Compounds and antimalarials

Abstract

To provide a compound which has low cytotoxicity and excellent antimalarial activity and can be synthesized conveniently and safely, and an antimalarial agent using the compound.SOLUTION: The compound is represented by the general formula (I) in the figure. The antimalarial agent contains the compound as an active ingredient. (In the general formula (I), R1 and R2 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl, alkoxy, aryl, carboxy or amino group.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compounds and antimalarials. [Background technology]

[0002] Malaria is an infectious disease caused by infection with protozoa belonging to the genus Plasmodium. It is transmitted by the Anopheles mosquito and causes symptoms such as intermittent fever attacks, anemia, and splenomegaly. Malaria has become a global infectious disease that has become more prevalent in recent years due to environmental changes, with between 200 million and 300 million cases and more than 600,000 deaths per year.

[0003] Malaria parasites that infect humans include Plasmodium falciparum (P. falciparum), which is found throughout the tropical regions of Africa, Asia, and Latin America; Plasmodium vivax (P. vivax), which is found in tropical and temperate regions around the world; Plasmodium malariae (P. malariae), which is found worldwide; and Plasmodium ovale (P. ovale), which is found mainly in tropical West Africa. Among these, infection with Plasmodium falciparum causes the most severe symptoms, and can easily progress to severe malaria within one to two weeks after onset, accompanied by encephalopathy, nephropathy, hemolytic anemia, pulmonary edema, cardiac damage, severe enteritis, etc., and can rapidly lead to multiple organ failure and death.

[0004] Representative drugs currently used to treat malaria include chloroquine, primaquine, pyrimethamine, artemisinin, and mefloquine. However, many of these drugs are highly toxic, and with the emergence of drug-resistant parasites, the spread of drug-resistant malaria has become a problem for chemotherapy. Quinine is the only drug effective against drug-resistant malaria, but it has an extremely high risk of causing renal failure, making it a high-risk treatment even given current medical standards. Given this situation, there is a growing demand for the development of new non-alkaloid drugs that have high antimalarial activity, low toxicity, and high safety.

[0005] Furthermore, known non-alkaloid compounds having antimalarial activity include the natural organic compound artemisinin and cyclic peroxide derivatives such as N-89 (see, for example, Patent Document 1) and N-251. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2000-229965 Summary of the Invention [Problem to be solved by the invention]

[0007] Artemisinin is currently widely used as a drug to treat resistant malaria, but its use alone does not completely cure malaria. Recently developed N-89 and N-251 have been reported to be capable of completely curing malaria, but they are not yet available as therapeutic drugs and are somewhat cytotoxic. Furthermore, artemisinin has the drawback of requiring multiple steps for chemical synthesis. Furthermore, N-89 and N-251 require hydrogen peroxide during the manufacturing process, which poses a risk of accidents due to intermediates or hydrogen peroxide.

[0008] The present invention has been made in view of the above circumstances, and provides a compound that has reduced cytotoxicity, excellent antimalarial activity, and can be synthesized simply and safely, and an antimalarial agent using the compound. [Means for solving the problem]

[0009] As a result of extensive research to achieve the above-mentioned object, the present inventors discovered that cyclic peroxide derivatives containing fluorine atoms with specific structures have extremely excellent antimalarial activity while suppressing cytotoxicity, and thus completed the present invention.

[0010] That is, the present invention includes the following aspects. (1) A compound represented by the following general formula (I):

[0011] [ka]

[0012] (In general formula (I), R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl group, alkoxy group, aryl group, carboxy group, or amino group.

[0013] (2) In the general formula (I), R 1 and R 2 are each independently a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group. (3) An antimalarial agent containing the compound according to (1) or (2) as an active ingredient. [Effects of the Invention]

[0014] According to the compound of the above aspect, it is possible to provide a compound that has reduced cytotoxicity, excellent antimalarial activity, and can be synthesized simply and safely. The antimalarial agent of the above aspect contains the compound, has reduced cytotoxicity, and has excellent antimalarial activity. DETAILED DESCRIPTION OF THE INVENTION

[0015] Hereinafter, a compound according to one embodiment of the present invention (hereinafter referred to as "this embodiment") will be described in detail.

[0016] ≪Compound≫ The compound of this embodiment (hereinafter, sometimes referred to as "compound (I)") is represented by the following general formula (I).

[0017] [ka]

[0018] (In general formula (I), R 1 and R2 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl group, alkoxy group, aryl group, carboxy group, or amino group.

[0019] Compound (I) is a fluorine atom-containing cyclic peroxide derivative that has a peroxide structure (OO structure) and two fluorine atoms bonded to an alicyclic structure, and thus has excellent antimalarial activity. That is, Compound (I) is useful as a drug for preventing and treating infections caused by malaria parasites.

[0020] Examples of malaria parasites to which compound (I) can be applied include Plasmodium falciparum (P. falciparum), which is distributed throughout the tropical regions of Africa, Asia, and Latin America, Plasmodium vivax (P. vivax), which is distributed in tropical and temperate regions around the world, Plasmodium malariae (P. malariae), which is distributed worldwide, and Plasmodium ovale (P. ovale), which is distributed mainly in tropical West Africa. Among these, compound (I) is preferably applied to Plasmodium falciparum (P. falciparum).

[0021] Furthermore, as will be shown in the Examples below, Compound (I) has reduced cytotoxicity.

[0022] Furthermore, as will be described later, compound (I) can be synthesized simply and safely by utilizing a photochemical reaction using oxygen or air in the process of introducing a peroxide structure (OO structure) during the reaction process.

[0023] Next, the structure of compound (I) will be explained in detail below.

[0024] <R 1 and R 2 > In general formula (I), R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl group, alkoxy group, aryl group, carboxy group, or amino group.

[0025] R 1 and R 2 may be the same or different, but are preferably the same since they can be easily synthesized.

[0026] [Halogen atom] R 1 and R 2 Examples of the halogen atom in the formula include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. Among these, a fluorine atom is preferred.

[0027] [Alkyl group] R 1 and R 2 The alkyl group in the formula (I) has from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, even more preferably from 1 to 6 carbon atoms, even more preferably from 1 to 4 carbon atoms, still more preferably from 1 to 3 carbon atoms, and particularly preferably from 1 to 2 carbon atoms. The alkyl group may be linear, branched, or cyclic.

[0028] Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, cyclopropyl, butyl, isobutyl, pentyl, etc. Among these, methyl and ethyl groups are preferred.

[0029] Examples of the substituent in the alkyl group include, but are not limited to, a halogen atom, an alkoxy group, an aryl group, etc. Examples of the halogen atom include those described above, and examples of the alkoxy group and the aryl group include those described below. Among these, for example, a halogen atom or an alkoxy group is preferred as the substituent in the alkyl group, and a fluorine atom or an alkoxy group is more preferred.

[0030] Examples of the alkyl group substituted with a fluorine atom include, but are not limited to, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group.

[0031] Examples of alkyl groups substituted with alkoxy groups include, but are not limited to, methoxymethyl groups and ethoxymethyl groups.

[0032] [Alkoxy group] R 1 and R 2 The alkoxy group in the formula (I) has from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, even more preferably from 1 to 6 carbon atoms, still more preferably from 1 to 4 carbon atoms, even more preferably from 1 to 3 carbon atoms, and particularly preferably from 1 to 2 carbon atoms. The alkoxy group may be linear, branched, or cyclic.

[0033] Examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, iso-propoxy, sec-butoxy, tert-butoxy, etc. Among these, methoxy and ethoxy groups are preferred.

[0034] Examples of the substituent in the alkoxy group include, but are not limited to, a halogen atom, an aryl group, etc. Examples of the halogen atom include those described above, and examples of the aryl group include those described below. Among these, for example, a halogen atom is preferred as the substituent in the alkoxy group, and a fluorine atom is more preferred.

[0035] Examples of alkoxy groups substituted with a fluorine atom include, but are not limited to, a fluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.

[0036] [Aryl group] R 1 and R 2 The aryl group in the formula (I) has 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms, and more preferably 6 to 8 carbon atoms. Such aryl groups include, but are not limited to, phenyl groups and the like.

[0037] Examples of the substituent on the aryl group include, but are not limited to, a halogen atom, an alkyl group, etc. Examples of the halogen atom and the alkyl group include those described above.

[0038] Examples of aryl groups substituted with halogen atoms include, but are not limited to, o-, m-, or p-halogen-substituted phenyl groups such as 4-fluorophenyl and 4-chlorophenyl.

[0039] Examples of the aryl group substituted with an alkyl group include, but are not limited to, o-, m-, or p-alkyl-substituted phenyl groups such as a 2-methylphenyl group, a 3-methylphenyl group, and a 4-methylphenyl group.

[0040] [Carboxy group] Examples of the substituent on the carboxy group include, but are not limited to, alkoxy groups, etc. Examples of the alkoxy group include those mentioned above.

[0041] Examples of carboxy groups substituted with alkoxy groups include, but are not limited to, carbomethoxy groups and carboethoxy groups.

[0042] [Amino group] The amino group having a substituent may be linear, branched, or cyclic in which the substituents are bonded to each other to form a ring structure.

[0043] Substituents on the amino group include, but are not limited to, alkyl groups and the like.

[0044] Examples of chain amino groups substituted with an alkyl group include, but are not limited to, a dimethylamino group and a diethylamino group.

[0045] Examples of cyclic amino groups include, but are not limited to, piperidyl groups and pyrrolidyl groups.

[0046] [Preferred R 1 and R 2 ] Among these, R 1 and R 2 are each independently preferably a hydrogen atom, a fluorine atom, a methyl group or an ethyl group, and R 1 and R 2 are more preferably the same and are a hydrogen atom, a fluorine atom, a methyl group, or an ethyl group.

[0047] Specifically, preferred compounds (I) include compounds represented by the following formulas (I-1) to (I-4) (hereinafter, sometimes referred to as "compound (I-1)"). Note that these compounds are merely examples of preferred compounds (I), and preferred compounds (I) are not limited to these. In the following formulas, "Me" represents a methyl group, and "Et" represents an ethyl group.

[0048] [ka]

[0049] <Method for producing compound (I)> Compound (I) can be produced, for example, by the method shown in the following chemical reaction formula. The method for producing compound (I) will be explained in detail below, dividing it into steps (i) to (iii) shown in the following chemical reaction formula. In the following chemical reaction formula, R 1 and R 2 is the R 1 and R 2 The compounds represented by general formulas (Ia) to (Ic) may be referred to as compounds (Ia) to (Ic), respectively.

[0050] [ka]

[0051] [Step (i)] In step (i), compound (Ia) is reacted with difluoromethylenephosphonium ylide generated in situ to obtain compound (Ib). Compound (Ia) is a known diketone compound. Compound (Ib) is a difluoromethylene ketone compound.

[0052] In the reaction in step (i), compound (Ia), sodium chloroacetate in an amount of 2 to 6 times (preferably 4 times) the molar amount relative to compound (Ia), tri(n-butyl)phosphine in an amount of 2 to 6 times (preferably 4 times) the molar amount relative to compound (Ia), and dry dimethylformamide (solvent) are thoroughly mixed, heated at 100°C to 130°C (preferably 110°C to 120°C) for 5 to 60 minutes (preferably about 15 minutes), and then heated at 120°C to 135°C (preferably about 130°C) for 10 to 60 minutes (preferably about 30 minutes).

[0053] Difluorocarbene generated by thermal decomposition of sodium chloroacetate at 100°C or higher and 130°C or lower (preferably 110°C or higher and 120°C or lower) reacts with tri(n-butyl)phosphine to produce difluoromethylenephosphonium ylide, which reacts with compound (Ia) to produce compound (Ib).

[0054] The resulting compound (Ib) can be easily isolated and purified from the reaction mixture by conventional separation means, such as column chromatography.

[0055] [Step (ii)] In step (ii), compound (Ib) obtained in step (i) is reacted with a methylenephosphonium ylide in a dry solvent to obtain compound (Ic). Compound (Ic) is a diene compound.

[0056] The solvent used in step (ii) includes tetrahydrofuran, ether, etc., and preferably tetrahydrofuran. When a Wittig reagent is used for the methylenation of compound (Ib), it is preferable to prepare a methylphosphonium ylide from a methylphosphonium salt in a molar amount of 2.0 to 3.0 times (preferably 2.2 times) the amount of compound (Ib) and tert-butoxypotassium in a molar amount of 1.5 to 2.5 times (preferably 2.0 times) the amount of compound (Ib), and react it with compound (Ib) at room temperature (about 25±5°C) for 30 minutes to 5 hours (preferably 2 hours).

[0057] The resulting compound (Ic) can be easily isolated and purified from the reaction mixture by conventional separation means, such as column chromatography.

[0058] [Step (iii)] In step (iii), compound (I) is obtained by photoreacting compound (Ic) obtained in step (ii) with a photosensitizer and a co-sensitizer in a suitable solvent in the presence of oxygen.

[0059] Examples of the solvent used in step (iii) include dichloromethane and acetonitrile, and preferably acetonitrile.

[0060] As the photosensitizer, 9,10-dicyanoanthracene, 2,4,6-triarylpyrylium tetrafluoroborate, 2,4,6-triarylpyrylium perchlorate, etc. can be used, and preferably 2,4,6-triphenylpyrylium tetrafluoroborate is used.

[0061] As the auxiliary sensitizer, aromatic hydrocarbons such as naphthalene, durene, and biphenyl, whose radical cations are stable and have a long life, can be used, with biphenyl being preferred.

[0062] The irradiation light is preferably long wavelength light of 350 nm to 400 nm, which is absorbed only by the photosensitizer. A xenon lamp or sunlight may be used as long as it can irradiate light with a wavelength of 350 nm to 400 nm. A Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W x 15 lamps = 30 W) may also be used.

[0063] In the reaction in step (iii), it is preferable to use a photosensitizer (preferably 2,4,6-triphenylpyrylium tetrafluoroborate) in an amount of 0.05 to 0.3 times (preferably 0.1 to 0.2 times) molar quantity relative to compound (Ic), and a co-sensitizer (preferably biphenyl) in an amount of 1.5 to 5.0 times (preferably 3.0 times) molar quantity relative to compound (Ic). The reaction temperature is preferably 20° C. or higher and 25° C. or lower, and the reaction time is preferably 5 minutes or higher and 30 minutes or lower.

[0064] The resulting compound (I) can be easily isolated and purified from the reaction mixture by conventional separation means, such as column chromatography.

[0065] As described above, compound (I) can be synthesized simply and safely by utilizing a photochemical reaction using oxygen or air in the process of introducing a peroxide structure (OO structure) in step (iii).

[0066] <Antimalarial drugs> The antimalarial agent of this embodiment contains the above-mentioned compound (I) as an active ingredient.

[0067] The antimalarial agent of this embodiment contains the above-mentioned compound (I), and thus has reduced cytotoxicity and excellent antimalarial activity.

[0068] In this specification, "containing as an active ingredient" means containing an amount of compound (I) effective to exert antimalarial activity while suppressing cytotoxicity.

[0069] When the antimalarial agent of this embodiment is used for the prevention or treatment of infections caused by malaria parasites, any of the routes of administration, such as oral administration, subcutaneous injection, intravenous injection, and topical administration, may be used.

[0070] In addition, examples of formulations include oral preparations such as powders, tablets, fine granules, pills, capsules, and granules, which are usually prepared as pharmaceutical compositions by mixing with pharmaceutically acceptable carriers, excipients, and other additives; and parenteral preparations such as eye drops, injections, and suppositories.

[0071] Subjects to be administered include, but are not limited to, humans, monkeys, dogs, cattle, horses, sheep, pigs, rabbits, mice, rats, guinea pigs, hamsters, and cells thereof. Among these, mammals or mammalian cells are preferred, and humans or human cells are particularly preferred.

[0072] The dosage of the antimalarial agent of this embodiment varies depending on the type of compound (I), the symptoms of the subject to be administered, the administration site, the administration method, etc. Those skilled in the art can appropriately select an appropriate dosage.

[0073] The antimalarial agent of this embodiment may be administered in a single dose or multiple doses. In the case of multiple doses, the agent may be administered, for example, every 2 to 12 hours, daily, or once every 2 days, 5 days, 1 week, 1.5 weeks, several weeks, 1 month, or several months.

[0074] Other Embodiments In one embodiment, the present invention provides a method for preventing or treating an infection caused by a malaria parasite, comprising administering an effective amount of Compound (I) to a human or animal patient in need of treatment. Examples of Compound (I) include those described above. Examples of malaria parasites include those described above.

[0075] In one embodiment, the present invention provides compound (I) for the prevention or treatment of infection caused by malaria parasites. Examples of compound (I) include those described above. Examples of malaria parasites include those described above.

[0076] In one embodiment, the present invention provides use of Compound (I) for the manufacture of an antimalarial agent or a pharmaceutical composition for the prevention or treatment of infections caused by malaria parasites. Examples of Compound (I) include those described above. Examples of malaria parasites include those described above. [Example]

[0077] The fluorine atom-containing cyclic peroxide derivatives of the present invention will be described in more detail in the following examples. However, the present invention is not limited to the following examples, and various modifications are possible.

[0078] <Production of Compound (I)> [Manufacturing Example 1] (Production of Compound (I-1)) Compound (I-1) was synthesized according to the following reaction scheme.

[0079] [ka]

[0080] 1. Step (i): Synthesis of 6,6-difluoro-1,5-di(p-methylphenyl)hex-5-en-1-one (compound (Ib-1)) 2.80 g (10.0 mmol) of 1,5-di(p-methylphenyl)penta-1,5-dione (compound (Ia-1)), 6.29 g (40.0 mmol) of sodium chlorodifluoroacetate, and 8.52 g (40.0 mmol) of tri(n-butyl)phosphine were dissolved in ultra-dehydrated dimethylformamide (10 mL). The reaction mixture was purged with nitrogen and heated and stirred in an oil bath. The temperature of the oil bath was raised to 130 °C within 10 min. At around 70 °C, both compound (Ia-1) and sodium chlorodifluoroacetate were completely dissolved. At around 100 °C, sodium chlorodifluoroacetate decomposed to form difluorocarbene, which reacted with tri(n-butyl)phosphine to form difluoromethylenephosphonium ylide. The oil bath temperature was maintained at 130°C for 30 minutes, whereby the difluoromethylenephosphonium ylide reacted with compound (Ia-1) to produce compound (Ib-1). Compound (Ib-1) was isolated and purified from the reaction mixture by column chromatography. Specifically, after the reaction was completed, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with sodium bicarbonate water, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed and the resulting crude product was separated by silica gel column chromatography (elution solvent: dichloromethane-n-hexane, 1:2) to obtain 1.46 g (47% yield) of compound (Ib-1) as a yellow oil.

[0081] The physical properties of compound (Ib-1) are shown below. colorless oil, C 20 H 20 F 2O , [MW314.37]. IR(KBr, cm-1):3088 ,3032 ,2954, 2926, 2900, 2871, 1684(C=O), 1608, 1573, 1515, 1453, 1409, 1378, 1362, 1328, 1314, 1303, 1274, 1180, 1120, 1106, 1077, 1036, 1019, 979, 938, 913, 870, 844, 821, 805, 728, 688, 655, 636. 1 H NMR(400 MHz, CDCl3) δ: 1.81 (quintet, 2H, J = 7.6 Hz), 2.34 (s, 3H), 2.40 (s, 3H), 2.49 (tt, 2H, J H-H(t) = 7.6 Hz, J H-F(t) = 2.4 Hz), 2.92 (t, 2H, J = 7.6 Hz), 7.13-7.18 (m, 2H), 7.19-7.26 (m, 4H), 7.76-7.82 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ:21.06 (qurtet, 1C), 21.55 (qurtet, 1C), 22.35 (t, 1C), 27.01 (t, 1C), 37.34 (t, 1C), 91.72 (s, 1C, J C-F(dd) = 19.8 Hz, 14.5 Hz), 128.03 (d, 2C, J C-F(t) = 3.0 Hz), 128.06 (d, 2C), 129.18 (d, 4C), 130.26 (s, 1C), 134.43 (s, 1C), 137.03 (s, 1C), 143.66 (s, 1C), 153.63 (s, 1C, J C-F(t) = 286.1 Hz), 199.28 (s, 1C, C=O).

[0082] 2. Step (ii): Synthesis of 1,1-difluoro-2,6-di(p-methylphenyl)hepta-1,6-diene (compound (Ic-1)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was reacted at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

[0083] To this solution, 6.29 g (20.0 mmol) of 6,6-difluoro-1,5-di(p-methylphenyl)hex-5-en-1-one (compound (Ib-1)) in tetrahydrofuran (30 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated by silica gel column chromatography (elution solvent: hexane) to obtain 3.23 g (yield 52% by mass) of compound (Ic-1) as a colorless oil.

[0084] The physical properties of the compound (Ic-1) are shown below. colorless oil, C 21 H 22 F2, [MW312.40]. IR(KBr, cm-1): 3085, 3027, 2925, 2867, 1626, 1567, 1514, 1447, 1407, 1379, 1306, 1232, 1188, 1166, 1121, 1107, 1056, 1039, 1020, 939, 894, 822, 795, 734. 1 H NMR(400 MHz, CDCl3) δ: 1.51 (quintet, 2H, J = 7.6 Hz), 2.33 (s, 6H), 2.39 (tt, 2H, J H-H(t) = 7.6 Hz, J H-F(t) = 2.4 Hz), 2.47 (t, 2H, J = 7.6 Hz), 4.96 (d, 1H, J = 1.2 Hz), 5.22 (d, 1H, J = 1.2 Hz), 7.06-7.15 (m, 6H), 7.20-7.25 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ:21.05 (q, 1C), 21.09 (q, 1C), 26.16 (t, 1C),27.07 (t, 1C), 34.57 (t, 1C), 91.89 (s, 1C, J C-F(dd)= 19.0 Hz, 16.0 Hz), 111.79 (t, 1C), 125.95 (d, 2C), 128.03 (d, 2C, J C-F(t) = 3.1 Hz),128.92 (d, 2C), 129.08 (d, 2C), 130.54 (s, 1C), 136.84 (s, 1C), 137.02 (s, 1C), 138.11 (s, 1C), 147.66 (s, 1C), 153.52 (s, 1C, J C-F(t) = 286.9 Hz).

[0085] 3. Step (iii): Synthesis of 8,8-difluoro-1,5-di(p-methylphenyl)-6,7-dioxabicyclo[3.2.2]nonane (compound (I-1)) A Pyrex test tube (20 cm long, 30 mm diameter) was charged with 62.5 mg (0.2 mmol) of compound (Ic-1) synthesized in step (ii) above, 7.9 mg (0.02 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl, and dissolved in 20 mL of dry acetonitrile. The solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen (or air) for 10 minutes. The test tube was attached to a Lionnet light irradiation system (350 nm lamp (maximum wavelength): 2 W × 15 = 30 W), and the solution was aerated with oxygen and stirred while being irradiated with light (350 nm wavelength) for 8 minutes. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was distilled off, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 1:2 (volume ratio)) to isolate 16.1 mg (yield 23% by mass) of compound (I-1).

[0086] The physical properties of compound (I-1) are shown below. Colorless prisms (recrystallization solvent: n-hexane), melting point: 115-116°C, C 21 H 22 F2O2, [MW 344.40]. IR (KBr, cm -1): 3062, 3027, 2979,2957,2946,2926,2860,1511,1467,1451,1432, 1415,1354,1333,1315,1244,1191,1170,1150,1107,1092,1065,1029,1020,996, 948,888,844,806,790,762,716,653,578,568,553,537,519,499. 1 H NMR(400 MHz, CDCl3)δ:1.90-2.00 (m, 1H),2.02-2.19 (m, 1H),2.20-2.38 (m, 3H),2.339 (s, 3H),2.343 (s, 3H),2.49-2.58 (m, 1H),2.79-2.98 (m, 2H), 7.15-7.21 (m, 4H), 7.28-7.33 (m, 2H),7.42-7.47 (m, 2H). 13 C NMR (100 MHz,CDCl3)δ:19.67 (t, 1C, J C-F(d) = 4.6 Hz),20.99 (q, 1C),21.06 (q, 1C),37.11 (t, 1C, J C-F(d) = 5.3 Hz),39.04 (t, 1C),43.79 (t, 1C, J C-F(dd) = 28.8 Hz, 23.5 Hz),83.13 (s, 1C, J C-F(dd) = 5.3 Hz, 4.6 Hz),86.03 (s, 1C, J C-F(dd) = 26.6Hz, 24.3 Hz),118.90 (s, 1C, J C-F(t) = 251.2 Hz), 124.23 (d, 2C), 126.00 (d, 2C), 128.76 (d, 2C), 129.23 (d, 2C), 134.70 (s, 1C, J C-F(d) = 3.0 Hz), 137.63 (s, 1C), 137.80 (s, 1C), 141.31 (s, 1C). Anal.calcd for C 21 H 22F2O2: C, 73.24%; H, 6.44%. Found: C, 73.40%; H, 6.46%. MS (ASAP) m / z 345 ([M+H] + ).

[0087] [Manufacturing Example 2] (Production of Compound (I-2)) Compound (I-2) was synthesized according to the following reaction scheme.

[0088] [ka]

[0089] 1. Step (i): Synthesis of 6,6-difluoro-1,5-di(p-ethylphenyl)hex-5-en-1-one (compound (Ib-2)) 3.08 g (10.0 mmol) of 1,5-di(p-ethylphenyl)penta-1,5-dione (compound (Ia-2)), 6.29 g (40.0 mmol) of sodium chlorodifluoroacetate, and 8.52 g (40.0 mmol) of tri(n-butyl)phosphine were dissolved in ultra-dehydrated dimethylformamide (10 mL). The reaction mixture was purged with nitrogen and heated and stirred in an oil bath. The temperature of the oil bath was raised to 130 °C within 10 min. At around 70 °C, both compound (Ia-2) and sodium chlorodifluoroacetate were completely dissolved. At around 100 °C, sodium chlorodifluoroacetate decomposed to form difluorocarbene, which reacted with tri(n-butyl)phosphine to form difluoromethylenephosphonium ylide. The oil bath temperature was maintained at 130°C for 30 minutes, whereby the difluoromethylenephosphonium ylide reacted with compound (Ia-2) to produce compound (Ib-2). Compound (Ib-2) was isolated and purified from the reaction mixture by column chromatography. Specifically, after the reaction was completed, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with sodium bicarbonate water, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed and the resulting crude product was separated by silica gel column chromatography (elution solvent: dichloromethane-n-hexane, 1:2 (volume ratio)) to obtain 1.83 g (53% yield) of compound (Ib-2) as a yellow oil.

[0090] The physical properties of compound (Ib-2) are shown below. yellow oil, C 22 H 24 F2O, [MW342.42]. IR(KBr, cm-1): 3086, 3030, 2966, 2933, 2896, 2873, 1684(C=O), 1607, 1570, 1515, 1458, 1413, 1365, 1308, 1263, 1231, 1181, 1155, 1109, 1061, 1019, 998, 983, 939, 924, 834, 784. 1H NMR(400 MHz, CDCl3) δ: 1.24 (t, 3H, J = 7.6 Hz), 1.25 (t, 3H, J = 7.6 Hz), 1.82 (quintet, 2H, J = 7.6 Hz), 2.50 (tt, 2H, J H-H(t) = 7.6 Hz, J H-F(t) = 2.4 Hz), 2.64 (qurtet, 2H, J = 7.6 Hz), 2.70 (qurtet, 2H, J = 7.6 Hz), 2.93 (t, 2H, J = 7.6 Hz), 7.16-7.21 (m, 2H), 7.22-7.28 (m, 4H), 7.79-7.84 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ:15.15 (qurtet, 1C), 15.36 (qurtet, 1C), 22.39 (t, 1C), 27.03 (t, 1C), 28.47 (t, 1C), 28.89 (t, 1C), 37.40 (t, 1C), 91.76 (s, 1C, J C-F(dd) = 19.0 Hz, 15.2Hz), 127.97 (d, 2C), 128.00 (d, 2C), 128.09 (d, 2C, J C-F(t) = 3.0 Hz), 128.18 (d, 2C), 130.50 (s, 1C), 134.66 (s, 1C), 143.34 (s, 1C), 149.85 (s, 1C), 153.67 (s, 1C, J C-F(t) = 287.6 Hz), 199.34 (s, 1C, C=O).

[0091] 2. Step (ii): Synthesis of 1,1-difluoro-2,6-di(p-ethylphenyl)hepta-1,6-diene (compound (Ic-2)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was reacted at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

[0092] To this solution, 6.85 g (20.0 mmol) of 6,6-difluoro-1,5-di(p-ethylphenyl)hex-5-en-1-one (compound (Ib-2)) in 30 mL of tetrahydrofuran was added, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed, and the resulting crude product was separated by silica gel column chromatography (elution solvent: hexane) to obtain 3.49 g (51% yield) of compound (Ic-2) as a colorless oil.

[0093] The physical properties of compound (Ic-2) are shown below. colorless oil, C 23 H 26 F2, [MW 340.45]. IR(KBr, cm-1): 3083, 3049, 3026, 2965, 2932, 2871, 1625, 1562, 1514, 1459, 1411, 1375, 1308, 1232, 1188, 1166, 1110, 1061, 1019, 966, 941, 893, 836, 783. 1 H NMR(400 MHz, CDCl3) δ: 1.23 (quintet, 3H, J = 7.6 Hz), 1.24 (quintet, 3H, J = 7.6 Hz), 1.53 (quintet, 2H, J = 7.6 Hz), 2.41 (tt, 2H, J H-H(t) = 7.6 Hz, J H-F(t) = 2.4 Hz), 2.48 (t, 2H, J = 7.6 Hz), 2.63 (qurtet, 4H, J = 7.6 Hz), 4.97 (d, 1H, J = 1.2 Hz), 5.23 (d, 1H, J = 1.2 Hz), 7.09-7.19 (m, 6H), 7.23-7.29 (m, 2H) 13C NMR(100 MHz, CDCl3) δ:15.37 (qurtet, 1C), 15.47 (qurtet, 1C), 26.19 (t, 1C), 27.06 (t, 1C), 28.47 (t, 2C), 34.57 (t, 1C), 91.91 (s, 1C, J C-F(dd) = 19.0 Hz, 15.2 Hz), 111.81 (t, 1C), 126.00 (d, 2C), 127.72 (d, 2C), 127.85 (d, 2C),128.07 (d, 2C, J C-F(t) = 3.1 Hz), 130.74 (s, 1C), 138.32 (s, 1C), 143.14 (s, 1C), 143.40 (s, 1C), 147.67 (s, 1C), 153.55 (s, 1C, J C-F(t) = 287.6 Hz).

[0094] 3. Step (iii): Synthesis of 8,8-difluoro-1,5-di(p-ethylphenyl)-6,7-dioxabicyclo[3.2.2]nonane (compound (I-2)) A Pyrex test tube (20 cm long, 30 mm diameter) was charged with 68.0 mg (0.2 mmol) of compound (Ic-2) synthesized in step (ii) above, 7.9 mg (0.02 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl, and dissolved in 20 mL of dry dichloromethane. The solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen for 10 minutes. The test tube was attached to a Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W × 15 = 30 W), and the solution was aerated with oxygen and irradiated with light (350 nm wavelength) for 8 minutes while stirring. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was distilled off, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 1:2 (volume ratio)) to isolate 18.4 mg (yield 25% by mass) of compound (I-2).

[0095] The physical properties of compound (I-2) are shown below. Colorless needle-like crystals (recrystallization solvent: n-hekissan), melting point: 94-95℃, C 23 H 26 F2O2, [MW 372.45]. IR(KBr, cm -1 ): 3091,3028,2963,2929,2871,1512,1455,1429,1413,1354,1333,1293,1261,1190,1170,1151,1105,1094,1065,1028,995,948,888,836,820,795,784,754,656,627. 1 H NMR(400 MHz, CDCl3)δ:1.23 (t, 3H, J = 7.6 Hz), 1.24 (t, 3H, J = 7.6 Hz), 1.90-2.01 (m, 1H), 2.04-2.20 (m, 1H), 2.21-2.39 (m, 3H),2.50-2.59 (m, 1H),2.64 (qurtet, 2H, J = 7.6 Hz),2.65 (qurtet, 2H, J = 7.6 Hz),2.80-3.00 (m, 2H),7.18-7.24 (m, 4H),7.31-7.36 (m, 2H),7.44-7.50 (m, 2H). 13 C NMR (100 MHz, CDCl3)δ:15.26 (q, 1C),15.42 (q, 1C),19.68 (t, 1C, J C-F(d) = 4.5 Hz),28.41 (t, 2C),37.12 (t, 1C, J C-F(d) = 4.6 Hz),39.05 (t, 1C),43.79 (t, 1C, J C-F(dd) = 28.8 Hz, 22.8 Hz),83.14 (s, 1C, J C-F(t) = 4.5 Hz), 86.04 (s, 1C, J C-F(dd) = 26.5 Hz, 24.2 Hz),118.94 (s, 1C, J C-F(t)= 251.9 Hz), 124.31 (d, 2C),126.06 (d, 2C),127.53 (d, 2C),128.03 (d, 2C),134.91 (s, 1C, J C-F(d) = 3.8 Hz),141.52 (s, 1C),143.95 (s, 1C),144.01 (s, 1C). Anal.calcd for C 23 H 26 F2O2: C, 74.17%; H, 7.04%. Found: C, 74.01%; H, 7.02%. MS (ASAP) m / z 373 ([M+H] + ).

[0096] [Manufacturing Example 3] (Production of Compound (I-3)) Compound (I-3) was synthesized according to the following reaction scheme.

[0097] [ka]

[0098] 1. Step (i): Synthesis of 6,6-difluoro-1,5-diphenylhex-5-en-1-one (compound (Ib-3)) 2.53 g (10.0 mmol) of 1,5-diphenylpenta-1,5-dione (compound (Ia-3)), 6.29 g (40.0 mmol) of sodium chlorodifluoroacetate, and 8.52 g (40.0 mmol) of tri(n-butyl)phosphine were dissolved in ultra-dehydrated dimethylformamide (10 mL). The reaction system was purged with nitrogen and then heated and stirred in an oil bath. The temperature of the oil bath was raised to 130 °C within 10 min. At around 70 °C, both compound (Ia-3) and sodium chlorodifluoroacetate were completely dissolved. At around 100 °C, sodium chlorodifluoroacetate decomposed to produce difluorocarbene, which reacted with tri(n-butyl)phosphine to form difluoromethylenephosphonium ylide. The oil bath temperature was maintained at 130°C for 30 minutes, whereby the difluoromethylenephosphonium ylide reacted with compound (Ia-3) to produce compound (Ib-3). Compound (Ib-3) was isolated and purified from the reaction mixture by column chromatography. Specifically, after the reaction was completed, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with sodium bicarbonate water, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated by silica gel column chromatography (elution solvent: dichloromethane-n-hexane, 1:2 (volume ratio)) to obtain 1.52 g (53% yield) of compound (Ib-3) as a yellow oil.

[0099] The physical properties of compound (Ib-3) are shown below. yellow oil, C 18 H 16 F2O, [286.32]. IR(KBr, cm-1): 3087, 3060, 3028, 2957, 2939, 2873, 1684(C=O), 1598, 1579, 1544, 1497, 1447, 1411, 1373, 1348, 1304, 1281, 1266, 1231, 1203, 1180, 1154, 1118, 1072, 1030, 1002, 988, 940, 924, 916, 859, 844, 795, 763, 720, 690, 660, 645. 1 H NMR(400 MHz, CDCl3) δ: 1.84 (quintet, 2H, J = 7.6 Hz), 2.53 (tt, 2H, J H-H(t) = 7.6 Hz, J H-F(t) = 2.4 Hz), 2.96 (t, 2H, J = 7.6 Hz), 7.24-7.29 (m, 1H), 7.30-7.39 (m, 4H), 7.40-7.47 (m, 2H), 7.50-7.58 (m, 1H), 7.86-7.92 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ:22.27 (t, 1C, J C-F(t) = 2.3 Hz), 27.01 (t, 1C), 37.46 (t, 1C), 91.93 (s, 1C, J C-F(t) = 17.5 Hz), 127.32 (d, 1C), 127.93 (d, 2C), 128.19 (d, 2C, J C-F(t) = 3.1 Hz), 128.49 (d, 2C), 128.53 (d, 2C), 132.94 (d, 1C), 133.31 (s, 1C, J C-F(d) = 1.5 Hz), 136.88 (s, 1C), 153.74 (s, 1C, J C-F(t) = 287.6 Hz), 199.58 (s, 1C, C=O).

[0100] 2. Step (ii): Synthesis of 1,1-difluoro-2,6-diphenylhepta-1,6-diene (compound (Ic-3)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was reacted at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

[0101] To this solution, 5.73 g (20.0 mmol) of 6,6-difluoro-1,5-diphenylhex-5-en-1-one (compound (Ib-3)) in tetrahydrofuran (30 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated by silica gel column chromatography (elution solvent: hexane) to obtain 4.83 g (yield 85% by mass) of compound (Ic-3) as a colorless oil.

[0102] The physical properties of compound (Ic-3) are shown below. colorless oil, C 19 H 18 F2, [MW 284.34]. IR(KBr, cm-1) : 3083,3058, 3027, 2935, 2867, 1627, 1601, 1575, 1496, 1445, 1386, 1343, 1306, 1232, 1167, 1122, 1074, 1056, 1029, 1002, 943, 897, 841, 778, 762, 697. 1 H NMR(400 MHz, CDCl3) δ: 1.53 (quintet, 2H, J = 7.6 Hz), 2.42 (tt, 2H, J H-H = 7.6 Hz, J H-F = 2.4 Hz), 2.50 (t, 2H, J = 7.6 Hz), 5.01 (d, 1H, J = 1.2 Hz), 5.25 (d, 1H, J = 1.2 Hz), 7.21-7.35 (m, 10H). 13 C NMR(100 MHz, CDCl3) δ:26.11 (t, 1C), 27.04 (t, 1C), 34.57 (t, 1C), 92.09 (s, 1C, J C-F(dd)= 20.0 Hz, 14.0 Hz), 112.62 (t, 1C), 126.08 (d, 2C), 127.16 (d, 1C), 127.33 (d, 1C), 128.18 (d, 2C, J C-F(t) = 3.0 Hz), 128.25 (d, 2C), 128.38 (d, 2C), 133.55 (s, 1C, J C-F(d) = 2.3 Hz), 141.02 (s, 1C), 147.86 (s, 1C), 153.61 (s, 1C, J C-F(dd) = 288.4 Hz, 285.3 Hz).

[0103] 3. Step (iii): Synthesis of 8,8-difluoro-1,5-diphenyl-6,7-dioxabicyclo[3.2.2]nonane (compound (I-3)) 56.9 mg (0.2 mmol) of compound (Ic-3) synthesized in step (ii), 7.9 mg (0.02 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl were placed in a Pyrex test tube (20 cm long, 30 mm diameter) and dissolved in dry acetonitrile (20 mL). The solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen for 10 minutes. The test tube was attached to a Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W × 15 = 30 W), and the solution was aerated with oxygen and irradiated with light (350 nm wavelength) for 15 minutes while stirring. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was distilled off, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 1:2 (volume ratio)) to isolate 10.7 mg (yield 17% by mass) of compound (I-3).

[0104] The physical properties of compound (I-3) are shown below. Colorless prism-like crystals (recrystallization solvent: n-hexane), melting point: 89-90°C, C 19 H 18 F2O2, [MW 316.34]. IR (KBr, cm-1 ): 3068,3037,2993,2951,2919,2882,2840,1493,1468,1447,1436,1392,1360,1329,1294,1259,1213,1184,1149,1106,1075,1059,1035,997,974,944,927,896,846,822,800,757,699,659,631,595. 1 H NMR(400 MHz, CDCl3)δ:1.92-2.02 (m, 1H),2.05-2.23 (m, 1H),2.23-2.40 (m, 3H),2.52-2.60 (m, 1H),2.84-3.01 (m, 2H),7.25-7.45 (m, 8H),7.54-7.60 (m, 2H). 13 C NMR (100 MHz, CDCl3)δ:19.64 (t, 1C, J C-F(d) = 4.6 Hz),37.15 (t, 1C, J C-F(d) = 4.6 Hz),39.05 (t, 1C),43.84 (t, 1C, J C-F(dd) = 28.8 Hz, 23.5 Hz),83.20 (s, 1C, J C-F(dd) = 5.3 Hz, 4.4 Hz),86.13 (s, 1C, J C-F(dd) = 26.5Hz, 24.3 Hz),118.87 (s, 1C, J C-F(t) = 251.9 Hz),124.25 (d, 2C),126.04 (d, 2C),127.87 (d, 1C),128.06 (d, 3C),128.60 (d, 2C),137.64 (s, 1C, J C-F(dd) = 3.8 Hz, 1.5 Hz),144.23 (s, 1C). Anal.calcd for C 19 H 18 F2O2: C, 72.14%; H, 5.74%. Found: C, 72.21%; H, 5.63%. MS (ASAP) m / z 317 ([M+H] + ).

[0105] [Manufacturing Example 4] (Production of Compound (I-4)) Compound (I-4) was synthesized according to the following reaction scheme.

[0106] [ka]

[0107] 1. Step (i): Synthesis of 6,6-difluoro-1,5-di(p-fluorophenyl)hex-5-en-1-one (compound (Ib-4)) 2.88 g (10.0 mmol) of 1,5-di(p-fluorophenyl)penta-1,5-dione (compound (Ia-4)), 6.29 g (40.0 mmol) of sodium chlorodifluoroacetate, and 8.52 g (40.0 mmol) of tri(n-butyl)phosphine were dissolved in ultra-dehydrated dimethylformamide (10 mL). The reaction mixture was purged with nitrogen and heated and stirred in an oil bath. The temperature of the oil bath was raised to 130 °C within 10 min. At around 70 °C, both compound (Ia-4) and sodium chlorodifluoroacetate were completely dissolved. At around 100 °C, sodium chlorodifluoroacetate decomposed to form difluorocarbene, which reacted with tri(n-butyl)phosphine to form difluoromethylenephosphonium ylide. The oil bath temperature was maintained at 130°C for 30 minutes, whereby the difluoromethylenephosphonium ylide reacted with compound (Ia-4) to produce compound (Ib-4). Compound (Ib-4) was isolated and purified from the reaction mixture by column chromatography. Specifically, after the reaction was completed, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with sodium bicarbonate water, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed and the resulting crude product was separated by silica gel column chromatography (elution solvent: dichloromethane-n-hexane, 1:2 (volume ratio)) to obtain 1.58 g (49% yield) of compound (Ib-4) as a yellow oil.

[0108] The physical properties of compound (Ib-4) are shown below. Yellow oily substance, C 18 H 14 F4O, [322.30]. IR(KBr, cm-1): 3074, 2961, 2936, 2873, 1686(C=O), 1599, 1458, 1409, 1367, 1299, 1201, 1157, 1119, 1096, 1036, 1014, 1001, 984, 939, 926, 837, 791, 740, 685, 657, 597. 1 H NMR (400 MHz, CDCl3) δ: 1.81 (quintet, 2H, J = 7.6 Hz), 2.49 (tt, 2H, J H-H(t) = 7.6 Hz, J H-F(t) = 2.4 Hz), 2.93 (t, 2H, J = 7.6 Hz), 7.02-7.15 (m, 4H), 7.27-7.34 (m, 2H), 7.88-7.96 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ:22.11 (t, 1C), 27.09 (t, 1C), 37.27 (t, 1C), 91.14 (s, 1C, J C-F(dd) = 19.8 Hz, 16.0Hz), 115.51 (d, 2C, J C-F(d) = 21.2 Hz), 115.65 (d, 2C, J C-F(d) = 22.0 Hz), 129.15 (s, 1C, J C-F(t) = 3.0 Hz), 129.89 (d, 2C, J C-F(dt) = 8.4 Hz, 3.0 Hz), 130.53 (d, 2C, J C-F(d) = 9.2 Hz), 133.29 (s, 1C, J C-F(d) = 3.1 Hz), 153.71 (s, 1C, J C-F(t) = 286.9 Hz), 161.90 (s, 1C, J C-F(d) = 245.9 Hz), 165.70 (s, 1C, J C-F(d) = 253.4 Hz), 197.80 (s, 1C, C=O).

[0109] 2. Step (ii): Synthesis of 1,1-difluoro-2,6-di(p-fluorophenyl)hepta-1,6-diene (compound (Ic-4)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was reacted at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

[0110] To this solution, 6.45 g (20.0 mmol) of 6,6-difluoro-1,5-di(p-fluorophenyl)hex-5-en-1-one (compound (Ib-4)) in 30 mL of tetrahydrofuran was added, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed, and the resulting crude product was separated by silica gel column chromatography (elution solvent: hexane) to obtain 5.15 g (81% yield) of compound (Ic-4) as a colorless oil.

[0111] The physical properties of compound (Ic-4) are shown below. colorless oil, C 19 H 16 F4, [320.32]. IR(KBr, cm-1): 3084, 3050, 2936, 2868, 1628, 1604, 1510, 1457, 1406, 1312, 1299, 1237, 1161, 1121, 1094, 1056, 1014, 944, 899, 838, 815, 740. 1 H NMR(400 MHz, CDCl3) δ: 1.49 (quintet, 2H, J = 7.6 Hz), 2.39 (tt, 2H, J H-H(t) = 7.6 Hz, J H-F(t)= 2.4 Hz), 2.46 (t, 2H, J = 7.6 Hz), 5.00 (d, 1H, J = 1.2 Hz), 5.20 (d, 1H, J = 1.2 Hz), 6.93-7.04 (m, 6H), 7.25-7.31 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ:25.88 (t, 1C), 27.04 (t, 1C), 34.62 (t, 1C), 91.25 (s, 1C, J C-F(dd) = 21.3 Hz, 14.4 Hz), 112.69 (t, 1C), 115.07 (d, 2C, J C-F (d) = 21.2 Hz), 115.35 (d, 2C, J C-F (d) = 21.2 Hz), 127.64 (d, 2C, J C-F(d) = 8.4 Hz),129.36 (s, 1C), 129.82 (d, 2C, J C-F(dt) = 7.6 Hz, 3.0 Hz), 136.97 (s 1C, J C-F(d) = 3.0 Hz), 146.73 (s, 1C), 153.37 (s, 1C, J C-F(t) = 286.9 Hz), 161.82 (s, 1C, J C-F(d) = 245.9 Hz), 162.26 (s, 1C, J C-F(d) = 245.1 Hz).

[0112] 3. Engineering (iii): 8,8-ジフフオロ-1,5-ジ(p-フルオロフェニルSynthesis of )-6,7-ジオキサビシクロ[3.2.2]ノナン(Compound (I-4)) 64.1 mg (0.2 mmol) of compound (Ic-4) synthesized in step (ii), 7.9 mg (0.02 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl were placed in a Pyrex test tube (20 cm long, 30 mm diameter) and dissolved in dry acetonitrile (20 mL). The solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen for 10 minutes. The test tube was attached to a Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W × 15 = 30 W), and the solution was aerated with oxygen and irradiated with light (350 nm wavelength) for 10 minutes while stirring. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was distilled off, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 2:3 (volume ratio)) to isolate 6.6 mg (yield 17% by mass) of compound (I-4).

[0113] The physical properties of compound (I-4) are shown below. Colorless prism-like crystals, melting point: 116-117°C (recrystallization solvent: n-hexane), C 19 H 16 F4O2, [352.32]. IR (KBr, cm -1 ): 3078,3041,2958,2934,2890,1601,1556,1508,1430,1409,1355,1329,1308,1292,1263,1229,1166,1098,1089,1065,1027,1016,999,952,897,836,810,792,768,699,662,623,600,573. 1 H NMR(400 MHz, CDCl3)δ:1.94-2.03 (m, 1H),2.05-2.19 (m, 1H),2.20-2.39 (m, 3H),2.48-2.56 (m, 1H),2.84-2.95 (m, 2H),7.03-7.10 (m, 4H),7.37-7.43 (m, 2H),7.49-7.56 (m, 2H). 13C NMR (100 MHz, CDCl3)δ:19.532 (t, 1C, J C-F(d) = 4.5 Hz), 39.986 (t, 1C, J C-F(d) = 4.5 Hz),38.981 (t, 1C),43.727 (t, 1C, J C-F(dd) = 28.8 Hz, 23.5 Hz),83.018 (s, 1C, J C-F(dd) = 5.3 Hz, 4.5 Hz),85.894 (s, 1C, J C-F(dd) = 26.5 Hz, 24.3 Hz),114.996 (d, 2C, J C-F(d) = 21.2 Hz), 115.493 (d, 2C, J C-F(d) = 22.0 Hz), 118.623 (s, 1C, J C-F(t) = 252.0 Hz), 126.224 (d, 2C, J C-F(d) = 8.3 Hz), 128.037 (d, 2C, J C-F(d) = 8.4 Hz),133.239 (s, 1C),139.834 (s, 1C),162.220 (s, 1C, J C-F(d) = 245.8 Hz), 162.478 (s, 1C, J) C-F(d) = 245.8 Hz). Anal.calcd for C 19 H 16 F4O2: C, 64.77%; H, 4.58%. Found: C, 64.90%; H, 4.64%. MS (ASAP) m / z 353 ([M+H] + ).

[0114] [Comparative Manufacturing Example 1] (Production of Compound (II-1)) The reaction formula and synthesis of compound (II-1) are as follows.

[0115]

change

[0116] 1. Step (i)': Synthesis of 2,6-di(p-methylphenyl)hepta-1,6-diene (compound (IIb-1)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was reacted at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

[0117] To this solution, 2.80 g (10.0 mmol) of 1,5-di(p-methylphenyl)penta-1,5-dione (compound (IIa-1)) in 30 mL of tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 3 hours. The mixture was then stirred at room temperature for 15 hours. After the reaction was complete, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed, and the resulting crude product was separated by silica gel column chromatography (elution solvent: hexane) to obtain 2.72 g (yield 98% by mass) of compound (IIb-1) as a colorless oil.

[0118] The physical properties of compound (IIb-1) are shown below. colorless oil, C 21 H 24 , [MW 276.42]. IR (KBr) cm -1 : 3082, 3048, 3024, 2989, 2941, 2865, 1605, 1566, 1513, 1447. 1 H-NMR (400 MHz, CDCl3) δppm: 1.61 (quintet, 2H, J = 7.2 Hz), 2.34 (s, 6H), 2.51 (t, 4H, J = 7.2 Hz), 4.99 (dt, 2H, J = 1.6 Hz, 1.2 Hz), 5.24 (d, 2H, J = 1.6 Hz), 7.07-7.13 (m, 4H), 7.23-7.28 (m, 4H). 13C-NMR (100 MHz, CDCl3) δppm: 21.07 (q, 2C), 26.64 (t, 1C), 34.770 (t, 2C), 111.63 (t, 2C), 125.95 (d, 4C), 128.91 (d, 4C), 136.96 (s, 2C), 138.21 (s, 2C), 147.98 (s, 2C).

[0119] 2. Step (ii)': Synthesis of 1,5-di(p-methylphenyl)-6,7-dioxabicyclo[3.2.2]nonane (Compound (II-1)) 55.3 mg (0.2 mmol) of compound (IIb-1) synthesized in step (i)', 15.8 mg (0.04 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl were placed in a Pyrex test tube (20 cm long, 30 mm diameter) and dissolved in dry acetonitrile (20 mL). The solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen for 10 minutes. The test tube was attached to a Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W × 15 = 30 W), and the solution was aerated with oxygen and stirred while being irradiated with light (350 nm wavelength) for 8 minutes. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was distilled off, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 1:1 (volume ratio)) to isolate 45.9 mg (yield 74% by mass) of compound (II-1).

[0120] The physical properties of compound (II-1) are shown below. Colorless plate crystals, C 21 H 24 O2, [MW 308.41]. Melting point: 198-199 °C. IR (KBr) cm-1: 3052, 3022, 2999, 2970, 2918, 2860, 1604, 1513, 1477, 1448. 1H-NMR (400 MHz, CDCl3) δppm: 1.85-1.94 (m, 1H), 1.98-2.11 (m, 1H), 2.14-2.21 (m, 2H), 2.25-2.42 (m, 6H), 2.33 (s, 6H), 7.12-7.17 (m, 4H), 7.30-7.35 (m, 4H). 13 C-NMR (100 MHz, CDCl3) δppm: 21.00 (q, 2C), 21.27 (t, 1C), 29.36 (t, 2C), 40.48 (t, 2C), 82.65 (s, 2C), 124.32 (d, 4C), 128.91 (d, 4C), 136.73 (s, 2C), 143.51 (s, 2C).

[0121] [Test Example 1] (Malaria parasite growth inhibition test) 1. Pre-culture of malaria parasites In this study, Plasmodium falciparum (P. falciparum FCR-3 Strain (ATCC 30932)) was used. The medium used in this study was filter-sterilized RPMI 1640 medium, adjusted to pH 7.4 and supplemented with 10% human serum (v / v). Plasmodium culture was performed at 36.5°C with an O2 concentration of 5% v / v, CO2 concentration of 5% v / v, and N2 concentration of 90% v / v. The hematocrit (volume ratio of red blood cells in the red blood cell suspension) was set to 5% v / v. The initial infection rate of Plasmodium falciparum at the start of culture was 0.1%. Cultures were performed using 24-well culture plates, with the medium changed daily and subcultured at an infection rate of 4%. The infection rate was measured by preparing thin smear samples, staining them with Giemsa or Diff-Quick, and measuring them under a microscope (oil immersion, 1000x magnification), and the malaria parasite infection rate was calculated using the following formula.

[0122] "Malaria parasite infection rate (%)" = {(number of infected red blood cells) / (total number of red blood cells)} x 100

[0123] 2. Infection of red blood cells by malaria parasites in the presence of candidate compounds Cultured malaria parasite-infected red blood cells were collected by centrifugation, washed with serum-containing medium, and then non-infected red blood cells were added to the culture to achieve an initial infection rate of 0.3%. The hematocrit at this time was 3%. Compound (I-1), one of the candidate compounds used in this study, was dissolved in dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or sterile water to prepare the designated samples. 5 μL to 10 μL of each sample was added to a 24-well culture plate. Samples were prepared in duplicate or triplicate. 10 μL of sterile water, DMF, or DMSO was added per well as a control. Next, 990 μL to 995 μL of pre-prepared Plasmodium falciparum culture medium was added and gently pipetted to uniformly suspend the cells in the culture medium. The culture plate was then incubated for 72 hours in a CO₂-O₂-N₂ (5 v / v%, 5 v / v%, 90 v / v%) incubator. Then, a thin smear was prepared for each well, stained, and observed under a microscope. The malaria parasite infection rate in the sample containing the candidate compound and the control sample was calculated. The 50% growth inhibitory concentration (EC 50 The results are shown in Table 1. In the formula, a represents the initial malaria parasite infection rate, b represents the malaria parasite infection rate when the sample was added, and c represents the malaria parasite infection rate when no sample was added (control).

[0124] "Growth rate (%)" = {(ba) / (ca)} x 100

[0125] [Test Example 2] (Mouse FM3A cell growth inhibition test) The F28-7 strain, a wild-type strain of mouse mammary carcinoma-derived FM3A cells, was used. The medium was ES medium supplemented with inactivated fetal bovine serum at 2 v / v%, and the cells were cultured at 37°C with a CO2 concentration of 5 v / v%. Under these conditions, the doubling time of FM3A cells was approximately 12 hours. After pre-culture, 5 x 10 cells were cultured in the logarithmic growth phase. 4 The cells were diluted with medium to give a concentration of 100 cells / mL.

[0126] The samples used were those prepared in Test Example 1 above. 5 μL to 10 μL of the sample solution was added to a 24-well culture plate (when medium or the like was added, the final concentration was 1 × 10 -4 mol / L(M) or more 1×10 -6 (The concentration was below 100 mol / L (M)). Samples were prepared in duplicate or triplicate. As controls, 10 μL of sterile water, DMF, or DMSO was added per well. Next, 990 μL to 995 μL of the prepared culture cell suspension was added and gently pipetted to uniformly suspend the cells in the medium. After 48 hours of culture, the number of cells in each well was counted using a cell controller (CC-108, Toa Medical Electrics Co., Ltd.), and the proliferation rate was calculated using the following formula: In the formula, A represents the initial cell number, B represents the control cell number after 48 hours, and C represents the cell number 48 hours after sample addition.

[0127] "Growth rate (%)" = {(CA) / (BA)} x 100

[0128] The cell growth inhibitory activity was calculated from the cell counts in the wells to which the samples were added and the control cell counts. This allowed us to evaluate the cytotoxicity of the samples and determine the cell growth inhibitory concentration (EC 50 The results are shown in Table 1. 50 The value refers to the concentration (molar concentration) of a sample that inhibits the growth rate of malaria parasites or FM3A cells in a culture medium by 50% when the sample is added, with the growth rate or infection rate of malaria parasites when no sample is added (control) being set at 100%.

[0129] The antimalarial activity of the samples was determined by the EC 50 The efficacy was evaluated from the ratio of the values ​​(chemotherapeutic index, see the formula below) and measured. For comparison, the same test was also performed on compound (II-1), which has the same bicyclic skeleton as compound (I-1) but does not have a fluorine atom on the skeleton, and chloroquine, which is used as an antimalarial drug. The results are shown in Table 1.

[0130] [Table 1]

[0131] For comparison, Table 2 also shows literature values ​​for the efficacy measurements of known antimalarial drugs quinine and artemisinin, as well as recently developed compounds with antimalarial activity, N-89 and N-251.

[0132] [Table 2]

[0133] Reference 1: Takaya Y et al., “Novel antimalarial guaiane-type sesquiterpenoids from Nardostachys chinensis roots.”, Tetrahedron Lett., Vol. 39, pp. 1361-1364, 1998. Reference 2: Kim HS et al., “Synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes.”, J. Med. Chem., Vol. 44, pp. 2357-2361, 2001. Reference 3: Japanese Patent Application Laid-Open No. 2000-229965 Reference 4: Yusuke Wataya et al., "Antimalarial Drugs," Pharmacia, Vol. 44, No. 1, pp. 32-36, 2008.

[0134] As a result, it was found that the compound of this embodiment has reduced cytotoxicity and has an excellent activity of inhibiting the proliferation of malaria parasites. [Industrial Applicability]

[0135] According to the compound of this embodiment, it is possible to provide a compound that has reduced cytotoxicity, excellent antimalarial activity, and can be synthesized simply and safely. The antimalarial agent of this embodiment contains the compound, has reduced cytotoxicity, and has excellent antimalarial activity.

Claims

1. A compound represented by the following general formula (I): 【Chemistry 1】 (In general formula (I), R １ and R ２ are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl group, alkoxy group, aryl group, carboxy group, or amino group.

2. In the general formula (I), R １ and R ２ The compound according to claim 1 , wherein each independently represents a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group.

3. An antimalarial agent comprising the compound according to claim 1 or 2 as an active ingredient.

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