Patent GB-845368-A (GB)
Title: Composition for the control of gastro-intestinal parasites in animals
IPC: A61K31/165
Filed: 1957-08-16
Abstract: The preparation of polynitrobenzamides of the formula:- <FORM:0845368/IV(b)/1> wherein R is an amino, monomethylamino, dimethylamino, monoethylamino, diethylamino, propylamino, dipropylamino, allylamino, hydroxethylamino, hydroxypropylamino, methoxyethylamino, or methoxypropylamino radical and Z is substituted phenyl radical of formula:- <FORM:0845368/IV(b)/2> in which X is hydrogen, amino, lower alkoxy or lower alkyl, Y is hydrogen, lower alkoxy or lower alkyl, and is amino, lower alkoxy or lower alkyl is described.  The polynitrobenzamides are used, in veterinary compositions (see Group VI) and are crystalline solids which are somewhat soluble in many organic solvents and of very low solubility in water.  The 2,4,6-trinitrobenzamides and 2- and 4-alkyl-3,5-dinitrobenzamides may be prepared by the reaction of 2,4,6-trinitrobenzoic acid or a 2- or 4-alkyl-3,5-dinitrobenzoic acid with thionyl chloride (SOCI2) or phosphorus pentachloride to produce the corresponding acid chlorides.  The acid chlorides are then reacted with at least 2 moles of aqueous ammonia or a suitable amine per mole of acid chloride to obtain the desired polynitrobenzamide or N-substituted polynitrobenzamide compounds.  The 4,6-dinitrobenzamides and 2- or 3-alkyl-or-alkoxy4,6-dinitrobenzamides may be prepared by diazotization of 4,6-dinitroaniline or a 2- or 3-alkyl-or-alkoxy-4,6-dinitroaniline to form the corresponding diazonium salt which is then reacted with cuprous or nickelous cyanide to obtain the corresponding nitrile.  Subsequent hydrolysis of the nitrile results in the formation of the corresponding polynitrobenzoic acid.  The acid is then reacted with thionyl chloride to obtain the acid chloride which is reacted with ammonia or a suitable amine to produce the desired benzamide compound.  In an alternative procedure, the 2- or 3-methyl-4,6-dinitrobenzamides may be prepared by oxidizing the 1,2-dimethyl-4,6-dinitrobenzene or 1,3-dimethyl-4,6-dinitrobenzene with dilute nitric acid whereby the 2- or 3-methyl-4,6-dinitrobenzoic acids are produced.  The latter acids may be treated as previously described to obtain the desired benzamide compounds.  The 2- or 4-amino-3,5-dinitrobenzamides are prepared by the nitration of 2-chlorobenzoic acid or 4-chlorobenzoic acid to obtain the corresponding 3,5-dinitro-chlorobenzoic acids which are then reacted with phosphorus pentachloride to form the corresponding acid chlorides.  These acid chlorides are then reacted with aqueous ammonia or a suitable amine in the proportion of two moles of ammonia or amine per mole of acid chloride.  Since the acyl chlorine is more reactive than the ring chlorine, such reaction results in the formation of 2- or 4-chloro-3,5-dinitrobenzamides or N-substituted-2- or 4-chloro-3,5-dinitrobenzamides.  The latter benzamide compounds thereafter may be reacted with excess alcoholic ammonia to replace the ring chlorine and obtain the desired 2- or 4-amino-3,5-dinitrobenzamide compounds.  The 2-amino-4,6-dinitrobenzamides may be prepared by the reduction of 2,4,6-trinitrobenzamide with sodium sulfhydrate (NaSH), whereby the ortho nitro group is selectively reduced to an amino group. The 2-or 4-alkoxy-3,5-dinitrobenzamides may be prepared by the reaction of a 2- or 4-chloro-3,5-dinitrobenzamide or an N-substituted-2- or 4-chloro-3,5-dinitrobenzamide with an alkali metal alkoxide whereby an alkoxy group is substituted for chlorine in the 2- or 4-chloro-3,5-dinitrobenzamide compound.  Specified nitrobenzamides are 3:5-dinitro-2-methyl-or-ethyl-or-methoxybenzamide, N-methyl-or-ethyl-or-allyl-or-(21-methoxy-ethyl) -or-(21-hydroxypropyl)-or-(21-hydroxyethyl) -3 : 5-dinitro-2-methylbenzamide, N:N-dimethyl-or-diethyl- or-diisopropyl-3:5-dinitro-2 -methylbenzamide, 2-or-4-amino-3:5-dinitrobenzamide, 3 : 5-dinitro-4-methoxy-or-methylbenzamide, 4:6-dinitro-2-methoxybenzamide, N-ethyl-3:5-dinitro-4-ethylbenzamide, 4:6-dinitro-3-ethyl-or-methyl-benzamide, N-methyl-3:5-dinitro-2-propoxybenzamide, N-methyl-4:6-dinitro-2-methylbenzamide, N-methyl-2:4:6-trinitrobenzamide, N-ethyl-4:6-dinitro-2-propylbenzamide, N-allyl-or-N:N-dimethyl-2:4-dinitrobenzamide, 2:4-dinitro-and -2:4:6-trinitro-benzamide.ALSO:Compositions for the control of gastro-intestinal parasites in animals e.g. coccidia comprise at least 0,001% by weight of a polynitrobenzamide compound in a liquid dispersion including a dispersing agent or in intimate admixture with an edible finely-divided solid.  The active ingredients are those having a formula Z.CO.R wherein R represents a radical selected from the group consisting of amino, mono- and dimethyl amino, mono- and diethylamino, propyl- and dipropylamino, allylamino, hydroxyethylamino, hydroxypropylamino, methoxyethylamino and methoxypropylamino and Z is a substituted phenyl radical selected from the group consisting of:-  <FORM:0845368/VI/1> wherein X is hydrogen, amino, lower alkoxy or alkyl, Q is amino, lower alkoxy or alkyl, and Y is hydrogen, lower alkoxy or lower alkyl.  Good results are said to be obtained from an orally administered daily dosage of 3 to 2,000 mgs. of the benzamide per trilogram of body weight, or where prophylactic treatment is required a continuous daily dosage of from 3 to 250 mgs. per kg. body weight is effective.  The invention contemplates the compositions in the form of capsules or tablets or in animal feed containing the compounds, and the dispersions may comprise water, ethanol, skim milk, edible oils, syrups.  The Specification describes the results of tests using the compositions against coccidiosis in chickens and pigs, such compositions comprising the active ingredients admixed with fullers earth or bentanite or attapulgite claz and sorbitan monopalmitate, or soybean meal diluted or admixed with mash or other animal feed.