Dibenzosberanyl piperazine derivatives and drug-resistance overcoming agents containing the derivatives

The present invention relates to a novel dibenzosveranyl piperazine derivative and a salt thereof, which are useful for treating a disease predisposition having drug resistance, and a pharmaceutical composition containing the compound as an active ingredient. Background Technology Chemotherapy for infections and cancers was once a very useful treatment for these diseases, many infections have been overcome, and complete cure of cancer seems not to be a dream. Was there. Examples of such infectious diseases include tuberculosis, which was thought to be a fatal disease, yellow fever, dengue fever, malaria, and leishmania, which hindered the development of tropical regions. In recent years, drug-resistant strains have emerged against such chemotherapy. That is, the emergence of strains in which conventionally effective drugs are almost ineffective. Moreover, since such resistant strains are resistant not only to exposed drugs but also to many unexposed drugs, infection with such resistant strains causes loss of therapeutic means. There are signs that the disease, which was thought to have been overcome, will re-emerge. In addition, the emergence of such resistant strains has also appeared in cancer chemotherapy, and many phenomena have been experienced in which the effect of chemotherapeutic agents is drastically reduced for cancer at the time of recurrence. And it has been found that the mechanism is due to the action of ATP-operated pumps (ABC pumps). Many similarities have been found in the gene structure of ABC pumps in these resistant cancers or resistant pathogens, and it is presumed that they are very similar mechanisms. For the disease predisposition having such drug resistance, R of the following general formula (II)¹Is a hydrogen atom and R²Dibenzosveranyl piperazines, which are oxy (or thio) aromatic hydrocarbons, have an action of overcoming such drug resistance, that is, an action of increasing susceptibility to a disease-predisposing drug when administered together with a drug. It has been known. However, even with such an action, the susceptibility may not return to the same level as that of the non-resistant strain, and a substance having a stronger drug resistance overcoming action, that is, an action of restoring the susceptibility to a drug to a disease predisposition that has acquired resistance. The development of excellent substances has been desired. An object of the present invention is to provide a substance having an excellent action of restoring sensitivity to a drug to a disease predisposition to which resistance has been acquired, that is, an action of overcoming resistance. Disclosure of the Invention In view of such a situation, the present inventors have made diligent research efforts in search of a substance having a stronger drug resistance overcoming action, and as a result, the dibenzo represented by the following general formula (I). We found a strong drug resistance overcoming effect on the sveranyl piperazine derivative, and completed the invention. That is, the present invention has the general formula (I) :.<img file="JP4189472B2_D0001.tif" />(In formula (I), R represents an aliphatic hydrocarbon group which may have a substituent containing a complex atom), or a dibenzosveranyl piperazine derivative or a physiologically acceptable salt thereof. It provides (physiologically acceptable salt). The present invention also comprises a pharmaceutical composition containing one or more selected from a dibenzosveranyl piperazine derivative represented by the general formula (I) and a physiologically acceptable salt thereof, particularly a drug for a harmful microorganism. It provides a pharmaceutical composition for overcoming resistance. The present invention also overcomes the drug resistance of one or more drugs, especially harmful microorganisms, selected from the dibenzosveranyl piperazine derivative represented by the general formula (I) and its physiologically acceptable salt thereof. It provides the use for the manufacture of pharmaceuticals to. The present invention is also characterized by administering an effective amount of one or more selected from the dibenzosveranyl piperazine derivative represented by the general formula (I) and a physiologically acceptable salt thereof. It provides a method for overcoming drug resistance of microorganisms. Best Mode for Carrying Out the Invention The compound of the present invention has a structure represented by the above general formula (I). The aliphatic hydrocarbon group represented by R in the above formula (I) preferably has a linear or branched chain structure having 2 to 30, preferably 3 to 20, particularly preferably 3 to 10. Further, among the aliphatic hydrocarbon groups, those having one or more double bonds and / or triple bonds, preferably 1 to 2 bonds are preferable. The aliphatic hydrocarbon group may have up to 5, preferably up to 2, complex atom-containing substituents. Here, examples of the complex atom include an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, and the like, and an oxygen atom among these is preferable. As the heteroatomic substituent, a hydroxyl group, an acyl group or an acyloxy group, particularly a hydroxyl group, an acyl group having 1 to 4 carbon atoms and an acyloxy group having 1 to 4 carbon atoms is preferable, and a hydroxyl group and an acyloxy group having 1 to 4 carbon atoms are preferable. More preferred. Among the compounds represented by the general formula (I), particularly preferable compounds are the general formula (II) :.<img file="JP4189472B2_D0002.tif" />(In equation (II), R¹Indicates an alkyl group having 1 to 4 carbon atoms, which is a hydrogen atom or may have a hydroxyl group, an acyl group having 1 to 4 carbon atoms or an acyloxy group having 1 to 4 carbon atoms;²Indicates an aliphatic hydrocarbon group having 2 to 30 carbon atoms, which may have an acyl group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, and / or a hydroxyl group). Is. R¹Examples of the alkyl group having 1 to 4 carbon atoms represented by (1) include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Examples of the substituent of the alkyl group include an acyl group having 1 to 4 carbon atoms such as an acetyl group or a propionyl group; an acyloxy group having 1 to 4 carbon atoms such as an acetoxy group and a propionyloxy group; and a hydroxyl group. R²As the group, an aliphatic hydrocarbon group having a linear or branched chain structure and having 2 to 30 carbon atoms, preferably 2 to 20 carbon atoms, particularly preferably 2 to 10 carbon atoms is preferable. Of these, those having one or two double bonds and / or triple bonds are particularly preferable. The aliphatic hydrocarbon group may have an acyl group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, or a substituent such as a hydroxyl group. Examples of these acyl and acyloxy groups are R.¹The same as those substituted with the alkyl group of. R¹And R²It is preferable that at least one of the above has a hydroxyl group, an acyl group or an acyloxy group. Among the compounds represented by the general formula (I) or the general formula (II) of the present invention, the following compounds are exemplified as particularly preferable compounds:<img file="JP4189472B2_D0003.tif" />1-Dibenzosveranyl-4- (2-hydroxydecane-9-en-1-yl) piperazine (Compound 1) represented by, the following formula:<img file="JP4189472B2_D0004.tif" />1-Dibenzosveranyl-4- (2-hydroxy-7-octenyl) piperazine (Compound 2) represented by, the following formula:<img file="JP4189472B2_D0005.tif" />1-Dibenzosveranyl-4- (2-hydroxy-5-hexenyl) piperazine (Compound 3) represented by, the following formula:<img file="JP4189472B2_D0006.tif" />1-Dibenzosveranyl-4- (2-hydroxy-3-butenyl) piperazine (Compound 4) represented by, the following formula:<img file="JP4189472B2_D0007.tif" />1-Dibenzosveranyl-4- (1-hydroxybutane-3-en-2-yl) piperazine (Compound 5) represented by, the following formula:<img file="JP4189472B2_D0008.tif" />1-Dibenzosveranyl-4- (4-hydroxy-2-butynyl) piperazine (Compound 6) represented by, the following formula:<img file="JP4189472B2_D0009.tif" />1-Dibenzosveranyl-4- (4-acetoxy-2-butynyl) piperazine (Compound 7) and<img file="JP4189472B2_D0010.tif" />1-Dibenzosveranyl-4- (2-hydroxydecanyl) piperazine (Compound 8) represented by. The compound of formula (I) or (II) can be produced, for example, by the following method A or method B. Method A: Dibenzosveranyl chloride and piperazine, which are commercially available, are condensed in the presence of an alkali to obtain dibenzosveranyl piperazine, and this and an aliphatic epoxide obtained by oxidizing an aliphatic hydrocarbon are combined. A method of ring-opening condensation. Method B: The dibenzosveranyl piperazine and chloride obtained by treating a polyol protected by excluding one hydroxyl group with a halogenating agent such as thionyl chloride are condensed in the presence of an alkali to desorb. How to protect. In the above methods A and B, the reaction temperature of the ring-opening condensation reaction and the condensation reaction is preferably about room temperature. The reaction time is about several hours to 24 hours, which varies depending on the reaction temperature. The compound of the present invention can also be treated with an acid and used as a salt. Physiologically acceptable salts that can be used include mineral salts such as carbonates, hydrochlorides, sulfates, nitrates, phosphates; and organic acid salts such as citrates, oxalates, and carbonates. Is particularly preferable. The compounds and / or salts thereof of the present invention are antimicrobial agents of harmful microorganisms such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), resistant tuberculosis bacteria, resistant Escherichia coli, resistant malaria protozoans, and resistant Leishmania protozoans. It has the effect of lowering the resistance to drug against harmful pathogenic microorganisms that have acquired resistance to the drug. When the compound of the present invention and / or a salt thereof is administered together with a chemotherapeutic agent, the drug resistance of the resistant pathogenic microorganism is lowered, so that even a chemotherapeutic agent which has not been successful in the past can exert its effect. Drugs that restore such susceptibility include antimalarial drugs such as chloroquine and mefloquine; antiprotozoal drugs such as anti-rifampic drugs such as antimony drugs; penicillins, cephalosporins, cephalosporins, and newquinolones. , Aminoglycoside and peptide antibiotics; Antimalarials such as rifampicin and streptomycin; Examples thereof include anticancer agents such as adriamycin, mitomycin, cisplatin, and 5FU. Drug-resistant strains have emerged as disease predispositions for all of these drugs. Verapamil and tricyclic compounds, which have been found to have a drug resistance-lowering effect, have not been put into practical use because their main drug effects have been exhibited before the drug resistance-lowering effect was exhibited, but the compound of the present invention is calcium. Since it has no antagonism, antidepressant action, or sleep-inducing action, it does not cause side effects in the range of tolerance overcoming action. The pharmaceutical composition of the present invention contains the above-mentioned compound of the present invention and / or a salt thereof as an active ingredient. Since the route of administration of the compound of the present invention is not particularly limited, the pharmaceutical composition of the present invention can be used without any particular limitation as long as it is a already known type of pharmaceutical dosage form. Any form such as granules, tablets, capsules, solutions, lyophilized preparations, oil gel preparations, aqueous gel preparations and the like is possible. Granules, tablets, and capsules can be coated, and can be coated with a water-soluble resin such as hydroxypropyl cellulose, an enteric film such as hydroxypropyl methyl cellulose, shellac, or eudragit, or a sugar coating. For such formulation, in addition to the compound of the present invention and a salt thereof, an optional component for formulation usually used in a pharmaceutical formulation can be contained. Examples of such optional components include excipients, binders, disintegrants, colorants, odorants, dispersants, emulsifiers, stabilizers, pH adjusters, isotonic agents and the like. The pharmaceutical composition of the present invention can be produced by treating these active ingredients and arbitrary ingredients according to a conventional method. The pharmaceutical composition of the present invention is suitable for medically obtaining the effect of overcoming the resistance of the compound of the present invention and its salt, but other than this, as long as the compound of the present invention or a salt thereof is used as an active ingredient. Even when it is used as a pharmaceutical composition due to its medicinal properties, it belongs to the technical scope of the pharmaceutical composition of the present invention. When the compound of the present invention is used for overcoming tolerance, the route of administration thereof is not particularly limited, and oral administration, intravenous injection, intraperitoneal injection, or infusion is performed. And rectal administration by suppository can be exemplified, but oral administration or rectal administration is preferable. The preferable dose of the compound of the present invention and / or a salt thereof for exhibiting the effect of overcoming resistance varies depending on the dosage form of the preparation, but is generally 10 to 1000 mg per day for one adult (body weight 60 kg), preferably. It is preferable to administer 5 to 500 mg in 1 to several divided doses. Examples The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.<u style="single">Example 1: Preparation of 1-dibenzosveranyl-4- (2-hydroxydecane-9-en-1-yl) piperazine (Compound 1)</u>The equivalent reaction of piperazine and dibenzosveranyl chloride was obtained to obtain dibenzosveranyl piperazine, and 1 part by weight of this dibenzosveranyl piperazine and 2 parts by weight of 1,2-epoxydecane-9-ene were subjected to methanol. After adding 4 Å, dissolve in 100 parts by weight of methanol, add 0.5 parts by weight of 1,5-diazabicyclo [5,4,0] undeca-5-ene (hereinafter referred to as DBU), reflux for 1 hour, and add solvent. After distilling off, the mixture was purified by silica gel column chromatography (eluting solvent; normal hexane: ethyl acetate = 10: 1 chloroform: methanol = 10: 1) to obtain 0.7 parts by weight (yield 29.1%) of the title compound 1. Obtained. Instrumental analysis data is shown below. MS (FAB): m / z 432 (M)⁺¹H-NMR (400MHz, CDCl₃) δ: 1.25-1.50 (8H, broad, H-7', 4', 5', 6', 3'), 2.04 (2H, m, H-8'), 2.22 (1H, dd, H-1'a), 2.26 (1H, dd, H-1'b), 2.29-2.70 (8H, Broad, H-12,14,13,15), 2.80 (2H, ddd, H-10a, 11a) ), 3.61 (1H, qd, H-2'), 3.97 (1H, s, H-5), 4.00 (2H, ddd, H-10b, 11b), 4.93 (1H, qd, H-10a'), 4.99 (1H, qd, H-10'b), 5.81 (1H, qd, H-9'), 7.04-7.20 (8H, benzene);¹³C-NMR (100MHz, CDCl₃) δ: 25.53 (C-3'), 28.82 (C-7'), 29.02 (C-5'), 29.61 (C-6'), 31.69 (C-10,11), 33.75 (C-8' ), 34.89 (C-4'), 51.95,53.5 (N-CH2), 64.05 (C-1'), 66.06 (C-2'), 79.02 (C-5), 114.11 (C-10'), 139.59 (C-9'), 125.42,127.63,130.67,139.12,139.21,139.24 (benzene).<u style="single">Example 2: Preparation of 1-dibenzosveranyl-4- (2-hydroxy-7-octenyl) piperazine (Compound 2)</u>Treatment was carried out in the same manner except that 1,2-epoxydecane-9-ene was replaced with 1,2-epoxy-7-octene in Example 1 to obtain 0.7 parts by weight (yield 18.0%) of the title compound 2. It was. The instrumental analysis results are shown below. MS (FAB): m / z 404 (M)⁺¹H-NMR (400MHz, CDCl₃) δ: 1.30-1.50 (6H, Broad, H-4', 5', 3'), 2.04 (2H, Broad, H-6'), 2.44 (2H, Broad, H-1'), 2.46-2.70 (8H, Broad, H-12,13,14,15), 2.80 (2H, ddd, H-10a, 11a), 3.80 (2H, Broad, H-2'), 3.95 (2H, ddd, H-10b) , 11b), 4.03 (1H, s, H-5), 4.93 (1H, qd, H-8'a), 4.98 (1H, qd, H-8'b), 5.79 (1H, qd, H-7) '), 7.04-7.20 (8H, benzene);¹³C-NMR (100MHz, CDCl₃) δ: 24.93 (C-4'), 28.87 (C-5'), 31.75 (C-10,11), 33.61 (C-6'), 34.76 (C-3'), 50.43,53.88 (N-) CH₂), 64.15 (C-1'), 65.68 (C-2'), 78.49 (C-5), 114.39 (C-8'), 139.55 (C-7'), 125.63,127.89,130.73,130.89,138.44 , 138.75 (benzene).<u style="single">Example 3: Preparation of 1-dibenzosveranyl-4- (2-hydroxy-5-hexenyl) piperazine (Compound 3)</u>In Example 1, 1,2-epoxydecane-9-ene was replaced with 1,2-epoxy-5-hexene and DBU was replaced with triethylamine in the same manner, and silica gel column chromatography (eluting solvent; chloroform: Purification with methanol = 10: 1) gave 0.9 parts by weight (yield 48.4%) of the title compound 3. The instrumental analysis results are shown below. Mass spectrum (EI): m / z 376 (M)⁺MS (EI): m / z 376 (M)⁺¹H-NMR (300MHz, CDCl₃) δ: 1.47 (2H, m, H-3'), 2.16 (2H, m, H-4'), 2.37 (2H, m, H-1'), 2.3-2.70 (8H, Broad, H-12 ~ 15), 2.79 (2H, ddd, H-10a, 11a), 3.64 (2H, qd, H-2'), 3.96 (1H, s, H-5), 3.99 (2H, ddd, H-10b, 11b), 4.94 (1H, qd, H-6'a), 5.02 (1H, qd, H-6'b), 5.82 (1H, m, H-5'), 7.03-7.20 (benzene);¹³C-NMR (75MHz, CDCl₃) δ: 29.84 (C-4'), 31.72 (C-10,11), 34.07 (C-3'), 51.69,53.48,53.45 (N-CH)₂), 63.92 (C-1'), 65.52 (C-2'), 79.03 (C-5), 114.58 (C-6'), 138.48 (C-5'), 126.45,127.66,130.70 (benzene).<u style="single">Examples 4: 1-dibenzosveranyl-4- (2-hydroxy-3-butenyl) piperazine (Compound 4) and 1-dibenzosveranyl-4- (1-hydroxybutane-3-en-2-yl) ) Preparation of piperazine (Compound 5)</u>The 1,2-epoxydecane-9-ene of Example 1 was treated in the same manner in place of 1,2-epoxy-3-butene to obtain a mixture of Compound 4 and Compound 5. This mixture was further purified by silica gel column chromatography (eluting solvent; normal hexane: ethyl acetate = 1: 1 1: 2), and 0.6 parts by weight (yield 37.2%) of the title compound 4 and 0.25 weight by weight of the compound 5 were added. Part (yield 17.3%) was obtained. The instrumental analysis results are shown below.<u style="single">Compound 4</u>MS (EI): m / z 348 (MH)⁺¹H-NMR (600MHz, CDCl₃) δ: 2.29-2.64 (8H, Broad, H-12,13,14,15), 2.36 (2H, td, H-1'a, H-1'b), 2.79,2.80 (2H, ddd, H) -10a, 11a), 3.97 (1H, s, H-5), 3.99,4.00 (2H, ddd, H-10b, 11b), 4.11 (1H, qd, H-2'), 5.13 (1H, qd, H-4'a), 5.31 (1H, qd, H-4'b), 5.75 (1H, qd, H-3'), 7.05-7.18 (benzene);¹³C-NMR (75MHz, CDCl₃) δ: 31.72,31.74 (C-10,11), 51.90,53.42 (N-CH)₂), 63.53 (C-1'), 67.65 (C-2'), 79.04 (C-5), 115.74 (C-4'), 138.41 (C-3'), 125.46,127.69,130.71,139.19,139.61 (Benzene) .mp 93 ° C<u style="single">Compound 5</u>MS (EI): m / z 348 (MH)⁺¹H-NMR (300MHz, CDCl₃) δ: 2.22-2.66 (8H, Broad, H-12,13,14,15), 2.76,2.82 (2H, ddd, H-10a, 11a), 3.05 (1H, qd, H-2'), 3.49 , 3.51 (2H, dd, H-1'a, H-1'b), 3.96 (1H, s, H-5), 3.98,4.00 (2H, ddd, H-10b, 11b), 5.15 (1H, 1H, qd, H-4'b), 5.25 (1H, qd, H-4'a), 5.72 (1H, qd, H-3'), 7.00-7.40 (benzene);¹³C-NMR (100MHz, CDCl₃) δ: 31.74 (C-10,11), 52.22 (N-CH)₂), 60.38 (C-1'), 68.17 (C-2'), 79.07 (C-5), 119.63 (C-4'), 133.07 (C-3'), 125.43,127.66,130.68,139.22,139.60 , 139.64 (benzene) .mp 123 ° C<u style="single">Examples 5: 1-dibenzosveranyl-4- (4-hydroxy-2-butynyl) piperazine (Compound 6) and 1-dibenzosveranyl-4- (4-acetoxy-2-butynyl) piperazine (Compound 7) ) Preparation</u>10 parts by weight of 1,4-butynediol is dissolved in 200 parts by weight of pyridine, 20 parts by weight of acetic anhydride is added dropwise while ice-cooling, the mixture is reacted for 2 hours, concentrated under reduced pressure, and silica gel column chromatography (elution) is performed. Purification with solvent; chloroform: ethyl acetate = 1: 1) gave monoacetin. 14 parts by weight of monoacetyline was dissolved in 20 parts by weight of anhydrous benzene, which was added dropwise to an anhydrous benzene solution in which pyridine and 17 parts by weight of thionyl chloride were dissolved, heated overnight at 60 ° C., and then with an equal amount of water and dichloromethane. Liquid-liquid extraction was performed, the dichloromethane layer was removed, and the mixture was concentrated to obtain a reaction product. Separately, 14 parts by weight of dibenzosveranyl piperazine was dissolved in 100 parts by weight of dimethylformamide, and 14 parts by weight of DBU and the reaction product dissolved in dimethylformamide were added dropwise thereto, and the mixture was stirred overnight at room temperature. After concentrating the reaction solution, the solution was extracted with an equal amount of chloroform and water, the chloroform layer was removed, concentrated, and then purified by silica gel column chromatography (eluting solvent; toluene: ethyl acetate = 2: 1). Compound 7 was obtained in an amount of 17.3 parts by weight (yield 65.3%). 1 part by weight of Compound 7 was dissolved in 200 parts by weight of methanol, 5.8 parts by weight of potassium carbonate was added, and the mixture was stirred at room temperature for 1 day and night. The reaction mixture was filtered, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluting solvent; chloroform: methanol = 10: 1) to obtain 0.6 parts by weight (yield 85.9%) of compound 6. These instrumental analysis data are shown below.<u style="single">Compound 6</u>MS (FAB): m / z 347 (M + H)⁺, 369 (M + Na)⁺¹H-NMR (600MHz, CDCl₃) δ: 2.3-2.60 (8H, Broad, H-12 ~ 15), 2.78,2.80 (2H, ddd, H-10a, 11a), 3.26 (2H, dd, N-CH)₂C =), 3.96 (1H, s, H-5), 3.99,4.00 (2H, ddd, H-10b, 11b), 4.26 (2H, dd, C = C-CH₂-OH), 7.06,7.11,7.16 (8H, benzene);¹³C-NMR (150MHz, CDCl₃) δ: 31.76 (C-10.11), 47.04 (N-CH)₂C =), 51.15,52.54 (N-CH₂), 51.69 (C-CH)₂OH), 79.05 (C = C-CH)₂-OH), 81.08 (C-5), 83.25 (N-CH)₂C =), 125.43,127.67,130.69,130.75,139.19,139.67 (benzene) .mp 129 ° C<u style="single">Compound 7</u>MS (FAB): m / z 388 (M)⁺¹H-NMR (600MHz, CDCl₃) δ: 2.08 (3H, s, OAc), 2.3-2.60 (8H, Broad, H-12 ~ 15), 2.79,2.80 (2H, ddd, H-10a, 11a), 3.28 (2H, dd, N- CH₂C =), 3.97 (1H, s, H-5), 4.00, 4.01 (2H, ddd, H-10b, 11b), 4.68 (2H, dd, C = C-CH₂-OAc), 7.0-7.20 (8H, benzene);¹³C-NMR (150MHz, CDCl₃) δ: 20.69 (CH₃CO), 31.73 (C-10,11), 46.97 (N-CH)₂C =), 51.69,52.40 (N-CH₂), 52.43 (C-CH)₂OAc), 78.88 (C = C-CH)₂-OAc), 79.02 (C-5), 82.15 (N-CH)₂C =), 125.40,127.65,130.67,130.73,139.18,139.65 (benzene), 170.18 (C = O)<u style="single">Example 6: Preparation of 1-dibenzosveranyl-4- (2-hydroxy-3-butenyl) piperazine (Compound 4) hydrochloride</u>1 part by weight of compound 4 is dissolved in 30 parts by weight of diethyl ether, 2 parts by weight of diethyl etheric hydrogen chloride is added thereto, the hydrochloride of compound 4 is precipitated, and the compound is recrystallized from a mixed solution of chloroform and ethyl acetate. Hydrochloride of 4 was obtained.<u style="single">Example 7: 1-Preparation of dibenzosveranyl-4- (2-hydroxydecanyl) piperazine (Compound 8)</u>To a solution of 139 mg (0.5 mmol) of dibenzosveranyl piperazine in 3 ml of methanol was added 0.13 ml (1 mmol) of 1,2-epoxydecane and 0.018 ml (0.25 mmol) of triethylamine, and the mixture was stirred overnight. After distilling off the reaction mixture, the mixture was separated and purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 81 mg (37.3%) of compound 8 as a pale yellow oil. MS (FAB): m / z 433 (MH)⁺, 457 (M + Na)⁺¹H-NMR (300MHz, CDCl₃) δ: 0.9 (3H, t, CH₃), 1.2-1.5 (12H, Broad, H-4', 5', 6', 7', 8', 9'), 2.2-2.3 (8H, m, H-1', 3'), 2.3- 2.7 (8H, Broad, H-12,14,13,15), 2.8 (2H, ddd, H-10a, 11a), 3.6 (1H, dddd, H-2'), 3.9 (1H, s, H- 5), 4.00 (2H, ddd, H-10b, 11b), 7.04-7.20 (8H, benzene). Example 8: (Example of preparation of preparation) Granules were prepared according to the formulation shown below. That is, the component of a) was charged into a pneumulmerizer, mixed by blowing air, and then the component of b) was sprayed and granulated, and dried by blowing air at 37 ° C. for 12 hours to obtain granules.<img file="JP4189472B2_D0011.tif" />Test Example 1: Compounds 1 to 7 were tested for in vivo using a murine chloroquine-resistant malaria strain to examine the resistance-overcoming effect of the compound of the present invention. The test followed the procedure shown below. Material: Chloroquine-resistant Plasmodium: Plasmodium chabaudi (AS strain: chloroquine-resistant (3CQ), Mouse: ICR female 4-5 weeks old (20-25 g). Method: 1) Preparation of compound; Test compound is mouse. Pre-dissolved in 1/10 volume of DMSO so that the final dose per animal is 50 mg / kg / 0.2 ml, diluted with 0.85% physiological saline, and 10% DMSO. It was made into a suspension. 2) Inoculation of Plasmodium chabaudi (AS strain: chloroquine-resistant (3CQ)); 5 × 10⁶(10 to the 6th power) / 0.2 ml Plasmodium-infected red blood cells (PRBC: Parasitized Red Blood) Cell) was also prepared in 0.85% physiological saline and inoculated from the tail vein of mice with a 26 × 1/2 gauge tuberculin needle. 3) Administration of compound and chloroquine; 2 hours after inoculation with Plasmodium, test compound (50 mg / kg / 0.2 ml) was intraperitoneally administered to 3 groups of mice per compound using a 21 x 1/2 gauge needle. Then, continue to prepare 3 kinds of chloroquine solutions with 0.85% physiological saline so that the final concentrations are 0 mg / kg / 0.1 ml, 2 mg / kg / 0.1 ml, and 3 mg / kg / 0.1 ml, respectively. Each of the three groups administered with the compound was also intraperitoneally administered with a 26 × 1/2 gauge Zwerklin needle. Only three chloroquine solutions were administered to each of the three control groups. The compound and chloroquine were administered 4 times in total on the 0th, 1st, 2nd and 3rd days after the inoculation of Plasmodium malaria. 4) Efficacy judgment; Every day after inoculation with Plasmodium malaria, the tip of the mouse tail was cut to the minimum with scissors to cause bleeding, and a blood thin smear Giemsa-stained specimen was prepared. Was counted and compared with the group to which only chloroquine was administered, to determine the effect of the test compound on overcoming chloroquine resistance. The test results are shown in Table 1.<img file="JP4189472B2_D0012.tif" />From the results in Table 1, it can be seen that all the compounds of the present invention reduce the resistance of chloroquine-resistant Plasmodium and increase the sensitivity to chloroquine. Test Example 2: The resistance overcoming effect of Compound 8 was investigated in the same manner as in Test Example 1. The time for determining the effect was set to the 4th day. The results are shown in Table 2.<img file="JP4189472B2_D0013.tif" />From Table 2, it can be seen that the dose responsiveness was clarified by administering Compound 8. This is because compound 8 overcomes chloroquine resistance. Industrial Applicability The compounds of the present invention exhibit an action of restoring susceptibility to a drug to a disease predisposition to which resistance has been acquired, that is, an action of overcoming resistance.