IL32213A - Substituted guanidines - Google Patents

Description

NOVEL SUBSTITUTED GUANIDINES 32213/3 ; The new compositions of the present invention contain as the active component compounds of the following formula: wherein R. and R_ are selected from the group consisting of halogen, trifluoromethyi, and cyano, and RQ are selected from the group consisting of hydrogen and halogen, g, R^, ?; and R^ are selected from the group con* ing of hydrogen and lower alkyl, and Rg is selected from the group consisting of hydrogen and lower allssinoyl. and the pharmacologically acceptable acid salts thereof.

^Bhere the subetituents ?; g and RQ indicate hydrogen, the application relies on the date of July 1st, 1968, and in all other cases the application relies on the date June 26th, 1969.

The acid salts can be, for example, nitrate, hydrochloride, hydrobromide, methooulfate, and. the like; The term loweralkyl is intended to include those having 1 to 4 carbon atoms and lower aJkanoyl, those having 1 to 4 carbons in addition to the carbonyl group. The term halogen includes chlorine, bromine, fluorine, and iodine.

The compounds of this invention are, in general, . crystalline solids, ranging in color from white to pale yellow, slightly soluble in water and lower alcohols and insoluble in benzene, toluene and chloroform.

The present invention also includes new bis(benzylldeneamino) guanidlnes of the formula: R 9 32213/2 wherein Rx, Ra, R6, Re, R7 and Rg are as. defined hereinbefore and pharmacologically acceptable acid salts thereof.

The. above active components and novel compounds can be prepared by reacting a compound of the formula: . ' . ! wherein Rx , Ra and Ra are as hereinabove described, . dissolved in a water miscible organic :solvent,. with an aqueous or aqueous alcoholic solution of a compound of the formula: (H3N-N-)2C=NH»HX . , ' R7 9 . wherein ^ is as hereinabove described and X is the anion of a pharmacologically acceptable acid. The mixture is heated "to * from 50° to the boiling point of the solvent and held there for from one to ten minutes and then cooled to room temperature.

The precipitated product is ' collected, washed with ethanol and/ or ether and dried. ' . '' Other methods of preparing the instant compounds are illustrated by the equation's which follow: e¬ where Rx, Ra, R3, and R^ are as hereinabove described and Z is chlorine or bromine.

Compounds in which R^ is loweralkanoyl are prepared by reaction of the compounds in which Ro, is H with the appropriate organic acid anhydride. mmi #JV in11 mi M mdii i i m imiwΜΙΦ/ΜΒΝΜI Hkkkhhi H I ljl hidMMUmW Among the active components and novel compounds within the scope of the present invention are the following: 1, 3-bis(k-chlorobenzylideneamino) guanidine nitrate , 1, 3-bis(4-chlorobenzylideneamino )guanidine hydrochloride, l,3-bis(4-chlorobenzylideneamino)guanidine methosulfate , 1, 3-bis (4-bromobenzylideneamino )guanidine nitrate, l,3-bis( -bromobenzylideneamino) uanidine hydro- chloride, l,3-bis(3>½-dichlorobenzylideneamino)guanidine nitrate, l,3-bis(>, -dichlorobenzylideneamino)guanidine hydrochloride, 1,3-bis ( -cyanobenzylideneamino)guanidine nitrate, l,3-bis(4-cyanobenzylideneamino)guanidine hydrochloride , 1, 3-bis ( -chloro-a-methylbenzylideneamino ) guanidine nitrate, l,3-bis(4-chloro-a-methylbenzylidene- amino)guanidine hydrochloride, l-( -bromobenzylidene- amino ) ->- (4-cyanobenzylideneamino ) guanidine hydrobromide, l-(4-bromobenzylideneamino)-3- ( -chlorobenzylideneamino)- guanidine hydrochloride .

The active components and novel compounds of the present invention are highly active antiprotozoal agents in warm-blooded animals. For example, these compounds have anticoccidial activity against Eimeria tenella as shown by the following test: The animals were Peterson cross cockerels, 7 days old and of approximately equal size and weight. These cockerels were divided into groups and the groups were placed in separate cages with wire floors. Medicated and control diets were then presented to the groups of birds 2 days before inoculation while they were still in uncontaminated quarters. During the entire period of the tests, the brids ate and drank ad libitum. Control groups were maintained on a standard unmedicated commercial type chicken diet. Test groups were maintained on the same standard diet in which a measured concentration of test compound had been incorporated homogeneously. The cockerels were inoculated once orally with sporulated oocysts of Eimeria tenella. The number of oocysts inoculated directly into the crops of all cockerels in the tests was sufficient to produce high mortality in the untreated controls. The quantity necessary to produce high mortality, was determined prior to the times of inoculation by giving graded quantities of oocysts to comparable birds. Seven days following inosulation the tests were terminated and the mortality rate was recorded for each group. The results of these tests appear in Table I and show conclusively that these compounds are highly effective as anticoccidial agents. The tests represent very severe laboratory challenges, and lower concentrations than those shown would be effective under practical field conditions.

TABLE I TABLE I - Continued The compounds of the present invention have high activity against other coccidial species in chickens. Thus, l,l-bis( -chlorobenzylidene amino )guanidine completely protected treated chickens from mortality due to Eimeria necatrix, and from poor weight gains due to E. acervulina, E. brunetti , E. maxima or E. mivati .

Methods used were essentially identical with those previously cited with appropriate modifications. Weight gains were determined 7 days after single experimental inoculations with the designated species of coccidia.

The results are summarized in Table II.

TABL&II Anticoccidial Activity of 1,¾?-Bis( 4-chlorobenzylideneamino) - guanidine Eimeria ppm in No. % % control spp . Diet Survival Weight gain Salt necatrix 0 19 21 31 metho- sulfate 15 20 100 80 20 100 103 acervulina 0 20 100 57 nitrate 45 20 100 99 brunetti 0 20 100 76 hydrochloride 15 20 100 100 20 100 95 maxima 0 20 100 58 hydrochloride 20 100 101 20 100 95 45 20 100 100 mivati 0 20 95 52 hydrochloride 15 20 100 86 20 100 91 20 100 100 φ It is anticipated that the compounds of this invention will prove widely useful in a variety of vehicles, modes or means of administration or dispersal for the purpose of minimizing, preventing, controlling, treating, ameliorating or curing protozoal infections with sensitive organisms. One of these infections is coccidiosis which is a protozoan parasitic disease widespread in animals, causing a greater economic loss among domestic and game animals in temperate climates than any other protozoan disease. Coccidiosis is the most important animal parasitic disease of chickens, the causative agents being protozoa of the genus Eimeria, and is also important in other domestic animals such as turkeys, sheep, cattle and pigs.

The present compositions and novel compounds are active in warm-blooded animals as anti-malarial agents. When tested in mice in the range of from 150 mg./kg. to 0 mg./kg. they show an activity comparable to quinine.

Although administration of the compounds for coccidiosis will generally be most practical in or with the feed, or in the drinking water, the compounds may also be administered to individual hosts in the form of tablets, drenches, capsules, or the like, or by in-jection. These latter methods of administration are, of course, less practical for treatment of large groups of animals than they are for treating limited numbers of animals, but they are quite practical for use on a small scale or on an individual basis.

With the compounds of the instant invention, medicated feeds are usually prepared by thoroughly admixing about 0.0005 to 0.05$ by weight and preferably about 0.0015 to 0.025 by weight of active compound with a nutritionally balanced animal feed, as for example, the chick feed described in the examples hereinafter.

Where it is desirable to prepare a concentrate or premix for ultimate dilution in feed to the above levels, generally about 1$ to 2 $ and preferably about 3$ to 10$ by weight of medicament is blended with an edible organic or inorganic carrier, e.g., corn meal or corn and soybean meal, or alfalfa, or mineral salts containing a small amount of an edible dusting oil such as, for example, corn oil, or soybean oil. The thus prepared premix may then be added to the complete animal poultry feed prior to administration.

EXAMPLE 1 Preparation of l,3-Bis( -chlorobenzylideneamino)guanidine nitrate, hydrochloride and methosulfate A boiling solution of 14.1 grams of 4-chloro-benzaldehyde (slight excess) in 250 milliliters of ethanol is stirred vigorously as a solution of 6.1 grams of 1,3-diaminoguanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is then allowed to stand for several hours. The precipitate which forms is collected, washed with hot ethanol, air-dried and finally dried at 60°C. under reduced pressure. The yield is 14.0 grams of product and the melting point is 198°C. with decomposition.

The hydrochloride or methosulfate salt may be prepared by this same procedure, substituting equivalent amounts of the appropriate guanidine salt and employing 0.5 milliliters of the appropriate acid. . The hydrochloride salt melts at 289-290o(J. with decomposition. The methosulfate salt melts at 217-224°C. with decomposition.

EXAMPLE 2 Preparation of l,3-Bis(4-chlorobenzylideneamlno)guanidine The free base of the title compound is prepared by suspending 8 g. of the nitrate salt (Example 1) in 200 ml. of anhydrous ethanol, adding 2.5 ml. of ION sodium hydroxide solution, stirring and heating until the reaction mixture becomes homogeneous, and finally cooling the solution and filtering the resultant solid. The melting point of the free base is l87-l88°C.

EXAMPLE 3 Preparation of 1,3-ΒΤΠ 4-bromobenzylideneamino)guanidine A boiling solution of 20.0 grams of 4-bromo-benzaldehyde in 250 milliliters of ethanol is stirred 3 vigorously as a solution of 6.1 grams of 1,^-diamino-guanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is allowed to stand for several hours. The precipitate which forms is collected, washed with hot ethanol, air dried and finally dried at 60°C. under reduced pressure. The yield is 16.5 grams of product and the melting point is 178°-l80°C. with decomposition.

EXAMPLE k Preparation of l, 3-Bis( 3,4-dichlorobenzylideneamino)- guanidine Nitrate A boiling solution of 17 .6 grams of 3, 4-dichlorobenzaldehyde in 250 milliliters of ethanol is stirred vigorously as a solution of 6 .1 grams of 1, 3-diaminoguanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is then allowed to stand for several hours.

The precipitate which forms is collected, washed with hot ethanol, air dried and finally dried at 60°C. under reduced pressure. The yield is 17.5 grams of product and the melting point is 195-196°C. with decomposition.

EXAMPLE 5 Preparation of l, 3-Bis( 4-cyanobenzylideneamino) guanidine A boiling solution of 1 .1 grams of 4-cyano-benzaldehyde in 250 milliters of ethanol is stirred vigorously as a solution of 6 .1 grams of 1 , 3-diamino-guanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is then allowed to stand for several hours. The precipitate which forms is collected, was ed with hot ethanol, air dried and finally dried at 60°C. under reduced pressure. The yield is 15 .1 grams of product and the melting point is 205 °-210°C. with decomposition.

EXAMPLE 6 Preparation of l, 3-Bis( -chloro-a-methylbenzylideneamino)- guanidine Nitrate A boiling solution of 15 . grams of 4-chloro-acetophenone in 250 milliliters of ethanol is stirred vigorously as a solution of 6 .1 grams of 1, 3-diamino-guanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is then allowed to stand for several hours. The precipitate which forms is collected, washed with hot ethanol, air dried and finally dried at 60°C. under reduced pressure. The yield is 8.7 grams of product and the melting point is 215°C. with decomposition.

EXAMPLE 7 Preparation of l, -Bis( 4-iodobenzylideneamino)guanidine Hydrochloride Following the procedure of Example 1 and substituting 4-iodobenzaldehyde for -chlorobenzaldehyde and 1, 2-diaminoguanidine hydrochloride for 1 , 5-diamino-guanidine nitrate the product of the example is obtained. The hydrochloride has a melting point of 288 ° -291°C, dec.

EXAMPLE 8 Preparation of 1, 5-Bis( -fluorobenzylideneamino)guanidine Nitrate Using the procedure of Example 1 and substituting 4-fluorobenzaldehyde for 4-chlorobenzaldehyde the product of the example is obtained. The nitrate has a melting point of 169° -170°C. , dec.

EXAMPLE 9 Preparation of Methyl thiocarbazimidate hydrochloride Excess methyl chloride is collected in a dry ice-acetone-cooled trap and added to a tared pressure vessel containing 91.1 g. of powdered thiosemicarbazide in 600 ml. of anhydrous ethanol. Weighing the vessel plus contents shows that 53 g. of methyl chloride has been added. The reaction mixture is magnetically stirred while heating in an oil bath temperature of 77 to 110°C. for 48 minutes. After 33 minutes, the reaction has become homogeneous. It is cooled in ice and the resultant rose-white solid filtered and dried in a vacuum oven. The yield of the title compound is 121 g. melting point 154-15 °C.

Substitution of dimethyl sulfate, ethyl iodide or propyl bromide for methyl chloride and allowing the reactions to proceed in refluxing anhydrous ethanol instead of under pressure, results in the pre-paration of methyl thiocarbazimidate methosulfate, ethyl thiocarbazimidate hydroiodide, and propyl thiocarbazimidate hydrobromide, respectively.

EXAMPLE 10 Preparation of MethyT 3-(4-cCTorobenzylidene)thiocarbazimi- date hydrochloride A solution of -8 g. of 4-chlorobenzaldehyde in 10 ml. of warm absolute ethanol is added all at once to a stirred solution of 5 g. of methyl thiocarbazimidate hydrochloride in 100 ml. of warm absolute alcohol. The reaction mixture is stirred at room temperature for about 15 minutes and cooled in ice. The white solid product is filtered off and air dried; melting point 212-2l4°C.

The following are prepared in like manner: methyl 3- (4-bromobenzylidene) thiocarbazimidate metho-sulfate from 4-chlorobenzaldehyde and methyl thiocar- bazimidate methosul ate, ethyl 3- (4-cyanobenzylidene)-thlocarbazimidate hydroiodide from 4-cyanobenzaldehyde and ethyl thiocarbazimidate hydroiodide, and propyl 3-( 3 , 4-dichloroberizylidene )thiocarbazimidate hydrobromide from , 4-dichlorobenzaldehyde and propyl thiocarbazimidate hydrobromide.

EXAMPLE 11 Preparation of MethyT~3-( -chIorobenzylidene)thiocarbazlmi- date hydrochloride A 10% molar excess of methyl chloride is added to 2.14 g. of 4-chlorobenzaldehyde thiosemicarbazone and 25 ml. of anhydrous ethanol in a pressure vessel.

The reaction mixture is magnetically stirred and heated in an oil bath for 1 1/2 hour. The crystalline title compound separates on cooling and is filtered off and air dried.

EXAMPLE 12 Preparation of l, 3-BTs(4-chlorobenzylideneamlno)guanidine : hydrochloride A solution of 101 g. of 4-chlorobenzaldehyde in 40 ml. of warm 9 ethanol is added portionwise to a stirred solution of diaminoguanidine hydrochloride in 4 0 ml. of 90$ ethanol at 70°C. Addition of the first portion causes rapid boiling and the reaction mixture is cooled to a little above room temperature before the remainder of the 4-chlorobenzaldehyde solution is added.

Stirring is continued for 15 minutes and the reaction mixture is cooled in ice, filtered, and air dried. The yield is 122 g. of solid, melting point 295°C. with decomposition.

The same product is obtained when l-amino-3-( 4-chlorobenzylideneamino)guanidine hydrochloride (Example 13) is allowed to react under similar conditions as above with an equimolar amount of 4-chlorobenzalde-hyde .

The same product is also obtained from the reaction of methyl 3-(4-chlorobenzylidene)thiocarbazimi-date (Example 10) with the hydrazone of 4-chlorobenzalde-hyde in refluxing 95$ ethanol . The hydrazone of 4-chlorobenzaldehyde is prepared according to the procedure for the synthesis of hydrazones of aromatic alde-hydes and ketones outlined in G. Newkome and D. Fishel, J. Org. Chem., 51, 677 (1966).

EXAMPLE I? Preparation of l-Amino"-5-(4-chlorobenzylideneamino) - guanidine hydrochloride To a solution of 2.6 g. of methyl 3- -chloro-benzylidene )thiocarbazimide in 10 ml. of boiling absolute ethanol is added 0.6 g. of hydrazine hydrate. The reaction mixture is cooled in ice and the solid 1-amino-3-(4-chlorobenzylideneamino)guanidine removed by filtration.

Similarly the reaction of methyl 3-(4-bromo-benzylidene )thiocarbazimidate methosulfate, ethyl 3-(4-cyanobenzylidene) thiocarbazimidate hydroiodide, and propyl 3·"·(3, -dichlorobenzylidene ) thiocarbazimidate hydrobromide with hydrazine yield, respectively, 1-amino-3-(4-bromobenzylideneamino)guanidine methosulfate, l-amino-3-(4-cyanobenzylideneamino)guanidine hydroiodide, and l-amino-3-(3,4-dichlorobenzylideneamino)guanidine hydrobromide .

The reaction of 4-chlorobenzaldehyde with a 4-fold molar excess of diaminoguanidine hydrochloride in boiling 90" ethanol also gives l-amino-3-(4-chlorobenzyl-ideneamino )guanidine hydrochloride, together with a small amount of 1, 3-bis(4-chlorobenzylideneamino) guanidine hydrochloride .

EXAMPLE 14 Preparation of l-(4-Bromobenzylideneamino)-3-(4-chloro- benzylldeneamino ) guanidine hydrochloride A solution of 1.85 g. of 4-bromobenzaldehyde in 10 ml. of ethanol is added to a solution of 2.48 g. of l-amino-3-(4-chlorobenzylideneamino)guanidine hydrochloride in 25 ml. of boiling 9 $ ethanol. The reaction mixture is cooled and the solid product removed by filtration and air dried.

In a similar manner the reaction of 1-amino- 3- (4-bromobenzylideneamino) guanidine methosulfate with 4-chlorobenzaldehyde gives the methosulfate salt of the subject compound. The reaction of l-amino-3- (4-cyano-benzylideneamino) uanidine hydroiodide with 4-chlorobenzaldehyde gives l-(4-chlorobenzylideneamino)-3-(4-cyanobenzylideneamino)guanidlne hydroiodide. The reaction of l-amino-3-( 3, 4-dichlorobenzylideneamino) guanidine hydrobromide and p_-chlorobenzaldehyde gives l-(4-chloro-benzylideneamino ) -3- (>,4-dichlorobenzylideneamino ) -guanidine hydrobromide .

EXAMPLE 15 Preparation of Chick Diet The following specific feed composition is an example of poultry feed as a carrier for the coccidiostats described hereinbefore.

Vitamin-Amino acid 0 .5$ Trace Minerals 0.1$ Sodium Chloride 0.3$ Dicalcium Phosphate 1.2$ Ground Limestone 0.5$ Stabilized Fat 4$ Dehydrated Alfalfa, 17$ protein 2$ Corn Gluten Meal, 41$ protein 5$ Menhaden Fish Meal, 60 protein 5$ Soybean Oil Meal, 44$ protein 30$ Ground Yellow Corn, Fine To 100$ The vitamin pre-mix in the above feed compo-sition is prepared from the following formulation. The expressions of quantity relate to units per kil gram of the feed composition.

Bytylated Hydroxy toluene 125 mg. di-Methionine 500 mg.

Vitamin A 3300 I.U.

Vitamin D3 1100 I.C.U.

Riboflavin 4 .4 mg.

Vitamin E 2 .2 I.U.

Niacin 27.5 mg.

Pantothenic Acid 8.8 mg.

Choline Chloride 500 mg.

Folic Acid 1 .43 mg.

Mendadione Sodium Bisulfate 1 .1 mg.

Vitamin Βχ2 11 meg.

Ground Yellow corn, Fine To 5 gm.

EXAMPLE 16 Preparation of l, 3-Bis(4-trlfluoromethylbenzylldeneamlno)- guanidlne hydrochloride A solution of 10 g. of -trifluoromethylbenzal-dehyde in the minimum amount of 95$ ethanol is added to a boiling solution of 3.6 g. of diaminoguanidine hydrochloride in 50 ml. of 95$ ethanol and a few ml. of water. The solution is stirred and allowed to cool and the solid removed by filtration and washed with 95$ ethanol and ether. The yield is 9.6 g. of white solid with. a melting point of 272-273 -5$ with decomposition.

A mixture of 1^« 1 grams of li-chlorobenzaldehyde, I..6 grams of methylhydrazine and 500 ml. of dried benzene is stirred at reflux in a continuous water removal apparatus until no further separation of water is noted. The benzene solution of the resultant methylhydrazone of ij.-chlqrobenzaldehyde is cooled to room temperature and treated with a solution of 5· 3 grams of cyanogen bromide in 100 ml. of benzene. The reaction .mixture is stirred at reflux for four hours, a white precipitate separating out during this time. The precipitate is filtered from the hot solution, washed and dried. It is recrystallized from ethanol of i;-chloi¾benzalx iyde and one molar equivalent of l,.3-f¾snlno-l , 3-dime thylguanidine hydTObranide are raf Ιηχβ in ethasol solution in 1he presents of a little kQ aqueous hydrobromi*c acid for a few minutes.

EXAMPLE 18 Preparation of l,3-Bis(t-chTorobenzylideneamino)-l, 3-di-n- butylguan ine hydrobromide The preparation of the above compound is carried out by the procedure of Example 17, an equivalent of n-butylhydrazine replacing the methylhydrazine . The isolated product after re-crystallization from ethanol-diethyl ether decomposes about 150°C.

EXAMPLE 19 Preparation of 1, 3-Bis (li-Chlorobenzylideneamino ) -l-methylguani- dine hydrobromide The preparation of -the title compound is carried out essentially by the procedure of Example 1, 7· 3 grams of 1,3-diamino-l-methylguanidine hydrobromide replacing the 1,3-di-aminoguanidine nitrate and 0.-5 ml* of &$ HBr being employed as catalyst. The yield of product is 1 .1. grams and the ■ ύ point is 276-278°C.

EXAMPLE 20 Preparation of 2-Acetyl-l , 3-bi3( -chlorobenzylideneaminoguani- dine A mixture of 20 g. of 1, 3-bis(p_-chlorobenzylideneamino ) guanidine free base and 9 ml. of acetic anhydride in 300 ml. of anhydrous ether is stirred at reflux for 16 hours 9 then filtered to give a solid containing starting material, and acetylated material. The solid is reacted with an additional 3 ml* of acetic anhyd ide in 300 ml. of toluene for 1 hour, cooled to room temperatu e end filtered. The solid (II4. g. ) is dissolved in 100 ml. of chloroform and treated with 50 ml. of 3 N hydrochloric acid, and the resulting solid is filtered, the crude product is slurried in 100 ml. of boiling chloroform, filtered, and dried - ■ form and aqueous sodium bicarbonate, and the chloroform layer is dried and evaporated to give 2-acetyl-l, 3-bis (lj.-chlorobenzyl-ideneamino)guanidine, melting, point 197-200°C. (dec . ) .

The reaction of 1, 3-bis (p_-chlbrobenzylideneamino )-guanidine free base with acetyl chloride in ether gives the same acetyl derivative according to thin layer chromatograph c evidence, along with recovered starting material.

When 1,3-bis (p_-chlorobenzylideneamino )-l,3-dimethyl-guanidine free base ia submitted to the above reaction conditions with acetic anhydride, ; there is obtained the corresponding 2-acetyl-l, 3-bis (i.-chlorobenzylideneamino)-l, 3-dimethylguani-dine .

Similarly, the reaction of 1 , 3-bis ( -cyanobenzylidene-amino)guanidine and propionic anhydride in refluxing ether gives 1, 3-bis (l+-cyanobenzylideneamino )-2-propionyl )guanidine.

Claims (5)

, . ~ " .· 322.1.3 / 2 " ,. r4 Where the substituents R7,. Rg and Rg indicate hydrogen, the application relies on the date July 1st, 1968, and in all other cases the application relies- on the - date June 26th, I960. ' "

1. 7. 68 ' . 26. 6. 69 1. A composition for the control of coccidiosis infections in poultr comprising an edible . carrier and about between 0.0005 and 0.65 by weight of a compound of the formula: wherein R x and R_. are selected from the group consisting of halogen, trifluorome thyl and .cyano, Rs ' and Re are selected from the group consisting of hydrogen and halogen, R3, R4, Ry and Rg are selected from the group consisting of hydrogen and lower alkyl, is selected from the group consisting of hydrogen and lower alkanoyl and the pharmaceutically acceptable acid .salts thereof.

2. A composition according to Claim 1, wherein said compound is administered in an edible carrier containing about between 0.0015% and 0.025% by weight of said compound.

3. A composition according to Claim 2, wherein said compound is 1, 3-bis(l+-chlorobenzylideneamino )guanidine hydrochloride. 1. 7. 68 i . A method of controlling coccidiosis and other 26. 6. 69 * protozoan infections in warm-blooded animals comprising administering orally or parenterally to said hosts a protozoacidally effective amount of a compound of the formula: ?9 ; ·

4. R3 R4

5. ' ■ ■ 'S32&3/2 . : . »