US3862226A

US3862226A - Bis-{8 beta-(4-N,N-diacetylaminophenoxy)ethyl{9 ether

Info

Publication number: US3862226A
Application number: US230126A
Authority: US
Inventors: Morton Harfenist
Original assignee: Burroughs Wellcome Co USA
Current assignee: SmithKline Beecham Corp
Priority date: 1972-02-28
Filing date: 1972-02-28
Publication date: 1975-01-21
Anticipated expiration: 1992-01-21

Abstract

Pharmaceutical formulations and their preparation, suitable for use in the treatment of liver fluke infections of mammals, of a compound of formula (I)

WHEREIN X and X1 are the same or different and each is hydrogen or an alkyl group having one to three carbon atoms. Also provided are novel compounds within formula (I) and processes for their preparations.

wherein R and R1 are the same or different and each is hydrogen, an optionally substituted saturated aliphatic hydrocabron group having one to seven carbon atoms, an unsaturated aliphatic hydrocarbon group having two to four carbon atoms, or together with R5 form an alkylene group having two to four carbon atoms; R2 and R3 are the same or different and each is hydrogen, a lower alkyl group having one to four carbon atoms or R5CO wherein R5 is hydrogen, an optionally substituted saturated aliphatic hydrocarbon group having one to seven carbon atoms, an unsaturated aliphatic hydrocarbon group having two to four carbon atoms, or taken together with R and/or R1 forms an alkylene group having two to four carbon atoms; and A is -CH2-, -(CH2)2-,-CH2-OCH2-or the group

Description

United States Patent [191 Harfenist [451 Jan. 21, 1975 BIS-[BETA-(4-N,N-DIACETYLAMINO- PHENOXY )ETHYL ]ETHER [75] Inventor: Morton Harienist, Chapel Hill, N.C.

[22] Filed: Feb. 28, 1972 [21] Appl. No.: 230,126

[52] U.S. Cl. 260/562 P, 260/239.3 R, 260/281, 260/326.44, 260/456 P, 260/562 N,

[51] Int. Cl. C07c 103/38 [58] Field of Search 260/562, 325

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 749,907 6/1956 England 260/562 OTHER PUBLICATIONS Raison et al. I, British J. Pharmacol. Vol. 10, pp. 191-99 (1955).

Chun-Chieh et al. Chem Abst., vol 54, col. 5528 (1960) Lammler et al., Arzneimitte Horschung, Vol. 12, p. 15-21 (1962).

Primary ExaminerHarry I. Moatz Attorney, Agent, or FirmDonald Brown; Dike, Bronstein, Roberts, Cushman & Pfund [57] ABSTRACT Pharmaceutical formulations and their preparation, suitable for use in the treatment of liver fluke infections of mammals, of a compou I 2 nd of formula (I) N CO- R (I) wherein R and R are the same or different and each is hydrogen, an optionally substituted saturated aliphatic hydrocabron group having one to seven carbon atoms, an unsaturated aliphatic hydrocarbon group having two to four carbon atoms, or together with R form an alkylene group having two to four carbon atoms; R and R are the same or different and each is hydrogen, a lower alkyl group having one to four carbon atoms or R CO wherein R is hydrogen, an optionally substituted saturated aliphatic hydrocarbon group having one to seven carbon atoms, an unsaturated aliphatic hydrocarbon group having two to four carbon atoms, or taken together with R and/or R forms an alkylene group having two to four carbon atoms; and A 18 CH (CI-I ,CH OCH or the group 'l z s' fz a x x wherein X and X are the same or different and each is hydrogen or an alkyl group having one to three carbon atoms. 7 Also provided are novel compounds within formula (I) and processes for their preparations.

1 Claim, N0 Drawings This invention relates to ethers, their synthesis, formulations containing them, their use in the treatment of liver fluke infections in mammals, and their use in the treatment of infections of insects in mammals.

Animals are infected with liver fluke when eating forage contaminated with encysted forms of cercariae, an intermediate stage in the life-cycle of the fluke. The cercariae emerge from the cysts in the intestine of the host animal, penetrate the intestine wall, and make their way to the liver. At this stage they are microscopic in size, but grow as they wander around the liver parenchyma. This causes considerable destruction of the liver tissue and can give rise to the syndrome of acute facioliasis which normally leads to death of the host when massive infections are present. If the animal survives, the flukes eventually reach the bile ducts where they mature into the adult worms. The presence of a massive infection in the bile ducts gives rise to the syndrom of chronic fascioliasis which is a serious debilitating disease of the host animal. Hitherto liver fluke remedies have been known to kill only the adult and semiadult worms, and the immature worms have been resistant to attack by such remedies.

It has not been found that the compounds of formula (I) are effective in combatting infections of liver flukes in mammals, and are especially active in combatting infections of immature worms of Fasciola spp.

. 3 r r locum-Quito N.CO.R1 (I) In formula (I), R and R are the same or different and each is hydrogen, an optionally substituted saturated aliphatic hydrocarbon group having one to seven carbon atoms, or an unsaturatedaliphatic hydrocarbon group having two to four carbon atoms, or taken together with R CO below form a 5 to 7 membered cyclic imide; R and R are the same or different and each is hydrogen, a lower alkyl group having one to four carbon atoms, or a group R CO wherein R is hydrogen, an optionally substituted saturated aliphatic hydrocarbon group having one to seven carbon atoms, and unsaturated aliphatic hydrocarbon group having two to four carbon atoms, or forms a cyclic imide with R and- /or R above; and A is -CH -(CH' or the group wherein X and X are the same or different and. each is hydrogen or an alkyl group having one to three carbon atoms.

When R or R is a saturated aliphatic hydrocarbon group it may be substituted by a hydroxy group, an amino group, an N-alkylamino group, an N,N- dialkylamino group, or a carbonyl group for example an acyl group, the alkyl and acyl groups referred to above each having from one to four carbon atoms.

When R or R is a saturated aliphatic hydrocarbon radical having more than two carbon atoms it may be a straight chain or branched-chain alkyl group or a cyclic group such as a cycloalkyl group, but it is preferably a straight-chain (n-) alkyl group; when R or R is an unsaturated aliphatic hydrocarbon group it is preferably an alkenyl group or an alkylalkenyl group, said groups preferably having one ethylenic linkage. A is preferably CH2, CH2CHz""O-CH2.CH2,

Cl-l. CH --O--CI-l CH -CH -CHO-CH CH or I CH CH CH CH As a preferred subclass within formula (I) are those Wherein X and X are the same or different and each is hydrogen or a methyl group.

It is believedthat all the compounds of formula (I) are novel with the exceptions of those compounds wherein R R methyl and either R R" H when A is CH or (CH or R R H or methyl when A is -CI-I CH -OCH .CH These compounds have been previously disclosed in the chemical literature as intermediates for the synthesis of derivatives thereof, but no biological activity has been previously ascribed to the compounds (J. Chem. Soc., 1931, 1765-71; Beilsteins Handbuch der Organischen Chemie, 13, 464; and ChemicalAbstracts, I960, 54, 5528f).

It will be appreciated by persons skilled in the art that acid addition salts may be formed by those compounds of formula (I) wherein one or more of the groups R, R and R are saturated aliphatic hydrocarbon groups substituted by an amino, N-alkylamino or N,N- dialkylamino group. Unless the context indicates otherwise, wherever in the following reference is made to compounds of formula (I) it should be understood that this term includes the acid addition salts of the compounds hereinabove defined.

The compounds of formula (I) have been found active against experimental infections of Fasciola gigantica in mice, infections of Fasciola hepatica in rabbits and in ruminants including sheep and cattle, and infections of Fasciola gigantica in calves.

The percentage kill of a liver fluke infection by a compound of formula (I) is of course dose dependent, and it has been found that the younger the worms, the lower is the dose required to combat the infection. Thus upon oral dosing of sheep infected with F. hepatica, a dose of 60 to 100 mg. of one of the known compounds of formula (I) (R R=CH R =R =H; A=CH -CH OCH .CH per kilogram body weight provides a nearly complete eradication (90-l00 percent) of flukes of 3 days to 6 weeksold. In most instances an oral dose of about 100 to 120 mg. of this same compound per kilogram is required to provide a nearly complete eradication of liver flukes of all ages, including adult worms of 9 weeks and older; and an oral dose of to I20 mg. per kilogram typically gives a clearance of to percent even in cases of severe clinical infections. For treatment of infections of adult worms alone an oral dose of this compound of between.

100 and 120 mg. per kilogram provides a nearly complete eradication, although the dosage can be increased to a level of up to 200 mg. per kilogram if desired.

A dose of a compound of formula (I) may be followed by a second dose within about 4 weeks, but practical considerations would probably dictate its administration after about 5 to 8 weeks. In the case of very light liver fluke infections, the second dose may be delayed for as long as 8 weeks.

Since in the field, it must be assumed that animals are continually subject to reinfection, it is especially advantageous in practice to administer these lower doses regularly during the appropriate season to about 4 to 8 week intervals.

A compound of formula (I) may be used in the treatment of liver fluke infections in mammals including F. hepatica in ruminants including sheep, cattle, goat and buffalo, and in the pig and horse; and F. gigantica in ruminants including sheep and cattle. The compound is preferably administered orally at a does between 40 and 200 mg. per kilogram.

In general it has been found that a dose of 80 to 120 mg. per kilogram is required to combat infections of both the mature and immature worms, and a dose of 60 to 100 mg. per kilogram for immature infections.

A compound of formula (I) may be administered for the treatment of liver fluke infections as the raw chemical, but preferably as an ingredient of a pharmaceutical formulation which contains in addition one or more inert carrier materials commonly used in pharmaceutical formulations as a vehicle for the active ingredient. The preferred formulations are those suitable for oral administration, containing from 5 to 95 percent by weight of a compound of formula (I). If presented as the raw chemical, then a compound of formula (I) is preferably in the form of a powder.

In the context of the present invention, the qualification inert means that the carrier is pharmaceutically acceptable to the hose of the infection to which the formulation is administered.

The presentation of an active ingredient (namely, a compound of formula (I)) in a pharmaceutical formulation may be as discrete units, such as tablets, capsules or cachets, each containing a predetermined amount of the active ingredient; as a powder or granules; or as a solution or a suspension in an aqueous liquid, a nonaqueous liquid, or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste; in the feed or a feed supplement intended for the host animal; in pellets, salt licks or block licks which are especially suitable for large animals such as sheep and cattle.

The formulations may be made by any of the methods of pharmacy but all methods include the step of brining into association by admixture the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately brining into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. The formulations contain one or more of the usual accessory ingredients used to prepare anthelmintic formulations including: solid and liquid diluents (for example, lactose, sucrose, glucose, starches, dicalcium phosphate or calcium phosphate for tablets, granules, dispersible and wettable powders, cachets and capsules; arachis oil, olive oil, or ethyl oleate for soft capsules; water, or vegetable oil for aqueous and nonaqueous suspensions, emulsions, and pastes); binders (for example, starch, sugar, glucose, methyl cellulose, gum acacia, Irish moss or gelatin for granules and tablets); surface active agents (for example sodium lauryl sulphate, cetrimide or polyoxyethylene sorbitan monolaureate for tablets, powders and granules; sodium salt of an alkyl naphthalene sulphonic acid, sorbitan monooleate, ceto-stearyl alcohol and an emulsifier condensate of nonylphenol and ethylene oxide, for pastes and wettable powders); lubricating agents (for example liquid paraffin, talc, stearic acid, magnesium stearate or polyethylene glycol for tablets); dispersing agents (for example, disodium salt of the condensation product of naphthalene sulphonic acid and formaldehyde, and calcium lignin sulphonate for wettable powders, pastes and suspensions); gelling agents (for example colloidal clays, sulphuric esters of a polysaccharide for aqueous suspensions); suspending and thickening agents (for example gum tragacanth, xanthan gum, alginates, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, and hydroxy-ethylcellulose for aqueous suspensions, aqueous based pastes and wettable powders); and humectants (for example glycerine for water-based pastes); and other therapeutically acceptable accessory ingredients such as preservatives, buffers and antioxidants, which are known to be useful as carriers in such formulations.

A tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Conveniently each tablet contains from 0.5g to 4.0g of the active ingredient.

Granules may be made by the technique of wet granulation comprising moistening the powdered active ingredient with a binder in an inert liquid, and drying the moist mass; or by the techniques of precompression or slugging. The granules may be administered to animals in an inert liquid vehicle; or in a cachet or capsule of hard or soft gelatin preferably with a liquid or powdered solid diluent; or in suspension with a water or an oil base. In a drench or suspension, it is preferable to include further accessory ingredients such as a dispers ing agent.

A dispersible or wettable powder may be made by admixing together the finely divided active ingredient with a wetting agent, and then administering the powder to the host animal as a suspension or dispersion in water. If desired a dispersing, suspending or thickening agent may be included. These formulations preferably contain from about 15 to 85 percent by weight of the active ingredient.

A paste may be formulated in a liquid diluent which suspends the active ingredient. A stiffening or thickening agent may be included, together with a wetting agent and an humectant if the liquid diluent is water. If an emulsion paste is needed (oil-out or water-out), then one or more surface active agents should be included. From about 25 to percent by weight of these paste formulations may be comprised of the active ingredient but if the lower concentrations are used, then sufficient stiffening or thickening agent should be included to provide the desired viscosity.

Suspensions of the active ingredient in an inert liquid carrier are essentially the same as pastes but of a lower viscosity. They may be formulated using water or other inert diluent as the liquid carrier in association with a dispersing or wetting agent. Other ingredients such as thickening, gelling and suspending agents may also be included. These formulations may contain a wide range of concentrations of active ingredient, but of course, if too high a concentration is included the viscosity of the formulation will increase and the formulation will become more of a paste than a suspension. Subject therefore to the concentration of the remaining ingredients, about 5 to 50% by weight of the formulations may be comprised by the active ingredient.

In feed supplements, the active ingredient is generally present in large amounts relative to the accessory ingredients, and the supplements may be added directly or after intermediate blending or dilution. Examples of accessory ingredients for such formulations include solid orally ingestible carriers such as corn meal, attapulgite clay, soya flour, wheat shorts, soya grits, edible vegetable materials, and fermentation residues. The active ingredient is usually incorporated in one or more of the accessory ingredients and intimately and uniformly dispersed by grinding, tumbling or stirring with conventional apparatus. Formulations containing about 1 to 90 percent by weight of the active ingredient are especially suitable for adding to feeds to provide a concentration desired to control infections by way of the animals rations.

A compound of formula (I) may be administered either alone as the sole treatment for a liver fluke infection, or in combination with other substances which may complement or supplement its activity. Such additional substances may be administered simultaneously as a separate dose or in combination with a compound of formula (I) in a formulation, and may comprise other anthelmintics having activity against other parasites, such as cestodes (tapeworms) or nematodes. Such additional substances include phenothiazine; piperazine derivatives, for example the citrate, adipate or phosphate salts; organo-phosphorus compounds for example 0,0-di-(2-chloroethyl) O-(3-chloro-4- methylcoumarin-7-yl)phosphate (Haloxon); 4-t-butyl- 2-chlorophenyl N-methyl O-methyl-phosphoramidate (Ruelene (Trade Name)); 0,0-diethyl O-(3-chloro-4- methyl-7-coumarinyl)phosphorothioate (Coumaphos); 0,0diethyl O-naphthaloximide phosphate (Naphthalophos); 0,0-dimethyl 2,2,2-trichloro-l-hydroxyethylphosphonate (Trichlorfon); benzimidazole anthelmintics including 2-(4-thiazolyl)benzimidazole (Thiabendazole);methyl S-n-butyl benzimidazole -2- carbamate (Parbendazole); and isopropyl 2-(4- thiazolyl)benzimidazole-S-carbamate (Cambendazole); quaternary ammonium anthelmintics including N-benzyl-N, N-dimethyl-N-(2-phenoxyethyl)ammonium salts such as the 3-hydroxy-2-naphthoate and embonate salts (Bephenium salts); N, N-dialkyl-4- alkoxy-a-naphthamidine anthelmintics including N,N- dibutyl-4-hexyloxy-a-naphthamidine (Bunamidine); dl-and l-2,3,5,6-tetrahydro- 6-phenylimidazo (2,1-b) thiazole salts (Tetramisole); trans-l-methyl-2-[2-(2- thienyl)vinyl]-l,4,5,6-tetrahydropyrimidine tartrate (Pyrantel tartrate); cis-l,4,5,6-tetrahydro-l-methyl-2- thienyl)vinyl]pyrimidine tartrate (Morantel tartrate); polyhalogenated benzanilide anthelmintics including 3,3',5,5,6-pentachloro-2,2-dihydroxybenzanilide (Oxyclozanide); 2-acetoxy-4'-chloro-3, 5- diiodobenzanilide (Clioxanide); 3,4',5- tribromosalicylanilide (Tribromsalan);3,5-diiodo-3'- chloro-4-(p-chlorophenoxy)salicylanilide (Rafoxanide); 5-bromo-2-hydroxy-4'-bromobenzanilide; 2,2- dihydroxy-3,3'-dinitro-5,5-dichloro-biphenyl (Menichlopholan); 2,2-dihydroxy-3,3',5,5, 6,6'-hexachlorodiphenylmethane (Hexachlorophene); 1,4-bis (trichloro-methyl) benzene (Hetol); 3-iodo-4-hydroxy- S-nitrobenzonitrile (Nitroxynil); and 5-chloro-N-(2'- chloro-4'-nitrophenyl) salicylamide (Niclosamide).

A particularly preferred combination comprises a compound of formula (I) and oxyclozanide, preferably in the ratio of 40 to mg./kg. and 3 to 15 mg/kg. respectively. Oxyclozanide is highly effective against adult liver flukes, and in combination with a compound of formula (I), complements its activity.

The compounds of formula (I) have been found active systemically against insect parasites of mammals as exemplified by activity against Stomoxys calcitrans, the stable fly,-following oral administration to host mice. The compounds have further been found active against infection in mammals of the larvae of flies of the genus Oestrus and especially against infections of the larvae of Oestrus ovis, the sheep nasal fly. V

Animals including the sheep, goat and camel become infected by the mature fly depositing the young larvae around the nostrils of the host, whence the larvae crawl upwards to live as parasites in the nasal cavity and adjoining sinuses. The larvae irritate the nasal mucosa causing the secretion of a viscid mucous exudate; erosion of the bones ofthe skull may occur and even injury to the brain, when locomotion of the host mayy be affected. Infected animals have a nasal discharge together with a depressed appetite which commonly results in emaciation and, in cases of severe infection, in death of the animal.

A compound of formula (I) may therefore be used for the treatment of Oestrus infections in mammals by producing a systemically effective insecticidal concentration of the compound in the body of the mammal upon administration of the compound to the mammal. The compound is preferably administered by the oral route; when administered in this manner systemic activity against insect parasites has been demonstrated at a dose level of up to 200 mg. per kilogram bodyweight of host or at a dose level of as little as 40 mg. per kilogram or substantially lower. A compound of formula (I) may be administered for the treatment of insect parasites as the raw chemical, but preferably as an ingredient of a pharmaceutical formulation as hereinbefore described.

Excluded from the scope of the present invention are non-sterile mixtures which are mere solutions and suspensions of the known compounds of formula (I) as hereinbefore defined in solvents and liquids known in the literature for use in the synthesis and isolation of the compounds by the methods described therein. Included within the scope of the present invention are such known solutions and suspensions which are pharmaceutically acceptable to the host of the infection to be treated and which contain in addition at least one other pharmaceutically acceptable substance.

ZAZ(II) wherein Z is a reactive nucleophilic atom or group and A is as defined above, with an alkali metal salt of a phydroxyacylanilide of the formula (III) AlkO 1- -CO.l3 (111) wherein Alk is conveniently potassium or sodium, B is R or R, and E is R or R, as defined above in formula (I). In formula (II), Z is preferably a halogen atom, for example chlorine, bromine or iodine, or is ptoluene-sulphonyloxy, but other alkanesulphonyloxy, arylsulphonyloxy or aralkylsulphonyloxy groups may also be used instead. The reaction is carried out in a liquid medium which is preferably a polar liquid and which conveniently may be an optionally aqueous alkanol, for example methanol, ethanol, or isopropanol, or may be dimethylsulphoxide, sulpholane, dimethylformamide, dimethylacetamide, N-methyl-Z-pyrollidone, or mixtures of the foregoing. If Z is chlorine, then it is preferable to include a small quantity of potassium iodine in the reaction mixture. The reactants are preferably present in about a 2 to 1 molar ratio of the compounds of formula (III) and (II) respectively, but a slight excess of a compound of formula (III) is conveniently used. The reactants may be heated together under an inert atmosphere, for example nitrogen, at the reflux temperature of the reaction mixture. It will be appreciated that the compounds of formula (I) most conveniently prepared by this method are those in which R R and R R.

It will of course be understood that in the course of the above reaction the compounds of formulae (IV) and (V) will be formed as transient intermediates n.co.n

N.CO.B

wherein Z, A, E and B are as defined above; and of course a compound of formula (I) may be prepared ab initio by reaction of a compound of formula (IV) or (V), with about an equimolar quantity of the compound of formula (II), under the conditions previously described above. It will be further understood that the compounds of formula (I) wherein R differs from R and R differs from R are preferably prepared in this manner.

The compounds of formula (III) identified above may be optionally formed in situ from the corresponding phenol using such basic reagents as sodium hydride, potassium hydroxide, sodium hydroxide, an alkali metal alkoxide, for example potassium tertiary butoxide, sodium ethoxide, sodium methoxide, or a mixture of an alkali metal carbonate and an aliphatic ketone, for example potassium carbonate and acetone.

The compounds of formula (I) may also be prepared by the acylation of an amine of formula (VI) wherein R and R are as defined above, and wherein both of R are hydrogen, or one is hydrogen and the other is a group M.CO where M is one of R and R as defined above; and wherein A is as defined above in formula (I). The acylation may be carried out by any known means and conveniently in a polar or non-polar liquid medium, the nature of which is dependent upon the acylating agent used. Thus if the acid is used, it is preferred to heat the reactants in excess of the acid. If an acid anhydride is used, then water, an aromatic hydrocarbon, such as benzene, a halogenated aliphatic hydrocarbon such as chloroform, an ether such as dioxane, or an excess of the acid anhydride may be used as the liquid medium. An aromatic hydrocarbon or an ether may also be used as the liquid medium if an acid chloride is chosen as the reactant. An ether, an aromatic hydrocarbon or a halogenated aliphatic hydrocarbon may also be used as the liquid medium if a ketone is used as the acylating agent. The medium may be an excess of the acylating agent above that demanded by the equation of the reaction, for example if using an alkyl ester. The formamido derivatives, that is to say those compounds of formula (I) wherein either or both of R and R are hydrogen, are preferably prepared by the use of formic acid, which may be present in excess to act as a solvent.

The compounds within formula (I) wherein either or both of the groups R and R are saturated aliphatic hydrocarbon groups substituted by an amino, N- alkylamino or N,N-dialkylamino group may. also be prepared by the reaction of ammonia or a primary or secondary alkyl amine, as appropriate, with the corresponding halo-substituted compound and this latter may itself be prepared from the amine of formula (VI) by haloacylation using, for example, a halo-substituted monocarboxylic acid such as monochloracetic acid.

Those compounds as hereinabove defined within formula (I) that form acid addition salts may be isolated as such or as the base thereof and may be optionally converted, as appropriate, to the base, an acid addition salt thereof or the salt of another acid by methods known in the art.

According to the present invention there are therefore provided the novel compounds of formula (I); and pharmaceutical formulations comprising the compounds of formula (I) in association with an inert carrier therefor; and methods of making such novel compounds and such pharmaceutical formulations. The present invention also provides a method for the treatment of infections of liver flukes in mammals comprising the administration to the host of the infection an effective amount of a compound of formula (I). The present invention also provides a method for producing a systemically effective insecticidal concentration of a compound of formula (I) in the body of a mammal comprising the administration to the mammal of said compound.

In the Examples Nos. 1 to 23, 26 and 27, the compound of formula (I) therein referred to is bis-[B-(4- acetamidophenoxy)ethyl] ether. The numbered Examples of the invention are included to indicate the precise manner in which the invention may be put into practice, and should not be construed as limiting in anyway the scope of the invention disclosed in this specification.

The following are examples of the synthesis of bis-[B- (4-acetamidophenoxy)ethyl] ether.

Synthesis of bis-[B-(4-acetamidophenoxy)ethyl] ether To a solution of p-hydroxyacetanilide (169 g., 1.12 M) in dimethyl sulphoxide (590 ml.) was added potassium tertiary butylalcoholate (112.5 g., 1.0 M). The reaction mixture spontaneously heated from about 50C to 90C and turned green. After stirring under nitrogen for about 5 minutes, bis-(B-chloroethyl) ether (82.5 g., 0.585 M) was added dropwise over about minutes with stirring. The reaction mixture was stirred overnight, and the majority of the dimethyl sulphoxide evaporated off. The remaining liquid was diluted with about 3 times its volume of water and the precipitate filtered to provide crystals, m.p. 105 110C. After two recrystallisations from a water/ethanol mixture, and washing with ethanol, the product had an initial m.p. l41.3 to 141 .7C. On raising the temperature, the compound solidified and then remelted at l6l162C.

Further synthesis of bis-[/3-(4-acetamidophenoxy)ethyl] ether Compound of formula Bentonite ((iclling Agent Bevaloid Dispersant (Trade Mark) (Dispensing agent) Sodium Benzoute (Buffering agent) Water Further synthesis of bis-[B-(4-acetamidophenoxy)ethyl] ether Compound of formula (I) Sulphitc Residue (Dispersing agent) (urmoss ((ielling agent) (Trade Mark) Water mixture was diluted with aqueous hydrochloric acid ml. of N-acid), then with water (300 ml.), and the mixture filtered to remove the platinum and a little solid. The filtrate was treated with acetic anhydride (50 ml.), and then with aqueous sodium hydroxide (50%), until the mixture was pH 9 to 10. Further acetic anhydride was added (50 ml.), the solution heated, charcoal added to remove colour, filtered, and water added to precipitate bis-[B-(4-acetamidophenoxy)ethyl] ether which was found to have an initial melting point of l42.7 to l43.lC. On raising the temperature, the compound resoliditied and then remelted at 154C.

Further synthesis of bis-[B4 4-acetamidophenoxy)ethyl] ether.

Sodium (5.1 g., 0.22 M) was dissolved in dried ethanol (200 ml.), and p-hydroxyacetanilide (33.2 g., 0.22 M) was added to the warm solution. After the anilide had dissolved, bis-(B-chloroethyl) ether (1 1.7 ml., 0.10 M) and potassium iodide (10 g.) were added and the mixture was refluxed with stirring for 16 hours. After removing a greater part of the ethanol by distillation in vacuo, the residue was poured into water (500 ml.), the precipitate filtered off and washed with aqueous sodium hydroxide (2N) and water. After drying, the product was recrystallized from industrial methylated spirits, and had a melting point of 142C. On raising the temperature, the compound resolidified and then remelted at l6l2C.

Further synthesis of bis-[1H4-acetamidophenoxy)ethyl] ether.

Sodium (0.80 g., 0.035 M) was dissolved in dried ethanol (40 ml.) and p-hydroxyacetanilide (5.45 g., 0.036 M) was added to the warm solution. After the phydroxyacetanilide had dissolved, bis-[0(4- toluenesulphonyloxy)ethyl] ether (6.60 g., 0.016 M) was added and the mixture refluxed with stirring for 24 hours. After concentration of the reaction mixture in vacuo and pouring it into water, a precipitate was filtered off, washed with aqueous sodium hydroxide (2N) and water. After drying the product was recrystallised from methylated spirit, final m.p. l6l2C.

EXAMPLE 1 AQUEOUS SUSPENSIONS (I) 5.0% 20.00% 40.00% 50.00% w/w The bentonite was dispersed in some of the water, the Bevaloid Dispersant and sodium benzoate added, and finally the finely ground active ingredient and balance of the water. The whole was mixed until uniform.

Bentonite is a colloidal clay consisting principally of montmorillonite, Al O HSiO l-l O, and Bevaloid Dispersant is disodium salt of the condensation product of naphthalene sulphonic acid and formaldehyde.

EXAMPLE 2 AQUEOUS SUSPENSIONS The Carmoss and sulphite residue were dissolved in ground active ingredient. The whole was mixed until the water, the finely ground active ingredient added, uniform. and the whole mixed until uniform. Gum Tragacanth is the dried mucilaginous exudation Sulphite residue is crude calcium lignin sulphonate; from the Astragalus species. Carmoss is a carragenate or a sulphuric acid ester of a 5 polysaccharide. EXAMPLE 5 AQUEOUS SUSPENSIONS Compound o1 formula (I) 20.00% w/w 50.00% w/w 5.0% w/w Keltrol (Trade Mark) (suspending agent) 0.20% do. 010% do. 03% do. Bcvaloid Dispersant (Trade Mark) 1.00% do. l.00% do. 1.0% do. Water 78.80% do. 48.90% do. 93.7% do 100.00% w/w 100.00% w/w 100.00% w/w EXAMPLE 3 AQUEOUS SUSPENSION The Keltrol was dissolved in the water, the Bevaloid c d H I (I) 5 07 I Dispersant added, and finally the finely ground active ompoun 0 ormu a 0 W W Neosyl (mum) 5.0% m ingredient. The whole was mixed until uniform wg g age t) 20 Keltrol 1s a xanthan gum, a high molecular weight lin- (Trade ar 1.5 do. Bevaloid Dispersant ear polysacchande' (Dispersing agent) 1.0 do. M

100.0% wlw EXAMPLE 6 AQUEOUS SUSPENSlONS Compound of formula (I) 20.00% w/w 50.00% w/w 5.00% w/w Manucol (Trade Mark) (suspending agent) 0.25% do. 0.15% do. 0.40% do. Bcvaloid Dispersant (Trade Mark) (Dispcrsing agent) 1.00% do. 1.00% do. 1.00% do. Water 78.75% do. 48.85% do. 93.60% do.

100.00% w/w |00.00'/, w/w 100.00% w/w The Carmoss and Bevaloid Dispersant were mixed The Manucol was dissolved in the water, the Bevawith the water, and then the finely ground active ingreloid Dispersant added, and finally the finely ground acdient and the Neosyl added. The whole was mixed until tive ingredient, the whole being mixed until uniform. uniform. Manucol is a sodium alginate.

Neosyl is a diluent of finely prepared silica which 40 functions as a stiffening agent. EXAMPLE 7 AQUEOUS SUSPENSIONS Compound of formula (I) 20.00% w/w 50.00% w/w 5.00% w/w Bevaloid Disperant (Trade Mark) (Dispensing agent) 1.00% do. 1.00% do. 1.00% do. Sodium hcnzoate (Buffering agent) 1.00% do. 1.00% do. 1.00% do. Polyvinyl pyrrolidone (PVP 90) (suspending agent) 8.00% do. 6.00% do. 15.00% do. Water 70.00% do. 42.00% do. 78.00% do.

100.00% w/w 100.00% w/w |00.00'/ w/w I EXAMPLE f1 AQUEOUS SUSPENSIONS 55 The polyvinyl pyrrolidone was dissolved in the water The gum tragacanth was dissolved in the water, the with stirring, and when dissolved the Bevaloid Disper- Bevaloid Dispersant then added and finally the finely sant and sodium benzoate added. Finally the finely ground active ingredient was added and mixed until uni- The Gum Arabic was dissolved in the water, the form. Bevaloid Dispersant and the finely ground active ingre- Polyvinyl'pyrrolidone is a polymerised form of v'inyldient added, and the whole mixed until uniform. pryollidone. Gum Arabic is the dried exudation from the stem and 5 branches of Acacia senegal.

EXAMPLE 8 AQUEOUS SUSPENSIONS EXAMPLE 10 AQUEOUS SUSPENSIONS Compound of formula (I) 5.0% w/w 20.00% w/w 50.0% \v/w Bevaloid Dispersant (Trade Mark) (Dispersing agent) 1.0% do. 1.00% do. 10% do. Sodium Bcnzoate (Buffering agent) l.0'/r do. 1.00% do. 10% do. Courlose F.700 (Trade Mark) (Suspcnding agent) 1.0% do. 0.60do. 0.5% do, Zircomplex P.A. (Trade Mark) (suspending agent) 2.5% do. |.60% do. l.25% do. Water 89.5% do. 75.80% do.. 46.25% d 100.0% W/W 100.00% w/w 100.0% w W Compound of l'orn1u|a(l) 20.0% \v/w 50.0% w/w 5.0% w/w Bevaloid Dispersant (Trade Mark) (Wetting agent) l.0'/ do. 10% do. L05; do. Courlose F 700 (Trade Mark) (suspending agent) 1.0% do. 0.5% do. 1.0% do. Water 78.05600. 48.5% do. 92.0% do.

100.0% w/w 100.0% w/w 100.0% w/w The Courlose was dissolved in the water, the Zircom- 30 the Courlose F 700 was dissolved in the water, the plex P.A. then added, followed by the Bevaloid Disper- Bevaloid Dispersant and the finely ground active ingresant and sodium benzoate and'finally the finely ground dient added, and the whole mixed until uniform. active ingredient. The whole was mixed until uniform. Courlose F 700 is sodium 'carboxymethylcellulose.

Courlose F 700 is the sodium salt of carboxymethyl- 5 EXAMPLE (1 AQUEOUS SUSPENSIONS Compound of formula (I) 20.0% W/W 50-07! W/W 5.071 w/w Bevaloid Dispersant (Trade Mark) (Wetting agent) l.0% do. (.0% do. l.0% do.

Natrosol 250 (Trade Mark) (suspending agent) 0.05% do. 0.03% do. 0.l% do.

Water 714.95% do. 40.97% at). 9% do 100.00% w/w 100.00% w/w 100.00% w/w cellulose; Zircomplex PA. is an organic complex of zirthe Natrosol was dissolved in the water, the Bevaloid comum. Dispersant and the finely ground active ingredient added, and the whole mixed until uniform. 50 Natrosol 500 is hydroxyethylcellulose.

EX PLE noueous S USPENSIONS EXAMPLE 12 OIL-BASED PASTES Compound of formula (l) 20.00% w/w 50.0% w/w 5.0% w/w Bevaloid Dispersant (Trade Mark) (Dispensing agent) l.0'// do. I.()% do. 10% do. Gum Arabic (Thickening agent) 0.5% do. 0.3% do. 2.0% do. Water 785% do. 48.7% do. 92.0% do.

100.0% w/w 100.0% w/w 100.0% w/w China clay (Solid Diluent) 20.0% w/w Mineral Oil (Liquid Diluent) 50.0% w/w 40.0% w/w (10.0% w/w 60.0% do, Compound of formula (l) 50.07! do. 60.0% do. 40.0% do. 20.0% do.

100.0% w/w 100.0% w/w 100.0% w/w 100.0% w/w The components were mixed in suitable equipment, Bentone 38 is a cationic bentonjte substituted with a to provide pastes of uniform consistency. quaternary ammonium base.

Mineral oil is a high boiling fraction of a refined pertroleum 01] containing not less than 96% unsulphonata- EXAMPLE l5 WATER-BASED PASTES Compound of formula (I) 23.0% 55.00? (0.00) 45.00, Kcltrol (Trade Mark) (suspending agent) 0.5% 0.50% 0.45% 0.55; tin. Ncosyl (Diluent) 18.3% 5.00% Glycerine (Humeetant) 23.0% 20.00% 04.00% 22.00% do. Water 35.2% 24.50% 10.55% 32.45% do 100.0% 100.00% 100.00% 100.00% w/w ble material. The Keltrol was dissolved in the water, the remaining ingredients incorporated, and the whole mixed until EXAMPLE l3 OIL-BASED PASTES uniform.

Mineral 011 (Liquid Diluent) 10.0% 40.0% 32.0% 49.5% w/w Vaseline (Thickening agent) 70.0% 10.0% 8.0% 5.5% 00. Compound of formula The Vaseline was dissolved in the mineral oil and the Keltrol is a xanthan gum, a high molecular weight linfinely ground active ingredient added and mixed in ear polysaccharide. suitable equipment until uniform.

Vaseline is petroleum elly. EXAMPLE l6 WATER-BASED PASTES Compound of formula (I) 20.0% 50.00% 60.00% 40.00% w/w Bevuloid Dispersant (Trade Mark) (Dispcrsing agent) 0.5% 0.50% 0.40% 0.60% do. Gum Tragucanth (Suspending agent) 3.5% 2.00% 1.60% 2.40% do. Glycerine (Humeetant) 16.0% 8.50% 8.00% l 1.00% do. Water 00.0% 39.00% 30.00% 46.00% do EXAMPLE 14 OIL-BASED PASTES The gum tragacanth was dlssolved 1n the mixture of China clay (Solid Diluent) 30.00% w/w Mineral Oil (Liquid Dilucnt 46.75% 36.25% 46.75% 51.00% do. Bentone 38 (Trade Mark) (Thickening agent) 2.50% 2.75% 2.50% 3.00% do. Industrial methylated spirits 0.75% 1.00% 0.75% 1.00% do. Compound of formula 100.00% l00.00% I00.(l0% 100.00% W/W The Bentone 38 was added to the mineral oil, and water and glycerine,and the finely divided active ingrestirred vigorously for 15 minutes, after which time the dient incorporated to provide a uniform paste. methylated spirits were added and the whole stirred for a further minutes. The finely ground active ingredi- EXAMPLE 17 PASTES Compound of formula (I) 50.0% 60.0% 50.0% 60.0% 20.0% w/w Polyethylene Glycol 400 40.0% 32.0% 50.0% 40.0% 45.0% w/w Polyethylene Glycol 4000 l0.0% 8.0% 5.0% w/w China clay (Solid diluent) 30.0% w/w 100.0% I 00.0% [00.0% I 00.0% l00.0% w/w ent was then added and the whole mixed until uniform. Both glycols, or the single glycol, as appropriate, Where China clay was an ingredient, it was included at were heated together, and when uniform, the finely the same time as the addition of the compound of forground active ingredient, (together with the China mula (I). V clay, if appropriate) was added, and the mixture stirred 3,862,226 in g 17 18 to provide a paste of uniform consistency. The raw materials were mixed together to provide a powder of uniform consistency. Perminal BX is the so- EXAMPLE PASTES dium salt of alkylated naphthalene sulphonic acid.

Compound of formula 50.0% w/w 60.0% w/w 40.0% w/w 20.0% \v/w Carmoss (Trade Mark) (Thickening agent) 2.0% do. 1.0% do. 2.5% do. 1.7% do. (ilyccrinc (Humectnnt) l0.0'// do. 8.0% do. 12.0% do. 8.3% do. water 33.0% do. 30.4% do. 45.5% do. H.771 do. China clay (Solid Dilucnt) 38.3% do.

100.0% w/w 100.0% w/w 100.0%w/w 100.0% w/w the Carmoss was dissolved in the water, the glycerine EXAMPLE 22 FEED PREMIXES added, followed by the active ingredient (and China Clay, if appropriate). The whole was mixed until unif Compound of formula (I) 1% w/w 80% w/w Cereal Base 99% do. do. Carmoss 1s a carragenate or a sulphurlc acid ester of a o] saccharide.

p y The two materials were mixed to provide a premix of EXAMPLE l9 PASTES 20 uniform consistency.

Compound of formula 60.0% w/w 70.0% w/w 45.0% W/W 20.0% w/w Manucol (Trade Mark) (Thickening agent) 0.3% do. 0.25% do. 0.4% do. l.5'/r do. Glyccrinc (Humcctant) 8.0% do. 6.00% do. ll.0// do. 5.0% dov Water 31.7% do. 23.75% do. 43.6% do. 38.5% do. China clay (Solid Dilucnt) 35.0% do.

100.0% w/w 100.0% w/yy 100.0% w/w 100.0% w/w The Manucol was dissolved in the water and glycer- EXAMPLE 23 PELLETS inc and the active ingredient (and China Clay, if appropriate) added and mixed until uniform.

Compound of formula (I) l% 80% Manucol is sodium algmate. 35 Cereal Base 99% 20% EXAMPLE 20 OIL-IN-WATER EMULSION PASTES The two ingredients were mixed, and the mixture Compound of formula (I) 5.0% w/w 50.0% w/w Sipol Wax A0 (Trade Mark) (Emulsifying agent) 6.25% do. 5.0% do. Mineral Oil (Liquid Dilucnt) 25.0% do. 200% do. Water 31.25% do. 25.0% do. China Clay (Solid Diluent) l7.50% do.

100.0% w/w V I 100% w/w The Sipol wax AC was dissolved in the mineral Oil at then fed to any conventional feedstuff pelleting plant. 60C, and this solution then added with vi orous stirring to the water, also at 60C. Stirring was continued EXAMPLE 24 until the emulsion was cooled to 25 C, at which Tablets were prepared from the following ingreditemperature the finely ground active ingredient (and m the China Clay where appropriate) was added, and the whole mixed until uniform.

per table! slpol wax AG ls Cetomacrogol Emulslfymg Wax l. Bis-[B-(4-acetamidophenoxy)ethyl] ether 2000 mg. 2. Starch B.P. 300 mg.- 3. Providone B.P.C. 50 mg, EXAMPLE 21 WETTABLE POWDERS 4. Magnesium stearate HP. 25 mg.

Compound of formula (I) 85.0% w/w 20.0% w/w Ncosyl (Trade Mark) (Dilucnt) 1.0% do. 24.0% do. Bevaloid Dispersant (Trade Mark) (Dispersing agent) 2.0% do. 2.0% do. Pcrminal BX (Trade Mark) (Wetting agent) 0.2% do. 0.2 do. Natrosol 250 (Trade Mark) (suspending agent) 1.7% do. 2.8% do. Sodium sulphate (suspending agent) l().l% do. 51.0% do.

LIIbUN EXAMPLE 25 Tablets were prepared from the following ingredients:

per tablet 2000 mg. 1000 mg. 50 mg. 250 mg. 30 mg.

Bis-[B-(4-acetamidophenoxy)ethyl] ether Microcrystalline cellulose Methylhydroxyethylcellulose Starch B.P.

Magnesium stearate Item 1, together with half the quantity of items 2 and 4, were granulated with a solution of item 3 in 50 percent aqueous ethanol, and then dried. The remainder of items 2 and 4 were added, and then item 5, and the whole mixed together. The resulting granules were dried and then compressed to form tablets.

EXAMPLE 26 TREATMENT OF F. HEPATICA No. of animals Age of F. heparica at time of treatment (weeks) Group No. Dose (mg/kg) 1 100 6 ll l 8 Untreated Controls mbh Each dose was calculated individually on the basis of bodyweight on the day before treatment. The dose was suspended in water, to which a little Hederol (a wetting agent, sold by Proctor & Gamble) was added, and given by drenching bottle.

The sheep were slaughtered ten to eleven weeks after infection and the livers were examined. The following result ere QWEPPQ;

Mean No. Dose Age of F. hepatica F. heptalica Percent- (mg/kg) at time of treatment found age (weeks) post mortem clearance 100 6 1.0 99 100 8 2.75 97 Untreated controls 83 In the same experiment, hexachlorophene at a dose of 10 mgjkg. gave clearances of 67 and 71 percent of 6- and 8-week old liver fiukes.

EXAMPLE 27 A further experiment was conducted in the manner described in Example 26, except that the sheep were dosed at 3 and 5 weeks with the compound of formula (I). The following results were obtained:

Dose Age of F. hepalica Mean No. I". hepalica (mg/kg.) at time of treatment found post mortem (weeks) at 6 weeks 9 (stunted) Controls 33 77 l00 I25 EXAMPLE 28 Synthesis of bis-[B-(4-formamidophenoxy)ethyllether A mixture of B,B'-bis-(4-aminophenoxy)ethyl ether (28.8 g.) and formic acid (23 ml. of 98-100percent) was mixed and heated overnight on a steam bath. The mixture was then poured with stirring into cold water (500 ml.). The resulting crystals were filtered from the supernatant liquid, and washed with water, to leave a crystalline solid mp. 15 l- C. This solid was recrystallized from hot ethanol (about 1.4 litre, 95percent) by adding hot water (about 1 litre), charcoaling while hot to remove most of the colour, filtering, and adding more water (about 1.5 litre) to the filtrate. The resulting solid m.p. l56.5-l57C, was again recrystallized from an ethanol-water mixture, m.p.' 156C.

Analysis: Calculated for C I-1 N 0 C,62.78; H, 5.85; N, 8.14.

Found: C, 62.80; H, 5.80; N, 8.10.

EXAMPLE 29 Synthesis of B-(4-acetamidophenoxy)ethyl /3-(4-propionamidophenoxy)ethyl ether p-Propionamidophenol (30 g.) dissolved in dry dimethylsulfoxide (200 ml.) was treated in a nitrogen atmosphere with potassium tertiary butoxide (18.5 g.). After having been stirred for about 10 minutes, the reaction mixture was treated with B-chloroethyl [3'-(4- acetamidophenoxy)ethyl ether (39 g.), and heated and stirred on a steam bath in a nitrogen atmosphere for 26 hours. The solution precipitated a voluminous purplishwhite solid on treatment with water (700 ml.). The solid was filtered from the aqueous solution, and washed with water. It had m.p. 137.2138.4 C. It was recrystallized from a hot ethanol-water mixture, charcoal added and the mixture filtered with a little filteraid, to gave a product of the same m.p. This was recrystallized again to give a first crop of off-white crystals melting on slow heating at 136.5 C. A tan coloured second crop m.p. 135 C came out later.

Analysis: Calculated for C ,H N O Molecular Weight 390.44: C, 65.62; H, 6.71; N, 7.18.

Found; C, 65.51; H, 6.83; N, 7.18.

EXAMPLE 30 Synthesis of B-(4-acetamidophenoxy)ethyl B-(4-formamidophenoxy)ethyl ether B-Chloroethyl B'-(4-acetamidophenoxy)ethyl ether (38.5 g.; 95 percent by assay; 0.142 Mole) was added to a stirred solution of p-formamidophenol (24.3 g., 0.18 Mole) and potassium tertiary butoxide (18 g.) (added in that order under nitrogen) in dry dimethyl sulfoxide (100 ml.). After addition of more dimethyl sulphoxide (100 ml.), the reaction mixture was stirred and heated on steam under nitrogen for 48 hours. It was then poured into water (about 2 litres), scratched to induce partial crystallization, and stored at 4 C. overnight. Decantation of some crystals and the aqueous solution from a matrix of crystals in oil, trituration of the latter with ether and filtration of the resulting solution-suspension, left a largely solid mass. Meanwhile, filtration of the alkaline aqueous decantate (above) gave crystals m.p. 100101 C, depressed in m.p. on admixture with starting halo-ether of m.p. 9798 C.

The residue of the ether trituration melted poorly at about 76.581 C after one recrystallization from an ethanOLbenZene-heXane mixture. It was then recrystallized from acetone water, charcoaling to remove colour. It crystallized slowly after seeding and scratching repeatedly, to give a product m.p. l02.5104C. This was again recrystallized from acetone water for analysis, m.p. 105.2108 C. Thin layer chromatography suggested the presence of or less of bis-[B-(4- acetamidophenoxy)ethyl] ether.

Analysis: Calculated for C,,H,,N,O,, Molecular Weight 358.39: C, 63.17; H, 6.23; N, 7.69. Found: C, 63.87; H, 6.28; N, 7.70.

EXAMPLE 31 Synthesis of bis-[fi-(4-butyramidophenoxy)ethy1]ether Calculated Found Analysis:

EXAMPLE 32 Synthesis of bis-[/3-(4-lactamidophenoxy)ethyl]ether A mixture of bis-[B-(4-aminophenoxy)ethyl] ether (17.1 g., 0.059 M) and ethyl lactate (40 ml., 0.36 M) were heated for about 50 hours until no more ethanol distilled off. The mixture was then evaporated to dryness in vacuo and extracted with hot water 1,500 ml. Concentration and cooling of the aqueous extracts caused precipitation of crystals, m.p. 127129C.

Calculated Found Analysis:

bJb-l EXAMPLE 33 Synthesis of bis-(4-acetamidophenoxy)methane A solution of p-hydroxyacetanilide (14.1 g.) and potassium tertiary butoxide (1 1.2 g.) in dimethyl sulphoxide (25 ml.) was added to methylene chloride (20.0 g.) dissolved in dimethyl sulphoxide (25 ml.) in a pressure bottle. The mixture was heated on a steam bath for 3 days, cooled, and poured into water (500 ml.). The precipitate which formed was filtered and washed with 0.5N sodium hydroxide 1500 ml.) and then with water (500 ml.). Recrystallisation from aqueous ethanol Synthesis of bis-[B-(4-acetamidophenoxy)isopropyl]ether acetamidophenoxy) isopropyl1ether, m.p. 166166.5C.

Analysis: Calculated C,65.98 H,7.05 N,7.00 Found -.C,65.76 C,7.08 N,6.94

EXAMPLE 35 Synthesis of bis-[B-(4-pivalamidophenoxy)ethyllether A suspension of bis-[B-(4-aminophenoxy)ethyl]ether (28.9 g., 0.1M) in pyridine (19.5 g., 0.245M) and dry tertiary butanol ml.) was added to warm (about 60C.) pivalyl chloride with stirring. An exothermic reaction occurred and the mixture was allowed to stand for 35 minutes after the addition was complete before being added to water (700 ml.). The crystals which slowly formed were recrystallised with charcoaling from aqueous ethanol (about 70 percent) to give bis- [B-(4-pivalamidophenoxy)ethyl]ether, m.p. 153.7 154.4C.

Calculated Found Analysis: :C,68 9 :C,68 4

EXAMPLE 36 p-Acetamidophenol (332 g.) dissolved in dry dimethylsulfoxide (900 ml.) was treated under a nitrogen atmosphere with potassium tertiary butoxide (234 g.) with sufficient cooling to maintain the temperature below about 65C. The reaction mixture was stirred and cooled to room temperature. B,B-bischloroethyl ether (577 g.) was added and the reaction mixture heated with stirring on a steam bath for 24 hours under a nitrogen atmosphere. The reaction mixture, reduced to about 750 ml. by distillation in vacuo, was poured into water (2.5 l.) and extracted with ether. The ether extracts and an ether-insoluble organic phase were combined and distilled. B-Chloroethyl /3-(4- acetamidophenoxy)ethyl ether was collected at l93-206C. and 550-600 microns and then recrystallized from ethanol-water, m.p. 100.6-10l.6C.

Calculated for C,,H, NO,-,Cl: C,55.92; Found: C,56.10;

This compound was used in the syntheses described in the foregoing Examples 29 and 30.

EXAMPLE 37 Synthesis of bis-[[3-( 4-acetoacetamidophenoxy)ethyl]ether bis-[fl-(4-Aminophenoxy)ethyl]ether (57.6 g.) dissolved in acetone (300 ml.) was treated with 450 ml. of 50 percent diketene in acetone. The reaction mixture was warmed and filtered through a filter-aid using 1.5 l. of warm acetone washes. The filtrate was cooled to 30C. and water added to incipient turbidity. It was then stored at 4C. during crystallization. The bis-[B- (4-acetoacetamidophenoxy)ethyl]ether was recrystallized from acetone, m.p. 129.2 129.7C.

Calculated for C,,H,,N,O,: C.63.l5; Found: C,63.29;

EXAMPLE 38 Synthesis of Bis-[H4N-Methyl-p-Acetamidophenoxy)Ethyl] Ether To p-Methylaminophenol sulphate (344 g.), suspended in percent ethanol (1,500 ml.), was added,

over a 20 minutes period with warming and stirring under a nitrogen atmosphere, acetic anhydride (307 g.) and 40 percent sodium hydroxide (285 ml.). The reaction mixture was allowed to stand overnight and the resulting product removed by filtration, washed with water, and recrystallized from ethanol to give N-methyl-pacetamidophenol (381 g.), m.p. 241.5243C.

Potassium tertiary butoxide (112 g.) was added to a solution of N-methyl-p-acetamidophenol g.) in dry dimethylsulfoxide (l l.) and the mixture stirred for 30 minutes under a nitrogen atmosphere. To this mixture ,B,B-bis-chloroethyl ether (70 g.) was added and the reaction mixture heated with stirring on a steam bath for 5 days under a nitrogen atmosphere. The reaction mixture was cooled, poured into water (3.5 l.) and throughly extracted with ether. The ether extracts were washed with N-sodium hydroxide, then water, and dried over anhydrous magnesium sulphate. The ether was evaporated and the resulting oil distilled to give bis-[B-(N-methyl-p-acetamidophenoxy)ethyl] ether b.p. 222C. at 0.05 mm of mercury.

Calculated for C H N O C,66.03; H,6.

Found: C,65.86; 11,7

EXAMPLE 39 Aqueous suspensions were prepared having the composition detailed below, wherein the compound of formula (l) is B-(4-acetamidophenoxy)ethyl B'-(4-propionamidophenoxy)ethyl ether.

The bentonite was dispersed in some of the water, the Bevaloid Dispersant and sodium benzoate added, and finally the finely ground active ingredient and balance of the water. The whole was mixed until uniform.

Bentonite is a colloidal clay consisting principally of montmorillonite, A1 O HSiO H O, and Bevaloid Dispersant is disodium salt of the condensation product of naphthalene sulphonic acid and formaldehyde.

EXAMPLE 40 Aqueous suspensions were prepared having the composition detailed below, wherein the compound of formula (I) is B-(4-acetamidophenoxy)ethy] B-(4-propionamidophenoxy)ethyl ether.

Compound of formula (I) 30.00% w/w 20.00% w/w 50.00% w/w Suiphitc Residue (Dispersing agent) 5.00% do. 5.00% do. 500% do. (C%lrn:os;4((]fl)|ing agent) 0.75% do. 0.75% do. 0.75% do.

fl! 11!" Water (14.25)? do. 74.25% do. 44.25% do. l00.00/r do. |00.00/1 do. 100.00% do.

The Carmoss and sulphite residue were dissolved in the water, the finely ground active ingredient added, Analysis: and h whole mixed until if Calculated for c n m o c.7102; H,8.94; N,5.l8 Sulphite residue is crude calcium lignin sulphonate; Found Carmoss is a carragenate or a sulphuric acid ester of a polysaccharide. EXAMPLE 44 EXAMPLE 41 Synthesis of Synthesis of bis [(4-acetamidophenoxy)methyl]ether blslB44cycloPrOPionamldophenoxy)ethyllather Bis[B-(4-Aminophenoxy)ethyl]ether (7.2g, 0.025 fg z g &3 g2a gg gfg zsz igsfigii5 2 3 mole) was dissolved in a mixture of chloroform (I00 mole) added to the warm solution. This solutiod was ml) i pyndme ml) and 9 was treated then treated with bis(chlor0methyl)ether (9.49g, 0.082 dropwise (.Wer 30 i at 5 l0 C with cyclopropylcap mole) over 10 mins at 20C- After Stirring for 21/2 boxyhc acid chloride (5.7g, 0.055 mole). After2 hours hours the mixture was filtered and the solid product Surfing h mixture was mtenid i the produc} Solid washed with dilute aqueous sodium hydroxide solution g? g dilute g i acld i W3- and with water. After dryingthe solid was recrystallized 25 ter rymg. t e so Id f recrysta 3 fromo 2- from methylated Spirit mpt' 17250474400 ethoxyethanol with charcoahng. MPt 189.5 -l9l.l C

i f r C H N O C 62 H 5 85. N 8 14 iil eulmed for c n u o C,67.90; noes; N,6.60 Found 0 2 5 ciszfsoinislsvilvisjoe EXAMPLE 45 EXAMPLE 42 Synthesis of l,2-bis(4-acetamidophenoxy)ethane Synthesis of A solution of sodium ethoxlde, prepared from soblS[B'(4'(B fil'dlmithlylagrylamldo)phenoxy)e' dium (0.65 g.) and ethanol (15 ml.), was added dropt y let er wise to a stirred solution of p-acetamidophenol (4.25 Bis[B-(4-Aminophenoxy)ethyl]ether (7.0g, 0.024 g.) in ethan0i;(10 ml.) at reflux. A mixture of 1,2- mole) was dissolved in a mixture of chloroform (150 40 dibromoethane (2.65 g.) and ethanol (5 ml.) was ml.) and pyridine (5 ml.) and the solution was treated added dropwise and boiling continued for a further 2 drop-wise with flfir thy y y hl d (5 0;, hours. After cooling, the solid product was collected by 0.050 m r 1 m a 1 Af 2 hours lrfiltration and thoroughly washed with water to yield ring the mixture was filtered and the isolated solid 1,2-bis(4-acetamidophenoxy) ethane, m.p. washed with dilute hydrochloric acid and then with wa- 265-266C.; it may be recrystallised from acetic acid ter. After drying the product was recrystallized from 2-ethoxyethanol/water with charcoaling to yield crys- EXAMPLE 46 I315, m.pt. 155.9l57.0C. Synthesis of 50 Bis[B-(4-acetamidophenoxy)n-propyl]ether Sodium (216g, 0.094 mole) was dissolved in dried l d f C O C 69 w H 7 3. 6 ethanol (200 ml) and p-hydroxyacetanilide (15.1g, j i or 5 3 hj 51 1 0.100 mole) added. After the p-hydroxyacetanilide had dissolved, bis-B,B'-(mesyloxy n-propyl)ether (11.lg, 55 0.038 mole) was added and the mixture refluxed with stirring for 37 hours. The ethanol was removed by dis- EXAMPLE 43 tillation in vacuo and the residue treated with 2N So- Synthesis of [B-( a p xy) hy l th dium hydroxide and extracted with chloroform. The oil Bis[/3 (4 AminophenOXy)ethyuether (72g, 0025 obtained on removing the chloroform was induced to mole) was dissolved in pyridine (75 m1) and treated solidify by cooling and scratching and the solid was redropwise with octanoyl chloride (103g, 0.063 mole) at crystaghzed o from methylated spmt' Mpt -10 to 0C over mins. After stirring for 2 hours, 138-3 during which time the temperature was allowed to rise to 20C, the mixture was filtered. The isolated solid was washed with dilute hydrochloric acid and then with 65 Anaysis. water and dried before recrystallizing from methylated Calculated for cnll u o c.6598; H,7.05, N,7.00 Found C.66.59; H,7.l7 N,7;00

spirit with charcoaling, m.pt. l60.2-16l.5C.

EXAMPLE 47 of chloroacetylchloride (5.0 ml., 0.0625 mole) in chlo- 1 roform (25 ml). After stirring for 1 hour the mixture was filtered and the solid washed with dilute hydrochloric acid and then with water before drying and recrystallizing from 2-ethoxyethanol. MPt 170.8-l73.1C.

4.41g. (0.010 mole) of the above-prepared bis[B-(4- chloroacetamidophenoxy)ethyl]ether was treated with dimethylamine (100 ml of a 50 percent solution in ethanol) and the mixture kept in a pressure vessel for 24 hours at room temperature and then for 16 hours at 60C. The solvent and excess dimethylamine were then removed by distillation in vacuo and the residue extracted with dilute hydrochloric acid, charcoaled and filtered before being made alkaline and extracted with chloroform. Evaporation of the chloroform yielded an oil which was crystallized from carbon tetrachloride.

MPt 85.687.2C.

Analysis:

Found C,62.60; H,7.44; N,l2.l6

EXAMPLE 48 Synthesis of Bis-[B-(4-N,N-diacetylaminophenoxy)ethyl] Ether A mixture of bis-[B-(4-acetamidophenoxy)ethyl] ether (8.1 g.) and acetic anhydride (40 ml.) was al- 0 lowed to stand at room temperature overnight. It was then heated at reflux for 6 hours. The reaction mixture was poured into water (1 l). The oil which separated was induced to crystallize by trituration in the presence of carbon tetrachloride. The resulting solid was recrystallized from an acetone/hexane mixture. The product, which is hygroscopic when moist with the recrystallization solvent, was dried at 50C. under reduced pressure, m.p. 9l92C.

ether.

Claims

1. BIS-(B(4-N,N-DIACETYLAMINOPHENOXYL) ETHER.