CS276344B6 - Fodder premix - Google Patents

Abstract

The feedstuff or feed premix contain a synergistic mixture of an ionophorous antibiotic and the compound (I), <IMAGE> wherein R1 is hydrogen, C1-4alkyl, nitro, CF3, OCF3, OCF2CF3 or OCF2CHF2; <IMAGE> R3 is hydrogen, C1-4alkyl, phenyl, aminophenyl, benzyl, nitroaminophenyl, dinitroaminophenyl or fluoroalkoxydinitrophenyl; and n is 1 to 3. The antibiotic may be monensin, narasin or salisomycin.

Description

(57)

A feed premix containing at least 5 mg of an ionophore antibiotic, for example monensin, narasin or salinomycin, together with conventional premix components such as vitamins, inorganic substances and microelements, and 10 to 130 mg of at least one compound of the formula I, wherein R is hydrogen,

Alkyl, nitro, CF, OCF, OCF, CF, or OCF _? CHF ₂ , R _? is -CHR -, -CO- or -NH ^í =, R is hydrogen something C, .alkyl ^ n is equal to an integer of 1 to 3, based on 1000 g feed to which the premix is added. The feed premix has increased anticoccidial activity.

CS 276 344 B5

The present invention relates to feed premixes comprising a synergistic mixture of an ionophore antibiotic and a quinoline derivative and thus having enhanced anticoccidal activity.

Productivity: animal husbandry depends on genetic factors on feeding and veterinary health conditions. Coccidiosis of poultry is a serious problem in broiler and rabbit breeding. At present, however, losses due to mortality due to intestinal coccidiosis are significantly lower than those caused by coccidia, which cause growth depression and poor food use in seemingly healthy breeding. Chickens or rabbits heavily infected with coccidia are much less resistant and cannot be sufficiently immunized against disease. It follows that at present, the losses caused by covert subclinical infections are much greater than those caused by clinical coccidiosis.

In broiler and rabbit breeding, a significant system of coccidiosis requires a planned system of preventive measures. Regular and continuous administration of compound feed containing current anticoccidial agents is a preventive measure commonly used against coccidiosis. The main criteria of these current anticoccidial agents are: high efficacy, broad spectrum at low toxicity and low residues, improved feed utilization and weight gain. Furthermore, these preparations should be applicable by incorporation into the feed, should be stable in the mixture formed with the feed, should not be incompatible, should be readily detectable in the mixture containing them, should not impede the development of immunity, resistance, their application should be economical.

The prophylaxis of coccidiosis usually consists in the addition of synthetic anticoccidial formulations or combinations thereof, for example to chicken feed.

At present, so-called ionophoric antibiotics are beginning to be applied in addition to synthetic anticoccidial agents. These include, for example, monensin; narasin, salinomycin or lasalocide. The most commonly used is monensin.

Monensin sodium is a biologically active compound with a polyether structure. It was isolated in 1967 from a special culture of Streptomyces cinnamonensis (c.f. Antimicrob. Agents and Chemother., 359, 1967). Its chemical properties have been described by A. Agtarap and J. W.hamberlin (c.f. Antimicrob. Agents and Chemother., 359, 1967). Its production and fermentation process are described in Hungarian patent No. 154327.

In general, anticoccidial agents inhibit the metabolism at various stages of the parasites or inhibit the action of enzymes.

During the biological mechanism of ionophoric antibiotics, the transport of certain alkali metal ions and disturbances in their distribution in cells plays an important role. Their effectiveness is based on the fact that these antibiotics can convert certain alkali metal ions through the cell membrane of coccidia. for example, monensin and salinomycin can do this with sodium and potassium ions, lasalocide with calcium and magnesium ions. A change in the intracellular colloidal osmotic pressure leads to decomposition of coccidia.

Surprisingly, it has now been found that if the ionophore antibiotic is not administered alone but is administered with at least one of the compounds of Formula I

H

CS 276 344 86 where R 1 represents hydrogen, C 1-6 alkyl, nitro, CF 3, OCF 2, OCF ₂ CF ₃ or OCF ₂ CHF ₂ ,

I ³

R _o represents -CH-, -C- or -NH-, the IR £

R is hydrogen, C ^ _ ₄ alkyl, phenyl, and n is any integer between 1 and 3, then. the number of coccidials detectable in the intestinal tract of the animals is so reduced that the infection rate is as low as zero.

Partially novel, partially known compounds of formula I can be prepared by condensation of trimethyl-1,2-dihydroquinoline or a suitable derivative thereof with an aliphatic aldehyde according to Japanese Patent Application Publication No. 8114516.

Compounds of formula I are mixtures of positional isomers, attributed to the carbon atoms to which they are attached R ₂ and R _^> izomernl These products are mixtures of the above condensation procedure and are usually not separated individual isomers.

The increased anti-coccidial efficacy evident by the simultaneous application of the ionophore antibiotic and the condensation product of formula I can be attributed to their synergistic effect. Furthermore, it has been found that if the synergistic mixtures contain ionophore antibiotics at the usual dose of 100 mg / 1 kg of feed, an unusually improved anticoccidial efficacy is evident, but there is also a slight decrease in weight gain. However, if the usual dose of an ionophore antibiotic in the feed. significantly reduces and is admixed with a compound of formula I at a dose of 10 to 130 mg / kg of feed, an improved anticoccidial effect remains, but weight gains are not reduced, even increased slightly.

A synergistic mixture of iontophoric antibiotics and compounds of formula I may be added directly to the feed or, alternatively, the synergistic mixture may be mixed with a carrier or other additive to form a premix, which is then added to the diet.

The invention thus relates to a feed premix comprising, together with conventional premix components such as vitamins, inorganic substances and microelements, at least 5 mg of an ionophore antibiotic, preferably monensin, narasin or salinomycin, and 10 to 130 mg of at least one compound of formula I, R ₂ and R are as above, meaning, based on 1000 g feed to which the premix is added.

Preferred compounds are those of formula IA

wherein R, R ₂ and R are as defined above. Based on 1 kg of feed, 5 to 120 mg of monensin, 5 to 70 mg of narasin, 5 to 60 mg of salinomycin are used, together with

CS 276 344 B6 of the formula I is admixed at a dose of 10 to 130 mg.

The invention is illustrated by the following non-limiting examples.

Example 1

To 1 kg of feed for chickens is added 100 mg of monensin and 120 mg of a compound of formula I wherein R₁ represents hydrogen, R ₂ -CH-, R = methyl n second

^R 3

This feed was used for hybrid cocks.

Example 2

To 1 kg of chicken feed add 100 mg of monensin and 120 mg of the compound of formula I, where R1 is nitro, R ₂ represents a -CH- group, R₁ is hydrogen and n = 2nd

^R 3

Example 3

The procedure is as in Example 2, but instead of 100 mg of monensin, 50 mg is used, and a compound of formula I wherein R @ 1 is -CF @ 1, R @ ₂ is --CH--, R @ ₂ is added _. ethyl and n = 2.

^R 3

Example 4

The procedure is as in Example 2, but using 70 mg of narasin instead of 100 mg of monensin, and mixed with the compound of formula I wherein R₁ represents -OCF ^, R ₂ -CH- group, R₁ is hydrogen and n = first

^R 3

Example 5 ' ³

The procedure is as in Example 2, but using 40 mg of narasin instead of 100 mg of monensin and admixing a mixture of compounds of formula I wherein R 1 is ethyl, R ₂ -CH-, R 1 is hydrogen and n = 2 and R 1 is OCF ₂ CF 3. R ₂ -CH-, R 2 is hydrogen and π = 1, in a ratio of 1: 1.

^R 3

Example 6

The procedure is as in Example 2, but using 40 mg of salinomycin instead of 100 mg of monensin and admixing 10 mg of a compound of formula I wherein R 1 is -OCF ₂ CHF ₂ , R ₂ is> CH-,

R 1 is methyl and n = 2.

Example 7

The procedure of Example 3 is followed, but 120 mg of compound I is replaced by a 1: 1 mixture of the compounds of formula I as defined in Examples 1 and 3.

Example 8

The procedure of Example 2, but using a compound of formula I wherein R₁ represents hydrogen, _R² represents a group -C n = 2nd

II o

Example 9

The procedure of Example 2, but using a compound of formula I, wherein R denotes hydrogen, R ₂ represents a -NH- group and n = 2nd

Example 10

The following compounds are mixed together: narasin sodium (20%) 50.00 g compound of formula I as defined in Example 1 (98% pure) 24.50 g carrier (ground grain) to 100.00 g

CS 276 344 B5

This preparation shall be used in such a quantity that the total added dose in the mixed poultry feed is 0,5% by weight.

Example 11

The following components are mixed together:

vitamin A 1 000 000 m. Vitamin D-3 260 000 m. j, Vitamin E 1 000. m. Vitamin K-3 150 mg vitamin 8-1 200 mg Vitamin B-2 460 mg Vitamin B-3 . 1 200 mg vitamin 8-6 150 mg vitamin B-12 1 mg nicotinic acid 3 500 mg Folic acid 100 ALIGN! mg antioxidant BHT 8 000 mg choline chloride 30 000 mg narasin (20%) 20 May 000 mg a mixture of compounds of formula I as defined in of Example 6 12 000 mg Zinc sulphate 28 000 mg calcium iodate 100 ALIGN! mg sodium selenium 20 May mg copper sulfate 2 000 mg iron sulfate 10 000 mg carrier (ground grain) to 1 000 5 · This preparation shall be used so that: total dose ve and mixed feed for broiler chickens

% was 1 wt.

Example 12 (tests)

The hybrid cocks are fed with the composition described in Example 1. A group of 11 hybrid cocks were infected under laboratory conditions with about 150,000 oocysts of the species Emeria tenella, which causes coccidiosis of the appendix. Chickens fed food containing no anticoccidial substances but having otherwise the same composition were also infected and serve as control (R), a group of uninfected chickens (NI) was used to compare weight gains.

The test lasted 8 days. The average body weight of the NI group is taken as 100%. Furthermore, macroscopic appendix lesions were evaluated in groups of 11 chickens.

study group average body weight ratio of apparent appendicitis lesions NI 100% 0 * 11 fed 100 mg of food monensin 4 per kg of food 91.7% 11 fed with the food described in Example 1 of 78.4% : 0 * 11 ' R 67.2% 11 11 ^x lesions are not detectable This data shows that that average body weight chickens fed with feed

the finding is reduced by a small proportion, but the infection of this population is reduced to zero. It follows that the risk of loss of death is significantly lower.

CS 276 344 B5

Example 13 (test)

The efficacy study described in the previous example is performed on chickens in groups of 11. The results are as follows:

study groups average mass physical ratio of apparent appendicitis lesions NI fed a diet containing 100 mg monensin 100% 96.4 81.8 % % 0 * 11 7 in 1 kg of food fed the food described in Example 2 11 1 fed the food described in Example 3 104.0 % 11 2 fed a diet containing 70 mg narasin 83.0 92.7 % 11 8 in 1 kg of food fed with the food described in Example 4 % 0 * 11 fed the food described in Example 5 107.0 % 5 fed with the food described in Example 6 105.0 % 11 4 fed the food described in Example 7 103.5 % 11 2 R 70.0 % 11 11 11

* lesions are not detectable.

From the above, it is apparent that when using the food prepared according to the invention, the degree of infection is in any case substantially reduced, the average body weight decreases, but even slightly or in some cases even increases. At the same time, in the case of a feed fed with the food prepared according to the invention, the risk of loss due to death is reduced in each case.

Example 14 (test)

The test described in Example 11 is carried out with groups of 69-71 animals.

The percentage of infection is given by the number of animals that host the developmental forms of coccidia in scraps from the caecum.

study groups average body weight kurata-hosts coccidia NI 100% 0% fed a diet containing 100 mg monensin in 1 kg of food . 90.3% 67.1% fed the food described in Example 3 89.7% 50.7% R 60.8% 100.0%

The degree of infection and the resulting risk of death are reduced in the diet group of the invention, while the body weights are not significantly altered as compared to the group of diet containing monensin alone.

Example 15

The experiment of Example 1 was carried out, but to each kilogram of feed was added 50 mg of monensin instead of 100 mg and .00 mg of a compound of formula I wherein R 1 is hydrogen, R 1 is -CH-, R 1 methyl and n = 1.

CS 276 344 65

Example 16

Operating as in Example 15, but to each kg of feed were added 50 mg of monensin and 45 mg of the compound of formula I wherein denotes hydrogen, R ₂ -CH-, methyl and n = 2, and 45 mg of a compound of formula I wherein R is hydrogen, R8 is -CH-,

Rj methyl and n = ^1.3

Example 17 (test)

The seven-day hybrid roosters were fed the feed described in Examples 15 and 16. These groups of 35 animals were infected orally with about 150,000 Eimeria tenella oocysts under laboratory conditions. For purposes of comparison, the chickens (R) were infected and fed the same feed containing no anticoccidial agent. A group of uninfected chickens (NI) is given for weight gain comparison. The test lasted 8 days. The average body weight of uninfected chickens (NI) is assumed to be 100%. Microscopic evaluation of the carriers of developmental stages of coccidia in scraps from appendicitis was carried out in each group.

Tested groups average body weight chickens-bearers coccidia NI 100% 0 35 fed with a diet containing 100 mg monensin per 87% 27 Mar: 1 kg of food 35 fed with a diet containing 50 mg monensin per 72% 35 1 kg of food 35 fed according to Example 15 92% 20 May 35 fed according to Example 16 85% 32 35 R 65% 35 35 There was no coccidial in the NI group infection.

The table shows that the body weight of chickens fed the food of the present invention does not decrease significantly, the infection is reduced by half compared to the amount of ionophoric anticoccidial agent used so far.

Example 18

To 1 kg of feed for rabbits sold under the name 54-4 Kornyei in Hungary 10 mg of monensin and 80 mg of a compound of formula I; wherein R is ethyl, R ₂ -CH- group, R₁ methyl and n = 2. i ³

The composition of said rabbit feed is as follows:

wheat 20% bran 19% grass meal 25% soybeans 5% sunflower 8% beet pulp 18% premix 5054-5 5%

100% crude protein content 15% crude fiber content 13%

Example 19

To 1 kg of rabbit feed described in Example 18, 5 mg of salinomycin and 80 mg of a compound of formula I, wherein R 1 is nitro, R ₂ is -CH-, R 1, ethyl and n = 2, are added.

CS 276 344 B5

Example 20 '

Following the procedure of Example 18, 7 mg of narasin was added instead of 10 mg of monensin.

Example 21

Following the procedure of Example 18, instead of 80 mg of the compound of formula I as defined in Example 18, a mixture of the compounds of formula I is added. This mixture contains 40 mg of the compound of formula I as defined in Example 19 and 40 mg of the compound of formula I -CH- group, R₁ ethyl and n = 1. i ^K 3

Example 22 (test)

Groups of rabbits weaned at 4 weeks of age are fed with the food described in Example 18. Group 20 rabbits were naturally infected with coccidia oocysts. For the purposes of the reference experiment, the group of rabbits (R) was fed a diet containing no anticoccidial agent, the group F was fed a rabbit diet containing 100 mg furazolidone per kg.

The test lasted 8 weeks.

The test results show that the number of coccidia oocysts decreases by 90 to 100% in the feces of rabbits fed an ionophoric antibiotic-containing compound and a compound of formula I, whereas in the R and F groups the reduction was zero, i.e. the infection did not decrease.

In all the groups fed the food described in Example 18, the composition of which corresponds to the present invention, the food utilization is improved by 5 to 10% compared to the groups R and F.

No differences between groups were observed for weight gains.

Example 23

The procedure of Example 18 is followed, but the compound of formula I is used wherein R 1 is phenyl instead of methyl.

Example 24

The procedure of Example 18 is followed, but the compound of formula I is used wherein R 1 is aminophenyl instead of methyl.

Example 25

The procedure of Example 18 is followed, but the compound of formula I is used wherein R ^ is benzyl instead of methyl.

Example 26

The procedure of Example 18 is followed, but the compound of formula I is used wherein R R is nitroaminophenyl instead of methyl.

Example 27

The procedure of Example 18 is followed, but the compound of Formula I is used wherein dinitroaminophenyl is used instead of methyl.

Example 28

The procedure of Example 18 is followed, but the compound of formula I is used wherein R 1 is fluoroalkoxydinitrophenyl instead of methyl.

Example 29

The procedure of Example 18 is followed, but the compound of formula I wherein R 6 is -C- is used.

O

CS 276 344 B5

Example 30

The procedure of Example 18 but use a compound of formula I wherein R ₂ represents a -NH- group.

PATENT CLAIMS

Claims (4)

A feed premix comprising conventional premix components such as vitamins, inorganic substances and microelements, further comprising at least 5 mg of an ionophore antibiotic, for example monensin, narasin or salinomycin, and 10 to 130 mg of at least one compound (I) wherein R | is hydrogen, G ^ alkyl, nitro, CF j, ^ OCF, OCF-CF ₂ 0CF J or _CHF2, -C- or -NH-, R _o is -CH ² 1 R, R 1 is hydrogen or C 1-6 alkyl and n is an integer of 1 to 3; based on 1000 g of food to which the premix is added. Second feed premixes according to claim 1, characterized in that the compound of Formula I comprises a compound of formula IA, (IA) wherein R, R ₂ and R 1 have the meaning given point. A feed premix according to claim 1, characterized in that it contains at least 10 mg of an ionophore antibiotic and 10 to 130 mg of at least one compound of formula I, wherein R 1 is hydrogen or C 1-6 alkyl, R ₂ is -CH-, R 1 is hydrogen or methyl and n is 1, 2 or 3. ' K-z CS 276 344 B5 A feed premix according to claim 3, characterized in that it contains at least 10 mg of an ionic antibiotic and 10 to 130 mg of at least one compound of the general formula I, wherein R R, R ^ and R ^ are as defined in point 3 and n is 2. .