JPH11228422A - Antimalarial agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine having strong antimalarial activity by utilizing a specified nucleoside derivative as an active ingredient. SOLUTION: This medicine is obtained by including a nucleoside derivative of the formula (R is a 1-6C alkyl or amino; Y is SO2 or CO; R2 ' and R3 ' are each H or hydroxyl group; X is N or CH; R2 and R6 are each H, a halogen or the like), a salt, hydrate or solvate thereof as an active ingredient. The compound of the formula in which R and R6 are each amino, Y is SO2 , X is N, R2 is Cl, R2 ' and R3 ' are each hydroxyl group, that is, 5'-o-sulfamoyl-2- chloroadenosine, a salt, hydrate or solvate thereof is especially preferable. The compound of the formula can be chemically synthesized and also can be produced by an actinomyces. This compound is preferably administered at a daily dose of 1-3,000 mg in 1-4 portions. The compound shows selectively antimalarial action at low concentrations.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an antimalarial agent containing a certain nucleoside derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Malaria is an infectious disease caused by parasitism of malaria parasites in red blood cells, which is mediated by Anopheles, and was thought to be temporarily eradicable. However, with the emergence of malaria parasites and vector mosquitoes, 300-500 million people worldwide are infected with malaria annually, and the estimated deaths are over 3 million annually, making it the most infectious disease affecting humanity. Has become. Imported infectious diseases tend to increase in Japan, and some cases die due to delay in diagnosis and treatment. Against this background, the WHO has also made the development of new chemotherapeutic agents an important goal.

On the other hand, 5'- o- sulfamoyl nucleoside is considered to be an analog of AMP (5'-adenylic acid), and was synthesized in 1978 as a substance that inhibits platelet aggregation induced by serotonin (Gough et al.).
al, J. et al. Med. Chem. , 21 , 520 (19
78)). In addition, as an antibiotic produced by various actinomycetes, nucleoside (Morton et al, J. Am.
Chem. Soc. , 91 , 1535 (1969)),
AT-265 (Takahashi et al, J. Am.
Antibiotics, 35 , 939 (198
2)), 5'- o- sulfamoyl adenosine (Ren
gaaraju et al, Sci. Reports
Meiji Seika Kaisha, 25 , 49
(1986)), 5'- o -sulfamoyltubercidin (Iwata et al, Sci. Reports).
Meiji Seika Kaisha, 26 , 17
(1987)).

[0004] Recently, studies on this use as a herbicide have been actively conducted and several reports have been made (Zeneca Li).
Mited, British Patent Publication No. 2284811 (199)
5); Kristinsson et al. , ACS
Symp. Ser. , 584 , 206 (199
5)). However, there has been no report as to the present inventors that these compounds have antimalarial activity.

[0005]

Means for Solving the Problems The present inventors have paid attention to the fact that nucleosides have various physiological activities, and have repeatedly studied various kinds of nucleosides. As a result, they have found that 5'- o- sulfamoyl nucleosides are contained. The inventors have found that certain nucleoside derivatives have strong antimalarial activity, and have completed the present invention. That is, according to the present invention, the following formula (I)

[0006]

Embedded image

(Where R is C₁~ C₆An alkyl group or
C₁~ C₆Substituted with an alkyl or phenyl group of
An optionally substituted amino group, Y is -SO_Two-Or -CO
-, R_Two'And R_Three′ Are each independently a hydrogen element or
Or hydroxyl group, X is N or CH, R_TwoAnd R₆Each
Each independently represents a hydrogen atom, a hydroxyl group, a halogen atom or C
₁~ C₆Substituted with an alkyl or phenyl group of
Represents an optionally substituted amino group)
Derivatives, their salts, hydrates or solvates thereof.
An antimalarial agent as an active ingredient is provided. Preferred of the present invention
According to a preferred embodiment, the following formula (II)

[0008]

Embedded image

5'- o -sulfamoyl-
An antimalarial agent comprising 2-chloroadenosine (AT-265) salt, hydrate or solvate thereof as an active ingredient is provided.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The antimalarial agent of the present invention contains a nucleoside represented by the above formula (I) as an active ingredient. The C ₁ -C ₆ alkyl group in the formula (I) includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group, an isopentyl group, and an n-alkyl group. Examples include a hexyl group and a cyclohexyl group. Examples of the halogen atom include chlorine, bromine and fluorine atoms.

The number of the alkyl group and the phenyl group as the substituent of the amino group may be one or two. The compound represented by the formula (I) can be used in the form of a salt. The salt at this time is a pharmaceutically acceptable salt of a mineral or organic acid, for example,
Hydrochloride, sulfate, nitrate, acetate, oxalate, tartrate, citrate, lactate and the like. The compound represented by the formula (I) may be used in a free form, an arbitrary hydrate or a solvate. Solvents that can form solvates include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like.

The nucleoside derivative represented by the above formula (I) can be chemically synthesized (Gough e).
tal, J.M. Med. Chem. , 21 , 520 (1
978); Kristinsson et al, AC
S Symp. Ser. , 584 , 206 (199
5)). Some are also known to be produced by actinomycetes (Morton et al, J. Am.
Chem. Soc. , 91 , 1535 (1969), T
Akahashi et al, J. Mol. Antibiot
ics, 35 , 939 (1982), Rengoara
jn et al, Sci Reports. Meij
i Seika Kaisha, 25 , 49 (198
6), Iwata et al, Sci. Reports
Meiji Seika Kaisha, 26 , 1
7 (1987)), and those obtained by culturing radioactive bacteria producing them and separating and purifying them by a known method may be used.

When the antimalarial agent of the present invention is used as a medicament, it can be formulated together with a usual pharmaceutical carrier into a formulation according to the administration route. For example, in the case of oral administration, it is prepared in the form of tablets, capsules, granules, powders, liquids and the like. In preparing a solid preparation for oral administration, conventional excipients, binders, lubricants, other coloring agents, disintegrants, and the like can be used.

As the excipient, for example, lactose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose,
Examples include glycerin, sodium alginate, gum arabic, etc., examples of the binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, shellac, and sucrose; examples of the lubricant include magnesium stearate, talc, and the like. In addition, conventionally known coloring agents and disintegrating agents can be used.

The tablets may be coated by a known method. The liquid preparation may be an aqueous or oily suspension, solution, syrup, elixir or the like, and is prepared by a commonly used method. When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to didepside, and subcutaneously,
Intramuscular and intravenous injections can be manufactured. As a base for producing a suppository, for example, an oily base such as cacao butter, polyethylene glycol, lanolin, fatty acid triglyceride, and witepsol (registered trademark of Dynamite Nobel) can be used.

Further, an antimalarial agent other than the nucleoside derivative represented by the above formula (I) used in the present invention may be used in combination, but the use with another antimalarial agent is not essential to the present invention. The dose varies depending on the patient's condition, body weight, age, etc. and cannot be taken uniformly. However, the amount of the nucleoside derivative of the formula (I) is usually preferably in the range of about 1 mg to 3000 mg per day. Is usually administered once to four times a day.

[0017]

The present invention will be described in more detail with reference to the following examples.
I will tell. Example 11 1 Assay of Antiprotozoal Activity by Cultured Plasmodium falciparum Cultured Plasmodium falciparum (FCR-3 (ATCC309)
32), an in vitro drug sensitivity test was performed.
Was. The medium was RPMI 1640 medium (Gibco, NY)
To which human serum (type A) was added to 10%
Using. The culture conditions for malaria parasites are O_TwoConcentration 5.0
%, CO_Two5.0% concentration and N _Two90% concentration, 3
Performed at 6.5 ° C.

The pre-cultured P. falciparum was diluted with uninfected erythrocytes so that the initial infection rate was 0.5%, and
The mixture was dispensed into a well culture plate, a sample solution was added, and the solution was mixed by pipetting. After culturing for 72 hours, a thin smear was prepared for each well,
The infection rate was measured under a light microscope. Protozoan growth inhibitory activity was calculated from the infection rate of the drug added and the control infection rate. Table 1 shows the results.

2 Assay of Cell Growth Inhibitory Activity by Mouse Breast Cancer-Derived FM3A Cells The cells were F2, a wild type of mouse breast cancer-derived FM3A cells.
8-7 strain (Japanese Cancer Rese
arch Resources Bank (JCRB)
The medium used was ES medium (Nissui Pharmaceutical) supplemented with fetal bovine serum to a concentration of 2%. The culture was performed at 37 ° C. at a CO ₂ concentration of 5.0%.

After the preculture, the cells that have entered the logarithmic growth phase are diluted with a medium to a concentration of 5 × 10 ⁴ cells / ml, placed in a 24-well culture plate, a sample solution is added, and the solution is pipetted. Was mixed. After culturing for 48 hours, the number of cells was counted for each well.
It was counted with a counter. The cell growth inhibitory activity was calculated from the number of cells in the well to which the drug was added and the number of control cells. Malaria parasite and mouse breast cancer-derived FM3A
The antimalarial effect of the sample was evaluated from the toxicity ratio between cells. Table 1 shows the results.

[0021]

[Table 1]

From the above results, it can be seen that the nucleoside derivative of the present invention has excellent antiprotozoal activity against malaria parasites, but has low cytotoxicity against animal cells and is an excellent antimalarial agent. Recognize. The compound of the present invention has a higher protozoan growth inhibitory activity than the mefloquine and pyrimethamine currently used, and has a high toxicity ratio and is a highly selective antimalarial agent.

[0023]

As described above, the nucleoside derivative represented by the formula (I) of the present invention exhibits a selective antimalarial action at a low concentration. Therefore, an antimalarial containing it is useful as a drug for preventing or treating malaria infection. is there.

Claims (2)

[Claims] 1. A compound represented by the following formula (I):(Where R is C₁~ C₆Alkyl group or C₁~ C₆of
May be substituted with an alkyl group or a phenyl group
Amino group, Y is -SO_Two-Or -CO-, R_Two'And R_Three′ Are each independently a hydrogen element or
Hydroxyl group, X is N or CH, R_TwoAnd R₆Are each independently a hydrogen atom, a hydroxyl group,
Halogen atom or C ₁~ C₆Alkyl group or
Represents an amino group which may be substituted with a phenyl group)
Nucleoside derivatives represented, their salts, their hydration
Antimalarial agent containing an active ingredient or solvate as an active ingredient. 2. A compound represented by the following formula (II): An antimalarial agent comprising, as an active ingredient, 5'- o -sulfamoyl-2-chloroadenosine represented by the following formula, a salt thereof, a hydrate or a solvate thereof.