Parasitic protozoa are ubiquitous in animals such as mammals, fowls, fish, and insects. Parasitizing their internal organs, skin, and eyes in most instances, these organisms inflict serious damages on the hosts, thus playing a great economic havoc with the animal, poultry, and fish industries. Coccidiosis, which is a protozoal disease in domestic fowls, is mostly caused by several species of protozoa belonging to the genus Eimeria, such as E. tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati. For example, E. tenella, parasitizes the intestinal canal wall, such as the cecal wall, of poultry to do fatal harm to the host. Thus, this infectious disease manifests itself in the form of erosion, inflammation and hemorrhage of the intestinal wall and blood retention in the cecum due to extensive invasion into the bowels, with the accompanying symptoms such as poor appetite and retarded growth. Internal parasitic protozoa are usually transmitted orally. However, in the case of coccidiosis, the oocysts of the parasites cannot be effectively inactivated even by the intensive disinfection with potassium dichromate solution and, moreover, their life span is as short as about 7 days. Therefore, one has to just sit and see the hazard speading.
In the case of fish, protozoa parasitizing their external organs are serious problems of concern. Their parasitization results in injuries of the skin and gills, weakens the resistance of the host to infections and even may directly cause death. In the culture of fish on a large-scale pisciculture farm, parasitic protozoa spread rapidly throughout the whole pond of fish and the consequent economic loss cannot be tolerated.
The same is true of insects. Taking bees as an example, protozoa represented by Nosema apis are playing havocs with apiculturists all over the world. The above protozoa destroy the internal organs of bees to compromise their resistance, thus making the hosts prone to other diseases.
A large number of chemicals are known for the control of parasitic protozoa but most of those chemicals are host-specific or of narrow spectrum and with some of the chemicals, the emergence of resistant protozoa has been reported. Furthermore, because of their weak activity, those chemicals have to be administered in massive doses, thus being not fully satisfactory from economic and ecological points of view. Therefore, development of a chemical substance that can be used for control of parasitic protozoa in vertebrate animals such as mammals, fowls, fish, and insects with a sufficiently broad spectrum as well as potent activity has been demanded.
As such a chemical, a 2-phenyl-6-azauracil derivative was found to have anticoccidial activity (J. Med. Chem., 22, 1483, 1979) and, accordingly, a variety of 6-azauracil derivatives were synthesized and evaluated. However, those compounds were found to be teratogenic and no further development was made. Then, as compounds overcoming the teratogenicity problem, 2-phenyl-1,2,4-triazinedione compounds such as a 2-(4-phenoxyphenyl)-1,2,4-triazine derivative [DE-A-2532363], a 2-[4-(1-cyano-1-phenylmethyl)phenyl]-1,2,4-triazine derivative, etc. were developed and some of them are already in field use as anticoccidial agents in the Europe and other countries including Australia, although they have not been approved for use as yet in the rest of the world including Japan and the United States.