JP2003146877A - Antileishmanial - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicament having sight side effects and effective for treating leishmania. SOLUTION: This antileishmanial comprises a triazole derivative of the formula (1) or a salt thereof as the active ingredient.

Description

Description: TECHNICAL FIELD [0001] The present invention relates to an anti-leishmanial drug effective for treating leishmaniasis. [0002] Leishmaniasis is a protozoan disease caused by Leishmania protozoa. An estimated 12 million patients suffer from the disease, and 350 million people are at risk for infection. Is one of the most important tropical parasitic diseases in the world exposed to Clinically, it is divided into three types: skin, mucous membrane / skin, and visceral type. In each case, the characteristic pathology is that leishmania parasitizes macrophage cells and proliferates, and granulation as chronic inflammation Is to form a tumor. Leishmania has evolved as an obligate intracellular parasitic protozoan with special parasitic adaptation ability to divide in macrophage cells, and in phago-lysosome where phagosome and lysosome are fused. Therefore, development of an effective chemotherapeutic agent is extremely difficult, and the first-line drug for leishmaniasis is an antimony agent that has been used since the 1940s. However, antimony drugs are injections with strong side effects, and require long-term administration and are expensive. In recent years, the emergence of antimony drug-resistant strains has also been reported, and the development of a safe and effective drug replacing antimony drugs has been desired. [0003] Amphotericin B, which is an antifungal agent, is a drug showing a remarkable effect on leishmaniasis, but is not so much clinically welcomed due to its strong side effects.
Although a therapeutic agent in which this is encapsulated in liposomes has been developed, it is an injection and extremely expensive, and has not been widely used. Ergosterol, as well as fungi, is a major component of Leishmania cell membranes.
For this reason, azole antifungal agents having ergosterol synthesis inhibitory activity have also been used for the treatment of leishmaniasis, and their effectiveness has been reported. However, at present, a drug having an effect superior to amphotericin B has not yet been developed. [0004] Accordingly, an object of the present invention is to provide a drug which has few side effects and is effective for treating leishmaniasis. [0005] In view of such a situation, the present inventors have conducted intensive studies and as a result, have found that a triazole derivative represented by the following formula (1) is effective for the treatment of leishmaniasis. The inventors have found that the present invention has been completed. That is, the present invention provides the following formula (1): [0008] The present invention provides an anti-leishmanial drug comprising a triazole derivative represented by the following or a salt thereof as an active ingredient. DETAILED DESCRIPTION OF THE INVENTION The triazole derivative used in the present invention is 2- (2,4-difluorophenyl) -1- (ethylsulfonyl) -1,1-1- represented by the above formula (1).
Difluoro-3- (1H-1,2,4-triazole-
1-yl) -2-propanol. The salts of the triazole derivative (1) include
The salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloride, nitrate, hydrobromide, p-toluenesulfonate, methanesulfonate, fumarate, succinate, lactate, etc. Acid addition salts of The triazole derivative (1) and salts thereof have optical isomers based on asymmetric carbon atoms, and any of these isomers or racemic forms may be used. Further, a solvate such as a hydrate may be used. The triazole derivative (1) and a salt thereof are
For example, it can be produced according to the method described in JP-A-11-240871. The anti-leishmanial drug of the present invention comprises the above-mentioned triazole derivative (1) or a salt thereof as an active ingredient, and is formulated into various dosage forms together with a pharmaceutically acceptable carrier according to a conventional method. Can be. In addition, the dosage form is not particularly limited and can be appropriately selected depending on the purpose of treatment, and may be, for example, any of an oral preparation, an injection, a suppository, an ointment, an external solution, a patch, and the like. It can be produced by a conventional formulation method known to those skilled in the art. When preparing an oral solid preparation, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. are added to the triazole derivative (1). ,
Tablets, coated tablets, granules, powders, capsules and the like can be produced by a conventional method. When preparing a liquid preparation for oral use, a flavoring agent, a buffer,
A liquid medicine, a syrup, an elixir and the like can be produced by a conventional method by adding a stabilizer, a deodorant and the like. When preparing an injection, a pH adjusting agent, a buffer, a stabilizing agent, an isotonic agent, a triazole derivative (1),
By adding a local anesthetic or the like, injections for subcutaneous, intramuscular, and intravenous injections can be produced by a conventional method. In preparing suppositories, the triazole derivative (1) may be added to a pharmaceutical carrier known in the art, for example,
Polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like can be produced by a conventional method after further adding a surfactant and the like as necessary. When preparing an ointment, a base, a stabilizer, a wetting agent, a preservative, and the like, which are usually used in the triazole derivative (1), are blended as required, and mixed and formulated by a conventional method. . When preparing a liquid for external use, a base, a stabilizer, a wetting agent, and a base usually used for the triazole derivative (1) are used.
Preservatives and the like are blended as necessary, and mixed and formulated by a conventional method. In the case of producing a patch, the above-mentioned ointment, cream, gel, paste or the like may be applied to a usual support in a conventional manner. The amount of the triazole derivative (1) to be incorporated in each of the above-mentioned dosage unit forms is not fixed depending on the condition of the patient to which the triazole derivative (1) is to be applied or its dosage form. About 10-50
00 mg, about 10 to 2000 mg for injections, about 1 for suppositories
Desirably, the amount is 0 to 3000 mg. In addition, the daily dose of the drug having the above-mentioned administration form is determined by the patient's symptoms,
The triazole derivative (1) is usually about 1 to 100 mg / kg, preferably about 1 to 40 mg / day per adult per day, although it cannot be determined unconditionally depending on body weight, age, sex, and the like.
The dose may be kg, and it is preferable to administer it once or twice or four times a day. Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 Various drugs were evaluated for their anti-leishmania growth inhibitory activity in vitro. That is, using Leishmania amazonensis, which is a causal insect of cutaneous leishmaniasis, and Leishmania donovani, which is a cause of visceral leishmaniasis, two promastigote-type insects (2 × 10 ⁵ cells / mL) were used.
After culturing at 5 ° C for 5 to 6 days, one control group without the drug was added.
When grown to 0 ⁷ cells / mL, and the worms number in the presence of each drug concentration were counted in a hemocytometer. Two to four experiments were performed for the same drug, and the 50% growth inhibitory concentration (IC ₅₀ ) of the protozoan was calculated from the average. As the drug, 2- (2,4-difluorophenyl) -1- (ethylsulfonyl) -1,2- (2,4-difluorophenyl) -1,
1-difluoro-3- (1H-1,2,4-triazol-1-yl) -2-propanol was used, and for comparison, fluconazole and amphotericin B, which were conventionally used as anti-leishmania drugs, were used. Table 1 shows the results
Shown in [Table 1] From the results shown in Table 1, the product of the present invention was superior to the anti-leishmanial drugs fluconazole and amphotericin B in the growth inhibitory effect on leishmania. Moreover, it was confirmed that the product of the present invention had almost the same growth inhibitory effect on two different Leishmania species. Example 2 (Tablets) Triazole derivative (1) 50 mg Crystalline cellulose 50 mg Lactose 50 mg Hydroxypropyl cellulose 18 mg Magnesium stearate 2 mg Total 170 mg Tablets having the above composition were produced by a conventional method.
The tablets could be sugar-coated tablets and film-coated tablets. Example 3 (Capsule) Triazole derivative (1) 50 mg Soft anhydrous silicic acid 25 mg Lactose 100 mg Starch 50 mg Talc 25 mg Total 250 mg The above components were filled in No. 1 capsule to obtain a capsule. Example 4 (Granules) Triazole derivative (1) 50 mg Lactose 600 mg Corn starch 200 mg Sodium carboxymethylcellulose 20 mg Hydroxypropylcellulose 130 mg Total 1000 mg Granules having the above composition were produced by a conventional method. Example 5 (injection) 3 g of the triazole derivative (1) was added to polysorbate 80
It was dissolved in a mixed solution of 20 g and 30 mL (24 g) of ethanol to make the total amount about 50 mL. After sterilization by filtration through a 0.2 μm membrane filter, the vial was filled with 5 mL and sealed. An injection having a triazole derivative concentration of about 60 mg / mL was obtained. Example 6 (syrup) 6 g of polysorbate 80 and 5 g of propylene glycol
After mixing 0.3 g of lemon essence and 0.6 g of the triazole derivative (1), the mixture is dissolved. 1 g of citric acid and 25 mL (33 g) of a simple syrup are added to this solution, and the total volume is made up to 50 mL with purified water, filled into a sterilization bottle, and sterilized by high-pressure steam. A syrup having a triazole derivative concentration of 12 mg / mL was obtained. The anti-leishmanial drug of the present invention has an excellent growth inhibitory effect on leishmania and is effective for the treatment of leishmaniasis.

   ────────────────────────────────────────────────── ─── Continuation of front page    (72) Inventor Kazuko Nishimura             16-16 Honcho, Itabashi-ku, Tokyo (72) Inventor Ken Katakura             1407-4-507 Tenma Oshimacho, Maebashi City, Gunma Prefecture (72) Inventor Koji Yokoyama             3261 Asahigaoka-cho, Hanamigawa-ku, Chiba-shi, Chiba             Wood stand 2-10-201 F term (reference) 4C086 AA01 AA02 BC60 MA01 MA04                       NA06 NA14 ZB38

Claims (1)

[Claim 1] The following formula (1) An anti-leishmanial agent comprising a triazole derivative represented by the formula (I) or a salt thereof as an active ingredient.