Antitrypanosomal drugs

Abstract

The objective is to provide novel anti-trypanosomal drugs useful for preventing or improving diseases caused by infection with Trypanosomiaceae protozoa. [Solution] 5-bromo-2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide or a pharmacoposophicalally acceptable salt thereof, or 5-bromo-2-(morpholinocarbonyloxy)-N-[2,5-bis(trifluoromethyl)phenyl]benzamide is useful for the prevention or improvement of diseases caused by infection with Trypanosomiaceae protozoa.

Description

Technical Field

[0001] The present invention relates to a novel anti - trypanosomal drug useful for preventing or ameliorating diseases caused by trypanosomatid protozoa infections.

Background Art

[0002] N - [2,5 - bis(trifluoromethyl)phenyl] - 5 - bromo - 2 - hydroxybenzamide and N - [2,5 - bis(trifluoromethyl)phenyl] - 5 - bromo - 2 - [(morpholinocarbonyl)oxy]benzamide are known to be useful for preventing or ameliorating various diseases and are also useful as various preparations (see Patent Documents 1 to 22 and Non - Patent Documents 1 to 5).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

[0004] [Non-Patent Document 1] Oncotarget.2014 Dec 15;5(23):12317-30. [Non-Patent Document 2] Int J Gynecol Cancer.2016 May;26(4):610-8. [Non-Patent Document 3] Am J Pathol. 2016 Mar; 186(3): 616 - 29.

Non - Patent Document 4

Non - Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, it has not been known that N - [2,5 - bis(trifluoromethyl)phenyl] - 5 - bromo - 2 - hydroxybenzamide and N - [2,5 - bis(trifluoromethyl)phenyl] - 5 - bromo - 2 - [(morpholinocarbonyl)oxy]benzamide are useful for the prevention or improvement of diseases caused by Trypanosomatidae protozoa infection. An object of the present invention is to provide a novel antitrypanosomal drug useful for the prevention or improvement of diseases caused by Trypanosomatidae protozoa infection.

Means for Solving the Problems

[0006] As a result of intensive studies to solve the above problems, the present inventors have found that N - [2,5 - bis(trifluoromethyl)phenyl] - 5 - bromo - 2 - [(morpholinocarbonyl)oxy]benzamide, which is known as a prodrug of N - [2,5 - bis(trifluoromethyl)phenyl] - 5 - bromo - 2 - hydroxybenzamide, is useful for the prevention or improvement of diseases caused by Trypanosomatidae protozoa infection, and thus have completed the present invention.

[0007] That is, the present invention is an antitrypanosomal drug containing N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide or a pharmacologically acceptable salt thereof or N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide as an active ingredient, and the like.

Effects of the Invention

[0008] According to the present invention, it is possible to provide a novel antitrypanosomal drug useful for the prevention or improvement of diseases caused by infection with protozoa of the family Trypanosomatidae.

Modes for Carrying Out the Invention

[0009] Hereinafter, embodiments of the present invention completed based on the above findings will be described in detail with reference to examples. Unless otherwise specified in the examples, commercially available reagent kits and measuring devices use the protocols attached thereto. It should be noted that the objects, features, advantages, and ideas of the present invention are clear to those skilled in the art from the description of this specification, and those skilled in the art can easily reproduce the present invention from the description of this specification. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention and are shown for illustrative or explanatory purposes and are not intended to limit the present invention thereto. It is clear to those skilled in the art that various modifications and alterations can be made within the spirit and scope of the present invention disclosed in this specification based on the description of this specification.

[0010] The antitrypanosomal drug according to the present invention contains N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide or a pharmacologically acceptable salt thereof or N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide (hereinafter, these compounds are simply referred to as "compounds according to the present invention") as an active ingredient.

[0011] In the present invention, an anti-trypanosomiatic drug means an agent (especially a pharmaceutical product) that is useful for preventing or improving diseases caused by infection with Trypanosomiasis protozoa. The diseases (trypanosomiasis) include, but are not limited to, Chagas disease caused by infection with the protozoan Trypanosoma cruzi, and sleeping sickness caused by infection with the protozoan Trypanosoma brucei. Improvement of the disease means not only curing the symptoms of the disease, but also improving the symptoms, suppressing the progression of the symptoms, preventing the appearance of the symptoms, and reducing the number of protozoa that cause the disease. Furthermore, the anti-trypanosomiatic drugs according to the present invention are useful not only for humans at high risk of developing the above-mentioned diseases or those who have developed the above-mentioned diseases, but also for non-human animals such as cattle, horses, pigs, goats, sheep, mules, chickens, ducks, geese, turkeys, quail, mice, rats, guinea pigs, dogs, monkeys, and cats.

[0012] N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide and N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide can be manufactured, for example, according to the methods described in U.S. Patent Application Publication No. 2004 / 0259877 and U.S. Patent Application Publication No. 2006 / 0094718. Furthermore, pharmacoposly acceptable salts of N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide can be manufactured by methods commonly used in the industry. Examples of such salts include metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts; and ammonium salts such as ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts, and dicyclohexylammonium salts.

[0013] The antitrypanosomiatic drug according to the present invention may be used in combination with, for example, benznidazole, nifurtimox, etc. When used in combination, these drugs may be administered together or separately to animals at high risk of developing the above-mentioned disease or those that have developed the above-mentioned disease.

[0014] The antitrypanosomial agent according to the present invention may consist solely of the compound according to the present invention, or it may be a composition further comprising one or more additives. As such additives, existing additives such as excipients, binders, lubricants, disintegrants, flavoring and odor-correcting agents, solvents, stabilizers, bases, wetting agents, preservatives, buffers, and osmotic pressure modifiers can be used.

[0015] The anti-trypanosomial drug according to the present invention may be in any dosage form, such as tablets, capsules, granules, powders, liquids, fine granules, powders, syrups, injections, topical preparations, sprays, patches, suppositories, etc. Furthermore, the anti-trypanosomial drug according to the present invention may be administered by any method, such as oral administration, intravenous administration, or other parenteral administration.

[0016] The anti-trypanosomiatic drug according to the present invention may be administered to the target subject in a single dose, intermittently, or continuously. A continuous administration method may include, for example, intravenous infusion. The target subject may be the animals described above.

[0017] The amount of the compound according to the present invention administered as an anti-trypanosomal agent varies depending on the recipient (e.g., weight and age), symptoms, and method of administration, but is usually 0.0001 to 10 g per administration. [Examples]

[0018] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to the following examples.

[0019] 5-week-old male C57BL / 6 mice were inoculated with Trypanosoma cruzi Y strain (1×10 5 The protozoan was administered intraperitoneally to the mice to infect them (Day 0 of infection). Four weeks after infection, N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide was orally administered to infected mice (n=5) three times a week at a dose of 50 mg / kg (body weight). As a control, infected mice that had not been administered the compound were prepared (n=5). Twelve weeks after infection, cardiac tissue was taken from the mice in the compound-administered group or the non-administered group, and the amount of protozoan was measured by qPCR. For qPCR, probes (SEQ ID NO: 1: 5'-TTGGTGTCCAGTGTGTG-3') and primers (SEQ ID NO: 2: 5'-ASTCGGCTGATCGTTTTCGA-3', SEQ ID NO: 3: 5'-AATTCCTCCAAGCAGCGGATA-3') targeting Trypanosoma cruzi satellite DNA were used. The qPCR was performed under the following conditions. After holding the cells at 95°C for 20 seconds, a cycle of 95°C for 1 second followed by 60°C for 20 seconds was performed 60 times. As a result, it was revealed that the amount of protozoa in the cardiac tissue was reduced by more than half in the compound-administered group compared to the control group.

[0020] Two weeks after infection, N-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-[(morpholinocarbonyl)oxy]benzamide was orally administered three times a week to the infected mice (n=5) at a dose of 50 mg / kg (body weight). As a control, infected mice that had not received the compound were prepared (n=5). Sixteen weeks after infection, left ventricular posterior wall thickness (LVPW;d, LVPW;s) was measured by cardiac ultrasound (echocardiography). As a result, it was found that the thinning of the left ventricular posterior wall observed in the control group due to protozoan infection was significantly suppressed in the compound-administered group.

Claims

[Claim 1] An antitrypanosomial agent containing 5-bromo-2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide or a pharmacopositically acceptable salt thereof, or 5-bromo-2-(morpholinocarbonyloxy)-N-[2,5-bis(trifluoromethyl)phenyl]benzamide as an active ingredient.