structure of 3-demethoxy-3-chloro-waltherion A (44). 1 H NMR (600 MHz, CD3OD) δ: 7.64 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.24-7.25 (m, 1H), 7.10 (dd, J = 0.9, 8.3 Hz, 1H), 6.73 (td, J = 1.0, 7.5 Hz, 1H), 6.60 (d, J = 6.5 Hz, 1H), 6.31 (dd, J = 1.7, 7.7 Hz, 1H), 4.75 (dd, J = 2.2, 8.0 Hz, 1H), 4.00 (s, 3H), 2.60 (s, 3H), 2.39-2.44 (m, 1H), 2.26-2.33 (m, 1H), 2.00-2,05 (m, 2H). 13 C NMR (150 MHz, CD3OD) δ: 175.4, 158.2, 148.3, 142.6, 140.6, 135.5, 134.5, 133.9, 132.7, 130.0, 121.2, 119.1, 118.1, 117.6, 112.4, 81.3, 79.1, 77.0, 56.1, 35.2, 23.1, 18.6. HRMS (FAB) m / z: Calcd for C 22 H 21 ClNO4, [M+H] + , 398.1159; found 398.1136 [α] D 25 = -99.0 (c 0.21, MeOH)

[0090] Synthesis Example 16: Synthesis of (7S,8R,11S)-2-ethoxy-7-(5-fluoro-2-methoxyphenyl)-7-hydroxy-3-methyl-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one:3-demethoxy-3-ethoxy-5'-fluoro-waltherion A (45) A synthetic intermediate was prepared by brominating the hydrogen atom at the 3-position of the oxo-4-quinolone (26) in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], and then the bromine atom of this synthetic intermediate was ethoxylated to prepare a synthetic intermediate. This synthetic intermediate was then reacted with synthetic intermediate 4 in the same manner as in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], except that 2-bromo-4-fluoroanisole was used instead of 2-bromoanisole used in Synthesis Example 1 [Synthesis of Waltherione A: Waltherione A(I)], as follows: To a solution of oxo-4-quinolone 26 (74.5 mg, 0.292 mmol) in DMF (3 mL), N-bromosuccinimide (NBS) (52.7 mg, 0.296 mmol) was added in three portions at 10-minute intervals at room temperature, and the mixture was stirred at room temperature for 3 hours. Toluene was added to the mixture, and the mixture was concentrated. The residue was purified by column chromatography (EtOAc:hexane = 3:1) to afford synthetic intermediate 3 (71.8 mg, 0.214 mmol) in 74% yield, in which the hydrogen atom at the 3-position of oxo-4-quinolone 26 was brominated. The following results of the physicochemical evaluation support the structure of synthetic intermediate 3: (8R,11S)-2-bromo-3-methyl-8,9,10,11-tetrahydro-1H-8,11-epoxycyclohepta[f]quinoline-1,7(4H)-dione, in which the hydrogen atom at the 3-position of the oxo-4-quinolone (26) is brominated. 1 H NMR (400 MHz, DMSO-d6) δ: 11.05 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 6.8 Hz, 1H), 4.69 (d, J = 11.6 Hz, 1H), 2.56 (s, 3H)2.31-2.45 (m, 2H), 1.81-1.91 (m, 1H), 1.62-1.71 (m, 1H). 13 C NMR (150 MHz, DMSO-d6) δ: 194.0, 172.4, 150.0, 149.0, 143.0, 128.5, 123.0, 118.0, 117.2, 109.0, 79.8, 74.9, 29.7, 23.5, 21.3. HRMS (FAB) m / z: Calcd for C 15 H 13 BrNO3, [M+H] + , 334.0079; found 334.0014. [α] D 25 = -37.6 (c 0.187, MeOH). A suspension of absolute ethanol (2.1 mL) and t-BuLi (1.0 mL, 1.62 mmol) was stirred at room temperature for 5 minutes in a round-bottom flask. The brominated synthetic intermediate (54.4 mg, 0.162 mmol) and CuI (29.5 mg, 0.406 mmol) were added to a 10-20 mL microwave reaction vial filled with argon. The suspension was stirred at room temperature for 5 minutes and then at 120 °C for 8 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, added with toluene, and concentrated. The residue was purified by column chromatography eluting with EtOAc-hexane (3:1) and EtOAc-acetone (1:1) to give a white solid (38.3 mg) of synthetic intermediate 4 in which the hydrogen atom at the 3-position of oxo-4-quinolone (26) was ethoxylated in 82% yield. The following results of the physicochemical evaluation support the structure of synthetic intermediate 4: (8R,11S)-2-ethoxy-3-methyl-8,9,10,11-tetrahydro-1H-8,11-epoxycyclohepta[f]quinoline-1,7(4H)-dione, in which the hydrogen atom at the 3-position of the oxo-4-quinolone (26) is ethoxylated. 1 H NMR (400 MHz, CD3OD) δ: 8.07 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 6.9 Hz, 1H), 4.68 (dd, J = 8.0, 1.8 Hz, 1H), 3.97-4.14 (m, 4H), 2.40-2.57 (m, 5H), 1.98-2.04 (m, 1H), 1.70-1.76 (m, 1H), 1.38 (t, J = 6.9 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ: 195.2, 175.0, 151.3, 142.5, 142.0, 141.5, 128.9, 123.3, 120.4, 117.3, 80.9, 76.0, 68.0, 30.0, 24.4, 15.7, 15.2. HRMS (FAB) m / z: Calcd for C 17 H 18 NO4, [M+H] + , 300.1236; found 300.1260. [α] D 25 = -92.0 (c 0.30, MeOH). To a solution of 2-bromo-4-fluoroanisole (0.02 mL, 0.157 mmol) in anhydrous THF (1.0 mL), t-BuLi solution (1.6 M hexane solution, 0.17 mL, 0.272 mmol) was added dropwise at −78 °C, and the reaction mixture was stirred at −78 °C for 55 min. The synthetic intermediate (26) (2.9 mg, 0.0134 mmol) was added via syringe. The 3-hydroxylated intermediate was then added to the reaction mixture. The reaction mixture was stirred for an additional 12 h, then quenched with saturated aqueous NH4Cl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:H2O=1:1) to give 3-demethoxy-3-ethoxy-5'-fluoro-waltherion A (45) as a white solid (3.3 mg) in 80% yield. The following results of its physicochemical evaluation support the structure of 3-demethoxy-3-ethoxy-5'-fluoro-waltherion A (45). 1H NMR (600 MHz, CDCl3) δ: 8.85 (brs, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 6.87-6.92 (m, 2H), 6.75 (d, J = 5.9 Hz, 1H), 6.13 (dd, J = 2.6, 9.6 Hz, 1H), 5.03 (s, 1H), 4.68 (dd, J = 1.8, 8.0 Hz, 1H), 4.19-4.24 (m, 1H), 4.01-4.06 (m, 1H), 3.98 (s, 3H), 2.35-2.44 (m, 5H), 2.08-2.12 (m, 1H), 1.99-2.05 (m, 1H). 13 C NMR (150 MHz, CDCl3) δ: 175.1, 156.8 (d, J = 238.7 Hz), 152.5, 142.7, 140.9, 140.2, 138.9, 136.7 (d, J = 5.8 Hz), 132.2, 130.2, 120.2, 119.1 (d, J = 24.9 Hz), 116.9, 114.5 (d, J = 24.0 Hz), 111.8 (d, J = 8.6 Hz), 80.0, 78.1, 75.9, 67.6, 56.2, 34.2, 22.4, 15.8, 15.3. HRMS (FAB) m / z: Calcd for C 24 H 25 FNO5, [M+H] + , 426.1717; found 426.1714 [α] D 25 = -116.5 (c 0.175, MeOH)

[0091] (Synthesis Example 17: (7S,8R,11S)-3-(bromomethyl)-7-(5-fluoro-2-methoxyphenyl)-7-hydroxy-2-methoxy-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one: Synthesis of 5'-fluoro-waltherion A (46) in which the 2-methyl group is replaced with a 2-bromomethyl group) 5'-Fluoro-waltherion A (37) obtained in Synthesis Example 8 was reacted with N-bromosuccinimide (NBS) as follows. To a solution of 5'-fluoro-waltherion A (37) (11.1 mg, 0.0279 mmol) in CHCl (1 mL), N-bromosuccinimide (NBS) (5.1 mg, 0.0286 mmol) was added at room temperature. The mixture was stirred at room temperature for 13 h, and then concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 1:1) to give 5'-fluoro-waltherion A (46) (11.0 mg) as a white solid in 80% yield, with the 2-methyl group replaced by a 2-bromomethyl group. The following results of its physicochemical evaluation support the structure of 5'-fluoro-waltherion A (46), in which the 2-methyl group is replaced by a 2-bromomethyl group. 1 H NMR (600 MHz, CDCl3) δ: 10.09 (brs, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.87-6.92 (m, 2H), 6.73 (d, J = 6.0 Hz, 1H), 6.14 (dd, J = 2.7, 9.6 Hz, 1H), 5.06 (s, 1H), 4.67-4.70 (m, 2H), 4.62 (d, J = 10.9 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 2.35-2.44 (m, 2H), 2.01-2.14 (m, 1H), 2.00-2.06 (m, 1H). 13C NMR (150 MHz, CDCl3) δ: 175.3, 156.8 (d, J = 239.1 Hz), 152.5 (d, J = 2.2 Hz), 142.6, 141.6, 139.4, 138.5, 136.4 (d, J = 6.1 Hz), 133.0, 130.9, 120.3, 119.1 (d, J = 24.9 Hz), 117.6, 114.6 (d, J = 23.1 Hz), 111.8 (d, J = 7.6 Hz), 80.1, 78.0, 75.9, 60.5, 56.2, 34.2, 23.3, 22.4. HRMS (FAB) m / z: Calcd for C 23 H 22 BrFNO5, [M+H] + , 490.0665; found 490.0626 [α] D 25 = -166.1 (c 0.12, MeOH)

[0092] (Synthesis Example 18: (7S,8R,11S)-3-(azidomethyl)-7-(5-fluoro-2-methoxyphenyl)-7-hydroxy-2-methoxy-4,7,8,9,10,11-hexahydro-1H-8,11-epoxycyclohepta[f]quinolin-1-one: Synthesis of 5'-fluoro-waltherion A (47) in which the 2-methyl group is replaced with a 2-azidomethyl group) 5'-Fluoro-waltherion A (46) obtained in Synthesis Example 17, in which the 2-methyl group was substituted with a 2-bromomethyl group, was reacted with sodium azide as follows. NaN (8.9 mg, 0.137 mmol) was added to a solution of 5'-fluoro-waltherion A (46) (4.8 mg, 0.00979 mmol), in which the 2-methyl group was replaced with a 2-bromomethyl group, in a 3:1 acetone-water mixture (3.5 mL) at room temperature. The mixture was stirred at room temperature for 275 h. Water and EtOAc were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by semi-preparative RP-18 HPLC (acetonitrile:HO = 1:1) to give 5'-fluoro-waltherion A (47), in which the 2-methyl group was replaced with a 2-azidomethyl group, as a white solid (3.0 mg) in 68% yield. The following results of its physicochemical evaluation support the structure of 5'-fluoro-waltherion A (47), in which the 2-methyl group is replaced by a 2-azidomethyl group. 1 H NMR (600 MHz, CDCl3) δ: 8.61 (brs, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.88-6.94 (m, 2H), 6.69 (d, J = 5.8 Hz, 1H), 6.11 (dd, J = 2.7, 9.5 Hz, 1H), 5.06 (s, 1H), 4.77 (d, J = 15.9 Hz, 1H), 4.73 (d, J = 15.9 Hz, 1H), 4.68 (dd, J = 1.8, 8.0 Hz, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 2.37-2.45 (m, 2H), 2.01-2.12 (m, 2H). 13C NMR (150 MHz, CDCl3) δ: 175.0, 156.8 (d, J = 239.1 Hz), 152.5 (d, J = 1.8 Hz), 143.0, 140.9, 138.5, 136.5 (d, J = 6.1 Hz), 135.4, 132.8, 131.0, 120.4, 119.1 (d, J = 24.6 Hz), 117.2, 114.6 (d, J = 23.1 Hz), 111.8 (d, J = 8.0 Hz), 80.0, 78.0, 75.8, 60.3, 56.2, 47.2, 34.1, 22.4. HRMS (FAB) m / z: Calcd for C 23 H 22 FN4O5, [M+H] + , 453.1574; found 453.1556 [α] D 25 = -137.5 (c 0.15, MeOH)

[0093] (Isolation Comparative Examples 1 to 5) Instead of the compounds of Synthesis Examples 1 to 18, paliasanines (paliasanines A to E), which are quinoline derivatives isolated by the present inventors, were used. [ka]

[0094] (Reference Comparative Example 1) Instead of the compounds of Synthesis Examples 1 to 18, paclitaxel (PXL), which is used to treat lung cancer, ovarian cancer, breast cancer, head and neck cancer, advanced Kaposi's sarcoma, and the like, was used.

[0095] (Preparation Examples 1 to 17 and Preparation Comparative Examples 1 to 5) The compounds of Synthesis Examples 1 to 17 and Isolated Comparative Examples 1 to 5 were dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM to prepare base solutions for preparing various concentrations for in vitro IC50 measurement.

[0096] (Examples 1 to 17 and Comparative Examples 1 to 5) The compounds of Preparation Examples 1 to 17, Isolation Comparative Examples 1 to 5, and Reference Comparative Example were used to measure the 50% inhibitory concentration (IC 50 The cancer cell lines used were the A549 cell line, a human alveolar basal epithelial adenocarcinoma cell line; the MDA-MB-231 cell line, a triple-negative breast cancer cell line that does not overexpress any of the estrogen receptor (ER), progesterone receptor (PgR), or HER2 protein; the KB cell line, an epidermoid carcinoma / Hela cell tumor; the KB-VAN cell line, a multidrug-resistant KB variant; and the MCF-7 cell line, which is HER2-negative (estrogen receptor (ER) positive, progesterone receptor positive, and HER2 negative). The IC was calculated using the TREND function from two concentrations that sandwiched a 50% growth inhibition rate. 50 asked for. The results are shown in Tables 2 and 3.

[0097] [Table 2]

[0098] As is clear from Table 2, the anticancer agents to which the present invention is applied, when containing compounds (I) and (31) to (41), which are 4-quinolone derivatives represented by chemical formula (1), exhibit IC50 values ​​on the order of μM, preferably 40 μM or less, against each of the cell lines of breast cancer, lung cancer, skin cancer, and / or colon cancer, demonstrating their usefulness as therapeutic agents for these cancers. In particular, the anticancer drugs containing compounds (36) to (38) showed high IC 50 The extremely low concentration of α-glucan was approximately 5 μM or less, indicating that it is a selective therapeutic agent for lung cancer and breast cancer. In particular, the anticancer drug containing compound (37) was isolated as a natural product and had a higher IC in the A549 cell line than the anticancer drug containing the fully synthesized compound (I): waltherion A. 50was 7-fold stronger, and IC 50 The selectivity index (SI) of anticancer drugs containing Waltherion A was 35 times higher than that of MDA-MB-231, the second highest after A549, demonstrating nearly 9 times the selectivity of the natural substance. On the other hand, the activity of the 5'-NH2,5'-OH derivative was significantly reduced. In contrast, paliasanines A to E, which are isolated as natural products having a quinoline skeleton similar to compound (I) and compounds (31) to (41) having a 4-quinolone skeleton, showed almost no anticancer activity. From this, it is clear that not only the basic skeleton of Waltherion A but also the R 1 ~R 5 It has been shown that the type of group is an important factor in anticancer activity, especially cancer specificity. [Table 3]

[0099] As is clear from Table 3, when the anticancer drug to which the present invention is applied contains compounds (42) to (47), which are 4-quinolone derivatives represented by chemical formula (1), the IC values ​​in A549 and MCF-7 cell lines are almost equal to those of compound (37). 50 The extremely low levels of EGFR1, EGFR2, and EGFR3 indicated that this compound is a selective cancer treatment for lung cancer and breast cancer. [Industrial Applicability]

[0100] The anticancer agent of the present invention can inhibit the proliferation of cancer cells such as breast cancer, lung cancer, skin cancer, and / or colon cancer, and in particular can specifically inhibit the proliferation of specific cancer cells, particularly lung cancer and breast cancer, which have high morbidity and mortality rates, and is useful for cancer treatment with minimal invasiveness to normal cells and few side effects.

Claims

1. The following chemical formula (1) 【Chemistry 1】 (In chemical formula (1), R １ ~R ５ is a linear, hydroxyl group, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkoxy group having 1 to 6 carbon atoms, a mercapto group, a linear, branched, or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, an amino group, a monoalkyl group or dialkyl group having a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic partial halogeno or per halogenoalkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, or a hydrogen atom, R ６ is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, a linear, branched or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an amino group, a monoalkyl group or dialkyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, or a hydrogen atom, R ７ represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, a linear, branched or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an amino group, a monoalkyl group or dialkyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, an aromatic ring group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, a hydrogen atom, a halogeno group, or an azide group, R 8 is a hydrogen atom or a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, X is a hydroxyl group, a linear, branched, or cyclic alkoxy group having 1 to 6 carbon atoms, a mercapto group, a linear, branched, or cyclic alkylthioether group having 1 to 6 carbon atoms, a halogeno group, an amino group, a monoalkyl or dialkyl group having a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, or a hydrogen atom. or a pharmaceutically acceptable salt thereof.

2. 2. The anticancer agent according to claim 1, which is a therapeutic agent for breast cancer, lung cancer, skin cancer, and / or colon cancer.

3. The 4-quinolone derivative is represented by the following chemical formula (2): 【Chemistry 2】 (In chemical formula (2), R ４ is a halogeno group, or a linear, branched, or cyclic partial halogeno or per halogeno alkyl group having 1 to 6 carbon atoms. and is specific to breast cancer and / or lung cancer.

4. The 4-quinolone derivatives were found to have an IC ５０ The anticancer agent according to claim 3, characterized in that the concentration is less than 3 μM.

5. 2. The anticancer agent according to claim 1, further comprising an excipient, a dispersant, a filler, a carrier, and / or a solvent.

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