THE TREATMENT AND PREVENTION OF SCOURS IN ANIMALS

Abstract: The husbandry of calves, lambs, foals or adult cattle may be improved by the administration, in order to combat scours, of a compound of the formula: <IMAGE> [wherein either R1 is phenyl, substituted phenyl, aralkyl, pyridyl or substituted pyridyl and R2, R5 and R6 are hydrogen, lower-alkyl, substituted-lower-alkyl, hydroxy, lower-alkoxy, lower-alkenyl, cyclo-lower-alkynyl, cyclo-lower-alkyl, lower-alkynyl, alkyl-sulphonyl or aralkyl-sulphonyl, with R5 and R5 optionally forming a 5 or 6 membered heterocyclic ring which may include 1 or 2 additional hetero atoms; or R5 is as R1 above and R6, R1 and R2 are respectively as R2, R5 and R6 above; and R3 and R4, which may be the same or different, are hydrogen, lower-alkyl, lower-alkoxy, lower-alkenyl, lower-alkynyl, cyclo-lower-alkyl or aralkylBD &uml& or an addition salt thereof. The preferred coumpounds (I) are those wherein R5 is 2,6-disubstituted-phenyl, and especially 1-(2,6-dimethyl-phenyl)-3-methylamidinourea and its hydrochloride salt. The compounds (I) are preferably administered orally or by injection in the form of liquid compositions containing electrolyte; or by incorporation of the compounds (I) in the daily dietary intake of the animals.

Description: —^ * _ " _ _*^ THE TREATMENT AND PREVENTION OF SCOURS IN ANIMALS. Scours, particularly in new-born calves, lambs and foals, is a major cause of death, especially under intensified commercial animal husbandry practices, where the disease accounts for large economic losses. The disease occurs commonly in calves, lambs and foals under ten days of age and is .character-.. . . ized by varying degrees of diarrhoea and dehydration. The disease known as adult bovine scours is also prevalent among wintering adult cattle, again frequently leading to death. The etiology and pathology of scours are not well understood, but it is generally attributed to factors which cause ordinarily harmless intestinal bacteria to proliferate. Regardless of the cause, the result is a net loss of electrolytes and fluids into the intestinal lumen. This loss leads to acidosis and dehydration, which in turn leads to other acute toxic effects. Generally, treatment for this condition involves correction of the acid/base inbalance, rehydration and treatment of intestinal infections, if present. Such treatments may - 2 - include the oral administration of anti¬ bacterial agents and electrolyte solutions. The usual antibacterial agents are anti¬ biotics and sulphonamides. •" •" ■ Despite these treatments, losses from calf scours are perhaps the single most serious economic loss of any disease or condition in cattle. It affects about 10% of the SO,000,000 calves born in the United 0 States each year. It is thought that the infectious .agents responsible for the disease include E. Coli, salmonella, IBE virus (infectious bovine rhinotracheitis) and "Nebraska virus". Ancillary causes such as 5 failure of the calf to obtain sufficient colustrum, stress, contaminated environment and physiologic immaturity all contribute to the problem. E. Coli is general * !.- * ? ' also the cause of 0 outbreaks of neonatal scours in lambs. While the economic losses do not approach that of calf losses, it is still significant to the industry. . Furthermore, young food-producing 5 animals are not the only ones affected by scours. BVD (bovine virus diarrhoea), caused by a myxovirus, and bovine winter dysentary, caused by vibrio "jejuni, are important factors in the cattle industry. 0 It is apparent that neither disease condition can be treated very effectively with drugs presently available, though there are many agents on the market which are used in the treatment of animal scours. Electrolyte solutions, antibiotics, sulphonamides and nitrofύrans make up the great majority. Many contain various binding, coating, absorbing and adsorbing agents and astringents. A few have scopola ine, the only common drug being used to slow peristalsis. Accordingly this invention seeks to provide improved medicaments and procedures for use in the treatment and prevention of animal scours, particularly scours in new born (less than ten days old) calves, lambs and foals, and in wintering adult cattle. In recent years, a variety of amidino- ureas have been shown to be effective anti- diarrhoeal agents in laboratory test animals ., and in humans. Pharmaceutically effective antidiarrhoeal agents such as the a idino- ureas are not known for use in the treatment of scours, particularly in calves and lambs where annual losses due to the disease are high. These compounds have demonstrated their activity in laboratory animals under test conditions designed to mimic gastro- intestinal disorders in humans by inducing symptomatic diarrhoea in the test animals. Such aminidinoureas and their pharmaceutical activity are described in Arzneimittel Forschung (Drug Research) , 28 (II), 1-4-33-1480 (1978). It has nov; been found that these anidino- ureas are particularly effective in reducing morbidity and mortality ratesin calves, lambs and foals suffering from scours, and in _ lx - adult cattle suffering from bovine winter scours, when orally or parenterally administered to such animals in effective amounts. 5 Accordingly, this invention provides a method of treating or preventing scours in calves, lambs, foals or adult cattle, which method comprises administering to calves, lambs, foals or adult cattle an 10 a idinourea, being a compound of the formula: [wherein either R, is phenyl, substituted phenyl (as defined herein), aralkyl, pyridyl or substituted pyridyl (as defined herein), 15 and E , R j - and Eg, which may be the same or different, are hydrogen, lower-alkyl, hydroxy, lower-alkoxy, lower-alkenyl, cyclo- -lower-alkenyl, cyclo-lower-alkyl, aralkyl, lo er-alkynyl, halo-alkyl, hydroxy-lo er- 20 -alkyl, lower-alkoxy-lower-alkyl, cyano- -lower-alkyl, a ino-lower-alkyl, mono- or di-(lower-alkyl)-amino-lower-alkyl, carbamoyl-lower-alkyl, mono- or di-(alkyl)- -carbamoyl-lower-alkyl, lower-alkoxy-carba oyl- 25 -lower-alkyl, aralkoxy-carbamoyl-lower-alkyl, acyl-lower-alkyl, alkyl-sulphonyl or aralkyl- -sulphonyl, or R ? is as just mentioned, and - 5 - E- together with Eg and the nitrogen to which they are both attached form a 5 or 6 membered heterocyclic ring which optionally may include 1 or 2 additional hetero atoms chosen independently from oxygen, nitrogen and sulphur; or E_ is phenyl, substituted phenyl (as defined herein), aralkyl, pyridyl or substituted pyridyl (as defined herein), 10 and R, , E and Eg, which may be the same or different, are hydrogen, lower-alkyl, hydroxy, lower-alkoxy, lower-alkenyl, cyclo- -lower-alkenyl, cyclo-lower-alkyl, aralkyl, lower-alkynyl, halo-alkyl, hydroxy-lower- 15 -alkyl, lower-alkoxy-lower-alkyl, cyano- -lower-alkyl, amino-lower-alkyl, mono- or di-(lower-alkyl)-amino-lower-alkyl, carba oyl- -lower-alkyl, mono- or di-(alkyl)-carba oy1- -lower-alkyl, lower-alkoxy-carbamoyl-lower- 20 -alkyl, aralkoxy-carbamoyl-lower-alkyl, acyl- -lower-alkyl, alkyl-sulphonyl or aralkyl-. -sulphonyl, or E g is as last mentioned and B-, together with R and the nitrogen to which they are both attached form a 5 or 6 2 membered heterocyclic ring which optionally may include 1 or 2 additional hetero atoms chosen independently from oxygen, nitrogen and sulphur; and R^ and R^_, which may be the same or 30 different, are hydrogen, lower-alkyl, lower-alkoxy, lower-alkenyl, lower-alkynyl, cyclo-lower-alkyl or aralkyl] or a pharmaceutically acceptable acid addition salt thereof. - 6 - As employed throughout this Specification the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Alkyl" means a saturated aliphatic hydrocarbon which may have a straight or branched chain, lower-alkyl being preferred. Also included within the term are cycloalkyl- -lower-alkyl groups such as cycloprcpylmethyl and the like. "Lower alkyl" means alkyl as above having up to about 6 carbon atoms. Suitable lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl and isopentyl. - - "Cyclo lkyl"means a monocyclic saturated hydrocarbon group having up to about 6 carbon atoms, preferably cyclopropyl, cyclo- pentyl and cyclohexyl. "Alkenyl" means an aliphatic hydrocarbon which contains one or more double bonds and which may have a straight or branched chain. Lower alkenyl is preferred. "Lower alkenyl" means alkenyl as above having up to about 6 carbon atoms, such as ethylene, propylene, butylene and isobutylene, etc. "Aryl" means phenyl or substituted phenyl. "Substituted phenyl" means phenyl substituted by one or more radicals chosen independently from halo, lower-alkyl, halo- -lower alkyl, nitro, a ino, acylamino, hydroxy, lower-alkoxy, aryl-lower-alkoxy, acyloxy, carboxy, cyano, halo-lower-alkoxy and lower-alkyl-sulphonyl. "Aralkyl" means alkyl (preferably lower-alkyl) substituted by one or more -= > aryl groups, e.g. benzyl or phenethyl, etc. "Substituted pyridyl" means pyridyl substituted by one or more radicals chosen independently from halo, lower-alkyl, halo- r-lower-alkyl, nitro, a ino, acylamino, hydroxy, lower alkoxy, aryl-lower-alkoxy, acyloxy, carboxy, cyano, halo-lower-alkoxy and lower-alkyl-sulphonyl. The substituents may be in the 2, 3 or 4- positions; preferred substituted pyridyls are those having a substituent on one or both carbon atoms vicinal to the carbon attached to the a idino or urea nitrogen. "Halo" and "halogen" include fluorine, chlorine, bromine and iodine. "Halo-alkyl" and "halo-phenyl" include alkyl and phenyl having one or more halo substituents which may be the same or different, such as trifluoromethyl, 1-chloro- -2-bromo-ethyl, chlorop enyl or 2-chloro-6- - -bromophenyl, etc. The term "acyl" means a radical of the formula ECO, wherein R is an organic radical, such as lower-alkanoyl or aroyl. In lower- alkanoyl R is alkyl, as in acetyl and propionyl and the like, and in aroyl R is aryl, as in bensoyl. The term "acyloxy" means a radical of the formula RC00, wherein E is an organic radical, such as acetoxy, prcpionoxy, - a - benzoyloxy and the like. The term "acylamino" means an organic amido group of the formula RCONH, where E is alkyl or aralkyl, preferably lower-alkyl 5 or aryl-lower-alkyl. "Alkynyl" means an aliphatic hydro¬ carbon containing one or more triple bonds, and which may have a straight or branched chain. Lower alkynyl is preferred. 10 "Lower alkynyl" means alkynyl of up to about 6 carbon atoms, such as propargyl, butynyl and pentynyl etc. Where in formula I E-, and R > or R_ and g orm a 5 or 6 membered heterocyclic 15 ring, this may be for instance pyridyl, pyrimidyl, pyrazolyl, imidazolyl, ^ oxazolyl, -,, thiazolyl, piperidyl, piperazenyl, morpholinyl or thio orpholinyl etc. Pyridyl is preferred. It should be understood that whereas 20 the structure of the a idinoureas of formula I is shown in a particular configuration for purposes of illustration, the a idino- ureasmay exist in various enolized or tautomeric forms, particularly where one of 25 , and E^_ is hydrogen, as shown, for example, by the following formula: * Certain of the amidinoureas can also be obtained as hydrates or in different polymorphic forms. The formulae used herein • to designate the amidinoureas are to be taken to include the structures actually shown along with their alternative or transient states. 5 Among the amidinoureas of formula I, a particularly preferred group suitable for use in accordance with this invention are those in which the B- substituent is phenyl or substituted phenyl, and particularly. 10 phenyl having substituents in the 2 and 6 positions (i.e. ortho to the carbon attached to the urea nitrogen). A preferred group of such amidinoureas are the compounds of the formula: 15 (wherein R-, , R ? , R-, R. and Eg, which may be the same or different, are lower-alkyl, hydroxy, lower-alkoxy, ■ lower-alkenyl, cyclo- -lower-alkenyl, cyclo-lower-alkyl, aralkyl, lower-alkynyl, halo-alkyl, hydroxy-lower- -alkyl, lower-alkoxy-lower-alkyl, cyano- -lower-alkyl, amino-lower-alkyl, mono- or di-(lower-alkyl)-amino-lower-alkyl, carbamoyl-lower-alkyl, mono- or di-(alkyl)- -carbamoyl-lower-alkyl, lower-alkoxy- -carba oyl-lower-alkyl, aralkoxy-carbamoyk- -lower-alkyl, acyl-lower-alkyl, alkyl- - -sulphonyl or aralkyl-sulphonyl; E represents zero, one, two or three substit- uents in any one or more of the para and meta positions, which substituents may-be independently chosen from halo, lower-alkyl, halo-lower-alkyl, nitro, a ino, acylamino,- hydroxy, lower-alkoxy, aryl-lower-alkoxy, acyloxy, carboxy, cyano, halo-lower-alkoxy and lower-alkyl-sulphonyl; and E' -and E", which may be the same or different, are chosen from halo, lower-alkyl, halo-lower- -alkyl, nitro, a ino, acylamino, hydroxy, - lower-alkoxy, aryl-lower-alkoxy, acyloxy, carboxy, cyano, halo-lower-alkoxy and lower- -alkyl-sulphonyl) and their pharmaceutically acceptable acid addition salts. Particularly preferred amidinoureas of formula II are those wherein the phenyl substituents are lower-alkyl, lower-alkoxy or halo; and one of E-,, E 2 , , and E^ is hydrogen, and the others are independently chosen from lower-alkyl, halo-lower-alkyl, and lower-alkoxy-lower-alkyl. The pre¬ ferred lower-alkyl substituents are methyl, ethyl, propyl and isopropyl. The preferred halo substituents are chlorine and bromine. The preferred halo-lower-alkyl substituents are chloromethyl and trifluoromethyl. A yet more preferred group of amidino¬ ureas suitable for use in this invention are the compounds of the formula: (wherein E, and E ? , which may be the same or different, are hydrogen, lower-alkyl, lower-alkoxy or hydroxy; and E' and E" , which may be the same or different, are hydrogen, halo or lower-alkyl) and their pharmaceutically acceptable acid addition salts. The most preferred compounds are l-(2,β-dimethylphenyl)-3-methylamidinourea and its pharmaceutically acceptable acid addition salts, especially the hydrochloride. The compounds of formula I, II or III can be used in this invention in the form of the base, or as salts prepared by reaction with pharmaceutically acceptable inorganic or organic acids. Suitable acid addition salts are, for example, the salts derived from the following acids:: inorganic acids such as hydrochloric acid, nitric acid, sulphuric acid, phosphorous acid and ortho- phosphoric acid etc; aliphatic mono- and di-carboxylic acids such as acetic acid, propionic acid, succinic acid, formic acid, caprylic acid, maleic acid, oxalic acid and malonic acid, etc.; phenyl-substituted- -alkanoic acids, hydroxy-alkanoic acids, aromatic-carboxylic acids and aliphatic- and aromatic-sulphonic acids such as ethyl- benzoic acid, phthalic acid, benzene- sulphonic acid, phenylpropionic acid, tartaric acid, citric acid, lactic acid, glycollic acid, phenylacetic acid, phenylbutyric acid -._• and methanesulphonic acid etc. Other pref rred amidinoureas for use in accordance with this invention are those disclosed in the Arzneimittel Forschung article identified above and in U.S. Patents 4,115,64-7; 4,088,785; 4,025,652; 4,115,564; 4,060,635 and 4,0S8,557; and in co-pending U.S. Patent Application Serial No. 671,762, the disclosures of which are Incorporated herein by reference. The amidinoureas of formulae I, II and III may be prepared by methods described in the art cited above. . Exemplary compounds prepared in accordance with such teachings for utiliza¬ tion in this invention are named below, wherein the urea nitrogens are designated as positions 1 and 3 respectively: l-(2,6-dimethylphenyl)-3-methylamidinourea; O-chlorophenylamidinourea; (2,3-dichlorophenylamidino)urea; (2,4-dichlorophenylamidino)urea; (2, -dichlorophenylamidino)urea; (3,4-dichlorophenylamidino)urea; (3, -dichlorophenylamidino)ure ; ( ,6-dic lorophenylamidino)urea; -chlorophenylamidinoure ; p-chlorophenylamidinourea; 3,4-difluorophenyla idinourea; m-bromophenylamidinourea; p-bromophenyla idinourea; 3, -dibromophenylamidinourea; 3-chloro-4-bromophenylamidinourea; 3- romo-4-chlorophenylamidlnourea; ■ 3-chloro-4- luorophenylamidinourea; 3-bromo-4-fluorophenylamidinourea; 3-fluoro-4-chlorophenylamidinourea; 2,6-dimethylphenylamidinourea; . ,6-diethylphenylamidinourea; 2-methyl-6-ethylphenylamidinourea; 2-methyl-6-methoxyphenylamidinourea; 2-methyl-6-ethoxyphenylamidinourea; 2-ethyl-6-ethoxyphenylamidinourea; 3, -dimethoxyphenylamidinourea; 3,4-•dihydroxyphenylamidinourea; 3,4, "* "--trimethoxyphenylamidinourea; 3,4, -trihydroxyphenylamidinourea; l-(2,6-dimethylphenylamidino)-3,3-(N-methyl- -3'-azapentamethylene)urea; l-(2,6-dimethylphenylamidino)-3,3-(N- * sethyl- -3'-azahexa ethylene)urea; l-(2,6-dimethylphenylamidino)-3,3~(3'-oxa- pentamethylene)urea; fOR£ 1-(2,6-dimethylphenyla idino)-3,3-( '-thia- tetramethylene)urea; l-(2,6-dimethylphenylamidino)-3,3-tetra- methyleneurea; l-(p-fluorophenylamidino)-3,3-( α , α '-dimethyl- pentamethylene)urea; l-(p-chlorophenylamidino)-3,3-(pentamethylene) urea; l-(2,6-dimethylphenylamidino)-3,5( α j α '-di- methylpentamethylene)urea; l-(2,6-dimethylphenylamidino)-3,3-penta- methyleneurea; l-(2,6-dimethylphenylamidino)-3,3-(α-methyl- pentamεthylene)urea; 1-(N-methylamidino)-3-(2,6-dimethylphenyl) urea; l-(N-methylamidino)-3-( ,6-diethylphenyl) urea; l-amidino-3-(2-methyl-6-chlorophenyl)ure ; l-amidino-3-(2-methyl-6-bromophenyl)urea; 1-amidino-3-(2-methyl-6-methoxyphenyl)urea; l-amidino-3-(2,6-dimethylphenyl)urea; l-amidino-3-(2-methyl-^6-ethylphenyl)urea; l-amidino-3-(2-ethyl-6-chlorophenyl)urea; 1-amidino-3-(2-ethyl-6-bromophenyl)urea; l-amidino-3-(2,6-diethylphenyl)urea; l-amidino-3-methyl-3-(2-methyl-6-chlorophenyl) urea; l-anidino-3-methyl-3-(2-methyl-6-bromophenyl) urea; l-amidino-3-methyl-3-(2-methyl-6-methoxyphenyl) urea; l-amidino-3-methyl-3-(2,6-dimethylphenyl) urea; 1-amidino-3-methyl-3-(2-methyl-6-ethyl- phenyl)urea; l-amidino-3-methyl-3-(2-ethyl-6-chloro- phenyl)urea; - 5 l-amidino-3-methyl-3-(2-ethyl-6-bromophenyl) urea; 1-amidino-3-methyl-3-(2-ethyl-6-methoxyphenyl) urea; l-amidino-3-methyl-3-(2,6-diethylphenyl)urea; 10 l-amidino-3-(2-methyl-6-chlorophenyl)urea; 1-amidino-3-(2-methyl-6-bromophen 1)u ea; ■ 1-amidino-3-(2-methyl-6-methylphenyl)urea; 1-amidino-3-( ,6-dimethylphenyl)urea; l-amidino-3-(2-methyl-6-ethylphenyl)urea; I5 l-amidino-3-(2-ethyl-6-chlorophenyl)urea; l-amidino-3-(2-ethyl-6-bromophenyl)urea; 1-amidino-3-(2-ethyl-6-methoxyphenyl)urea; 1-amidino-3-(2,6-diethylphenyl)urea; 1-amidino-3-methyl-3-(2-methyl-6-chloro- 20 phenyl)urea; 1-amidino-3-methyl-3-(2-methyl-6-bromophenyl) urea; 1-amidino-3-methy1-3-(2-methyl-6-methoxyphenyl) urea; 2 1-amidino-3-methyl-3-(2,6-dimethylphenyl)urea; l-amidino-3-methyl-3-(2-me * tiιyl-6-ethylphenyl) urea; 1-amidino-3-methyl-3-(2-ethyl-6-chlorophenyl) urea; 30 l-amidino-3-methyl-3-(2-e h l-6-brcmophenyl) urea; 1-amidino-3-methyl-3-(2-eth 1-6-methoxyphenyl) urea; l-amidino-3-methyl-3-(2,6-diethylphenyl)urea; and the pharmaceutically acceptable acid addition salts of the above compounds. It will be appreciated that this invention provides an improved method of animal husbandry wherein to 'increase pro¬ duction one alministers to calves, lambs, foals or. adult cattle a curative dose for the treatment of scours of an amldinourea as described above; equally, it provides an improved method of animal husbandry wherein to increase production one administers to calves, lambs, foals or adult cattle a prophylactic dose for the prevention of scours of an amidinourea described above. The. methods of this invention are particularly useful in the treatment or prophylaxis of scours in very young calves, lambs or foals under 10 days old, and of bovine scours in wintering cattle. When less than 10 days old a lamb may be expected to weigh from about 5 lb (2.27 kg) to about 20 lb (9-07 kg) and a calf from about 10 lb (4.45 kg) to about 50 lb (22.68 kg). Since the amidinoureas are readily absorbed into the bloodstream from the stomach and intestines when taken orally, a preferred method of treatment is .to give " the drug orally. However oral administra¬ tion is sometimes unreliable or impractical, for example where the animal is not eating or cannot swallow or has difficulty in swallowing, in which case other methods of administration which permit the drug to be absorbed from the gastrointestinal tract, - 17 - or which deliver a solution of the drug directly to the bloodstream, can be employed. In particular, it is often highly convenient to employ parenteral injection, 5 most usually via the intramuscular route. The administration of the amidinoureas to the animals in question may be accom¬ plished by a variety of methods, for example by direct administration to the animal, 10 either alone or accompanied by a pharma¬ ceutically acceptable carrier in a veterinary composition; or by incorporation, either alone or as part of a feed pre-mix or other composition, in the animals' * daily solid or 15 liquid dietary intake. Where the amidinoureas are " to be ad- " '"" ministered to very young animals, and e^edally to calves, lambs or foals under 10 days old, a preferred route is for the amidinoureas to be 20 administered to the animals by injection .or orally in the form of a liquid veterinary composition. Accordingly, this invention provides a liquid veterinary composition in a unit dosage 25 form suitable for parenteral injection or oral administration comprising from about 1 to abou 2*=i mg, preferably from about 10 to about 25 mg and most preferably about 15 mg, of an amidino urea defined above, together with a phar aceut 30 ically acceptable liquid carrier. A liquid veterinary composition for oral administration may usefully be presented in a bottle with a teat or in a plunger- applicator bottle. . As mentioned above, the debilitating effects of scours result partially from electrolyte imbalance in the suffering animals, so that it is recommended that 5 a solvent or diluent forming the liquid carrier of the veterinary compositions, whether designed for injection or oral administration, should incorporate electrolyte in order to replenish the fluid 10 electrolyte balance of the animal. The precise composition of the electrolyte replenisher incorporated in the liquid veterinary compositions will depend on the age and the general health and condition of 1 the animal, but in many cases it is appropriate to use a commercially available '"' electrolyte replenisher. These generally include sodium chloride alone or in combina¬ tion with potassium salts, calcium salts, 20 lactates or bicarbonates, and typical examples are Einger's Solution, Darrow's Solution (for injection), Einger's Injection and Lactated Einger' s Injection. These and other examples of commercially available 2 electrolyte replenishers may be found in the "Pharmacopeia of the United States". A particularly preferred liquid veterinary composition of this invention Is one in which the carrier Is a solvent or 30 diluent comprising a saline solution of substantially isotonic concentration. Liquid veterinary compositions intended for oral administration may be presented in the form of solutions, suspensions, syrups, - 19 - elixirs, oil-in-water emulsions, water-in- oil emulsions, or other similar liquid forms which may be administered orally. . Where an amidinourea is to be admini- stared to adult animals, for instance to wintering adult cattle, it may be incorpora¬ ted in a solid veterinary composition containing a pharmaceutically-acceptable solid carrier and intended for oral 10 administration. Such a solid composition may be used as well as or instead of the liquid compositions described above. Suitable solid forms are tablets, hard or soft capsules, lozenges, chewable lozenges, pills, 1 powder or granules. The unit dosage of amidinourea employed in a solid composition-, is the same as for a liquid composition, i.e. from about 1 to about 2 mg, preferably from about 10 to about 2 C* mg, and most preferably 20 about 15 mg. Solid or liquid veterinary compositions intended for oral use may be prepared according to methods known generally in the art. Such compositions may contain, In 25 addition to a solid or liquid carrier and an amidinourea, one or more *sweetening agents, flavouring agents, colouring agents and preserving agents, in order to provide a pharmaceutically elegant and palatable 30 preparation. Examples of pharmaceu ically acceptable carriers which may be incorporated in solid compositions are inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch or alginic acid; binding agents, for example starch, gelatin 5 or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to make them more 10 effective, for example to delay disintegration or absorption, or to make them more palatable, " or for other reasons for which orally admini¬ stered drugs have been previously provided in coated form. 1 Hard gelatin capsules may in particular contain an inert solid diluent, for example ** calcium carbonate, calcium phosphate or kaolin. Soft gelatin capsules will usually contain an oily medium, for example arachis 20 oil, liquid paraffin or olive oil. Liquid compositions for oral use are preferably aqueous, so as to permit the inclusion of an electrolyte. Ingredients suitable for incorporation in the carrier 25 of an aqueous liquid suspension are for example suspending agents such as sodium carboxymethylcellulose, me h lcellulose, hydroxypropylmethylcellulcse, sodium alginate, polyvinylpyrrolidine, gum tragacanth and gum 30 acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxy- ethanol, condensation products of ethylene oxide with partial esters derived from fatty 5 acids and a hexitol, for example polyoxyethyl- ene sorbitol mono-oleate or condensation products of ethylene oxide with partial esters derived from fatty acids and. hexitol anhydrides, for example polyoxyethylene 10 sorbitan mono-oleate. Aqueous suspensions may also in particular contain one or more preservatives, for example ethyl- or n-propyl— -p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and I5. one or more sweetening agents, such as sucrose. Oily suspensions may be formulated by suspending the amidinourea in a vegetable oil, for example arachis oil, olive oil, sesame 20 oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example • beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth 5 above, and flavouring agents may here also be added to provide a palatable oral preparation. These compositions may also be preserved by the addition of an an i-oxidant such as ascorbic acid. 0 Where the liquid veterinary compositions of this invention are in the form of oil-in- water emulsions, the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs in particular may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. ' _ The liquid veterinary compositions of this invention may, as hereinbefore des¬ cribed, be formulated for injection. For example they may take the form of a ' sterile in ectable aqueous suspension formulated according.to the known art and containing those suitable dispersing or wetting agents and suspending agents which have been mentioned above. An injectable composition is preferably a sterile injectable solution or suspension of the amidinourea in a parenterally-acceptable diluent or solvent, for example a sterile aqueous solution buffered to a pH of 4.0 to 7.0 and made Isotonlc with sodium chloride. The compositions of this invention may be prepared by conventional methods, that is by bringing the amidinourea into association with the carrier by mixing. When the composition is in the form of an aqueous suspension, this may be prepared by adding water to a mixture of the solid ingredients, i.e. the amidinourea and any suspending, wetting, flavouring, colouring or sweetening agents etc. As mentioned before, the amidinoureas may be administered by incorporation thereof into the animals' daily solid or liquid dietary intake, for example as part of the daily animal feed or dissolved in drinking water. This method of administration is a preferred one, especially when the amidino- ureas are employed prophylactically. Accordingly, this invention provides daily dietary intake for an animal contain¬ ing a dose, which is prophylactic or curative of scours, of an amidinourea defined above. The daily dietary intake for very young animals will of course largely consist of milk, or an aqueous solution of milk solids. Where these are normally fed to the young in a bottle, it is convenient to incorporate the amidinourea in the milk. This can be done in the case of very young calves, which are normally bottle weaned. However, other young animals, such as foals and lambs, are usually weaned by their mothers, in which case administration of the amidinourea in milk is not practical. Of course, administration in milk is useful in all cases where the mother is for some reason not capable of weaning her young. The daily dietary intake of adult animals, for instance of adult cattle, will consist of rather more bulky materials 5 * such as silage, oats, barley or bran. It is sometimes impractical to incorporate the amidinourea directly into such materials, so it is preferred to provide the amidinourea in the form of a feed pre-mix which can be 10 easily mixed with the animals' dally dietary intake. Accordingly, this invention provides a feed pre-mix for incorporation into the daily dietary intake of an animal, which pre-mix 15 comprises an amidinourea as defined above and a portion of the daily dietary intake, or other nutrient material. Thus the pre-mix will sometimes take the form of a portion of the animal's daily 20 dietary intake containing a relatively high proportion of amidinourea compared with that found in the intake actually presented to the animal after incorporation of the pre- mix. 25 The pre-mix may advantageously contain other nutrient material, such as essential nutrients or minerals commonly incorporated in feed supplements for animals. The pre-mix of this invention may be 30 prepared by bringing the amidinourea into association with a portion of the animal's daily dietary intake and/or with other nutritive material. The amidinoureas may be administered to the animals in association with other agents having the same or different pharmacological properties, such as anti¬ bacterial agents, antiviral agents or anti- 5 emetic agents. In particular, the amidino¬ ureas may be administered in association with agents known to be active against scours, such as neo ycin, although the amidinoureas have been found to be at least as effective 10 as neomycin. The dosage regimens employed in accord¬ ance with this invention are those which are prophylactically effective or which ensure maximum response in an animal suffering from 1 scours until improvement is obtained. After improvement the minimum effective dosage which gives relief should be administered. For calves, lambs, foals and adult cattle the overall average effective dose 20 will be found to be about 0. c' mg/kg to about 5 mg/kg of body weight, and preferably from about 0.5 mg/kg to about 2.5 mg/kg, admini¬ stered 1 to 4 times daily. The dosage given to adult cattle will in general be slightly 25 lower than that for calves, lambs or foals, although larger animals will normally have larger tolerances. However, 4t should always be borne in mind when selecting the appropriate 30 dosage in any specific case that considera¬ tion must be given to weight, general health, age and other factors which may influence response to the amidinourea. Response upon oral administration of the amidinourea usually follows within 10 to 30 minutes and is maintained for 1 to 4 hours. The amidinourea should be administered 5 prophylactically or within about ten hours (preferably within about five hours) after the onset of scours, and thereafter as required to maintain an effective drug level in the bloodstream for the continuous 10 relief of scours. This invention provides a package comprising an amidinourea as defined above, together with instructions for use in a method of animal husbandry in which the 15 treatment or prevention of scours in animals is indicated, for example, to increase production. Finally, this invention provides an amidinourea as defined above for use in the 2O treatment or prevention of scours in animals. The following formulations are given in illustration of the liquid veterinary compositions of this invention and of other veterinary compositions which may be useful In the treatment or prevention of scours in animals. Formulation 1. A sterilized aqueous solution for oral administration containing l-(2,6-di-methyl- 10 -phenyl)-3-amidinourea hydrochloride was made up from the following ingredients: 1-(2,6-dimethylphenyl)-3- -amidinourea hydrochloride mg Sodium chloride 86 g 15 Potassium chloride 3 mg Calcium chloride HoO 3.3 m De-ionised water q.v. ' 100 cm- 5 . Formulation 2. A sterile solution suitable for inter- 20 peritoneal injection, containing 10 mg of l-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride in each 10 ml (1:1 wt./vol.), was prepared from the following ingredients: l-(2,6-dimethylphenyl)-3- 25 -methyl-amidinourea hydrochloride 10 g Benzyl benzoate 100 c ^ Methylparaben 1 S Propylparaben 0.5 g 30 Cottonseed oil q. 500 c ^ ΕEAγr Formulation 3» 500 ampoules, each with 2 ml of solution containing 15 mg of 1-(2,6-dimethyl- phenyl)-3-methylamidinourea hydrochloride, 5 were prepared from the following types and amounts of materials: l-(2,6-dimethylphenyl)-3- - ethyl-amidinourea hydrochloride 7- > 5 g 10 Ascorbic acid 1 ε Sodium bisulphite O. •5 ε Sodium Sulphite 1 ε Deionised water q.s. 1000 cur 3 Formulation 4. 15 An aqueous solution for parenteral administration was prepared as follows: 50 g of l-(2,6-dimethylphenyl)-3- -methylamidinourea hydrochloride and 5 g of pronyl p-hydroxybenzoate were dissolved 20 and diluted to - * * " ,000 cur with twice- distilled water after the addition of modified sorensen buffer solution in an amount sufficient to adjust the pH value to a pH of 6.0. Sodium chloride was 25 dissolved therein in an amount sufficient to render the resulting solution isotonic. The resulting solution was passed through a bacteriological filter, and the filtrate autoclaved at 120°C for fifteen minutes to 30 yield a parenterally applicable solution * which contains 50 mg of l-(2,6-dimethylphenyl)- -3-methylamidinourea hydrochloride in 5 c of the solution. - 29 - Formulation 5. Tablets of δsO mg were prepared by maximum compression of a mixture of the following ingredients: 5 l-(2,6-dimethylphenyl)-3- - ethyl-amidinourea hydrochloride 500 mg Triealeium phosphate 200 mg Talc 50 mg 10 Magnesium stearate 10 mg Polyvinyl acetate 40 mg Protective excipients such as ethyl- cellulose, dibutylphthalate, propylene glycol, wax (white and/or carnauba), I5 spermaceti, methylene chloride and rectified diethyl ether may optionally be included among the ingredients. Formulation 6: A lot of tablets, each containing 20 20 mg of 1-(2,6-dimethylphenyl)-3-methyl- amidinourea hydrochloride were prepared from the following ingredients: l-(2,6-dimethylphenyl)-3- -methyl-amidinourea 25 hydrochloride 1 kg- Diealeium phosphate 1 kg * Methylcellulose USP 75 kg Talc 150 g Cornstarch 200 g 30 Magnesium stearate 10 g The amidinourea and dicalcium phosphate were mixed thoroughly and granulated with a 7 * % solution of methylcellulose in water and passed through #8 screen and air-dried. The dried granules were passed through a τ^-12 screen and combined with the talc , starch and magnesium stearate with thorough mixing, after which the composition was compressed into tablets . Formulation 7: A lot of two-piece hard gelatin capsules, each containing 25 mg of l-(2,6- -dimethylphenyl)-3-methylamidinourea hydrochloride, were prepared from the following types and amounts of ingredients: l-( 2 , 6-dimethylphenyl) -3- -methyl-amidinourea hydrochloride 500 g Die ale ium phosphate 500 g Talc - 150 g Magnesium stearate 5 g The ingredients were mixed thoroughly and filled into capsules for oral adminlstra- tion to animals at the rate of about one every four hours. If desired, slow release or delay release forms could be provided, depending on choice of capsules and formulating ingredients. Formulation 8: Tablets for oral administration, each containing 25 mg of l-(2,6-dimethylphenyl)-3- -methylamidinourea hydrochloride, were prepared from a mixture of the following ingredients: 1-(2,6-dimethylphenyl)-3- -methyl-amidinourea hydrochloride 500 g Lactose U.S. . 350 S Potato starch U.S.P. 346 ε The mixture was moistened with an alcoholic solution of 20 g of stearic acid and granulated through a sieve. After drying, the following ingredients were 5 added: Potato starch U.S.P. 320 g Talc 400 g Magnesium stearate 500 g Colloidal silicium 10 dioxide 64 g and the whole was thoroughly mixed and compressed into tablets. Formulation 9: Capsules were prepared from the 15 following mixture: 1-(2,6-dimethylphenyl)-3- -methyl-amidinourea hydrochloride 15 g Magnesium stearate 3 g 20 Finely divided silica sold under the trademark CAB-0-SIL by Godfrey L. Cabot, Inc., Boston, MA 2 g Lactose 369 g 25 The mixture was-filled into gelatin capsules, each capsule containing """ CO mg of the mixture and thus 15 mg of l-(2,6-dimethylphenyl)-3- -methylamidinourea hydrochloride. - 0 - 0 - 0 - 30 By analogous procedures, other amidinoureas of general formula I above can be formulated in a similar manner for either oral "or parenteral administration as injectable or infusible solutions. The solid or liquid formulations can also be dispersed in the feed or dissolved in drinking water or the liquid diet of the animal. The amidinoureas of general formula I may also be formulated for rectal administration, for example as a suppository.

Claims: CLAIMS 1. A method of treating scours in calves, lambs or foals which comprises administering to the afflicted animal an effective amount of an anti-scouring agent of the formula: [wherein either R, is phenyl, substituted phenyl (as defined herein), aralkyl, pyridyl or substituted pyridyl (as. defined herein), and E , E- and Eg, which may be the same or different, are hydrogen, lower- alkyl, hydroxy, lower-alkoxy, lower-alkenyl, cyclo-lower-alkenyl, cyclo-lower-alkyl, aralkyl, lower-alkynyl, halo-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower- -alkyl, cyano-lower-alkyl, amino-lower- -alkyl, mono- or di-(lower-alkyl)-amino- -lower-alkyl, carbamoyl-lower-alkyl, mono- or di-(alkyl)-carbamoyl-lower-alkyl, lower- -alkoxy-carbamoyl-lower-alkyl, aralkoxy- -carbamoyl-lower-alkyl, acyl-lower-alkyl, • alkyl-sulphonyl or aralkyl-sulphonyl, or R is as just mentioned and E^ together with Eg and the nitrogen to which they are both attached form a 5 or 6 membered hetero- cyclic ring which optionally may include 1 or 2 additional hetero atoms chosen independ¬ ently from oxygen, nitrogen and sulphur; -$UR£ OL-PI or E_ is phenyl, substituted phenyl (as defined herein) aralkyl, pyridyl or substituted pyridyl (as defined herein) and E- j , E 2 and Eg, ' which may be the same or different, are hydrogen, lower-alkyl, hydroxy, lower-alkoxy, lower-alkenyl, cyclo-lower-alkenyl, cyclo-lower-alkyl, aralkyl, lower-alkynyl, halo-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower- -alkyl, cyano-lower-alkyl, amino-lower- -alkyl, mono- or di-(lower-alkyl)-amino- -lower-alkyl, carbamoyl-lower-alkyl, ono- or di—(alkyl)-carbamoyl-lower-alkyl, lower- -alkoxy-carba oyl-lower-alkyl, aralkoxy- -carbamoyl-lower-alkyl, acyl-lower-alkyl, alkyl-sulphonyl or aralkyl-sulphonyl, or E Is as last mentioned and R, together with E p and the nitrogen to which they are both attached form a 5 or 6 membered hetero- cyclic ring which optionally may include 1 or 2 additional hetero atoms chosen independently from oxygen, nitrogen and sulphur; and E^ and E , which may be the same or different, are hydrogen, lower-alkyl, lower-alkoxy, lower-alkenyl, lower-alkynyl, cyclo-lower-alkyl or aralkyl] or a- phar aceutically-acceptable acid addition salt thereof. 2. A method of animal husbandry wherein to increase production one administers to calves, lambs, foals or adult cattle a curative dose for the treatment of scours of a compound of the formula: [wherein either R, is phenyl, substituted phenyl (as defined herein), aralkyl, pyridyl or substituted pyridyl (as defined herein), and E 2 , E- and Eg, which may be the same or different, are hydrogen, lower- alkyl, hydroxy, lower-alkoxy, lower-alkenyl, cyclo-lower-alkenyl, cyclo-lower-alkyl, aralkyl, lower-alkynyl, halo-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower— -alkyl, cyano-lower-alkyl, amino-l.ower- -alkyl, mono- or di-(lower-alkyl)-amino- -lower-alkyl, carbamoyl-lower-alkyl, ono- or di-(alkyl)-carbamoyl-lower-alkyl, lower- -alkoxy-carbamoyl-lower-alkyl, aralkoxy- -carbamoyl-lower-alkyl, acyl-lower-alkyl, alkyl-sulphonyl or aralkyl-sulphonyl, or E 2 is as just mentioned and E- together with Eg and the nitrogen to which they are both attached form a 5 or 6 membered hetero¬ cyclic ring which optionally may include 1 or 2 additional hetero atoms chosen independ¬ ently from oxygen, nitrogen and sulphur; or E ς is phenyl, substituted phenyl (as defined herein) aralkyl, pyridyl or substituted pyridyl (as defined herein) and R, , E 2 and Rg, which may be the same 5 or different, are hydrogen, lower-alkyl, hydroxy, lower-alkoxy, lower-alkenyl, eyelo-lower-alkenyl, eyelo-lower—alkyl, aralkyl, lower-alkynyl, halo-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower- 10 -alkyl, cyano-lower-alkyl, amino-lower- -alkyl, mono- or di-(lower-alkyl)-amino- -lower-alkyl, carbamoyl-lower-alkyl, mono- or di—(alkyl)-carbamoyl-lower-alkyl, lower- -alkoxy-carbamoyl-lower-alkyl, aralkoxy- 15 -carbamoyl-lower-alkyl, acyl-lower-alkyl, alkyl-sulphonyl or aralkyl-sulphonyl, or Eg is as last mentioned and E-, together with E 2 and the nitrogen to which they are both attached form a 5 or 6 membered hetero- 20 cyclic ring which optionally may include 1 or 2 additional hetero atoms chosen independently from oxygen, nitrogen and sulphur; and E^ and E , which may be the same or 25 different, are hydrogen, lower-alkyl, 1o er-alkoxy, lower-alkeny1, 1o er-alkynyl, cyclo-lower-alkyl or aralkyl] or a pharmaceutically-acceptable acid addition salt thereof. 30 3. A method of animal husbandry wherein to increase production one administers to calves, lambs, foals or adult cattle a prophylactic dose for the prevention of scours of a compound of the formula I 35 (defined in claim 2) or a phar aceutically- O-.'PI acceptable acid addition salt thereof . 4. A method as claimed in any one of claims 1, 2 , . and 3 in which a compound of the formula: 5 (wherein B-^, E 2 , E^, E^ and Eg, which may be the same or different, are lower-alkyl, hydroxy, lower-alkoxy, lower-alkenyl, cyclo- -lower-alkenyl, cyclo-lower-alkyl, aralkyl, lower-alkynyl, halo-alkyl, hydroxy-lower- 10 -alkyl, lower-alkoxy-lower-alkyl, cyano- -lower ' -alkyl, amino-lower-alkyl, mono- or di-(lower-alkyl)-amino-lower-alkyl, carbamoyl- -lower-alkyl, mono- or di—(alkyl)-carbamoyl- -lower-alkyl, lower-alkoxy-carbamoyl-lower- 15 -alkyl, aralkoxy-carbamoyl-lower-alkyl, acyl-lower-alkyl, alkyl-sulphonyl or aralkyl- -sulphonyl; represents zero, one, two or three substituents in any one or more of the para and meta positions, which substituents 20 may be independently chosen from halo, lower- -alkyl, halo-lower-alkyl, nitro, amino, acyl- a ino, hydroxy, lower-alkoxy, aryl-lower- -alkoxy, acyloxy, carboxy, cyano, halo-lower- -alkoxy and lower-alky1-sulphonyl; and E' and E", which may be the same or different, are chosen from halo, lower-alkyl, halo- -lower-alkyl, nitro, amino, acylamino, hydroxy, lower-alkoxy, aryl-lower-alkoxy, 5 acyloxy, carboxy, cyano, halo-lower-alkoxy and lower-alkyl-sulphonyl) or a pharma- ceutically-acceptable acid addition salt thereof . is administered to the -animal. 5. A method as claimed In claim , in 10 which a compound of the formula: (wherein R, and E 2 , which may be the -same or different, are hydrogen, lower-alkyl, lower-alkoxy or hydroxy; and E 1 and R", which may be the same or different, are 15 hydrogen, halo or lower-alkyl) or a pharmaceutically-acceptable acid addition salt thereof is administered to the animal. 6. A method as claimed in claim 5, In which l-(2,6-dimethyl-phenyl)-3-methylamidino- 20 urea or 1-(2,6-dimethyl-phenyl)-3-methy1- amidinourea hydrochloride is administered to the animal. - 39 - 7. A method as claimed in claim 1, in which the compound or salt is administered in an amount of from 0.5 to 5 mg/kg one to four times daily. 5 8. A liquid veterinary composition in a unit dosage form suitable for parenteral injection or oral administration comprising from 1 to 25 rg and preferably from 10 to 25 mg of a compound or salt as 10 defined in claim 1,.-together with a pharmaceutically-accep able liquid carrier. 9. A liquid veterinary composition as claimed in claim 8 in which the carrier is a solvent or diluent comprising an 15 electrolyte for replenishing the fluid electrolyte balance of the animal to which the composition is to be administered. 10. A liquid veterinary composition as claimed in claim 9, in which the carrier 20 is a solvent or diluent comprising a saline solution of substantially isotonic concentra¬ tion. 11. Daily dietary intake for an animal, for example milk or an aqueous solution of 25 milk solids, containing a dose, which is prophylactic or curative of scours, of a compound or salt as defined in claim 1. 12. A feed pre-mix for incorporation into the daily dietary intake of an animal, for 30 example silage, oats, barley or bran, which pre-mix comprises a compound or salt as defined in claim 1. and a portion of the daily dietary intake or other nutritive material. 13. A feed pre-mix according to claim 12, which includes one or more essential nutrients 5 or minerals. 14. A compound or salt as defined in claim 1 for use in the treatment or prevention of scours in animals. 15. A package comprising a compound or 10 salt as defined in claim 1 together with instructions for use in a method of animal husbandry in which the treatment or prevention of scours in animals is indicated, for example, to increase production.

Inventors: CHOU BILLY JA-RAY, RILEY RICHARD LINN, YELNOSKY JOHN, CHOU, BILLY, JA-RAY, RILEY, RICHARD, LINN, YELNOSKY, JOHN
Applicants: RORER INT OVERSEAS, RORER INTERNATIONAL (OVERSEAS) INC.
Application year: 1981
Main classification: A61K31
IPC codes: A61K31