Agents for combating Neospora spec

Plant protecting and regulating compositions – Plant growth regulating compositions – Organic active compound containing

Reexamination Certificate

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C504S304000, C504S347000, C514S155000, C514S478000, C514S485000, C514S646000

Reexamination Certificate

active

06753298

ABSTRACT:

The present invention relates to compositions for controlling diseases caused by parasites of the genus Neospora. The compositions according to the invention are based on inhibitors of the microtubulin system of plants.
Neosporosis is a disease of animals cause by parasites of the genus Neopspora, in particular
Neospora caninum
. Neospora infections are known in dogs, cattle, sheep, goats and horses.
The final host of Neospora spec such as
N. caninum
, and thus the complete life-history of the parasite, are as yet unknown. What is known as yet about the life-history of this parasite are only the asexual reproductive stages in the form of schizogony and the single-celled tachyzoites/bradyzoites. Tachyzoites are single-celled infectious parasitic stages with a size of 3-7×1-5 &mgr;m, which are formed in cysts in the tissue following intracellular multiplication. This reproductive process is termed endodyogeny.
The reproduction by tachyzoites preferentially takes place in organelles such as muscles and nerve cells. This is why the pathological symptoms following natural infection occur preferentially in these tissues. In dogs, for example, natural infection from week 5 to 6 leads to disease symptoms with signs of hypersensitivity due to inflammations of the nerve roots and increasing paresis of the hind legs. Further histopathological findings occur in the nerve system, preferentially in the brain and spinal cord. Extensive non-suppurative inflammations, glial proliferations and perivascular infiltrations with mononuclear cells (macrophages, lymphocytes, few plasma cells), in some cases also eosinophiles and neutrophiles, dominate here. Necrotic-degenerative changes occur in the muscular system and are even macroscopically visible. What is notable are long pale longitudinal stripes, in addition to a more or less pronounced atrophy.
In California and Australia,
Neospora caninum
infections are considered a main cause for abortion in herds of cattle.
In cattle, the disease symptoms are similar to those found in dogs. Ataxias occur, the articular reflexes are greatly reduced, and pareses occur on the hind legs, in some cases on all four legs. The histological symptoms are similar to those found in dogs: non-suppurative meningitis and myelitis predominate.
Only a very limited amount of information is available as yet on the in-vivo efficacy of substances suitable for controlling Neosporosis since adequate in-vivo test systems have yet to be developed. In experimentally infected mice, sulphadiazine (administered by drinking water) proved to be effective only when the treatment was prophylactic, i.e. before the onset of the infection. In dogs, the treatment with sulphadiazine and clindamycin is only successful when it starts very early at the first sign of clinical symptoms due to inflammation of the nerve roots.
The present invention relates to compositions for controlling diseases caused by protozoans of the genus Neospora, which are characterized in that they comprise one or more active compounds which inhibit the microtubulin system of plants.
Microtubuli (MT) belong to an important filament type of the cytoskeleton. The main component of this structure is tubulin, a globular polypeptide with a molar mass of 50,000 Daltons. During the intracellular aggregation of the microtubuli, subunits (heterodimers) composed of &agr;- and &bgr;-tubulin associate to first form protofilaments, which then give rise to a microtubulin tube of approximately 25 nm.
In biological organisms, MT have important functions with regard to cell shape and cell movement. In particular, MT are involved in maintaining cell polarity. Together with associated proteins (MaPs), MT are responsible, in a stable and permanent arrangement, for the gliding mechanism in cilia, a biological structure which specializes in causing repetitive movements.
Polymerization (synthesis) and depolymerization (degradation) are based on an exchange of tubulin molecules between the MT and a stock which is dissolved in the cytoplasma. The sensitive balance of synthesis and degradation within a cell can be disturbed by substances which increase, or inhibit, polymerization. This process can be blocked by tubulin-binding substances, the so-called MT inhibitors. MT inhibitors are a group of structurally diverse compounds which can be produced by fungi, plants or marine organisms or synthesized in the laboratory. Colchicine, an alkaloid obtained from the autumn crocus, binds firmly to tubulin and thus prevents polymerization. Other inhibitors which have been known for a long time are vinblastin, vincristin and taxol. Taxol stabilizes the MT structures and prevents their degradation (Wilson L (1975) Life Sci. 17: 303-310). Benzimidazoles (BZ) are an example of a class of compound with therapeutic activity against helminths (Horton RJ (1990) Parasitology Today 6(4): 106; Townsend LB and Wise DS (1990) Parasitology Today 6(4): 107-112). BZ are synthetic inhibitors of in-vitro polymerization of mammalian tubulin, which show a higher in-vivo affinity for helminth tubulin than for the mammalian cell (Lacey E (1988) Int. J. Parasitol. 18, 885-936). Competitive ligands binding studies on H3-colchicine confirm that BZ interact with the colchicin-binding domain and thus prevent polymerization (Friedman Pa. and Platzer EG (1978) Biochim. Acta 544, 605-614).
In plant cells, the MT system participates especially in generating cell shape and cell polarity and also governs chromosomal distribution during mitosis. Herbicides which act on the MT system thus interrupt the cell cycle (Hess FD (1987) Rev. Weed Sci 3: 183-203). The morphological consequence of the herbicidal action are giant cells with giant nuclei, polynucleate cells, tissue swellings and eventually growth is halted permanently.
Even though the sequence of tubulin from various species shows a high degree of homology, drastic differences exist in some cases between plant and animal tubulin. Thus, for example, animal tubulin polymerizes spontaneously in vitro, while this is not the case with plant tubulin. This means that it is not possible from the outset to extrapolate, to animal tubilin, findings which have been obtained with and on plant tubulin, and vice versa.
Active compounds which can be used in accordance with the invention are compounds which inhibit the microtubulin system of plants. These preferably include herbicidal compounds of the classes of the 2,6-dinitroanilines and the N-arylcarbamates.
Especially preferred are 2,6-dinitroanilines of the following formula (I)
in which
R
1
represents hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkoxy, alkenyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, halogenoalkyl, halogenoalkenyl, halogenoalkoxy, halogenoalkenyloxy, aminosulphonyl, alkylsulphonylamino,
R
2
represents hydrogen, halogen, amino, alkyl, alkoxy,
R
3
represents hydrogen, alkyl, alkenyl, alkinyl, cycloalkyl-alkyl, alkyloxy, halogenoalkyl,
R
4
represents alkyl, alkenyl, alkinyl, cycloalkyl-alkyl, alkyloxy, halogenoalkyl,
R
3
and R
4
together with the nitrogen to which they are bonded form a heterocyclic radical.
Especially preferred are the N-arylcarbamates of the formula (II)
in which
R
5
represents hydrogen, halogen,
R
6
represents hydrogen, alkyl, alkenyl,
R
7
represents alkyl, alkenyl, alkinyl, halogenoalkyl, halogenoalkenyl, halogenoalkinyl,
n represents 1 or 2.
Optionally substituted alkyl alone or as a constituent of one of the radicals alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, halogenoalkyl, cycloalkylalkyl in the general formulae denotes straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2

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