BE581423A - - Google Patents

Description

       

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 if Ccî: i ':, Sï'ITü! 3S TIS2RÀPEüI 5E5 JI iL.L3A3LE3 i ::,.; : .ED2CI: I VET2 :: lINA: 1.S ".
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  Priority of a patent application filed in;, Ats-inis of America, August 12, 1958 under No. 754,535 in the name of Joseph John URSPRUNG

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The present invention relates to therapeutic compositions which can be used in veterinary medicine.



  More particularly, it relates to therapeutic compositions which are suitable, in particular, for the treatment of a well-known disease of poultry, namely coccidiosis.



   Coccidiosis is a particularly insidious problem in poultry farming. This disease occurs
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 characterized by infection with protozoan dts which are found in the digestive tract, especially in the intestines of young animals usually 2-14 weeks old. The disease, which is characterized by intestinal disorders, anemia, haemorrhages, etc., causes considerable destruction of poultry and leads to significant economic losses.



   Of the two generally recognized types of coccidiosis, the first, namely cecal cocciaiosis, is caused by the coccidium Eimeria tenella, and the second type, namely intestinal coccidiosis, by the coccidii, E. acervulina,
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 E. nectatrix, C. maxima, E. hagani, 2Î. = .. itis, 2. Draecox, and E. brunetti. These two types are reconsidered to be; ps acute coccidiosis "and" chronic coccidiosis ".



   It was found, surprisingly, that an ae triazine derivative of the following formula:
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 which can be qualified as "3,5-aic4to-2,3) 4) 5-ttratYQJ-1) - 4-triazine", when it is administered by the oral route,

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 at low doses, is very effective in combating coccidiosis in poultry. The agent in question can be used
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 both for the cause of infection of coccidiosis and for the prevention of this infection in poultry.



   The agent of the present invention can be administered by mouth to poultry in a suitable vehicle or carrier. It is generally advantageous and, therefore, preferred to add the agent to the feed given to the poultry, so that a therapeutic dose of the agent is absorbed with the daily ration of the animals.

   The agent can be added directly to the food itself or under the
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 in the form of a pre-mix or a concentrate. A pre- or concentrate of the therapeutic agent in a vehicle is commonly used for adding the agent to food.
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 As suitable vehicles, which can be liquid or solid, water, various flour, nta: -¯Te: t soybean oil flour, this flour can be used .- :. >? s, cottonseed flour, sunflower seed flour, linseed oil flour, corn on the cob flour, as well as mixtures of minerals which
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 are co,%, nun4-rr-ent used in food for the living.

   A particularly effective carrier or vehicle is the feed itself of the poultry, that is to say a small proportion of the feed administered to the poultry. The carrier or vehicle facilitates a uniform distribution of the active ingredients in the finished food in which the premix is incorporated. This
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 a is important, because qa'ou = â requires only a small amount of the active agent. It is important that the triazine compound is = ¯µianged uniformly in the pre-mebge and,, 3vi.ï1J3Cle ..!. ^. Nt,: ... ns the feed.

   In this regard, the triazine compound can
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 be disoriented or dissolved in a suitable oily vehicle, such as soybean oil, Dais oil, cottonseed oil. -l.:1al');ues, or ::., cc;:, s c.a-t.5 an organic solvent vol- latil, after which it is mixed with the vehicle or carrier.

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   It will be understood that the proportions of actively contained in the concentrate can vary widely, the amount of active compound present in the feed can be adjusted by incorporating into this feed the desired proportion of premix, to obtain a desired percentage of the feed. therapeutic agent.



   High activity concentrates can be mixed by the poultry feed manufacturer with protein carriers or carriers, such as soybean meal or other flour, to produce concentrated supplements which can be administered directly to poultry.



  In these cases, the poultry are left to console their food - usual diet. These concentrated supplements can also be added directly to the poultry feed, in order to produce a nutritionally balanced feed containing a therapeutically effective dose of the triazine compound according to the present invention.

   The blends are thoroughly kneaded, using standard procedures or methods, noted in jacketed kneaders to ensure homogeneity. The feed for poultry should contain about 50 to 80 oatmeal. about 0-10% animal protein, about 5-30 vegetable protein, about 2-4% mineral salts, as well as additional vitamin sources.



   The triazine compound according to the invention can be used in sensiblment low doses in food, for the prevention or the treatment of coccidiosis. In general, the food compositions of the present invention comprise a minor proportion of the triazin compound and a major proportion of a nutritionally balanced food, as described above. Food compositions containing only 0.01% by weight of the triazine compound in question have been found to be effective in combating coccidiosis.

   Higher amounts, for example up to 0.1; by weight and more, of said compound may

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 also be employed. Of course, concentrations of less than 0.01% by weight of the triazine compound provide some control of the infactio.



     Since 3.5-diketo-2,3,4,5-tetrahydro-
1,2,4-triazine is acidic in nature, metal salts can be prepared therefrom. These salts can also be used in the food compositions and the food supplements according to the invention. The salts of the alkali metals and alkaline earth metals are particularly effective, which have appreciable solubility in water and can be administered to poultry, in solution in abrea water.



   For this purpose, water containing 3.1 to 1.0 by weight of the active agent can be used. Appropriate alkali metal salts include, among others, sodium, potassium and lithium salts. As salts of alkaline earth metals which can be used, there may be mentioned the barium, calcium and strontium salts. salts are readily prepared by methods well known in the art.



   In general, it is preferred to employ from 0.01% to about
0.1% by weight of the active compounds in the food compositions. The use of larger amounts, although possible, is not preferred because it does not result in appreciable advantages.



   Of course, the feed compositions and feed supplements may also contain other useful therapeutic agents, including antibiotics, to promote the growth and health of poultry.



  The compositions and supplements in question can also contain sulfonamide compounds, which can increase the effectiveness of the triazine compounds according to the invention.



   The therapeutic agent according to the invention can be prepared by a number of methods described in the chemical literature, for example by the method described in J. Am. Chem. Soc. $ 80.97 (1958), which describes the preparation

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   @ isotopic of the present process. It is obviously not envisaged that the compound in question should contain its carbon isptopes; it is only indicated that this synthesis can be applied. Other references to the synthesis of this compound are :. J. Am.



  Chem. Soc. 78, 1258 (1950) and ibidem, 78, 1938 (1950)
The following examples are given by way of illustration and should not be considered as limiting the scope of the invention, many modifications being able to be made to these examples without departing from the scope of the invention EXAMPLE
A typical poultry feed is prepared with the following composition:

   
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<tb>%
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> But <SEP> yellow <SEP> ground <SEP> 51,28
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Flour <SEP> oil <SEP> from <SEP> seeds <SEP> from <SEP> self <SEP> a <SEP> (51%) <SEP> 38.15
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Oil <SEP> of <SEP> but <SEP> o, 10
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> CaCO3 <SEP> 1.20
<tb>
<tb>
<tb>
<tb>
<tb> Dicalcium <SEP> Phosphate <SEP> 1.35
<tb>
<tb>
<tb>
<tb>
<tb> Salt <SEP> 0.61
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Delmix <SEP> (mixture <SEP> of <SEP> minerals <SEP> commercial <SEP> containing <SEP> 0.1
<tb>
<tb>
<tb>
<tb> of <SEP> CaC03 <SEP> and <SEP> of <SEP> small <SEP> quantities <SEP> of <SEP> salts
<tb>
<tb>
<tb>
<tb> of <SEP> iron, <SEP> zinc, <SEP> manganese, <SEP> etc, <SEP> Limestone
<tb>
<tb>
<tb> Products <SEP> Corporation <SEP> of <SEP> America,

   <SEP> New
<tb>
<tb>
<tb> Jersey)
<tb>
<tb>
<tb>
<tb>
<tb> Vitamin <SEP> A <SEP> (5305 <SEP> UI / lbs) <SEP> 0.1
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Vitamin <SEP> D3 <SEP> (681 <SEP> UIC / lb) <SEP> 0.05
<tb>
<tb>
<tb>
<tb>
<tb> Klotogen <SEP> F <SEP> (commercial <SEP> form <SEP> of <SEP> vitamin <SEP> K- <SEP> 0.0003
<tb>
<tb>
<tb> Abbott <SEP> Laboratories)
<tb>
<tb>
<tb>
<tb>
<tb> <SEP> pyridoxine hydrochloride <SEP> <SEP> 0.0006
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> D, <SEP> L-methionine <SEP> 0.140
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Niacin <SEP> USP <SEP> 0.0025
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Choline <SEP> of <SEP> Choline <SEP> (25) <SEP> 0.2
<tb>
<tb>
<tb>
<tb>
<tb> Riboflavin <SEP> 0.06
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Panthothenate <SEP> of <SEP> calcium <SEP> (45%) <SEP> 0,

  002
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Myvamix <SEP> (commercial <SEP> form <SEP> of <SEP> vitamin <SEP> E) <SEP> 0.05
<tb>
 

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 Various proportions of 3,5-diketo, 3, t, 5-tetrazzy-dro-1,2,4-triazine were first premixed with a portion of this food composition, then mixed with all the com. - position, so as to obtain food containing respec-
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 tively O, Olio, 0.025ià, 0.05, 0, 'D75-1-1 and 0.1 by weight of the active agent.



   Eight day old chickens are urilized in the following tests. The chickens are inoculated by mouth with E tenella, after receiving the auditioned feed composition of the drug for 24 hours. A control group of animals in identical numbers is also inoculated, but the animals in this group are given normal food free of drugs. The results of the tests are given in the following table.
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<tb>



  Agent% <SEP> Number <SEP> of% <SEP> of <SEP> mortality <SEP> Index <SEP> of <SEP> lsion
<tb>
<tb>
<tb>
<tb> in <SEP> the feed <SEP> chickens <SEP> animals <SEP> Control <SEP> animals <SEP> Control
<tb>
<tb>
<tb> treated <SEP> animals <SEP> treated <SEP> animals
<tb>
<tb>
<tb> infected <SEP> infected
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.1 <SEP> 20 <SEP> 0 <SEP> 70 <SEP> 1.2 <SEP> 3.7
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 20 <SEP> 0 <SEP> 80 <SEP> 1.1 <SEP> 3.8
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 20 <SEP> 0 <SEP> 30 <SEP> 0.9 <SEP> 3.3
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.075 <SEP> 20 <SEP> 0 <SEP> 30 <SEP> 0.9 <SEP> 3.3
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.05 <SEP> 20 <SEP> 0 <SEP> 80 <SEP> 1.3 <SEP> 3.8
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 20 <SEP> 0 <SEP> 40 <SEP> 1,6 <SEP> 3,

  4
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 20 <SEP> 0 <SEP> 30 <SEP> 1.5 <SEP> 3.3
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.025 <SEP> 20 <SEP> 0 <SEP> 30 <SEP> 1.8 <SEP> 3.3
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 20 <SEP> 0 <SEP> 60 <SEP> 1.5 <SEP> 3.6
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.01 <SEP> 20 <SEP> 20 <SEP> 80 <SEP> 3.0 <SEP> 3.8
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 20 <SEP> 15 <SEP> 40 <SEP> 3.0 <SEP> 3.4
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 20 <SEP> 10 <SEP> 30 <SEP> 2.9 <SEP> 3.3
<tb>
 Legend lesion index: 4- death
3 = severe infection
2 = moderate infection
1 = mild infection

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 The indices of lesions are determined by sacrificing
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 putting the chickens alive after eight days and examining the c = u-.1 a 'microscope.

   It has been found that the therapeutic agent according to the invention combats, in a similar manner, d, W. ¯ ¯) r. -13.: 3 .a coccidium.



   EXAMPLE II
The procedure of Example I is repeated, using the following compositions instead of that described:
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<tb>%
<tb>
<tb> But <SEP> yellow <SEP> 71.9
<tb>
 
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 Flour de, r.; Iaes de soa (45 ,.) -, Q
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<tb> Salt <SEP> iodized <SEP> 0.5
<tb>
<tb> phosphate <SEP> dicalcium <SEP> 0.5
<tb>
<tb> CaCO3 <SEP> 1.1
<tb>
 
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 f, V4'Jttiml1ie-1> mixture of vitamins o, 5
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<tb> Mixture <SEP> of <SEP> mineral <SEP> salts <SEP> in <SEP> traces <SEP> 0.5
<tb>
 
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 The vitamin premix contained: Vitamin A (23..0 "0 IU; Vitamin D (ôa? 050 U. r}; Ji ta.:.ine 312 (1.2 mg); ri '00 - flavin (3C mg ); pantothenic acid (4CJ mg) with sufficient load to make one pound.

   The i41 a: z; e of trace mineral salts contained the following proportions:
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 FeS04 3.0 g% 1 of mixture Cu304 0.5 é / 1 ?? g CoC12 0, S g / lv g l'mîü 5,0 g / 100 g n co 9, O g / l 9 g
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<tb> ZnCO3 <SEP> 9,0g / 100 <SEP> g
<tb>
 Equivalent results are obtained.



   EXAMPLE III
The procedure of Example I is repeated using the sodium salt, the potassium salt and the sodium salt.
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 lithium 3,5-diketo-2,3,., 5-tetrahydrJ-l,?,: - triazim respectively to the liëu of the compound itself. We get
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 r ": 50.1 :." t comparable.

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  EXAMPLE IV.
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 The sodium salt of 3,5-diketo-3,;,., 5¯t.trahydro-1,2,4-tiazine is prepared by dissolving the compound in an aqueous solution containing an equivalent amount. of sodium hydroxide. By concentrating the resulting solution, the desired sodium salt is obtained.



   By applying this general procedure, the potassium and lithium salts of the compound in question are similarly prepared, as well as the barium, calcium and strontium salts from the respective hydroxides.



   The barium, calcium and strontium salts of the compound are used in the procedure of Example I instead of 3,5-diketo-2,3,4,5-tetrahydro-1,2,4-triazine. with comparable results.
 EMI9.2
 REVENtV1) ICATIOrS.



   1.- Food supplement, containing as the main active ingredient 3,5-diketo-2,3,4,5-tetrahydro-1,2,4-triazine or an alkali metal or alkaline earth metal salt of this compound.


    

Claims (1)

2. A food composition for poultry, containing the active ingredient indicated in claim 1 and a suitable load for this ingredient. 3. A composition according to claim 2 containing aes nutritionally balanced amounts of carbohydrates, protein, vitamins and minerals, as well as one of the compounds indicated in claim 1. 4. A composition according to either of claims 2 and 3 comprising grain, animal protein, vegetable protein, vitamins and minerals, and a compound according to claim 1. . 5.- Composition according to one or the other of the claims EMI9.3 tions 2 to 4, comprising a minor proportion of a substance according to claim 1 and a major proportion of a common food composition containing about 50 to 80% <Desc / Clms Page number 10> grain, about 0 to 10,., animal protein, -nvuron 5 to 30% vegetable protein, about 2 to 4% minerals, as well as sources of additional vitamins. 6.- Composition according to one or the other of claims 2 to 5, consisting of / a common food composition containing grains, vegetable proteins, animal proteins, vitamins and minerals, this composition containing at least minus 0.01% by weight, based on the composition, of a compound according to claim 1. 7. - Supplement for feed and feed composition for poultry, in substance, as described in the examples. 8.- Process for preparing a composition for feeding poultry, characterized in that a compound selected from the group comprising 3,5-diketo-2,3,4,5-tetrahudro-1,2,4- is incorporated. triazine and the alkali and alkaline earth metal salts of this compound in a suitable carrier or vehicle. 9. The method of claim 8, wherein the carrier or vehicle comprises nutritionally balanced amounts of carbohydrates, proteins, vitamins and minerals. 10. A method according to claim 8, wherein the carrier or vehicle contains grains, animal proteins, vegetable proteins, vitamins and minerals. 11. A method according to claim 8, wherein the triazine compound is present in a minor proportion and the vehicle or carrier contains 50 to 80 cc, C to 10%, animal protein, 5 to 30% vegetable protein, 2 to 4.- mineral matter, as well as supplemental vitamin sources. <Desc / Clms Page number 11> 12. - A method according to any of claims 8 to II, wherein the composition contains at least 0.01 of the triazine compound. 13.- Process for combating coccidiosis in poultry, characterized in that a compound selected from the group comprising 3,5-diketo-2,3,4,5-tetrahydro-1,2 is administered thereto. , 4-triazine as well as the alkali and alkaline earth metal salts of this compound, in a vehicle or support therefor.