IL42355A - Phosphonoureido and thioureido compounds their preparation and anthelmintic compositions containing them - Google Patents

Abstract

Cpds of formula (I)- where A = bivalent arylene; T = (thio)uredio; Z = NR3R4, ureido or thioureidoacyl (1-28C) R3 and R4 = H or monovalent 1-18C aliphatic R1 and R2 = opt. substd. 1-8C aliphatic benzyl or monovalent aromatic. They are pref. prepd. by reacting a cpd (IV) pref. in aprotic solvent with a cpd (V) and reacting the group NR3R4 either before or afterwards with an acylisocyanate or replacing isothiocyanate with a uradoacyl group [FR2187336A1]

Description

42355/2 Phosphonoureido and thioureido compounds, their preparation and anthelmintic compositions containing them ROHM AND HAAS COMPANY C:- Ο5ΟΟ This invention relates to anthelmintic compounds and compositions, to their preparation and use for the treatment of intestinal parasites in most creatures such as mammals and birds.

Helminthiasis is a disease affecting man and animals and is manifested by the infection of the host with parasites known as helminths. It is a widespread disease caused by a variety of helminths found in ruminants such as sheep, cattle, and goats; equines such as horses and mules; domesticated small mammals such as dogs and cats; poultry and man. For example, tapeworms in sheep and cattle are represented by the genera Moniezia and Thysanosoma; tapeworms in horses are commonly of the genera Anoplocephala and Para-rxoplecephal important tapeworms of dogs and cats include the Dipylidium and Taenia genera, as well as Echinococcus in dogs; and poultry tapeworms include Davainea and Rail-lietina. In man, diphyllobothriasis, hymenolepiasis, dipy-lidiasis, taeniasis, echinococcosis, and cysticercosis, are important tapeworm infections, most of which are transmitted by animals.

Roundworms found in sheep and cattle are of the genera Strongyloides, Oesophagostomum, Bunostomum, Haemon-chus, Ostertaqia, Trichostronqylus, Cooperia, Nematodirus and Chabertia. Similarly, the nematode genera commonly affecting horses are Stronqylus, Strongyloides, Trichonema, Parascaris . and Qxyu is . Common roundworms of dogs and cats -• are Toxocara and Toxascaris ; hookworms (Ancylostoma ) and whip- worms (Trichuris) afflict dogs as well. Some of the intestinal nematodes of man cause trichinosis, trichuriasis, strongyloid- iasis, ancylostomiasis, oxyuriasis and ascariasis. The most economically important fluke of domestic sheep and cattle is Fasciola Hepatica ; this parasite bears some resemblance to the organism causing schistosomiasis in man.

At present, general anthelmintic treatment usually involves treating the diseased host with specific anthelmintic agents having selective anthelmintic properties. It would be more desirable to provide an anthelmintic composition having a wide spectrum of activity, for example ridding the host animal simultaneously of tapeworms, flukes and roundworms.

In accordance with the present invention, there are provided novel phosphonoureido or thioureido arylene anthelmintic compounds of the formula: X 0 HR3 where ^ and R2 each represent ^-C^ alkyl optionally substituted by halogen; X represents oxygen or sulfur; A represents o-phenylene, o-naphthylene or o-phenanthrylene each optionally substituted by halogen; and represents hydrogen or a group of the formula: X1 II -CNHR 4 where X1 is oxygen or sulfur and R4 represents alkanoyl of optionally substituted by alkyl, alkylene or halogen, or benzoyl optionally substituted by alkyl, nitro or mono- or polychloroalkyl .

Compounds of the above formula may be prepared by a process comprising reacting an arylene compound of the formu , A and being as above defined, with a substantially equimolar amount of a compound of the formula X 0 OR and R^ being as defined above. ^0R2 When,in the above process, it is desired to produce a compound of the formula indicated wherein R^ in the arylene reactant is hydrogen, there may be included the additional step of reacting the product of the process of Claim 1 with a substantially equimolar amount of a compound of the formula C= -R4.

In this specification the term "lower" when used in respect of alkyl means containing up to 4 carbon atoms.

The anthelmintic compounds of the invention are arylene compounds whose free valences are satisfied by (1) a uradophos-phono group attached to the arylene nucleus through a free valence of the urado group and (2) a nitrogen-containing sub-stituent which is either an amino group or a uradoacyl group attached to the arylene nucleus through a free valence of the urado group. In typical compounds of the formula A is o-phenylene, o-naphthylene, o-phenanthrylene or chlorophenylene, R_ may be hydrogen or a group of the n formula -CNHR^, 4 may be methylsulfonyl, benzenesulfonyl, acetyl, propionyl, benzoyl, toluyl; and ^ and R2 maV >e for example methyl or ethyl.

The preferred anthelmintic compounds have the ureido- or thioureido-phosphono group and the NH ^ group on vicinal carbon atoms of the arylene ring, i.e. the groups are ortho to each other. The ortho-arylene compounds appear, according to our observations, to be markedly more potent than the corresponding meta-arylene and para-arylene derivatives. The orthophenylene (including the substituted orthophenylene) and orthobenzophenylene compounds are particularly preferred.

These compounds have been found to be highly effective, both therapeutically and prophylactically , against certain genera of tapeworms, roundworms and flukes when administered orally to animals.

Particularly preferred new anthelmintic compounds are those wherein X is 0 or S; ^ and l^, are, independently , - lower alkyl (e.g. methyl, ethyl, iso-propyl , n-butyl) , halo lower alkyl (e.y. 2-chloroethyl , trifluoroiri thyl) ; and is hydrogen, or X' -CNH ^ t erei ' is 0 or S and erein R^ is lover alkyl r-ulfo.nyl (e.g. jrethanesulfonyl , ethane-cull forcyl) , benrenc-culfonyi, substituted bensenesulfcnyl (e.g. 3,4--tri-inet ylenebensenesulfonyl or 4-dim thylauinobenzene sulfon/1) , lov.-er alkanoyl (e.g. acetyl, propionyl) , benzoyl or substituted benzoyl (as defined hereinbefore) . The most preferred compounds include such compounds in which X is 0, R_ is -CJJHR. and , is lov/er alkvl sulfonyl or in which 3 4 o 4 X is S, R.. is - iHR^ and is benzenesulfonyl or substituted benzen'esulfonyl . One example is the compound S 0 Further preferred classes of compounds are such compounds in which (a) X is 0, R3gis -CNHR^ and is lower alkanoyl , (b) X is s gR3 is -C HRj and is lower alkyl sulfonyl, (c) is -CNHR^ and R^ is benzenesulfonyl or p-toluenesulfonyl , (d) X is SfgR3 is -CNHR^ and R^ is lower alkanoyl, and (e) R^ is -CNHR^ and R^ is benzoyl or substituted benzoyl (as defined hereinbefore) . Examples include the following compounds : 0 II NHCNHP(OCH CH ), NHCNHSO, -CH 3' O and O Other examples will be found in the specific Examples hereinafter.

The terms "substitu ed phenyl", "substituted ben-zenesulfonyl" and "substituted benzoyl" refer to structures containing a benzene ring substituted me a and/or para to the point of attachment to the rest of the molecule, wherein the substituent (s) may be as defined above.

Phosphonoisothiocyanate reactants for use in the process of the invention can be made by reacting an appropriate dialkyl- or diary! - phosphonochloridate with potassium thio- cyanate in - · acetone, toluene or ethylene glycol dimethyl ether (glyme). The phospho?socyanates can be made by reacting the appropriate chlorophosphate with ammonia in ether to yield the corresponding phosphcramide which is then reacted with oxalyl chloride and heated.

Aryl or alkyl sulfonylisothiocyanate suitable for use in stage II may be made by condensing a substituted sulfonamide with carbon disulfide in the presence of potassium hydroxide in dimethylformamide. The dipo- tassium substituted sulfonyl iminodithiocarbonate which is isolated is then reacted in toluene with thionyl chloride or phosgene to give the sulfonylisothiocyanate.

The arylsulfonylisocyanates may be prepared by reacting the appropriate arylsulfonamide with oxalyl chloride in chlorobenzene and heating to yield the product. The alkylsulfonylisocyanates may be prepared in accordance with the process described in U.S. Patent specification 3,185,677. The alkanoyl and aroylisothio- cyanates may be prepared by reaction of an acid chloride with lead thiocyanate in acetone or benzene.

The alkanoyl and aroylisocyanates may be prepared by reacting the appropriate amide with oxalyl chloride in dichloroethane and heating to yield the product.

The preparation of preferred embodiments of the invention, and some of- the precursors thereof, will now be described for the purpose of illustration only, in the following procedures in which the term "glyme" refers to ethylene glycol dimethyl ether and all temperatures are in degrees Celsius.

Procedure 1 - Synthesis of Dialkyl -cxc-niarylphosphonoiso- thiocyanate precursors Diethyl and diphenyl chlorophosphates were purchased from Adrich Chemical Co. The other alkyl chlorophosphates were synthesized according to the procedure of de Roas and Toet, Rec. trav. chim. , 77, 946-55 (1058).

The appropriate dLalkyl or -diaryl -chlorophos-phate (1 mole) was added dropwise to an ice-cooled solution of potassium thiocyanate (1.1 mole) in 500 ml of dry acetone. The suspension which formed was stirred at room temperature for 2 days and was concentrated in vacuo. The residue was suspended in 300 ml benzene and washed with cold water until the washings recorded a pH of 5. The benzene solution was dried with magnesium sulfate and then concentrated in vacuo, giving a yellow-orange liquid. The infrared spectrum of these materials showed a strong isothiocyanate band at 4.6-5.1 microns.

Table 1 presents the results of four such syntheses.

Table 1 Dialkyl -or diaryl phosphonoisothiocyanates R Yield Procedure 2 - Synthesis of Dialkylphosphonoisocyanate precursors An ice cooled solution of (20q, 0.116 mole) diethylchlorophosphate in 250 ml ether was saturated with ammonia, yielding a white suspension that was vacuum filtered. The first crop was dried, affording a yield of 16.3 g. (0.114 mole) diethylphosphoramide, melting point 50-51°.

To a solution of (16.3 g, 0.114 mole) diethyl-phosphoramide in 50 ml 1, 2-dichloroethane, oxalyl chloride (18.4g, 0.145 mole) was added dropwise. The solution which formed was refluxed and stirred for 24 hours and was concentrated in vacuo. The residual oil was vacuum distilled, yielding 10 g (56% yield) pure product, boiling point 102°/15 mm.

Procedure 3 - Synthesis of Aryl or Alkylsulfonylisothio-cyanate precursors To a solution of the aryl or alkylsulfonamide (1 mole) and carbon disulfide (1 mole) in 500 ml dry dimethylformamide, potassium hydroxide was added as pellets. The suspension which formed was stirred at 42355/2 room temperature for 2 hours, and then more potassium hydroxide (1 mole) was added. The temperature of the exothermic reaction was kept at 35° with ice cooling.

A thick suspension formed which was stirred 24 hours at room temperature and was then vacuum filtered.

The first crop of material was of high purity. Table 2 presents the results of two such syntheses.

To the dipotassium salt (0.48 mole), phos- gene (0.5 mole in a 12.5% benzene solution) was added with ice cooling and stirring. The resultant suspension was stirred at room temperature for 24 hours under anhydrous conditions and then filtered. The potassium chloride residue was washed with ether (3 x 100 ml), and the filtrate and washings were concentrated in vacuo. The yellow-orange oil obtained was of high purity. The infrared spectrum showed an isothiocyanate band at 4.9-5.4 microns. Table 3 presents the results of two such syntheses.

Table 2 Dipotassium Alkyl or Arylsulfonyl Melting Point iminodisothiocyanates R Yield (°C) R-S0„N 95% 281° (decomposed) CH CH - 80% 229° (decom posed) 242-248° (decom posed) Table 3 Alkyl or Aryl Sulfonylisothiocyanates R Yield CH3CH2- 91% Procedure 4 - Synthesis of Aryl sulfonylisocyanate precursors Oxalyl chloride (16.5 g. , 0.13 mole) was added in one portion to an ice cooled suspension of the aryl sulfonamide (0.1 mole) in 100 ml of anydrous chloro-benzene. The mixture was allowed to warm to room temperature and was then refluxed and stirred for 24 hours. The suspension was cooled and vacuum filtered through diatomaceous earth. The filtrate was stripped of its solvent content in vacuo, and the residue was vacuum distilled to yield the product. The product v/as identified by the infrared band at 4.5 microns, characteristic of isocyanate.

Table 4 presents the results of four such syntheses.

Table 4 Aryl sulfonylisocyanate R Yield Boiling Point (see notes 1 and 2) Note 1 - Reaction was initiated in ethylene dichloride solvent was then changed to chlorobenzene to effect thermal decomposition of the intermediate at about 148° Note 2 - Reaction performed with 0.0475 moles of the sulfonamide and 0.06 moles of oxalyl chloride. Product decomposes rapidly at high temperature.

Procedure 5 - Synthesis of Alkanoyl or aroylisothio- cyanate precursors The appropriate alkanoyl or aroyl chloride (0.25 mole) was added to a benzene suspension of lead thiocyanate (97 g; 0.3 mole), and the mixture was refluxed and stirred for 24 hours and then vacuum -filtered,, through dia omaceows^earih-^he^f-i-Lt-ra=fee=-was-= concentrated in vacuo and was vacuum distilled. The infrared spectrum of these materials showed strong Q isothiocyanate bands at 4.8-5.2 microns and " R-C- bands a 5.8-5.9 microns.

Table 5 presents the results of six such syntheses.

Alkanoyl or Aroyliso thiocyanates ' R Yield Boiling Point CH3- 40% 57°/32mm II CH3CH2- 81°/60mm RCN = C = S C1CH-- 35% 98°/50mm ng 5°) Procedure 6 - Synthesis of Alkanoyl or aroylisocyanate precursors To a solution of the appropriate amide in ethylene dichloride, oxalyl chloride was added dropwise. The solution formed was refluxed and stirred for 24 hours and was concentrated in vacuo. The residual oil was vacuum distilled.

Tabie"~6 resents- the"- results'- of-^two-such syntheses.

Table 6 Aro lisocyana e R .yjeld Boiling Point R 52.5 94-95 °/4.5mm Yield Amide Oxalylchloride (mole ) (mole) Solvent (a) 0.1 0.12, 200 ml (b) 0.1 0.13 350 ml Note 3 - Solid showed slight decomposition at 90°; decomposition product remained solid to 225°. Another sample showed total decomposition when placed in preheated 130° bath.

Procedure 7 - Preparation of Mono(&ialkylphosphono)bhio- ureides To a solution of the desired _o-phenylene diamine (1 mole) in dry glyme (300 ml), the phospho-noisothiocyanate (1 mole) was added dropwise with ice cooling. After the suspension was stirred for 24 hours, the product was isolated by filtration. The initial crop yielded pure product. Table 7 presents the results of two such syntheses.

Table 7 ' " Mono(dialkylphosphono)hio ureides R , Y-t^^»--^-Mel :i-n --^-o3r.i¾fc^- Carbon ~ Hydrogen Nitrogen Calcd. Found Calcd. Found Calcd. Found (a) 43.6 43.10 5.99 6.12 13.85 13.71 (b) 47.11 47.25 6.70 6.45 12.78 12.78 Procedure 8 - Preparation of l-( 3-dialkylphosphonothio- ureido )-2-( 3-alkyl or ary'l sulfonylureido ) benzene compounds To a suspension in glyme or other solvent as indicated, of the appropriate monc(dialkylphosphono)thi-oureide (DAPT) prepared generally according to Procedure 7, the arylsulfonylisocyanate (AIC) was added dropwise rapidly. During the course of a slightly exothermic reaction, the mixture became a solution; except as otherwise indicated, it was maintained at room temperature for the indicated reaction period, and a precipitate formed. The product was isolated by vacuum filtration and was identified by elemental analysis and infrared spectrum.

Table 8 presents the results of six such syntheses of which (b) and (b' ) are alternative runs of^the---satne^compound.-^= Table 8 sed) ed) ed) DAPT AIC Reaction Other (mole) (mole) Solvent Time Conditions (a) 0.0123 0.0123 15 ml glyme 24hr. Heated to 50° for 2 min. at end of reaction whereupon ppt. formed (b) 0.00595 0.00595 benzene 2-1/2 Reaction conhr. ducted at reflux (b« ) 1.0 1.0 150 ml glyme 1 hr. (c) 0.01 0.01 15 ml glyme 4 hr. Water used to produce ppt. (d) 0.02 0.02 15 ml glyme 15 in. (e) 0.0092 0.0092 15 ml glyme 24 hr.

Procedure 9 - Preparation of l-( 3-Dialkylphor,phonothioureido)- 2-( 3-aroylureido) b ene ComDounds The mono(dialkylphosphono) thioureide (DAPT) prepared generally in accordance with procedure 7 and the aroylasocyanate (AIC) were permitted to react at room temperature in the manner indicated. The product was isolated by vacuum filtration and identified by elemental analysis and infrared spectrum.

Table 9 presents the results of two such preparations.

Table 9 Melting Point Compound ( °C) N See note 4 -NHCNHCR sed) DAPT AIC Reaction Other (mole) (mole) Solvent Time Conditions (a) 0.01 0.01 10 ml glyme 10 mn, Product formed immediately (b) 0.01 0.01 100ml aceto- 30 min. Reactants added nitrile . simultaneously to the solvent.

Suspension of product formed immediately Note 4 - At 177° compound appears to change to a substance which decomposes at 235-240° to a yellow liquid.

Procedure 10 - Preparation of Mono (dialkylphosphoncXireides Diethylphosphonoisocyanate (10 g. , 0.05575 mole) in 5ml glyme was added dropwise to an ice-cooled solution of jo-phenylenediamine (6.03 g. , 0.055.75 mole) in 25 ml glyme. The suspension was stirred at room temperature for 72 hours and was then vacuum filtered, yielding 12.5 g. product (76% yield), melting point 137-140° ( slight decomposition) . The compound was identified by infrared spectrum and elemental analysis.

Procedure 11 - Preparation of l«(3-Dialkylphosphonoureido) 2-( 3-alkanoyl or aroyl or alkyl sulfonyl or arylsulfonylureido or - thioureido)benze e Compounds The monc(dialkylphosphono)ureide (DAPU) prepared generally according to Procedure 10 was suspended in glyme, and then the appropriate alkanoyl, aroyl-, alkyl- sulfonyl, or aryl-sulfonyl-isocyanate or sothiocyanate (AIC) was added. A solution formed, with mild exotherm, and then a suspension resulted, which was stirred at room temperature for the indicated time. The suspension was vacuum filtered, and the product was identified by elemental analysis and infrared spectrum. Each of the compounds possessed the carbonyl band of the phosphono- urea at 5.9-6 microns.

Table 10 presents the results of five such preparations.

Table 10 0 (d) CH3C- 0 S (e) CH3CH2C- DAPU AIC Glyme Reaction Melting Point (mole) (mole) (ml) Time Yield ( °C) (a) 0.01 0.03 20 30 min. 78% 169-171° (decomposed) (b) 0.01 0.02 20 30 min. 71% 169-170° If If (c) 0.00523 0.00523 10 30 min. 86% 136-140° ( see note 5 ) " " (d) 0.01 . 0.025 20 30 min. 59 183-184° .

It It (e) 0.01 0.03 20 18.hr. 37% 183.5-185° ft It (See note 5). .

Note 5 - Suspension permitted to stand at room temperature overnight before separating product.

Procedure 12 - Preparation of l-( 3-Di.alkylphosphonothiou- reido )-2-( 3-alkylsulfonyl thioureido )benzene Compounds To a fine suspension of the appropriate mono (dialkylphosphono);hioureide (0.2 mole) in dry glyme (400 ml) the desired sulfonylieothiocyanate ].,;...... ,, (0.3 mole) was added dropwise at room temperature. The temperature was not allowed to exceed 35° while the solution was stirred for the time indicated in Table 11. The product was isolated by filtration of the reaction mixture and was found to be pure. Table 11 presents the results of four such syntheses.

Table 11 Compounds R P_* X S 0 (a) CH3- CH3CH2- H- II II •(b) 148-151° (decomposed) 27% 18 hr. (c) 165-165.5° (decomposed) 72% 15 min. (d) 168° (decomposed) 84% 30 min.

Procedure 13 - Preparation of l-( 3-Dialkylphosphonothio- ureids)-2-( 3-alkanoyl and aroylthioureido) benzene Compounds To- a fine suspension of the appropriate mono dialkyl-phosphonothioureide ( DAPT in Table 12) in dry glyme, the desired acyl or aroylisothiocyanate (AITC in Table 12) was added dropwise at room temperature. A solution formed immediately, with slight exotherm, followed by formation of a precipitate. The reaction was permitted to. proceed at room temperature for the time indicated. The product was isolated by vacuum filtration of the suspension. Table 12 presents the results of seven such syntheses.

• Table 12 Compounds R* (a) CH CH CH - HCNHP( OR* ) 2 (b) CH^CH^- CH3CH2- (c) CH. C1CH2CH2- NHCNHCR II II s o - 2? - (d) CH3CH2- Reaction DAPT AIC Mel inq Point ( °C) Yield Time (Mole) (Mole )Glyme (a) 157.5-159° 74% 30 min. 0.01 0.03 30ml (b) 155-156.5° 84% ' 15 min. 0.02 0.04 30ml (c) 162-164° (decomp. ) 91% 3 hr. 0.01 0.03 20ml (d) 129-130° (decomp. ) 17.8% 24 hr. 0.02 0.02 25ml (e) 175-176° (decomp. ) 81% 25 hr. 0.02 0.04 20ml (f) 160-162.5 "(decomp. ) 77% 5 min. 0.01 0.01 10ml (g) 130.5-132.5° (decomp. l% 5 hr. 0.01 0.01 10ml All of the aforesaid procedures have been described with reference to crthophenylene diamines. The same preparative techniques were employed on other aromatic diamines, such as 1, 2-naphthalenediamines; 3,4-naphthalene-diamines; 1,2 or 2, 3-anthracenediamines; 1,2 or 2,3, or 9 , 10-phenanthrenediamines. For example, the 2, 3-naphthalene derivative corresponding to the compound described in preparative method 8(b) was produced in the same manner as compound 8(b) using 2 , 3-naphthalenediamine in place of orthophenylenediamine. The compound' resulting from this synthesis had a decomposition temperature of 175° - 25 - to 178 °C. It has a theoretical structure of C -H R7 .O^PS Theoretically, this compound contains 50.17% carbon, 4.94% hydrogen and 10.18% nitrogen. The compound produced had 50.61% carbon, 5.03% hydrogen and 10.3% nitrogen.

This compound had essentially the same anthelmintic activity as the corresponding 8(b) compound having a phenylene nucleus in place of the naphthalene nucleous.

The 2 , 3-naphlhalene derivative corresponding to the compound described in preparative method 7 (Table 7 (a)) as produced in the same manner as compound 7(a) using 2 , 3-naphthalene diamine in place of orthophenylene diamine. The compound resulting from this synthesis had a decomposition temperature of 148 to 15 °C and a theoretical structure of Theoretically this compound contains 50.98% carbon, 5.71% hydrogen and 11.89% nitrogen. The compound produced had 50.79% carbon, 5.78% hydrogen, 11.79% nitrogen. This compound had effective anthelmintic activity but was somewhat less effective than the corresponding 7(a) compound having a phenylene nucleus in place of the naphthalene nucleus.

The 9 , 10-phenanthrene derivative corresponding to compound 7(a) was also produced using 9 , 0-phenanthrene diamine in place of orthophenylene diamine. The compound resulting from this synthesis had a decomposition temperature of 175 to 177°C. and a theoretical structure of C^F^^C^PS. Theoretically this compound contains 56.56% carbon, 5.50% hydrogen, 10.42% nitrogen and 7.68% phosphorus. The compound produced had 56.55% carbon, 5.41% hydrogen, 10.13%' nitrogen and 7.40% phosphorus. This compound had effective anthelmintic activity but was somewhat less effective than the corresponding 7(a) compound having a phenylene nucleus in place of the phenathrene nucleus in its prophylactic properties.

All of the compounds described in this application can be used as anthelmintics for combatting infections for example in ·. ' .. ■ cats, dogs, and avian, animals sheep,/ porcine, bovine, equine/and man. These compounds can be administered in liquid or preferably tablet form to the host.

The compounds of this invention may be combined advantageously with other anthelmintics, such as thiabendazole, phenothiazine, piperazine, tetramisole, pyrantel, niclosamide, bunamidine, and the combinations of the new anthelmintics with known anthelmintics possess clinical utility. Appropriate dosag forms containing a plurality of anthelmintically active compounds are accordingly contemplated by the present invention.

Thus anthelmintic compositions of the invention comprise one or more of the anthelmintic compounds of the invention in a solid composition with a pharmaceutically acceptable diluent, coating agent, "-^^ carrier, binder, filler, suspending agent, disintegrating agent, lubricant, feedstuff, diet supplement, ing agen thickening agent, preservative, flavoui and/or other pharmaceutically active compound or in the form of a solution or dispersion of such a solid composition in a liquid diluent.

' Solid compositions may suitably be provided in the form of a capsule, bolus,:, tablet or drench which are suitably prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, coating agents, disintegrating agents, lubricating agents, binders, thickening agents, and/or preservatives. Suitable binders include lactose, sodium chloride, kaolin, calcium sulphate, starch paste, calcium carbonate, gelatin, methyl cellulose and ethylcellulose. Potato starch and dried corn are suitable disintegrators.

Lubricants include calcium stearate, magnesium stearate, talc, hydrogenated vegetable oils and cocoa butter.

Coating agents include acacia kaolin, shellac, sucrose, powdered starch, cellulose- acetate, phthaiate, -beeswax, polyvinylpyrrolidone, and calcium carbonate. Examples of other carriers or diluents are solid orally inges-tible carriers such as distillers dried grains, com meal, citrus meal, fermentation residues, ground oy^_ster shells, attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycellia, soya grits and crusted limestone.

Further carriers or diluents include alcohol, glycerin and citric acid, thickening agents include tragacanth, carrageenin and pectin; surface active agents include sodium lauryl sulphate and benzalkonium chloride; preservatives include benzoic and sorbic acid.

Mixing of the anthelmintic agent with the other solid ingredients may be effected by grinding, stirring, milling or tumbling them together.

For capsules the active ingredient is usually mixed with the other component(s) such as the diluent and then the mixture is charged into the capsule.

Boluses usually contain the active ingredient a binder and a lubricant compounded together.

A typical tablet formulation would include a binder disintegrator, lubricant, flavouring agent and coating. Chew able flavoured tablets may be preferred.

The ingredients for capsules .are generally agitated sufficiently to obtain a uniformly powdered product which is then utilized for the filling of gelatin capsules, both the hard-shelled and soft elastic types. Capsules should be chosen which are of such a 42355/2 size as to be capable of accomodating a sufficient quantity of material to provide an effective amount of anthelmintic per unit. 'Of course, larger or smaller capsules for different concentrations of active agent may be readily employed where desired or necessitated.

Where an animal is afflicted with helminthiasis, the treatment thereof comprises the oral administration in a therapeutically effective amount of at least one of the anthelmintics of the invention. The actual dosage to be administered at one time or over any extended period will, of course, vary with the particular animal being treated.

The active ingredient may be administered in the form of a liquid drench or in emulsion. In the former application the solid active ingredient is usually mixed with a suspending agent such as Dentonite and the solid product is added to water just before administration. Flavoured liquids are preferred.

The active ingredient may be administered in animal feed formulations. The active ingredient compounded with a carrier and/or any other ingredient mentioned above may be in pellet form for admixture for example with pellet form sheep feed. Furthermore when the diluent is sodium chloride the anthelmintic agent can be administered in the form of a salt lick or . a method of combating a helminth infection in a host animal other than a human being which comprises administering a com- 'V" pound according to the invention, alone or in a composition as herein described, to the animal in an anthelmintically effective dose.

In the case of a human being, such factors as age, weight, extent of helminthiasis and general health of the patient and the like must be considered in determining the dosage to be employed in any given situation. Of course, the appropriate dose ma be administered as a single daily dose or, more preferably, extended through multiple doses of 2, 3 or 4 times daily.

For use against species of roundworms as well as tapeworms, the compounds are most desirably administered at a dosage of about 12 to 100 mg/kg body weight while for use against tapeworms only, the effective dose may be somewhat lower e.g. 3 to 50 mg/kg body weight. The overall dosage range is 3 to 500 mg/kg body weight.

Preferred formulations of compositions of the invention are new given in the following examples showing formulations for tablets and chewable tablets.

EXAMPLE I A tablet of the following composition is formulated: Active compound 220 mg.

Lactose 53*23 mg.

Magnesium Aluminium Silicate Gel ...2.24 mg.

Starch 3*13 mg* Calcium Stearate 0.65 mg.

Microcrystalline Cellulose 35*75 mg.

TOTAL 325 mg.

A granulation, containing water by the use of Magnesium Aluminium Silicate and starch in the form of of pastes, is tableted to form flat level, double or quarter scored, uncoated tablets, of 6 to 9 S.C.A. hardness. The appropriate number (and fraction) of tablets is administered to the host, e.g. one tablet per 20 lbs. body weight.

EXAMPLE II An alternate formulation is in the form of a palatable chewable tablet. Each chewable tablet contains: Active Compound 110 mg.

Dried Fish Meal 1027 mg.

Dried Liver Powder, Bovine 1027 mg.

Soybean Oil Meal 97 mg.

Cane Sugar 239 mg.

TOTAL 2500 mg. 3 J 42355/3

Claims (2)

1. CLAIMS 1. An anthelmintic compound of the formula: where R^ and R2 each represent C^-C^ alkyl optionally substituted by halogen; X represents oxygen or sulfur; A represents o-phenylene, o-naphthylene or o-phenanthrylene each optionally substituted by halogen; and R^ represents hydrogen or a group of the formula: X* -CNHR4 where X" is oxygen or sulfur and R^ represents alkanoyl of up to 4 carbon atoms optionally substituted by halogen, alkanesulfonyl of up to 4 carbon atoms, benzene-sulfonyl optionally substituted by alkyl, alkylene or halogen, or benzoyl optionally substituted by alkyl, nitro or mono- or polychloroalkyl .
2. 2. A compound as claimed in Claim 1 wherein X is 0, R-. is -CNHR . and R. is "lower" alkyl sulfonyl. 42355/3 compound as claimed in Claim 2 having th formula 0 0 4. A compound as claimed in Claim 2 having the formula 0 0 CH3) 2 5. A compound as claimed in Claim l^ vherein X 0 S, R3 is -CNHR4 and R4 is benzenesulfonyl or substituted benzenesulfonyl . 6. A compound as claimed in Claim 5, having the formula 0 NHCNHP(OCH2CH3)2 NHCNHSO —@ CH, 0 42355/3 7. A compound as claimed in Claim 5, having the formula v 0 tl NHCNHP ( CCH2QH3 ) 2 HCNHSO2-T£ 0 6 , A compound as claimed in Claim 5 , having the formula S 0 •I It NHCNHS0„- —CH 9. A compound as claimed in Claim 1, wherein X is 0 II R3 is -CNHR4 and R4 is "lower" alkanoyl. .10. A compound as claimed in Claim .9 , having the formula 0 0 S 0 11. A compound as claimed in Claim 1, wherein X is S, R3 is -CNHR4 and R4 is "lower" alkyl sulfonyl. 12. A compound as claimed in Claim 11, having the formula S 0 compound ar- claimed in Claim 11, having th formula S 0 2 g 14. A compound as claimed in Claim 1', wherein II - - - -- -- ,. -CNHR^ and is benzenesulfonyl or p-toluenesulfonyl . 15. A compound as claimed in Claim 14, having the formula S 0 II II NHCNHP(OCH2CH3);? NHCNHSO ~ CH3 compound as claimed in Claim 14., having formula S 0 II II s compound as claimed in Claim 14 , having th formula S 0 s 18. A^compound as claimed in Claim 1, wherein X II is S, R3 is -CNHRj and R4 is "lower" alkanoyl. 19. A compound as claimed in Claim 18, having the formula S 0 .NHCNHP(OCH2CH3>2 S 0 2 20. A compound as claimed in Claim 1, wherein II is -CNHR^ and is benzoyl or substituted benzoyl. 21. A compound as claimed in Claim 20, having the formula 0 )2 S 0 22. A process for the preparation of a compound as claimed in Claim 1, which comprises reacting an arylene compound of the formula , A and R being as defined in Claim 1, with a substantially equimolar amount of a compound of the formula , X, and R2 being as defined in Claim 1. A process according to Claim 22 for the production of a compound wherein Rg in the arylene reactant is hydrogen, the process including the additional step of reacting the product of the process of Claim 1 with a substantially equimolar amount of a compound of the formula X C=N-R4. 24. A process as claimed in Claim 22 as applied to the preparation of a compound as claimed in any of Claims 1 to 21. 25. A process as claimed in Claim 22 substantially as described in any of foregoing procedures 7 to 13. 26. A compound as claimed in Claim 1 whenever prepared by a process as claimed in any of Claims 22 to 25. 27. An anthelmintic composition which comprises one or more of the compounds as claimed in any of Claims 1 to 21 in a solid composition with a pharmaceutically acceptable diluent, coating agent, carrier, binder, filler, suspending agent, disintegrating agent, lubricant, feedstuff, diet supplement, thickening agent, preservative, flavouring agent and/or other pharmaceutically active compound or in the form of a solution or dispersion of such a solid composition in a liquid diluent. 28. A composition as claimed in Claim 27 in the form of a tablet, particularly a chewable flavoured tablefcy or a flavoured liquid. 29. A process for the preparation of a composition as claimed in Claim 27 which comprises mixing one or more of the anthelmintic compounds as claimed in any of Claims 1 to 21 into a solid composition with a pharmaceutically acceptable 42355/3 diluent, coating agent, carrier, binder, filler, suspending agent, disintegrating agent, lubricant, feedstuff, diet supp lement, thickening agent, preservative, flavouring agent, and/or other pharmaceutically active compound, or into a liq uid composition comprising a solution or dispersion of such a solid composition in a liquid diluent. 30. A method of combating a helminth infection in a host animal other than a human being which comprises administering a compound as claimed in any of Claims 1 to 21 optionally in a composition as claimed in Claim 27 or 28 to the animal in an anthelmintically effective dose. 31. The method of Claim 30 wherein the host animal is avian. 32. The method of Claim 30 wherein the host animal is a cat. 33. The method of Claim 30 wherein the host animal is a dog. 34. The method of Claim 30 wherein the host animal is a sheep. 35. The method of Claim 30 wherein the host animal is porcine . 36. The method of Claim 30 wherein the host animal is a bovine animal. 37. The method of Claim 30 wherein the host animal is equine. 38. The method of any of Claims 31 to 37 wherein the composition is administered at a dosage of 3 to 500 mg/kg of body weight of the host. 42355/3 The method of any of Claims 31 to 37 wherein the composition is administered at a dosage of 3 to 50 mg/kg of body weight of the host. 40. The method of any of Claims 31 to 37 wherein the composition is administered at a dosage of 12 to 100 mg/kg of body weight of the host. HE:mr