DE2104345A1 - Tris-benzylideneaminoguanidines - for combatting coccidiosis in domestic animals - Google Patents

Abstract

Agents for combatting coccidiosis contain as active substance a tris-(4-halobenzylideneamino)-guanidine of formula (I) : (where Hal is Cl or Br) or a non-toxic physiologically tolerable salt thereof. The agents are suitable for the treatment and prophylaxis of coccidiosis in domestic animals such as swine, sheep, calves, rabbits and, esp. poultry such as hens and turkeys. (I) are as active as and better tolerated than the known cpd. robenzidene. They are advantageously administered in the fodder at a concn. of 50-1,000 (pref. 80-200) ppm.

Description

Means for combating coccidiosis According to Science 1970 (Vol; 168), Pages 373 to 374 is Robenzidene; 1. bis (4-chlorobenzylideneamino) guanidine hydrochloride, known as an active ingredient against coccidiosis.

The invention relates to an agent for combating coccidiosis, which is characterized in that it is a tris (4-halobenzylideneamino) guanidine of the formula I as the active ingredient wherein Hal is chlorine or bromine, or contains a non-toxic, physiologically acceptable salt of this compound.

As physiologically compatible salts of tris (4-halobenzylidene-wmino) -guanidines there are inorganic salts such as hydrochlorides, hydrobromides, sulfates, Methosulfates, phosphates or organic salts such as acetates, propionates, lactates in Consideration.

Tris (4-halobenzylideneamino) guanidines of the formula I or

Their salts can be prepared by using an eutspeaking agent Reacts 4-halobenzaldehyde with a salt of triaminoguanidine and optionally from the reaction the guanidine base is produced by adding a base which has a pK value of 5 or less. The first step in the reaction is advantageously carried out in a solvent or spreading agent. Preferably one works in an alcoholic aqueous solution such that one becomes an alcoholic one Solution of 4-halobenzaldehyde adds an aqueous solution of triaminoguanidine salt. The reaction temperature is expediently 60-80 ° C. A small addition of acid as a condensation catalyst is advantageous. To release the base you can next to Ammonia organic bases such as methyl amine, dimethylamine, trimethylamine, ethylamine, Use triethylamine, pyrrolidine and piperidine; in particular, basic ones come inorganic compounds such as alkali and alkaline earth bicarbonates, carbonates or -hydroxides into consideration.

The tris - (4-halobenzylideneamino) guanidines and their non-toxic ones Physiologically compatible salts can in principle be those to be protected from coccidiosis Administered to animals as such. However, it is advisable to use the new one Active ingredients mixed with a suitable inert carrier material.

The usual feed mixes can be used as carrier material especially those for poultry.

The invention therefore also relates to feed mixtures which characterized by a content of tris (4-halobenzylideneamino) guanidines of the formula I. are. The concentration of the active ingredient in the feed came to be between 50 and 1,500 ppm, preferably between 80 and 200 ppm.

To produce the feed according to the invention, the active ingredients mixed in solid form with the usual animal feed.

It is advisable to first mix the active ingredients with part of the feed to be mixed homogeneously, the one made of solid, inert and well-tolerated carrier materials consists. The usual inorganic substances in animal nutrition can be used as such carriers and organic, physiologically well-tolerated products such as calcium carbonate, Calcium phosphates or flour from different types of grain. Proves to be cheap besollders the use of wheat afterjnehi. Such a Vorrnischujlg will then with the remaining components of the feed in a further mixing process so that a feed mixture with a uniform active ingredient content is obtained will.

The following example gives a feed composition that Particularly suitable for the rearing of chicks: 7.0% Dorscliinehl 5.0% wheat bran 5.0 barley meal 1.0% carbonate 18.0% soy meal, extr. toasted fodder lime 41.5% corn meal 1.0% phosphoric acid 20.0% wheat meal fodder lime 1.5 ffi vitamin premix The following vitamins are contained in 1 kg of the finished feed mixture: 4000 IU vitamin A 1.0 mg vitamin K 3 500 lE vitamin D 3 5.0 mg vitamin B 12 2.5 mg vitamin E 2.25 mg pantothensic acid 1.6 mg vitamin B 2 potassium The feed according to the invention In addition to a compound of the formula I, other therapeutic and growth-promoting compounds can be used Contain agents such as antibiotics.

Tris- (4-halobenzylideneamino) -guanidines of the formula 1 and their physiological Compatible salts are suitable for the therapy and prophylaxis of coccidiosis in domestic animals such as pigs, calves, sheep and rabbits, especially poultry such as chickens and turkeys.

The effectiveness of tris- (4-chlorobenzylideneamino) -guanidine and Tris- (4-bromobenzylideneamino) -guanidine against poultry coccidiosis corresponds roughly to that of the well-known active ingredient Robenzidene.

In terms of tolerability, however, these new active ingredients are superior to the Robenzidene, as from the compatibility tests listed below emerges.

The following test results were obtained on male chicks. These are divided into groups of four chicks each and then the average weights determined per group. Prophylactic treatment begins 2 days before infection and is carried out until the end of the respective test indicated below. the Active ingredients to be tested are uniformly and mechanically the feed of the above specified composition mixed.

The chicks are offered food and water for free consumption. The chicks are placed in groups of four in wire cages at a temperature of 300C and a relative humidity of 65 46 held.

For the purpose of infection, the chicks are on the third day after the start prophylactic treatment with such an amount of sporolated oocysts a laboratory strain of Eimeria tenellä applied with the help of a stomach tube, that at this dosage in the infected people carried along as controls, but untreated animals generally manifested 5-6 days after infection Symptoms of illness appear, such as blood in the feces, severe weight loss and first Deaths.

The mortality during the entire test duration of 13 days is in the control groups in each case over 80% (in the more severe infection 100 %). The peak of the disease appears 5 - 6 days after infection with a correspondingly high mortality. Surviving chicks show significant weight loss compared with the uninfected and untreated chicks (zero control).

During the duration of the experiment, the fecal findings showed those with tris- (4-chlorobenzylideneamino) -guanidine or tris- (4-bromobenzylideneamino) -guanidine treated groups of animals no deviation from the norm. The same goes for the zero controls.

In contrast, the infected but not treated control groups showed 4 - 7 days after the infection, there was a lot of blood in the thin feces.

Dissection of the treated chicks at the end of the experiments gave none pathological change in the appendix. The same goes for the zero controls. In contrast, the animals of the infected control groups showed pronounced hemorrhagic effects Inflammation of the appendix.

-To assess the coccidiostatic effect on the one hand the Weight development of the chicks used. After the end of the test, the average weight will be determined per test group and the percentage average change in weight certainly. In addition, the number of Non-sporolated oocysts excreted in the feces are determined and assessed as follows: Number of oocysts Scoring number: per visual field: 1 1 2 - 10 2 11 - 50 51 - 200 4 201 - 400 5 over 4oo 6 The prophylactic effect of tris- (4-chlorobenzylidellamino) -guanidine which is added to the feed specified above in a dosage of 80 ppm is shown in the table below: Test animals: Gevicht survivors Oocyst index increase: Animals: O - 6 treated chicks 129.9% 8/8 0.12 infected Control) - o / 8 null control 109.2% 8/8 0 *) Each chick was as above reported infected with 500,000 oocysts.

It turns out that with prophylactic use of 80 ppm tris (4-chlorobenzylideneamino) guanidine the chicks in the feed despite infection for the duration of the experiment of 13 days Exhibited weight gain considerably greater than that of the zero control, and that all treated chickens survived the infection, while the animals received the untreated, infected controls were received without exception.

To determine the compatibility of tris- (4-chlorobenzylideneamino> -guanidine two groups of four chicks each, which were three days old at the start of the experiment, 1,000 ppm of the active ingredient (A) mentioned are added to the above-mentioned feed.

For comparison,} 000 ppm of the known bis (4-chlorobenzylideneamino) guanidine were used (Robenzidene) (R) applied to other groups of chicks in the same way. The results after a test duration of 17 days the following table contains: Active ingredient: Weight gain: Surviving animals: 262.0% 8/8 R 35.1% 1/8 untreated 154.2 ffi 8/8 It turns out that all animals the high dosage of the active ingredient A survived, while only 1 out of 8 animals received the same dosage of the active ingredient R survived.

The prophylactic effect of tris- (4-bromobenzylideneamino) -guanidine, which was admixed in a dose of 120 ppm to the mother specified above, is shown in the table below: Weight Survivor Oocyst Index Test animals: increase: animals: O - 6: treated chicks) 68.0% 8/8 infected control *) 2.4 ffi 1/8 5.7 zero control 67.6% 8/8 - *) Each chick was as above reported infected with 120,000 oocysts.

It turns out that with prophylactic use of 120 ppm tris (4-bromobenzylideneamino) guanidine the chicks in the feed despite infection for the duration of the experiment of 13 days Had weight gain equal to that of the zero control and that was all treated chicks survived the infection, while the mortality of the untreated, infected control animals was over 80%.

To determine the compatibility of tris (4-bromobenzylideneamino) guanidine two groups of 4 chicks each, which were three days old at the start of the experiment, 1000 ppm of the active ingredient (B) mentioned are added to the above-mentioned feed.

For comparison, 1000 ppm of the known bis (4-chlorobenzylideneamino) guanidine (Robenzidene) (R) applied to other groups of chicks in the same way. The results after a test duration of 17 days the following table contains: Active ingredient: Weight increase: Surviving animals: B 197.4 ffi 8/8 p 35.1% 1/8 untreated 154.2 % 8/8 control It turns out that all animals the high dosage of the active ingredient B survived, while only 1 out of 8 animals received the same dosage of the active ingredient R survived.

Claims (5)

P a t e n t a n s p r ü c h e: 1) Agent for combating coccidiosis, characterized in that it is a tris (4-halobenzylideneamino) guanidine of the formula I as the active ingredient wherein Hal is chlorine or bromine, or contains a non-toxic, physiologically acceptable salt of this compound. 2) Mixture of feed, characterized by a content of one Tris (4-halobenzylideneamino) guanidine of the formula I in claim 1 or on one of its physiologically compatible salts. 3) Mixture of feed, characterized by a content of 50 to 1500 ppm of a tris (4-halobenzylideneamino) guanidine of the formula I in claim 1, or t one of its physiologically acceptable salts. 4) Filter mixes for poultry, characterized by a Content of 80 - 200 ppm tris (4-chlorobenzylideneamino) guanidine or one of its physiologically compatible salts. 5) Feed mixture for poultry, characterized by a content of 80-200 ppm tris (4-bromobellzylideneamino) guanidine or one of its physiological compatible salts.