BE569663A - - Google Patents

Description

       

   <Desc / Clms Page number 1>
 



   The present invention relates generally to the prevention and treatment of coccidiosis. More particularly, it relates to imidazole compounds which are effective in combating coccidiosis. More
 EMI1.1
 particularly still, it relates to the 4) 5 * imidazoldioarboxamide and certain of its derivatives, as well as new composiQEop6icontaining these substances.



   Coccidiosis is a common and widespread disease of poultry, which is caused by various species of protozoan parasites of the genus Eimeria
 EMI1.2
 such as ¯E. tenella., ',, ¯E. necatrix, E. acervulina, 13. maxima 3, hagani and ¯E. brunet- ti. E. tenella is the causative agent of a serious and often fatal infection of the oecum of chickens, manifested by severe and prolonged hemorrhage, accumulation of blood in the cecum and passage of blood in the urine. E. neoatrix attacks the small intestine of chickens and causes the disease called
 EMI1.3
 "intestinal coccidiosis". Related species of ooocidia, such as ¯E. meleagridis and ¯E. adenoides are microorganisms causing coccidiosis in turkeys.

   When left untreated, $: far1fnem.érè; r: es cie co.oo: ni # e. "Leads to poor weight gain, reduced feed efficiency, and high mortality of Poultry The elimination or control of this disease is, therefore, a factor of great importance to the poultry industry.
 EMI1.4
 



  It has now been found that 4,5 - smidazol-dicarboxamide, 1-ethyl- .4,5-imidazoldicarboxamide and 1-methyl-4, µ-imiàzoldicarboxamide, as well as some of their acylates are very active against protozoa. to which coccidiosis is due. As described in more detail later in this specification, the development of coccidiosis is prevented when small amounts of these substances are administered to poultry. The present invention therefore relates to a novel method for preventing and treating coccidiosis. A further subject of the invention is novel compositions which, when added to animal feed, are extremely effective in preventing coccidiosis.



  The invention also relates to animal feeds containing certain imidàzoldioarboxamidiques compounds. The subject of the invention is also novel compounds.
 EMI1.5
 ', sweats which constitute very powerful coccidiostatic agents. Other subjects will emerge from the following detailed description of the invention.



  4) 5 "imidazoldioarboxamide has the following structural formula:
 EMI1.6
 
This compound constitutes a high melting point solid material exhibiting limited solubility in water. In accordance with the present invention,
 EMI1.7
 it has been found that 4,5-imidazoldicarboxamide itself constitutes a very potent coccidiostatic agent, which can be used successfully to prevent or treat coccidiosis, when administered to poultry. He also
 EMI1.8
 It has been found that 1-ethyl-4y5-imidazoldicarboxemide and 1-methyl-45-im.- dazoldicarboxamide are also very active coccidiostatic agents, which can be used to prevent or treat this disease.

   It has also been discovered that certain lower mono- and di-acyl derivatives of these imidazoldicar-
 EMI1.9
 boxamides..oonstituent powerful coscidiostatic agents. These compounds are advantageously administered to poultry, as an ingredient in the feed supplied to animals, although they can also be administered in solution or in solution.

 <Desc / Clms Page number 2>

 suspension in the drinking water, when the properties of the substance allow it. According to a preferred embodiment of the invention, the latter relates to new compositions for the treatment of coccidiosis, in which these imidazoldicarboxamides constitute the active ingredient. In these compositions, the imidazoldicarboxamides are dispersed or intimately mixed with a diluent or an inert vehicle.

   As diluent or inert vehicle, a vehicle is used which is non-reactive with respect to 4,5-imidazolidicarboxamides and which can be administered without danger to the animals to be treated. The carrier or diluent is preferably a carrier or diluent constituting or capable of constituting an ingredient in the feed for the animal.



   The preferred compositions according to the present invention are feed supplements, in which the active ingredient is present in relatively large amounts and which are suitable for addition to poultry feed, either directly or after a mixing or mixing stage. intermediate dilution.

   As examples of vehicles or diluents suitable for such compositions, mention may be made of ingredients used in animal feed, such as dried still grains, corn flour, citrus flour, residues of corn. fermentation, crushed oyster shells, at-tapulgus clay, wheat bran, soluble molasses products, corn husk flour, edible vegetable substances, roasted decoded soybean flour, soybean meal, antibiotic mycelia, soybean groats, crushed limestone and the like. The 4,5-imidazolidcarboxamides are intimately dispersed or mixed with the solid inert vehicle, by methods such as grinding, stirring, kneading or the like.

   By properly selecting diluents and varying the ratio of vehicle to active ingredient, compositions of any desired concentration can be prepared.



  Compositions containing from about 1% to about 40% by weight and preferably from 2 to 25% by weight of active ingredient are particularly suitable for addition to poultry feed. Compositions containing about 2.5 to 10% by weight oocoidiostatic agent are very satisfactory. The active compound is ordinarily dispersed or evenly mixed in the diluent, but in some cases it can be sorbed onto the vehicle. The optimum concentration of coccidiostatic agent in said food supplements depends to some extent on the particular 4,5-imidazoldicarboxamide employed.

   Since it is convenient for the feed manufacturer to use about 1 English pound of feed supplement for each tonne of finished feed, the preferred concentration of either of the coccidiostatic agents according to the invention in a food supplement is a function, among other things, of the content of the desired active ingredient in the finished food.



   Among the imidazolidicarboxamidic compounds according to the invention, which prevent or serve to combat coccidiosis, it is preferred to use 4,5-imidazolidacrboxamide or 1-ethyl-4,5-imidazoldicarboxamide, because these substances fight coccidiosis, when they are supplied in very low doses in the diet of the animal. With 4,5-imidazoldicarboxamide, good results are obtained by administering the compound to chickens in an amount corresponding to about 0.0005% to 0.02% by weight of the feed consumed daily. For optimum results, it is preferred to administer from about 0.00075% to 0.0075% by weight of the food consumed.

   Higher or lower amounts of the substance can of course be administered, depending on the particular circumstances present.



   4,5-Imidazoldicarboxamide and 1-methyl-4,5-imidazolidicarboxamide can be prepared as described in example 3 given below. For the treatment of poultry, compositions of these substances in a vehicle or diluent are uniformly dispersed in the animal feed.



  Typical examples of animal feed supplements containing 4,5-imidazoldicarboxamide intimately dispersed in the feed are as follows:

 <Desc / Clms Page number 3>

 
 EMI3.1
 Ae q. 5-zmzdazoldicarboxamid8 e .. e a e. e. s ..... er ..5f English pounds dried grain from still .............. 95.0 "" 3. 4f5-imidazoldicarboxamideeaee.s..vee ..... ..ÜlQ ground oyster shells ................ 75.0 fi Il Mycelia d'antlblGltiquesl9f!? E! 9! E! Flefeee.!) 5! It "0. 4,5-imidazoldicarboxamide ................... 2,5" "wheat bran (30-80 meshes) ........ ........ f69.0 "soluble dried vitamin fermentation products JJ,, .t1 ........ eeseeee ...... e .. ev. j f, 37! 5 "" 11 D.

   Q.r imldazolGdicarboxamide. e e .. e. e .. e .. o e ..! e 5! English pounds citrus flour ........................... 95) 0 ft It E. 4imidazoldicarboxamideoe .... ss ...,. e ... 'r'f "' t corn flour ............................. 75: 0 Il Il P. 45-lmidaZOldicarboxamideeeee..sss.e ... eese. '"Still dried corn kernels ...... 99) 0" G. t. 5-im.dazoldicarboxamide eoeoe. See ... e .. s ... f 5 He "
 EMI3.2
 
<tb> <SEP> corn flour <SEP> ............................. <SEP> 92.5 <SEP> "<SEP>"
<tb>
<tb> H. <SEP> 4,5-imidazoldicarboxamide .................. 40,0 <SEP> "<SEP>"
<tb>
 
 EMI3.3
 üialSoo.essv..ss..eeow.e ... wee.e6 "I.

   4y5-imiclazoldicarboxamide.eotoootboèùoooooo ** Q95 ""
 EMI3.4
 
<tb> grains <SEP> from <SEP> but dried <SEP> <SEP> from <SEP> still ...... 99.5 <SEP> "
<tb>
 
To prepare these food supplements and other similar supplements, the active ingredient is added to the vehicle and the whole is mixed for a sufficient time so that the coccidiostatic agent is dispersed substantially uniformly throughout the body. vehicle.



   The invention also relates to the novel compound which is 1-lehyl-4,5-
 EMI3.5
 imidazol, dicarboxamide. This substance, which is also very effective in preventing ooccidiosis, can be prepared from 4.5 "methyl i! Nidazoldicarboxylate, by treating the latter compound with sodium lower alkoxide and with ethyl iodide in an alcoholic solvent at an elevated temperature.



  The 1-ethyl compound thus obtained is treated with an excess of aqueous ammonia, so as to form the diamide. Food supplements consisting of 1-ethyl-4,5-imidazoldicarboxamide intimately mixed with an inert vehicle are prepared from the
 EMI3.6
 as described above - for 4-j5-imidazoldicarboxamide, as illustrative examples of such supplements, the following may be mentioned:

     
 EMI3.7
 A. 1-ethyl- °! 5-imidazoldicarboxamidee ... e. 7.5 British pounds distiller's dried grain .......... 92.5 "B. 1-ethyl- °, 5-imidazoldicarboxamide..e .... 5.0"
 EMI3.8
 
<tb> flour <SEP> from <SEP> soya <SEP> seeds <SEP> .............. <SEP> 50.0 <SEP> "
<tb>
<tb> oatmeal <SEP> end <SEP> of <SEP> soybean <SEP> (containing <SEP> of <SEP> the
<tb>
<tb> lecithin) ...... ***. * ............. * .... 45.0 <SEP> "<SEP>"
<tb>
 
 EMI3.9
 C. 1-ethyl-4, 5-imiàazolàicarboxamiàe * o, * .. 1 0.0 "soluble products of molasses * oooe * ooe9QeO" "1-ethyl-Q., 5-imidazolaicarboxamide, ..... 15, 0 "distiller's corn kernels ......... 55.0" "corn germ flour ............... 30.0" "E.

   1-ethyl- °, 5-imidazoldicarboxamideeo..se 2,5 "4, 5-imiàazolàicaiboxamiàe * o ....... ***** 5) 0" "sound of blBo.s .... ew .em .e.ee..eo.ss4., tI If
 EMI3.10
 
<tb> grains <SEP> dried <SEP> from <SEP> still .......... 50.0 <SEP> "
<tb>
 

 <Desc / Clms Page number 4>

 
 EMI4.1
 F. 1-ethyl-74,5-imidazoldicarboxamide ....... 25.0 UK pounds. grain of dried corn from distillate ... 75.0 111 il G. 1-ethyl-4,5-imidazoldioarboxamide ... oo.40.0 "te
 EMI4.2
 
<tb> <SEP> corn flour <SEP> ......................... <SEP> 60.0 <SEP> "<SEP> "
<tb>
 
Supplements are ordinarily prepared by grinding, grinding or mechanical kneading of the ingredients, in order to ensure good distribution of the active compound, although other techniques, such as spraying, can be employed, if desired.



   For best results, when used as a prophylactic agent to combat coccidiosis in chickens, it is administered
 EMI4.3
 poultry 1-ethyl- °, 5-imidazoldicaboxamide from about 0.003% to about 0.015% by weight of the daily feed. Favorable results are obtained when about 0.002% to 0.025% of the compound by weight based on the feed consumed is administered.



  To fight severe infections somewhat higher doses of 1-.
 EMI4.4
 ethyl- °, 5-imidazoldicarboxam3de can be used.



  It has been found, moreover, that 1-methyl-4,> imiàazolaicarboxamiàe is effective in combating coccidiosis infections in chickens, when administered at doses of between approximately 0.01% and 0.05% and, preferably, at doses of 0.015% to 0.04% by weight relative to the amount of food consumed daily. For the treatment of coccidiosis, compositions containing the 1-methyl compound uniformly dispersed in one or more inert vehicles are prepared and the resulting supplements are then mixed with the poultry feed so that the latter exhibits the desired content of active compound.



   As illustrative examples of food supplements containing the 1-methyl compound, the following products may be mentioned:
 EMI4.5
 1-methyl-4> 5-imidazoldicarboxamide-1590 British pounds soluble products of molasses ...... 85.0 B. 1-methyl- ° s 5-imidazoLdicarboxamideQ 25y 0 "grain flour of s0 jaooeoso. O 0 bone '15.0 "" C. 1-methyl- °, 5-imidazoldicarboxamidëe 20.0
 EMI4.6
 
<tb> flour <SEP> of <SEP> sprouts <SEP> of <SEP> but <SEP> dried <SEP> .... <SEP> 3050 <SEP> "
<tb>
<tb> grains <SEP> from <SEP> but <SEP> from <SEP> still ..... 50) 0 <SEP> "<SEP>"
<tb>
 
 EMI4.7
 D. 1-methyl-4? 5'ida.zoldioar'boxamide.10.0 ""
 EMI4.8
 
<tb> <SEP> citrus <SEP> flour ................... 60.0 <SEP> "<SEP>"
<tb> <SEP> soy flour <SEP> ..................... 30.0 <SEP> "<SEP>"
<tb>
 
 EMI4.9
 E.

   1-methyl-q., 5-imidazoldicarbo $ amidee ° 0.0 soy beans ..................... 60.0 "" F. 7.- methyl- °, 5-5.midazoldicarbogamide. 2.5 "mycelia shot of antibioticsooooooooee * o5OyO"
 EMI4.10
 
<tb> stone <SEP> limestone <SEP> crushed ............. 47? <SEP> 5 <SEP> "
<tb>
 It was also discovered that the lower mono- and di-acylated derivatives
 EMI4.11
 eurs of ° 95-imidazoldicarboxamide, 1-ethyl-4e5-imidazoldicarboxamide and 1-methyl-45-imidazoldicarboxamicley o that is to say the compounds in which one or both carbamido radicals are substituted by a lower acyl radical , are active compounds to prevent coccidiosis in poultry.



  It is assumed that the new di-acyl compounds have the following structural formula:

 <Desc / Clms Page number 5>

 
 EMI5.1
 in which R denotes hydrogen or a methyl or ethyl radical and R 'denotes a lower alkyl radical, such as methyl, ethyl or propyl.



   These di-acyl compounds are prepared from the corresponding imidazoldicarboxamides by treating the latter with a lower aliphatic acid anhydride, such as acetic or propionic anhydride at elevated temperature. Optimum results are obtained when the acylation reaction takes place under relatively mild conditions. Thus, it is neither necessary nor desirable to employ any of the common acylation catalysts, such as puridine, nor is it desirable to heat the reaction mixture for long periods of time. periods.
 EMI5.2
 



  Monoacylated 4y5-imidazoldicarboxamides are obtained by moderate alkaline hydrolysis of q.5-bis- (N-dialcaxbamyl) -itnidazols. It is preferred to treat these latter compounds with a dilute aqueous alkali metal hydroxide, such as sodium or potassium hydroxide, at room temperature, so as to effect partial hydrolysis. The resulting products may have either of the following structural formulas, depending on which of the two lower acyl radicals is removed during hydrolysis:
 EMI5.3
 in which formulas R denotes hydrogen or a methyl or ethyl radical and R ′ denotes a lower alkyl radical. When R denotes a radical other than hydrogen, two mono-acyl compounds are possible.

   These products are, therefore, referred to herein as 1-ethyl-4 (or 5) -acyl lower carbamyl-5 (or. 4)
 EMI5.4
 -imidazolcarboxamide and 1-methyl-4 (or 5) -acyl lower carbamyl-5 (or 4) - imidazolcarboxamide.



   Food supplements containing mono- and di-acyl derivatives
 EMI5.5
 lower levels of 4,5-imidazoldicarboxamide, 1-methyl-4> 5-imidazoldicarboxamide and 1-ethyl- °, 5-imidazoldicarboxamide are prepared by mixing these derivatives with a suitable vehicle or diluent, as described above in connection with la °, 5-i.midazoldicarbogamide itself.

   As illustrative examples of such food supplements, in which the carrier is a food ingredient, the following may be mentioned:
 EMI5.6
 A. 4s5-bis- (N-acetylcarbamyl) -imidazol. 1090 British pounds. corn kernels, still dried ................... e 8 .0 8 .0 - 0 0 .... 90.0 "" B. 4 , 5-bis- (N-acetyl carbamyl) -imiaazol. 20.0 II "

 <Desc / Clms Page number 6>

 
 EMI6.1
 
<tb> <SEP> citrus <SEP> flour ....................... 40.0 <SEP> English <SEP> pounds.
<tb>
<tb> <SEP> crushed oyster shells <SEP> ............ 40.0 <SEP> "<SEP>" <SEP> "
<tb>
 
 EMI6.2
 0. 4-Acethyloarbamyl-4-imidazoloarboxamide 15.0 ";

  ""
 EMI6.3
 
<tb> <SEP> soybean <SEP> oatmeal .......................... 40.0 <SEP> "<SEP>"
<tb>
<tb> <SEP> residues from <SEP> fermentation ................ 45.0 <SEP> "<SEP>"
<tb>
 
 EMI6.4
 D. 1-ethyl-4y 5-bis- (N-acethylcarbamyl) - '.: Imidazol ....... e ... e ................. ..12.5 "" soluble molasses .......... 87.5 "" E. 1-ethyl-4 (or 5) -acethylcarbamyl- 5 (or 4) -imidazolcarboxamide.ee. ee..e ....... r15l0 "" corn flour ......................... 85.0 If F. a- methyl-4,5- (I1-acetethylcarbaznl) -imi-. dazfll. e .. e ..... s, e. o ..... o 0 0, o. e s o e .... 5! 0 11 wheat bran .., ...., e. r, s s .., o a r s, .... s, a 7! 0 If "G. 4! 5-bist (bT-propionylcarbamyl) -imidazo1.40l0" "soybean flour .............. 60.0 fi H. 4! 5- 'bis;

  (N-acethlcarbamyl) -imidazol, .e 5.0 "" wheat bran .................. o .......... 50.0 ""
 EMI6.5
 
<tb> residues <SEP> from <SEP> fermentation ................ ° 5,0 <SEP> "<SEP>"
<tb>
 
The amount of acyl-imidazol required to combat coccidiosis in hens is very low and feed supplements of the type described are obviously further diluted by mixing them with poultry feed, prior to administering the active ingredients to that. -this.

   So
 EMI6.6
 proportions of 45-bia- (N-acgtylcarbamyl) -imidazol and 45-bis- (N-propionylcarbamyl) -imidazol of between approximately 0.002% and approximately 0.025% by weight of the
 EMI6.7
 active ingredient in the diet for chickens are sufficient to combat coccidiosis, although for optimum results it is preferred to employ a dose of active ingredient of between about 0.003% and 0.015%.



  When 1-ethyl-4,5-bis- (N-lower acyl carbamyl) -imidazols are employed, such
 EMI6.8
 as 1-ethyl-4,5-bis- (N-acethylcarbamylhimiaazol, as a coccidiostatic agent for poultry, good results are obtained by administering from 0.01% to 0.05
 EMI6.9
 about% of the coccidiostatic agent by weight relative to the feed, optimum results being obtained with doses of about 0.015% to 0.04% by weight of the ration supplied to the animals. Slightly higher doses of active ingredient in the finished feed are desirable for effective control and prevention of coccidi-
 EMI6.10
 ose, when using 1-methyl-4) 5 "imidazoldioarboxamide derivatives.



   Feed supplements of the type illustrated above are usually further diluted with materials, such as cornmeal or soybean meal, before being incorporated into feeds for animal feed. In this intermediate stage, the coccidiostatic agent content of the vehicle or diluent is brought from about 0.1% to about 1.0% by weight.



  This dilution serves to facilitate a uniform distribution of the substance in the finished food. Finished food is food that contains a source of fat, protein, carbohydrate, minerals, vitamins and other nutritional factors.



   In the foregoing description of the invention, emphasis has been placed on solid compositions in which the active ingredient is mixed with a vehicle in a feed supplement, in a premix or in the final feed. for poultry. This constitutes the preferred mode of administration of the imidazols.



  Another method of treatment is to dissolve or suspend the imidazole compounds in the drinking water of the animals. The amount of coccidiostatic agent which can be administered in this way is obviously limited by the solubility of the product in water or by the amount of this product which can be suspended in water without undue deposit. . For the latter purpose, one can use

 <Desc / Clms Page number 7>

 
 EMI7.1
 read emulsifiers or surfactants. The 1-ethyl- °, 5-imidazoldicarboxamide and 1-methyl-4,5-imidazoldicarboxamide are sufficiently soluble in water to make the administration, via the drinking water of the animals, very satisfactory.

   This technique is less suitable with 4,5-imidazoldicarboxamide, because this substance is sparingly soluble in water, although solubilizers can frequently help to increase the solubility of this substance.



   The present invention is not limited to coccidiosta-
 EMI7.2
 ticks containing only one of °, 5-.midazoldicarboxam, des as the active ingredient.



  The invention also encompasses the methods for treating coccidiosis and the compositions used therefor, in which the concomitant administration of
 EMI7.3
 45imidazoldicarboxamide and 1 or more other co-cidiostatic agents.



     For this purpose, it is possible to prepare compositions containing one of the imidazole compounds referred to above mixed with one or more of the other imidazoldicarboxamides and / or with one or more other coccidiostatic agents known previously, such as sulfaquinoxaline, d ' other compounds
 EMI7.4
 sulfa, 4,4'-diritixrnitaàlide complex: 2-hydroxy-4,6-dimethylpyrimidine, 3,3'-dinitrodiphenyldisulfide, arsanilic acid, 3-amino-4-hydroxy-phenylarsonic acid, 5-nitrofurfural semi-carbazon and the like.



   Those skilled in the art will understand that special food supplements containing vitamins, antibiotics, growth promoters and other nutrients may additionally contain the imidazole compounds of the present invention. A typical supplement of this kind is the following:

   
 EMI7.5
 
<tb> Ingredients <SEP> Quantity / pound <SEP> of
<tb>
<tb> supplement
<tb>
<tb> grams
<tb>
<tb>
<tb>
<tb> .Riboflavin ............................................ < MS> 0.64
<tb>
<tb>
<tb> DL <SEP> pantothenate <SEP> of <SEP> calcium .............................. <SEP> 2 , 10
<tb>
 
 EMI7.6
 .Niaoineo.08000..e080800..080808000800 ................. 8 3.67 Choline chloride ....... <, .. 0.0 .... .................... 50.00 vitamin B12 concentrate ....................... ....... 1.30 mg. procaine penicillin ...................................., 0.84 Vitamin A (100,000 u./g ............................... 3.38 Vitamin 1l 3.t (2000000uo / go) oo.oo oo. * ................... o 0.68 acid '1,2'Sé1Y1111 1l8 0 oeeoosoeoeeoseooeowea osmoaeeeveowe.

   18.36 hydroxy toluene butyleeoooooeooosorooeeoneeoe.sw oow sw 23.15 DL-methionineo 0.1) .00000 GO 0 "0 0.000000" o. o ... 0.0 '.......... "23.15 4.5-13ri1da, ZOldicarboxamiU.eoooeooovoeoeseoooeoveoeeeeeya 23.00 grains of dlStl..a, t6urooooeeeoo.eeaeooeooooeeog'pooeoeoe q, x, ad 1 English pound
The following examples are given by way of illustration and not by way of limitation.



   EXAMPLE 1.



  1-ethyl-4,5-imidazoldicarboxamide.



   3.6 g of metallic sodium was dissolved in 900 ml of methanol.
 EMI7.7
 



  27y3 g of q.5-imidazoldicà, dimethyl rboxylate, then 25 g of ethyl iodide was added. The resulting solution was heated at reflux temperature for 16 hours. At the end of this period, the solvents were removed by vacuum distillation and 300 ml of ammoniacal water was added to the residual syrup. This mixture was mixed or stirred occasionally and was allowed to stand at room temperature for about 60 hours.



   After this time, the solid product which had formed was filtered off, washed with a little cold water and air dried. There was thus obtained 17 g of crude product, melting at 215 C.

 <Desc / Clms Page number 8>

 



   The crude product was dissolved. in 850 ml of boiling anhydrous ethanol and the hot solution was filtered through a hot-jacketed Buchner funnel, to remove a small amount of undissolved solid. The slightly cloudy filtrate was filtered again, after being treated with a small amount of activated charcoal, to form a clear solution. The solution was concentrated to a volume of about 2/3, then cooled in an ice bath for 1 hour. The precipitated 1-ethyl-4,5-imidazoldicarboxamide was isolated by filtration and air dried. 12.1 g of compound were obtained; M.p. 215-216 C. Calculated for C7H10O2N4: N = 30.75%; Found: N = 30.89%. 0 2 4
EXAMPLE 2.



   The coccidiostatic activity of 4,5-imidazol-idcarboxemide, 1-ethyl-4,5-imidazoldicarboxamide and 1-methyl-4,5-imidazoldicarboxamide in chickens was determined by the following method;
Groups of 10 chickens 2 to 3 weeks old were fed with a mash containing varying amounts of the compound to be tested. The active compound was dispersed uniformly in the food. After living for 24 hours on this ration, each chicken was inoculated with 50,000 sporulated oocysts of R, tenella.



   Other groups each comprising 10 chickens were fed with a similar mash containing no coccidiostatic agent. These groups of chickens were also infected after 24 hours and served as positive or infected control animals. As positive control animals, 2-4 groups each comprising 10 chickens were employed. In some cases, other groups also comprising 10 chickens were fed with a similar mash free of coccidiostatic agent and were not infected with coccidiosis. These groups of animals served as normal control animals.



   The feed was given to the chickens for 8 days after the date of infection. At the end of this period, infected animals still alive were sacrificed. The number of oocysts was determined by microscopic examination of a homogenized product of cecum.



   The results obtained, using the indicated doses of coccidiostatic compound, are indicated, in the form of average values, in the following Table I:

 <Desc / Clms Page number 9>

   TABLE 1
 EMI9.1
 
<tb> Test <SEP> Compound <SEP>% <SEP> of <SEP> compound <SEP>% <SEP> morta- <SEP> Number <SEP> of <SEP>% <SEP> of <SEP>
<tb>
<tb>
<tb>
<tb>
<tb> N <SEP> in <SEP> ration <SEP> ity <SEP> Oocysts <SEP> gain <SEP> of
<tb>
<tb>
<tb>
<tb>
<tb>. <SEP> x <SEP> 10- <SEP> weight
<tb>
<tb>
<tb>
<tb> in <SEP> ani-
<tb>
<tb>
<tb> ailments <SEP> over-
<tb>
<tb>
<tb>
<tb> alive
<tb>
 
 EMI9.2
 ------------ r ----------- r- '' ----------- r nr --- 11 ----- y1- P1- w -! - vr T ----- T -.

   -ya
 EMI9.3
 
<tb> 1 <SEP> 4,5-imidazoldicarboxamide <SEP> 0.02 <SEP> 0 <SEP> (<SEP> 0.1 <SEP> 77
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.01 <SEP> 0 <SEP> 1.3 <SEP> 80
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.005 <SEP> 0 <SEP> (<SEP> 0.1 <SEP> 70
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.0025 <SEP> 20 <SEP> 1.2 <SEP> 75
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> infected <SEP> - <SEP> 37 <SEP> 10.7 <SEP> 37
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 2 <SEP> 1-ethyl-4,5-imidazoldicar- <SEP> 0.02 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 123
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> boxamide <SEP> 0.01 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 126
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.005 <SEP> 10 <SEP> 15,

  4 <SEP> 120
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Animals <SEP> from <SEP> control <SEP> infected <SEP> - <SEP> 20 <SEP> 13.7 <SEP> 55
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> normal- <SEP> - <SEP> - <SEP> 121
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 3 <SEP> l-ethyl-4,5-imidazoldicarbo- <SEP> 0.02 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 78
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> xamide <SEP> 0.01 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 80
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.005 <SEP> 0 <SEP> 8.4 <SEP> 78
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> - <SEP> 25 <SEP> 10.9 <SEP> 59
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 4 <SEP> l-ethyl-4,5-imidazoldicar- <SEP> 0.02 <SEP> 0 <SEP> (<SEP> 0.1 <SEP> 89
<tb>
<tb>
<tb>
<tb>
<tb> boxamide
<tb>
<tb>
<tb>
<tb> 0.01 <SEP> 0 <SEP> 2,

  0 <SEP> 91
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.005 <SEP> 0 <SEP> 17.5 <SEP> 86
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> infected <SEP> - <SEP> 37 <SEP> 10.7 <SEP> 38
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 5 <SEP> 1-methyl-4,5-imidazoldicar- <SEP> 0.1 <SEP> 0 <SEP> 0.1 <SEP> 50
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> boxamide <SEP> 0.05 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 57
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 0.025 <SEP> 0 <SEP> 1.3 <SEP> 56
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> infected <SEP> - <SEP> 12.5 <SEP> 19.9 <SEP> 43
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> normal- <SEP> - <SEP> 60
<tb>
 
 EMI9.4
 6 1-methyl-4,5-imidazoldicarbo-0.10 (0.1 45
 EMI9.5
 
<tb> xamide
<tb> 0.05 <SEP> 0 <SEP> <<SEP> 0,

  1 <SEP> 61
<tb> 0.025 <SEP> 0 <SEP> 1.6 <SEP> 64
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> infected <SEP> - <SEP> 0 <SEP> 14.9 <SEP> 44
<tb>
 

 <Desc / Clms Page number 10>

   TABLE I.
 EMI10.1
 
<tb>



  Test <SEP> Compound <SEP>% <SEP> of <SEP> compound <SEP>% <SEP> mortality <SEP> Number <SEP> of <SEP>% <SEP> of
<tb>
<tb>
<tb>
<tb>
<tb> N <SEP> in <SEP> ration. <SEP> Oocysts <SEP> gain <SEP> of
<tb>
<tb>
<tb>
<tb>
<tb> x <SEP> 10- <SEP> weight
<tb>
<tb>
<tb> in <SEP> ani-
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> ailments <SEP> over-
<tb>
<tb>
<tb>
<tb>
<tb> alive.
<tb>
 
 EMI10.2
 



  I; mth: 4? 5-izn.dazo7.dicar-
 EMI10.3
 
<tb> boxamide <SEP> 0.02 <SEP> 10 <SEP> 1.6 <SEP> 109
<tb>
<tb> 0.01 <SEP> 20 <SEP> 18 <SEP> 83
<tb>
<tb> 0, <SEP> 005 <SEP> 40 <SEP> 16 <SEP> 73
<tb>
<tb> Animals <SEP> from <SEP> control <SEP> infected <SEP> - <SEP> 20 <SEP> 13.7 <SEP> 55
<tb>
<tb> <SEP> control <SEP> animals <SEP> normal. <SEP> - <SEP> - <SEP> 121
<tb>
 
 EMI10.4
 8 4, 5-.midazoldicarboamide 0.001 0 7, 4 80
 EMI10.5
 
<tb> 0.002 <SEP> 0 <SEP> 3.6 <SEP> 116
<tb>
<tb> 0.004 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 110
<tb>
<tb> 0.008 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 106
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> infected <SEP> - <SEP> 70 <SEP> 8, <SEP> 2 <SEP>.

   <SEP> 21
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> normal <SEP> - <SEP> 0- <SEP> 96
<tb>
 
 EMI10.6
 9 4, 5-imidazol di aanboxamide 0.001 0 22, 2 35
 EMI10.7
 
<tb> 0.002 <SEP> 0 <SEP> 0.5 <SEP> 67
<tb>
<tb>
<tb>
<tb> 0.004 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> @ <SEP> 63
<tb>
<tb>
<tb>
<tb> 0.008 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 64
<tb>
<tb>
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> infected <SEP> - <SEP> 15 <SEP> 35.8 <SEP> 30
<tb>
<tb>
<tb> Animals <SEP> of <SEP> control <SEP> normal- <SEP> 0 <SEP> - <SEP> 60
<tb>
   EXAMPLE 3.
 EMI10.8
 



  (a) 4 5-.midazoldicaxboxamide.



  20 g of dimethyl 5-imidazoldiearboxylate was dissolved in 400 ml of concentrated ammonium hydroxide. After about 30 minutes 4,5-imidazoldioarboxamide started to precipitate. The mixture was allowed to stand at room temperature for about 20 hours. At the end of this period, the product was isolated by filtration and air dried. 16 g of 4,5-imidazoldioarboxamide were obtained, melting at over 360 ° C.
 EMI10.9
 



  (b) 1-methyl- °, 5-imidazoldicarboxamide.



   14 g of sodium were dissolved in 3.4 1 of methanol and to the solution obtained 88.5 g of dimethyl 4,5-imidazoldicarboxylate were added, followed by 100 g of methyl iodide. The solution was heated at reflux temperature for 4 hours, then concentrated in vacuo to about half of its volume. A small amount of activated charcoal was added and the mixture was filtered. Ammonia gas was passed through the filtrate at 0-5 C until the solution was saturated with ammonia. This solution was left to stand at room temperature for 16 hours. During this period, we obtained a
 EMI10.10
 precipitate of 1-methyl-5-imidazoldicarboxamide which was isolated by filtration, washed with cold methanol and air dried.

   There was thus obtained 69.5 g of 1-methyl-4,5-imiàazoldiaarboxamiàe, melting at 270-277 C.



  EXAMPLE 4.



  (a) °, 5-bis- (IÙ-acetylcarbam'1) -imidazol.



  2 grams of 4,5-imidazoldioarboxamide was heated at reflux for 15 hours in a mixture of 100 ml of acetic anhydride and 10 ml of acetic acid. At the end of this period, the heating at reflux was stopped and the light brown reaction mixture was concentrated in vacuo to dryness at

 <Desc / Clms Page number 11>

   100 C. The residue thus obtained was suspended in water and the suspension was allowed to stand at room temperature for about 1 hour, then filtered. In this way, 2 g of crystalline 4,5-bis- (N-acetylcarbamyl) -imidazol were obtained. After recrystallization from methanol or acetic acid, the
 EMI11.1
 material melted at 259-260 ° C. Calculated for Q gH 0 N: 0 = ° 5.38; H = 4.23%; N = 23.53; Bq. neutral: 238.

   Found: C = 45.42 Fi = z26%; N, 23.77%; Bq. neutral: 241.



  The anticocaidiosis activity of 4) 5 "'bis- (N-acetyloarbamyl) -imidazol in chickens was determined by the method described in Example 2. The results are given in the following table:
 EMI11.2
 
<tb>% <SEP> in <SEP> Number <SEP> of <SEP>% <SEP> Mortality <SEP> Oocysts. <SEP>% <SEP> of <SEP> gain <SEP> of <SEP> weight.
<tb>
<tb> ration <SEP> chickens.
<tb>
<tb>
<tb>



  0.004 <SEP> 10 <SEP> 0 <SEP> 6.5 <SEP> 63
<tb>
<tb>
<tb> 0.008 <SEP> 10 <SEP> 0 <SEP> <<SEP> 0.1 <SEP> 72
<tb>
<tb>
<tb> Animals <SEP> of <SEP>
<tb>
<tb> control
<tb>
<tb> infected <SEP> 30 <SEP> 40 <SEP> 9.9 <SEP> 42
<tb>
<tb>
<tb> Animals <SEP> of
<tb>
<tb> control
<tb>
<tb> normal <SEP> 10 <SEP> 0- <SEP> 74
<tb>
 
 EMI11.3
 (b) 4-aaet $ ularbaoeyl-5-imidazolaaiboxamide.



  2.4 g of 4t5'bis- (N-acetyloarbamyl) -imidazol obtained as described above was added to 25 ml of water, after which 10 ml of 1 N sodium hydroxide was added. added, with vigorous stirring, to the resulting suspension.



  The resulting clear solution was left to stand at room temperature for about 60 hours. During this time, a precipitate of 2 g of 4-acetylcarbamyl-5-imidazolcarboxamide was obtained. After recrystallization from methanol, this
 EMI11.4
 product melted at 285 ° C. Calculated for 07H803N4 - 0 = 42.86; H, 4.10%. Found: C, 43.30%; H - 4s 26%.



   This substance prevented coccidiosis and prevented mortality due to coccidiosis in chickens when administered at 0.004% by weight of the diet.



   EXAMPLE 5.
 EMI11.5
 



  1-eth, yl-q., 5-bis- (N-acetylcarbamy.,) Imidazol.



  2 g of 1-ethyl-4,5-imidazoldicarboxamide were heated under reflux for 4 hours in 50 ml of acetic anhydride. At the end of this time, the reaction mixture was concentrated to dryness in vacuo at 100 ° C. and the residue obtained was crystallized from 20 ml of methanol. 1.4 g of 1-ethyl-
 EMI11.6
 4,5-bis- (N-acetylcarbamyl) -imiaazol; M.p. 140 - 142 C. On recrystallization from methanol, the melting point of the obtained 1-ethyl -. S5-bis- (N acetylcarbamyl) -imidazol, increased to 145-146 C.



   The monoacetylated compound was prepared by the procedure described in Example 5.
 EMI11.7
 



  1-methyl-45-bis- (N-acetylcarbamyl) -imidazol and 1.-methyl-4 (or 5) - aoetylcarbamYl-5 (or 4) -imidazolcarboxamide are prepared from 1-methyl- q.s5 -imidazoldicarboxamide by the procedures described in Examples 4a and 4b.



     EXAMPLE 6.
 EMI11.8
 



  4,5-bis- (N-propionylcarbamyl) -imidazol.

 <Desc / Clms Page number 12>

 



  10 g of 4,; - imidazoldioarboxamide were added to 500 ml
 EMI12.1
 anhydridēpropionique and 50 ml of propiohic acid. The resulting mixture was stirred and heated at 125 C for 27 hours. The temperature was then raised to the point of reflux, after which a clear solution formed. The reaction mixture was cooled slowly to 100 C and kept at this.
 EMI12.2
 temperature for 1 hour, so as to crystallize °, 5-bis- (N-propionylc, rba my.-imidazol. The solid material was filtered off, washed with ether and dried. It melted at about 238 C. By recrystallization from ethanol the melting point was raised to 239 - 240 C. Calculated for C11H14N4O4:
 EMI12.3
 C, 49.61%; H, 5930%.

   Found: a C = 49.36%; H, 5.27%.



   Coccidiosis and mortality in chickens were controlled by administering this substance to the animals at a dose of 0.004% by weight of the feed consumed.



    CLAIMS.



   1. A composition for use against coccidiosis, comprising
 EMI12.4
 4,5-Imidazoldioarboxamide intimately dispersed in a feed ingredient.



   2. Composition usable for the prevention and treatment of
 EMI12.5
 coccidiosis, comprising 4,5-imidazoldioarboxamide intimately dispersed in animal feed.



   3. Composition usable against coccidiosis, consisting of an ingredient in animal feed containing, in intimate dispersion, about 0.1 to
 EMI12.6
 about 40% by weight of Q.95-imidazoldicarboxamide.



   4. Composition usable against coccidiosis, consisting of an ingredient in animal feed containing, in intimate dispersion, about
 EMI12.7
 1.0% to about 25% by weight of 4e5-imidazoldicarboxamide.



   5. Composition usable against coccidiosis, consisting of a feed ingredient containing, in intimate dispersion, about 2.5
 EMI12.8
 at 5% by weight of °, 5-imidazoldicarboxamide.



   6. Composition usable against coccidiosis consisting of an animal feed containing, in intimate dispersion, from about 0.0005% to in-
 EMI12.9
 about 0.02% by weight of 45-imidazoldicarbozamide.



   7. Composition usable against coccidiosis, consisting of an animal feed containing, in intimate dispersion, from about 0.00075% to
 EMI12.10
 about 0.0075% by weight of 415-imidazoldicarboxamide.
8. A composition for use against coccidiosis comprising 1 - @@ ethyl-4,5-imidazolcarbodamide intimately dispersed in an animal feed ingredient.



   9. Composition usable for the prevention and treatment of
 EMI12.11
 coccidiosis, comprising 1-ethyl-4e5-imidazoldicarboxamicle in complete dispersion in animal feed.



   10. A composition for use against ooocidiosis, consisting of an ingredient in animal feed containing, in intimate dispersion, about,
 EMI12.12
 0.1% to about 40% by weight of 1-ethyl-4,5-imidazoldicanboxamide.



   11. Composition usable against coooidiosis, consisting of an ingredient in animal feed, containing, in intimate dispersion, 1.0%
 EMI12.13
 to about 25% by weight of 1-ethyl- °, 5-imidazold, carboxamide.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

12. Composition usable against coccidiosis, consisting of an ingredient of animal feed containing, in intimate dispersion, about 5% by EMI12.14 weight âë 1-e: J; y1-4, '5':. ': i1ftidazoldicarl: Mxamide. <Desc / Clms Page number 13> 13. Composition usable against coccidiosis, consisting of an animal feed containing, in intimate dispersion, from about 0.002% to about EMI13.1 0.025% by weight of 1-ethyl-4j5-imidazoldicarboxamide. 14. Composition for use against coccidiosis $ comprising 1-methyl- ° 5.-imid, zoldicarboxamide in intimate dispersion in an ingredient of animal feed * 15. Composition usable for the prevention and treatment of EMI13.2 cQocidiosis,., comprising 1-methyl-4,5-imidazolaiaaiboxatiàe intimately dispersed in animal feed. 16 / Composition usable against coccidiosis, consisting of a feed ingredient containing, in intimate dispersion, about EMI13.3 1% to about 40% by weight limethyl-í5-imidazoldiaarboxamide. 17. Composition usable against coccidiosis, consisting of an ingredient in animal feed containing, in intimate dispersion, about EMI13.4 About 2.5% by weight of 4-llmethyl> imiàazoleicarboxamiàe. 18. Composition usable against coccidiosis, consisting of a feed ingredient containing, in intimate dispersion, about 10% EMI13.5 by weight of 1-methyl- ° 95-imidazoldicarboxamide. 19. Composition usable against coocidiosis, consisting of an animal feed containing, in intimate dispersion, from about 0.01% to about EMI13.6 0.05% en'pôia-à de.-Metlyl-q., 5-imidazoldicarboxamide. 20. A composition for use against coccidiosis comprising a compound of formula EMI13.7 in intimate dispersion in an animal feed ingredient, R, in the formula given above, denoting hydrogen or a methyl or ethyl radical, while, in this same formula, R 'denotes an alkyl radical inferior. 1 21. A composition for use against coccidiosis, comprising a compound of the formula: EMI13.8 in intimate dispersion in animal feed, R, in the formula given above, denoting hydrogen or a methyl or ethyl radical, while R ', in this same formula, denotes a lower alkyl radical. <Desc / Clms Page number 14> 22. A composition for use against coccidiosis consisting of an animal feed ingredient containing, in intimate dispersion, about 0.1 EMI14.1 % to about 40% by weight of 4,5-bis- (N-acetylaaibamyl) -imiaazol. 23. Composition for use against coccidiosis, consisting of an ingredient in animal feed containing an intimate dispersion of about 2% EMI14.2 to about 25% by weight of 4,> bis- (N-acetylcaibamyl) -imiaazol * 24. Composition usable against coccidiosis, consisting of an animal feed containing, in intimate dispersion, from about 0.002% to about EMI14.3 $ 025% by weight of 4) 5-bis- (N-aoetylcarbamyl) -imidazol. 25. Composition usable against coccidiosis, consisting of a feed containing :, in intimate dispersion, from about 0.002% to about EMI14.4 0.025% by weight of 1, ethyl-4,5-bis- (N-piopionylaaTbamyl) -imiaazol. 26. Composition usable against ooccidiosis, consisting of an animal feed containing, in intimate dispersion, from about 0.01% to about EMI14.5 OyO5% enpo-ir3s of 1-ethyl-4,> bis- (N-aaetylcarbamyl) -imiaazol. @ 27. A composition which can be used against coccidiosis, comprising a compound of formula: EMI14.6 in intimate dispersion in a food ingredient: for animals, @ clans. The formula given above designating hydrogen or a radical 0 "-C-R ', while R denotes hydrogen or a methyl or ethyl radical and R' denotes a lower alkyl radical, at least one Y being hydrogen. 28. A composition for use against coccidiosis., Comprising 4- EMI14.7 aoetyloarbamyl-5-imidazoloarboxamide intimately dispersed in animal feed. 29. A composition for use against coccidiosis, consisting of an ingredient in animal feed containing, in intimate dispersion, about EMI14.8 0.1% to about 40% by weight of 1-ethyl-q. 5-bis- (N-acé tlcaxbamyl -üni .: ol '.