JPS5824412B2 - pile coccidia agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an agent for preventing and treating coccidiosis for animals, which contains a pyridine derivative represented by the formula or an acid addition salt thereof as an active ingredient.

In the above formula, R is formyl, acetyl, propionyl, butyryl, inbutyryl, valeryl, isovaleryl, 2-methylbutyryl, pivaloyl, hexanoyl, 2-methyl-valeryl, 3-methylvaleryl, 4-methylvaleryl, 2-ethylbutyryl, hexanoyl, octanoyl, 2 -Ethylhexanoyl, nonanoyl, 3, 3, 5-
Trimethylhexanoyl, decanoyl, undecanoyl, n-lauroyl, myristoyl, pentadecanoyl,
Alkanoyl groups such as balmitoyl and stearoyl; alkenoyl groups such as acryloyl, crotonoyl, 3-butenoyl, methacryloyl, tigloyl, sorboyl, 10-undecenoyl, and oleoyl; or N-methylcarbamoyl, N-ethylcarbamoyl, N-n-propylcarbamoyl , N-isopropylcarbamoyl,
It represents a linear or branched lower alkylcarbamoyl group such as N-n-butylcarbamoyl and N-isobutylcarbamoyl.

In addition, the acid addition salts of the pyridine derivatives represented by the formula (1) include salts of organic acids or inorganic acids, such as hydrochloric acid, sulfuric acid,
Examples include pharmaceutical non-toxic salts such as nitric acid, oxalic acid, maleic acid, tartaric acid, malonic acid, citric acid, phthalic acid, and naphthalene disulfonic acid salts.

Coccidiosis is a disease caused by coccidia (C) of the protozoan sporozoa.
It is a parasitic protozoa belonging to the order occidia,
It is an infectious disease that causes gastrointestinal disease and malnutrition in poultry and livestock, causing death.It is most common in chickens, and also affects domestic rabbits, goats, sheep, cows, ducks, quail, turkeys, etc. , causing great damage to the livestock industry.

Coccidia Eimeriaceae (Ei meridae)
), there are more than ten genera such as Eimeria and Isospora, and coccidiosis in poultry and livestock is often caused by the genus Eimeria.

Oocysts (Oocysts) are excreted with feces, and under suitable conditions 24-48
After some time, the virus forms spores, becomes infectious, and can be transmitted orally.

Oocysts initially reproduce asexually within the mucosal cells of the host's cecum or small intestine, during which time they develop the most severe symptoms, and then sexually reproduce to form oocysts, which are excreted with feces. This makes it extremely contagious.

A number of preventive treatments using chemotherapeutic agents have been proposed for such coccidiosis in poultry and livestock, and in particular, sulfa drugs, sulfur compounds, nitrofuran derivatives, nitrozenide, nicarbazin, Pyrimidine derivatives (antithiamine drugs), quinoline derivatives, guanidine derivatives, antibiotics, etc. have been introduced, but each has drawbacks such as efficacy, antiprotozoal spectrum, safety for target animals (and the tendency to develop drug resistance, etc.). It cannot be said to be a suitable drug.

The preventive and therapeutic agent for coccidiosis of the present invention is effective against all members of the genus Eimeria, and is particularly effective against Eimeria tenella, the most pathogenic caecal parasite.
lla).

Furthermore, the active ingredient of the present invention is highly effective against strains resistant to thiamine-based coccidial agents that are currently widely used.

The pyridine derivatives (D is a new compound) which are anticoccidial agents for animals of the present invention, and all of these compounds and their organic or inorganic acid salts are useful as anticoccidial agents.

Representative examples of the compound having the formula (I) used in the anticoccidial agent of the present invention are as follows.

(1) N-formyl 2-nitroinicotinamide (2) N-acetyl 2-nitroinicotinamide (3) N-7” ropionyl 2-nitroisonicotinamide (4) N-butyryl 2-nitroinicotinamide (5) N-imbutyryl 2-nitroisonicotinamide (6) N-valeryl 2-nitroisonicotinamide (7) N-1' sovaleryl 2-nitroisonicotinamide (8) N-2-methylbutyryl 2-nitro Isonicotinamide (9) N-hybaroyl 2-nitroisonicotinamide
α0) N-hexanoyl 2-nitroisonicotinamide αυ N-2-methylbutyryl 2-nitroisonicotinamide (12) N-3-methyl-valeryl 2-nitroisonicotinamide 5 (13) N-4-methyl -Valeryl 2-nitroisonicotinamide (14) N-2-ethyl-butyryl 2-nitroisonicotinamide (15) N-heptanoyl 2-nitroisonicotinamide (16) N-octanoyl 2-nitroisonicotinamide ( 17) N-2-ethylhexanoyl 2-nitroinicotinamide (18) N-nonanoyl 2-nitroisonicotinamide (19)'N-3,3,5-trimethylhexanoyl 2
-Nitroisonicotinamide (20) N-decanoyl 2-nitroisonicotinamide (21) N-undecanoyl 2-nitroisonicotinamide (22) N-n-lauroyl 2-nitroisonicotinamide (23) N -Myristoyl 2-nitroisonicotinamide (24) N-pentadecanoyl 2-nitroinicotinamide (25) N-valmitoyl 2-nitroisonicotinamide (26) N-stearoyl 2-nitroisonicotinamide (27) N -Acryloyl 2-nitroisonicotinamide (28) N-crotonoyl 2-nitroisonicotinamide (29) N-3-butenoyl 2-nitroinicotinamide (30) N-meccryloyl 2-nitroisonicotinamide (3υ N -Tigloyl 2-nitroinicotinamide (32) N-Sorvoyl 2-nitroinicotinamide <33) N-Undecenoyl 2-nitroinicotinamide (34J N-oleoyl 2-nitroinicotinamide (3■ 4 -(4-y'f-propylarophanoyl)-2-nitropyridine (36) 4-(4-ethylallophanoyl)-2-nitropyridine (37) 4-(4-n-propylarophanoyl)
-2-nitropyridine (38) 4-(4-inpropylarophanoyl)-2
-Nitropyridine (3914-(4-n-butylarophanoyl)-2-
Nitropyridine (404-(4-isobutylarophanoyl)-2-nitropyridine) The compound represented by the above formula (I) is the compound (II) (Journal of the American Chemical Society) as shown in the following formula. (JAC8) Vol. 76, p. 3167 (1954)] is reacted with thionyl chloride to form an acid chloride, and then the sodium salt or potassium salt of the acid amide (RNHY; R is an alkanoyl group or an alkenoyl group) is reacted with thionyl chloride to form an acid chloride. and Y represents a sodium atom or a potassium atom) at room temperature.

Any solvent may be used as long as it does not interfere with this reaction, but commonly used solvents include evabenzene, toluene, chloroform, methylene chloride,
Examples include ethenobe dimethylformamide and pyridine.

In addition, acid amide (RNH2) was prepared for compounds in the presence of pyridine.
; R represents an alkanoyl group or an alkenoyl group).

Furthermore, a compound obtained by contacting a compound with ammonia is mixed with an acid anhydride (R20; R represents an alkanoyl group or an alkenoyl group) at 10°C to 150°C in the presence of a catalytic amount of sulfuric acid, toluenesulfonic acid, etc. It can also be obtained by contacting with

When R of compound (I) is an alkylcarbamoyl group,
It is obtained by heating compound (1) with isocyanate (R'NCO;R' represents a lower alkyl group or alkenyl group) in the presence or absence of a solvent.

Any solvent may be used as long as it does not interfere with this reaction, but commonly used solvents include toluene,
An aromatic solvent such as xylene.

The reaction is accelerated by heating, preferably 100 to 180
It is best to do this at ℃.

After the reaction, the desired product is obtained by a conventional method.

For example, after the reaction, the desired compound is obtained by filtering the crystals or, if necessary, performing purification by chromatography and recrystallization.

Next, the above method will be explained in more detail by referring to a reference example.

Reference Example I Synthesis of N-octanoyl 2-nitroisonicotinamide 1.21 of 2-nitroisonicotinic acid was mixed with thionyl chloride at 30 mA! and reflux for 4 hours.

Excess thionyl chloride was distilled off to obtain oily 2-nitroisonicotinic acid chloride 0.9S'.

When this acid chloride was added to aqueous ammonia under cooling, crystals were obtained, and recrystallization from ethanol-ether gave 0.72f of 2-nitroisonicotinamide.

Melting point (decomposition) 173℃ Elemental analysis value Calculated value as C6H5N303: C, 43, 12; N 13.02; N, 25.1
5 Experimental value: C, 43,19; H, 3,05; N125.0
6 Add 2 drops of concentrated sulfuric acid to a mixture of 0.8 P of 2-nitroisonicotinamide and 2.4 ml of n-octanoic anhydride, and stir at room temperature for 16 hours.

The reaction solution was poured into ice water, made weakly alkaline with 5% sodium bicarbonate, and extracted with ethyl acetate.

After washing the extract with water and drying, the solvent is distilled off.

The obtained residue was purified by silica gel chromatography and further recrystallized from ethyl acetate-n-hexane to obtain 1.3 fl of the desired white crystals.

Melting point 108-110℃ Elemental analysis value C14H1, N30
Calculated value as 4: C157,32;H,6,53;N,
14.33 Experimental value: C, 57,16; H, 6,63; N114.1
9 The following compound was synthesized according to the above method.

N-acetyl 2-nitroisonicotinamide Melting point 18
1-183℃ (recrystallized from ethyl acetate) Elemental analysis value Calculated value as C8H7N304: C, 45,94; H, 3,37; N, 20.0
9 Experimental value: C145,83; H, 3,43; N, 19.9
8 N-Inbutyryl 2-nitroisonicotinamide Melting point 153-155°C (ethyl acetate-n-
Recrystallized from hexane) Elemental analysis value Calculated value as C4゜H1□N304: C,
50,63; H, 467; N, 17.72 Experimental value: C, 5'0.80; H, 481; N, 17.
64 N-crotonoyl 2-nitroisonicotinamide Melting point 152-153°C (recrystallized from ethyl acetate-n-hexane) Elemental analysis value Calculated value as C1oH0N304: C, 51,06; H, 3,86; N117. 8
7 Experimental value: C, 51,08; H, 3,72; N, 17.7
5 Reference Example 2 Synthesis of 4-(4-isopropylarophanoyl)-2-nitropyridine 0.8 parts of 2-nitroisonicotinamide and 1.71 parts of isopropylisocyanate were added to 30 rrLl of toluene and refluxed for 6 hours.

Cool and remove 0.41 insoluble raw material.

For solution F, the residue obtained after concentration was purified by silica gel chromatography and recrystallized from ethyl acetate-n-hexane to obtain the desired compounds o and osy.

Melting point 132-133℃ Elemental analysis value Calculated value as C1oH42N404: C1
47,62; H, 4,80; N22.22 Experimental value: C147,55; Hl 4.97; N122
．． 15 The following compound was synthesized according to the above method.

4-(4-ethylallophanoyl)-2-nitropyridine Melting point 196-198°C Elemental analysis value Calculated value using C9H1oN404: C145.38; N14.23; N123.
52 Experimental value: C, 45, 21; N14.09; N123.
62 To carry out the present invention, the compound represented by the general formula (I) or its organic acid or inorganic acid salt is used, if necessary, in combination with a physiologically harmless carrier.

It is usually added to animal feed or dispersed or dissolved in drinking water.

Examples of animal feed include flour, hulls, fermentation residues, lees, and sugars.

This feed may be mixed with crushed limestone, talc powder, etc., and the mixture is made into a solid or semi-solid by methods such as crushing, stirring, and layer inversion.

The above preparations of the invention may contain other anticoccidial agents such as sulfa drugs such as sulfa chlorpyrazine, sulfadimethoxine, sulfaquinoxaline; or thiamine derivatives such as pecrothiamine, amprolium, dimethiarium; quinoline derivatives such as butyrate, decoquinate, methylbenzochloride. ate; antifolates such as pyrimethamine, cyaveridine; antibiotics such as monensin; or other anticoccidial agents such as 3-hydroxy-5-hydroxymethyl-2-methylpyridine, phlopidol (3,5-dichloro-2,6-dimethyl-4
The dosage concentration of the anticoccidial agent of the present invention, which may contain viridinol), lobenzidene, etc., cannot be determined unconditionally depending on the type of poultry or livestock, administration method, purpose of administration, symptoms, etc., but for example, it may be added to feed for prevention. If you do, 25~
Used at 250 ppm, 500-1000 for treatment
Used in ppm.

Next, a test example showing the effect of the anti-coccidiosis agent of the present invention will be given.

Test Example Test Materials and Test Methods (1) Test chicks: white-bred Ghuon breed, male chicks, 14 days old from the start of the experiment (first-day chicks are used immediately after hatching, and the young chick formulation does not contain an anticoccidial agent until the start of the test) The animals were fed and kept in isolation.

) (2) Test coccidium: Eimeria tenella (Ei
42,000 spore-forming oocysts of Meria tenella) per bird were directly orally inoculated into the pouch for infection.

(3) Test chemicals: Six types of compounds shown in Table 1 were used.

(4) Concentration of test drug added to feed: 200% of test drug added to commercially available compound feed for young chicks that does not contain anticoccidial drugs.
ppm mixed.

(5) Test method: The above test chicks are raised in isolation from coccidiosis chickens, their health conditions are observed, and the weights of normal chicks are measured. There is no significant difference in the average weight of each group (5% risk level). The birds were divided into 10 birds per area.

Furthermore, two groups were established: an infection-free control and a no-medication and infection-free control.

A certain number of oocysts were inoculated in all plots except for the no-infection-free, no-medication control plot, and feed containing the test drug was fed at the same time, and the two control plots had the same composition (without the test drug added). Feed from the same lot was fed.

(6) Judgment: Body weight was measured at fixed times from the start of the test (at the time of administration and infection) to the end (7 days after infection), and the number of oocysts excreted in the feces was counted every day from 6 to 7 days after infection. It was measured.

Seven days after infection, all surviving chicks were necropsied, and the degree of cecal lesions caused by coccidia was determined according to Johnson and Reed, Experimental Parasitology, Vol. 28, pp. 30-36 (1970). (Johnson and Re1d)
Judgment was made using the 0 to 405 step method.

The amount of weight gain from the start of the test to the end of the test is defined as the amount of weight gain.
The average salary increase was divided by the number of science and mathematics for each test group.

The number of oocysts in 1 g of feces excreted on the 6th and 7th days after infection was added for each test section to determine the number of oocysts.

Test results It is shown in Table 1.

The anti-coccidial agent of the present invention was found to be more effective than the control group without infection.

Also, no side effects were observed. When administering these drugs, among the coccidia developmental stages, the asexual reproductive stage,
and the second asexual reproductive phase are the most effective.

Claims (1)

[Scope of Claims] 1. An anti-coccidial agent containing a pyridine derivative represented by the general formula (wherein R represents an alkanoyl group, an alkenoyl group, or an alkylcarbamoyl group) or an acid addition salt thereof as an active ingredient.