JP2000229965A - Peroxide derivative having antimalarial activity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having low toxicity and extremely high antimalarial activity and useful as an antimalarial agent. SOLUTION: This compound is represented by formula I [ring C is a (substituted)alicyclic hydrocarbon ring; and (n) is 0-6], e.g. 1,2,6,7- tetraoxaspiro[7.11]nonadecane. The compound of formula I is obtained by reacting a compound of formula II (Me is methyl) (e.g. methoxymethylenecyclododecane) with ozone in the presence of hydrogen peroxide in a solvent such as ether, preferably at -70 to 20 deg.C for 5-30 min to afford a compound of formula III [e.g. (cyclododecylidene)bishydroperoxide]] and reacting the compound of formula III with a compound of formula IV (X is a halogen) (e.g. 1,3-iodopropane) in the presence of a base such as cesium hydroxide in a solvent such as dimethylformamide, preferably at 10-30 deg.C for 1-48 hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel compound useful for the prevention and treatment of infectious diseases caused by malaria parasites.

[0002]

2. Description of the Related Art Malaria is known as Plasmodium.
um) is a contagious disease caused by the transmission of protozoa belonging to the genus
It shows symptoms such as anemia and splenomegaly. In recent years, malaria has begun to rampage due to changes in nature and the environment, with an estimated 300 to 500 million infected cases and 150 deaths annually.
It is an important disease of the world with ~ 3 million people. Malaria parasites that infect humans include P. falciparum, which is distributed throughout tropical regions of Africa, Asia, and Latin America, and Plasmodium vivax, which is distributed in parts of the tropics and temperate zones around the world. P. viva
x), Plasmodium vivax malaria parasites distributed throughout the world (Pm
alariae) and protozoa such as oval malaria parasite (P. ovale) mainly distributed in tropical West Africa. Among them, P. falciparum shows the most severe symptoms, and encephalopathy and kidney disease 1 to 2 weeks after onset. The disease easily progresses to severe malaria with illness, hemolytic anemia, pulmonary edema, heart failure, severe enteritis, etc., often showing multiple organ failure within a short period of time and causing the host to die. Representative of the currently used drugs include chloroquine, primaquine, artemisinin, mefloquine, pyrimesamine and the like,
Many of these drugs are highly toxic, and protozoa resistant to more drugs have emerged. The spread of drug-resistant malaria has become a problem of chemotherapy in recent years. Although quinine exists as the only effective drug for drug-resistant malaria, it is extremely likely to cause renal failure and is a high-risk therapeutic drug based on current medical standards. Under such circumstances, development of a new drug having high antimalarial activity and high safety is desired. As compounds similar to the present invention, there are known, for example, organic peroxide compounds described in JP-B-59-46266 and JP-A-8-67704, which are used as initiators in the production of polymers. It is only.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound having low toxicity and extremely high antimalarial activity.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve such problems, and as a result, the peroxide derivative represented by the following general formula (1) has extremely high antimalarial activity. And found that the present invention was completed. That is, the present invention relates to a peroxide derivative represented by the general formula (1).

Embedded image [Wherein, C represents an alicyclic hydrocarbon ring group which may have a substituent, and n represents an integer of 0 to 6. ]

In the above general formula (1), examples of the alicyclic hydrocarbon ring group which may have a substituent of C include, for example, cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, and cyclohexylidene. Butylidene, cyclooctylidene, cyclononylidene, cyclodecylidene,
A monocyclic alicyclic hydrocarbon group having 3 to 12 carbon atoms such as a cycloundecylidene or cyclododecylidene group; Examples thereof include a cross-linked ring such as a tylidene group or a polycyclic alicyclic hydrocarbon group, and preferably have 6 to 12 carbon atoms.
Is a monocyclic alicyclic hydrocarbon group or an adamantylidene group, more preferably a cyclohexylidene, cyclododecylidene or adamantylidene group. Examples of the substituent which the alicyclic hydrocarbon ring group of C may have include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl. A linear or branched lower alkyl group having 1 to 6 carbon atoms such as a linear or various branched pentyl group; methoxy, ethoxy, n-propoxy, i-propoxy,
n-butoxy, i-butoxy, sec-butoxy, te
Examples thereof include linear or branched lower alkoxy groups having 1 to 6 carbon atoms such as linear or various branched pentyloxy groups exemplified as rt-butoxy, and are preferably lower alkyl groups. Preferably it is a tert-butyl group. Among the compounds of the present invention, a preferred compound is a compound in which C is an alicyclic hydrocarbon ring group which may have a lower alkyl group as a substituent in the general formula (1),
More preferably, the compound in which C is a 4-tert-butylcyclohexylidene, cyclododecylidene or adamantylidene group, and n is 1 to 4. The present invention also includes an antimalarial agent containing the compound represented by the general formula (1).

[0006]

Embodiments of the present invention will be described below in detail. The compound of the present invention represented by the above general formula (1) can be produced by the following method.

Embedded image [Wherein, C and n are the same as above. X represents a halogen atom. In the above reaction scheme, the halogen atom represented by X is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a bromine atom or an iodine atom.

<Reaction step (i)> O
rg. Chem. , 62 , 4949 (1997). That is, a known compound represented by the general formula (2) is reacted with ozone in a suitable solvent in the presence of hydrogen peroxide to obtain a bishydroperoxide compound represented by the general formula (3). The solvent used in this step is not particularly limited as long as it does not participate in the reaction, and examples thereof include ether, tetrahydrofuran, and acetonitrile, with ether being preferred. Hydrogen peroxide having a concentration of 30 to 100% can be used. In the reaction, hydrogen peroxide is used in an amount of 1 to 10 times, preferably 1 to 3 times the molar amount of the compound (2), and ozone is added in an amount of 0.1 to 10 times.
It is used in an amount of 5 to 5 moles, preferably 1 to 2 moles.
The reaction temperature is -70 to 20C, and the reaction time is 5 to 30.
Minutes. The obtained compound (3) is obtained by a usual separation means,
For example, it can be easily isolated and purified from the reaction mixture by column chromatography, recrystallization and the like. The compound (3) obtained in the above reaction step (i) can be used in the reaction step (ii) without isolation.

<Reaction step (ii)> The above reaction step (i)
Is reacted with a compound represented by the general formula (4) in a suitable solvent in the presence of a base to obtain a compound of the present invention represented by the general formula (1). As the base used in this step, for example, potassium hydroxide,
Alkali metal hydroxides such as sodium hydroxide and cesium hydroxide; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; and tertiary amines such as triethylamine and diisopropylethylamine are used, preferably cesium hydroxide. is there. The solvent is not particularly limited as long as it is a non-aqueous solvent. In particular, highly polar solvents such as dimethylformamide and dimethylsulfoxide are preferred. It is also possible to add a crown ether such as 18-crown-6 as a reaction accelerator. In the reaction, the compound (4) and the base are used in an amount of 1 to 3 moles with respect to the compound (3). When a reaction accelerator is added, 1 to 1
A 10 molar amount is used. The reaction temperature is 0 to 50 ° C, preferably 10 to 30 ° C, and the reaction time is 1 to 48 hours. The obtained compound (1) can be easily isolated and purified from the reaction mixture by a usual separation means, for example, column chromatography, recrystallization and the like.

When the compound of the present invention is used for prevention and treatment of infectious diseases caused by malaria parasites, the administration route is as follows.
Any of oral, subcutaneous injection, intravenous injection, topical administration and the like may be used. In addition, as the preparation, oral preparations such as powders, tablets, fine granules, pills, capsules, granules and the like, which are usually manufactured using pharmaceutically acceptable carriers and excipients, ophthalmic drops Preparations, injections, suppositories and the like. Pharmaceutically acceptable carriers and excipients, other additives include glucose, lactose, gelatin, mannitol, starch paste, magnesium trisilicate, corn starch, keratin, colloidal silica, and the like.
Auxiliaries such as stabilizers, extenders, colorants and fragrances may be included. Each of these preparations can be produced by a commonly used production method known to those skilled in the art. The compounding amount of the compound of the present invention in the preparation is preferably 0.1 to 100% by weight, more preferably 0.1 to 80% by weight, and 0.1 to 50% by weight.
% By weight is preferred. The daily dose varies depending on the patient's condition, body weight, age, sex and the like, and cannot be determined unconditionally.
It is preferable to administer 1 to 1000 mg, preferably 1 to 600 mg once or in about 2 to 4 divided doses.

[0010]

Next, the present invention will be described in detail with reference to Production Examples, Examples and Test Examples. <Production Example 1> Synthesis of (cyclododecylidene) bishydroperoxide (compound a) Saito et al. (Saito, I .; Nagata, R .; Yuba, K .; Mat)
uura, T .; TetrahedronLett. 1983, 24, 1737) and 25 ml of a 2.5 mol ether solution of hydrogen peroxide prepared as described in 1983, 24, 1737), methoxymethylenecyclododecane 630 as a known compound.
mg (3.00 mmol) was dissolved and ozonized at −70 ° C. (Normal ozonation apparatus (Nippon Oz)
Oxygen was blown in at a flow rate of 50 l / hr for 15 minutes using one Model ON-1-2 (manufactured by Nippon Ozone Co., Ltd.) to generate an ozone equivalent to the used methoxymethylenecyclododecane). After the reaction,
After adding 70 ml of ether, the organic layer was washed with aqueous sodium hydrogen carbonate and then with saturated saline, and then dried over anhydrous magnesium sulfate. Subsequently, 232 mg (yield 33%) of the title compound a was obtained by silica gel column chromatography (distillate: ether-hexane, 2: 8). The physical properties are shown below. Melting point: 140-141 ° C ¹ H NMR (CDCl ₃ ) δ: 1.2-1.8 (m, 22 H),
8.13 (br s, 2 H) ¹³ C NMR (CDCl ₃ ) δ: 19.28, 21.86, 22.1
5, 6.02, 26.19, 26.29, 112.64.

<Production Example 2> (4-tert-butylcyclohexylidene) bishydroperoxide (compound b)
546 mg (3.00 mmol) of 4-tert-butyl-2-methoxymethylenecyclohexane was dissolved in 25 ml of an ether solution containing hydrogen peroxide prepared in the same manner as in Production Example 1, and ozonation was performed at -70 ° C. After completion of the reaction, the mixture was treated in the same manner as in Production Example 1 above, and then subjected to silica gel column chromatography (distillate: ether-hexane,
2: 8) to give 285 mg of the title compound b (yield 47).
%)Obtained. The physical properties are shown below. Melting point: 83-84 ° C (ether-hexane) ¹ H NMR (CDCl ₃ ) δ: 0.87 (s, 9 H), 1.1-1.8
(m, 9 H), 9.27 (s, 2H) ¹³ C NMR (CDCl ₃ ) δ: 23.32, 27.58, 29.70,
32.31, 47.39, 110.00. Elemental analysis: Anal.Calcd. For C ₁₀ H ₂₀ O ₄ : C, 58.80; H,
9.87. Found: C, 58.87; H, 9.80.

<Production Example 3> Synthesis of (2-adamantylidene) bishydroperoxide (compound c) 2-methoxymethylene adamantane 712 was added to 25 ml of an ether solution containing hydrogen peroxide prepared in the same manner as in Production Example 1.
mg (4.00 mmol) was dissolved and ozonated at -70 ° C. After completion of the reaction, the mixture was treated in the same manner as in Production Example 1 above, and 335 mg (yield 42%) of the title compound c was obtained by silica gel column chromatography (distillate: ether-hexane, 2: 8). The physical properties are shown below. Melting point: 144-145 ° C (ether-hexane) ¹ H NMR (CDCl ₃ ) δ: 1.7-2.1 (m, 14 H), 8.8
2 (s, 2 H) ¹³ C NMR (CDCl ₃ ) δ: 26.94, 31.14, 33.68,
36.98, 112.88.

Example 1 Synthesis of 1,2,6,7-tetraoxaspiro [7.11] nonadecane (Compound 1) Cesium hydroxide monohydrate 504m in an argon atmosphere
g (3.00 mmol) in dimethylformamide solution 1
0 ml was adjusted. Using a syringe, 348 mg of the compound a obtained in Production Example 1 (1.50 mmol) was added to this solution.
l) of 5 ml of a dimethylformamide solution,
666 mg (2.25 mmol) of 3-diiodopropane
Of dimethylformamide was added at 0 ° C. over 10 minutes each. Thereafter, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, 70 ml of ether was added, and the organic layer was washed with aqueous sodium bicarbonate and then with saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (distillate: ether-hexane, 1:25) to give 164 the title compound 1.
mg (yield 40%). The physical properties are shown below. Melting point: 83-84 ° C (hexane) ¹ H NMR (CDCl ₃ ) δ: 1.3-1.7 (m, 22 H), 2.1-
2.2 (m, 2 H), 4.12 (dt, J = 12.5, 5.0 Hz, 2 H), 4.
31 (dt, J = 12.5, 5.0 Hz, 2 H) ¹³ C NMR (CDCl ₃ ) δ: 19.36, 21.90, 22.17,
25.91, 26.07, 26.25, 30.40, 73.94, 112.13. Elemental analysis: Anal. Calcd. For C ₁₅ H ₂₆ O ₄ : C, 66.14; H,
10.36. Found: C, 65.91; H, 10.42.

Example 2 Synthesis of 1,2,6,7-tetraoxaspiro [8.11] icosane (Compound 2) 348 mg of compound a obtained in Production Example 1 (1.50 mm
ol) and cesium hydroxide monohydrate 504 mg (3.0
0 mmol) was dissolved in 25 ml of dimethylformamide, and 698 mg (2.2) of 1,3-diiodobutane was added thereto.
5 mmol) was added over 10 minutes. Thereafter, the reaction was carried out at room temperature for 16 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1, and then subjected to silica gel column chromatography (distillate: ether-hexane,
1:25) to give 129 mg (yield 3) of the title compound 2.
0%). The physical properties are shown below. Melting point: 97-98 ° C (hexane) ¹ H NMR (CDCl ₃ ) δ: 1.3-1.7 (m, 24 H), 2.2-
2.3 (m, 2 H), 3.66 (t, J = 12.2 Hz, 2 H), 4.26 (dd,
J = 12.2, 3.9 Hz, 2 H) ¹³ C NMR (CDCl ₃ ) δ: 19.30, 21.89, 22.17,
25.95, 26.11, 26.43, 30.93, 32.51, 73.85, 111.82. Elemental analysis: Anal. Calcd. For C ₁₆ H ₃₀ O ₄ : C, 67.10; H,
10.56.Found: C, 66.66; H, 10.49.

Example 3 Synthesis of 1,2,6,7-tetraoxaspiro [9.11] henicosan (compound 3) Cesium hydroxide monohydrate 1008 mg (6.00 mmol)
l) was dissolved in 20 ml of a dimethylformamide solution, and 696 mg (3.00 mg) of the compound a obtained in Production Example 1 was added thereto.
mmol) dissolved in dimethylformamide 20m
1 and 1,3-diiodopentane 1458 mg (4.5
0 mmol) in dimethylformamide solution 20
ml was added over 1 hour at 0 ° C. using a separate syringe. Thereafter, the reaction was carried out at room temperature for 16 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 above, and 153 mg of the title compound 3 (yield 17%) was obtained by silica gel column chromatography (distillate: ether-hexane, 1:25). )Obtained. The physical properties are shown below. Melting point: 51-52 ° C (hexane) ¹ H NMR (CDCl ₃ ) δ: 1.3-1.8 (m, 24 H), 19-
2.1 (m, 4 H), 4.1-4.2 (m, 4 H) ¹³ C NMR (CDCl ₃ ) δ: 19.26, 21.92, 22.25,
24.89, 25.97, 26.06, 26.65, 28.45, 76.64, 110.89.

Example 4 Synthesis of 1,2,6,7-tetraoxaspiro [8.11] docosane (Compound 4) Cesium hydroxide monohydrate 1008 mg (6.00 mmol)
l) was dissolved in 20 ml of a dimethylformamide solution, and 696 mg (3.00 mg) of the compound a obtained in Production Example 1 was added thereto.
mmol) dissolved in dimethylformamide 20m
l and 1,3-diiodohexane 1521 mg (4.5
0 mmol) in dimethylformamide solution 20
ml was added over 1 hour at 0 ° C. using a separate syringe. Thereafter, the reaction was carried out at room temperature for 16 hours. After completion of the reaction, the reaction mixture was treated by the above treatment method, and then subjected to silica gel column chromatography (distillate: ether-hexane, 1:25) to give 168 mg of the title compound 4.
(18% yield). The physical properties are shown below. Melting point: 48-49 ° C. (hexane) ¹ H NMR (CDCl ₃ ) δ: 1.3-1.8 (m, 30 H), 4.02
(t, J = 4.8 Hz, 4 H) ¹³ C NMR (CDCl ₃ ) δ: 19.35, 21.89, 22.23,
25.00, 26.02, 26.13, 26.43, 26.99, 74.63, 112.06.

Example 5 Synthesis of 7,8,12,13-tetraoxaspiro [6.8] tridecane (Compound 5) Compound b 125 mg (0.61 mm) obtained in Production Example 2
ol) and 205 mg of cesium hydroxide monohydrate (1.2
2 mmol) was dissolved in 15 ml of dimethylformamide, and 272 mg of 1,3-diiodopropane (0.2 mg) was added thereto.
92 mmol) was added over 10 minutes. Thereafter, the reaction was continued at room temperature for 16 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 above, followed by silica gel column chromatography (distillate: ether-hexane, 1:25) to give 38 mg of the title compound 5 (yield 26%). )Obtained. The physical properties are shown below. Melting point: 58-59 ° C (hexane) ¹ H NMR (CDCl ₃ ) δ: 0.86 (s, 9 H), 1.1-1.8
(m, 9 H), 2.1-2.3 (m, 2 H), 4.10-4.2 (m, 2 H), 4.3-
4.5 (m, 2 H) ¹³ C NMR (CDCl ₃ ) δ: 23.34, 23.61, 27.64,
28.59, 30.35, 31.93, 32.37, 47.44, 73.76, 74.02, 1
07.92. Elemental analysis: Anal. Calcd. For C ₁₃ H ₂₄ O ₄ : C, 63.91; H,
9.90. Found: C, 63.60; H, 9.97.

Example 6 Spiro [tricyclo [3.
3.1.1 ^3,7 ] decane] 2,3 ′-[1,2,4
5] Synthesis of Tetroxocan (Compound 6) Compound 313 mg (1.57 mm) obtained in Production Example 3
ol) and cesium hydroxide monohydrate 528 mg (3.14)
mmol) in 15 ml of dimethylformamide,
695 mg of 1,3-diiodopropane (2.35
mmol) was added over 10 minutes. Thereafter, the reaction was carried out at room temperature for 16 hours. After completion of the reaction, the reaction mixture was treated by the above treatment method, and then subjected to silica gel column chromatography (distillate: ether-hexane, 1:25).
73 mg (yield 19%) of the title compound 6 was obtained. The physical properties are shown below. Melting point: 34-35 ° C (hexane) ¹ H NMR (CDCl ₃ ) δ: 1.6-2.3 (m, 16 H), 4.12
(dt, J = 12.9, 5.6 Hz, 2 H), 4.35 (dt, J = 12.5,
4.8 Hz, 2 H) ¹³ C NMR (CDCl ₃ ) δ: 27.06, 30.30, 31.81,
33.67, 33.98, 37.25, 73.94, 109.95.

<Culture Assay for Plasmodium falciparum> In this experiment, P. falciparum FCR
-3 strain (ATCC 30932) was used. Further, in order to verify the effect of the compound of the present invention on a resistant strain of chloroquine which is commercially available as an antimalarial agent, P. falciparum K1 strain
Chloroquine-resistant malaria parasite was used. The medium used for the experiment was a filter-sterilized RPMI1640 medium, the pH was adjusted to 7.4, and human serum was added to 10%. The culture of malaria parasites was performed at an O ₂ concentration of 5%, a CO ₂ concentration of 5%, and N ₂ concentration.
The test was performed at a concentration of 90% and a temperature of 36.5 ° C. The hematocrit value (the ratio of the volume of red blood cells in the red blood cell suspension) was 5%. The initial infection rate of P. falciparum at the start of the culture was 0.1%. The cells were cultured using a 24-well culture plate, the medium was changed every day, and subculture was performed at an infection rate of 4%. The infection rate was determined by preparing a thin-layer smear, performing Giemsa staining or Diff-Qick staining, and then using a microscope (oil immersion, 1
000 ×), and the malaria parasite infection rate was calculated by the following equation. Malaria parasite infection rate (%) = {(infected red blood cell count) / (total red blood cell count)} × 100

Test Example 1 Malaria parasite growth inhibition screening test Cultured malaria parasite-infected erythrocytes were collected by centrifugation, washed with a serum-containing medium, non-infected erythrocytes were added, and the initial infection rate was 0.3%. And At this time, the hematocrit value is 3%. The sample used in the experiment was dissolved in sterilized water, dimethylformamide (DMF) or dimethylsulfoxide (DMSO) to obtain a sample of a predetermined concentration. 2
Samples were added to a 4-well culture plate in an amount of 5 to 10 μl each. Samples were taken in duplicate or triplicate. As a control, 10 μl / well of sterilized water, DMF or DMSO was added. Next, 990 to 995 μl of a previously prepared P. falciparum culture was added, and the mixture was gently pipetted and uniformly suspended in a medium. Culture plates _{CO 2 -O 2 -N 2 (5} %, 5
%, 90%) After culturing for 72 hours in an incubator, a thin smear was prepared for each well,
After staining, the cells were observed under a microscope, and the infection rate of the reagent added and the control infection rate were calculated. From the malaria parasite infection rate obtained above, the proliferation rate was calculated by the following formula, whereby the 50% growth inhibitory concentration (EC ₅₀ ) against malaria parasite was determined. Table 1 shows the results. Proliferation rate (%) = ｛([b] − [a]) / ([c] −
[A])｝ × 100 a: initial infection rate b: infection rate when sample was added c: infection rate when no sample was added (control)

<Test Example 2> Murine FM3A cell proliferation inhibition test F28-, a wild strain of mouse breast cancer-derived FM3A cells
Seven strains were used. As a medium, inactivated fetal bovine serum was added to an ES medium to a concentration of 2%, and the cells were cultured at a CO ₂ concentration of 5% at 37 ° C. The doubling time of FM3A cells under these conditions was about 12 hours. Preculture was performed, and cells that had entered the logarithmic growth phase were diluted with a medium so as to have a concentration of 5 × 10 ⁴ cells / ml. The sample used was prepared at the time of measuring the antimalarial activity of malaria parasite. The sample solution was added to the 24-well culture plate in an amount of 5 to 10 μl each (the final concentration was 1 × 10 ⁻⁴ to 1 × 10 ⁻⁶ by adding a medium or the like). Compounds are prepared in duplicate or triplicate, and 10 μl of sterile water, DMF or DMSO is used as a control.
Wells were added at the same time. Next, the prepared cell suspension was added in an amount of 990 to 995 μl, and the suspension was gently pipetted and uniformly suspended in a medium. After culturing for 48 hours, the number of cells in each well was counted using a cell controller (CC-108, Toa Medica).
1 Electrics), and the growth rate was calculated from the following equation. Proliferation rate (%) = ｛([C] − [A]) / ([B] −
[A])｝ × 100 A: initial number of cells B: number of control cells 48 hours later C: number of cells 48 hours after addition of sample The cell growth inhibitory activity was calculated based on the number of cells in the well to which the sample was added and the control. It was calculated from the cell number. From this, the cytotoxicity of the sample was evaluated and expressed as the cell growth inhibitory concentration (EC ₅₀ ). EC ₅₀ value means malaria parasite,
Alternatively, the growth rate of a control in which no sample is added to the medium of FM3A cells, or the concentration of a sample that inhibits the growth rate of a control by 50% by adding a sample to a malaria parasite infection rate of 100% (molar concentration) indicate). Table 1 shows the results. Antimalarial activity of the sample is evaluated from the ratio of The EC ₅₀ values for samples of Plasmodium for FM3A cell (chemotherapeutic coefficient, see the following formula), was efficacy determined. A similar test was also performed on chloroquine, which was used as an antimalarial agent for reference. Table 1 shows the results. Chemotherapy coefficient = (EC ₅₀ value of sample against mouse FM3A cells) ÷ (EC ₅₀ value of sample against Plasmodium falciparum)

[0022]

[Table 1]

As a result, it was found that the compound of the present invention has low cytotoxicity and has a malaria parasite growth inhibitory activity. It was also found that the effect was maintained for chloroquine-resistant protozoa.

<Test Example 3> Mice infected with murine malaria parasite
Protozoan control test using worms. and Richrds, W.C. H. G. Antimala
rial drugs I, in: W. Peters, W. H. G. Richards
(Eds.), Springer-Verlag, Berlin, 1984, pp. 229-
The test was performed according to the 4-day suppressive test described in 230.
The murine malaria parasite used (P. berghei NK65 strain) is highly toxic
Protozoan strains that infect this murine malaria parasite
All die within 10 days of infection. Pass on
Blood malaria parasite-infected mice have a blood infection rate of 10
The experiment was started when the percentage became%. Perform ether anesthesia
The mouse was subjected to heart blood sampling, and phosphate buffered saline 1m
5 × 10 per liter⁶Protozoa / ml
200 μl intraperitoneal feeling in mice not infected with insect suspension
Dyed (i.p.). 2 hours after protozoan infection, suspended in olive oil
Orally or intraperitoneally (Compound 5 is intraperitoneally administered)
Administration only). The administration period is once a day for 4 consecutive days
Blood is collected from the tail of the mouse on the fourth day of the experiment. Blood collection
A thin layer smear was prepared from the blood sample, and microscopically analyzed by Giemsa staining.
The erythrocyte infection rate was determined under a microscope (Falciparum malaria as described above).
Protozoan culture assay was performed in the same manner). Solvent only
Rate of drug-administered group to control group administered
Of the 50% protozoan inhibitory concentration (ED
₅₀Value) and 90% protozoan inhibitory concentration (ED ₉₀Value)
Was. Table 2 shows the results.

[0025]

[Table 2]

From the above results, it was found that the compound of the present invention has an excellent malaria parasite growth inhibitory activity.

[0027]

Industrial Applicability The compound of the present invention has an excellent antimalarial action and is useful as an agent for preventing and treating infectious diseases caused by protozoa such as malaria. It is also effective against chloroquine-resistant malaria.

[Brief description of the drawings]

FIG. 1 is a table showing a comparison table of chemical structural formulas of compounds in each of Production Examples and Examples.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Masatomo Nojima 3-7 Shinsenri-Higashicho, Toyonaka-shi, Osaka A37-105 F-term (reference) 4C022 NA04 4C086 AA01 AA03 BA16 MA01 MA04 NA14 ZB38

Claims (4)

[Claims] 1. A peroxide derivative represented by the general formula (1). Embedded image [Wherein, C represents an alicyclic hydrocarbon ring group which may have a substituent, and n represents an integer of 0 to 6. ] 2. The peroxide derivative according to claim 1, wherein in the general formula (1), C is an alicyclic hydrocarbon ring group which may have a lower alkyl group as a substituent. 3. The peroxide according to claim 1, wherein, in the general formula (1), C is a 4-tert-butylcyclohexylidene, cyclododecylidene or adamantylidene group, and n is 1 to 4. Derivatives. 4. An antimalarial agent containing a compound represented by the general formula (1).