Control of ectoparasites

Abstract: A series of 1,3-propanediones having a perfluoroalkyl group or a perfluorocycloalkyl group on one carbonyl, and a 3,5-disubstituted phenyl group on the other, are useful when administered to animals for the control of ectoparasites.

Description: The present invention relates to novel 1,3-propanediones, which have a 3,5-disubstituted phenyl group and a C₂-C₄ perfluoroalkyl or C₃-C₆ perfluorocycloalkyl group on the carbonyls, their preparation and use in the control of ectoparasites. The control of ectoparasites, such as fleas, ticks, biting flies and the like, has long been recognized as an important problem in animal husbandry. The traditional treatments for domestic animals were topically applied insecticides, such as the famous dips for sheep. Indeed, such treatments are still in wide use. However, the more modern thrust of research has been towards compounds which can be administered to the animals, especially orally, and which will control ectoparasite populations by poisoning individual parasites when they ingest the blood of the treated animal. Such novel compounds are provided by the present invention. South African Patent 71/4221 discloses insecticidal activity of 1,3-propanediones having a trifluoromethyl group on one carbonyl, and a substituted phenyl group on the other carbonyl. Ectoparasiticidal use of some of their compounds is disclosed. Canadian Patent 862,068 shows a group of 1,3-propanediones, having a phenyl or napthyl group on one carbonyl and a perhalomethyl or perhaloethyl group on the other carbonyl. The compounds are said to be insecticides but there is no reference to treatment of animals. U.S. Patent 3,636,214 shows some 1,3-propanediones having an aryl group on one carbonyl and a trifluoromethyl or other haloalkyl group on the other carbonyl. However, this document describes the use of such compounds only for the purpose of controlling fungi, especially in the soil. EP-A-0 202 903 discloses a method of controlling a population of insect or acarina ectoparasites with 1,3-propanediones having a halo, trifluoromethyl, nitro, chloroethenyl or bromoethenyl substituted phenyl or thienyl group on one carbonyl and a perfluoroalkyl or perfluorocycloalkyl group on the other carbonyl. There is, however, no reference to compounds in which the substituted phenyl group is a 3,5-dichlorophenyl group, such compounds being particularly effective against ectoparasites. The present invention provides compounds of the formula wherein R¹ is a C₂-C₄ alkyl or a C₃-C₆ cycloalkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms but excluding a 1,1,2,2,2-pentafluoroethyl group, and the sodium, potassium and lithium salts thereof. The present invention also provides a method of controlling a population of insect or acarina ectoparasites which consume the blood of a host animal which comprises administering to the host animal an effective amount of a compound of the formula wherein R¹ is a C₂-C₄ alkyl or a C₃-C₆ cycloalkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms, or a sodium, potassium or lithium salt thereof. Throughout the present document, all temperatures are expressed in degrees Celsius. All expressions of percentage, concentration and the like are in weight units unless otherwise described. The R¹ groups of the compounds of use in the method of the present invention include fluorinated alkyl and cycloalkyl groups such as -CF₂CF₃, -CF₂CF₂H, -CFHCF₃, -CF₂CF₂CF₃, -CF₂CF₂CF₂H, -CF₂CFHCF₃, -CF₂CF₂CF₂CF₃, -CF₂CF(CF₃)₂, -CF₂CF₂CF₂CF₂H, -CF₂CF(CF₂H)CF₃, -CF₂CF₂CFHCF₃, -CF₂CH(CF₃)₂, 1,2,2,3,3-pentafluorocyclopropyl, 1,2,2,3-tetrafluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 1,2,2,3,3,4,4-heptafluorocyclobutyl, 1,2,2,3,4,4-hexafluorocyclobutyl, 1,2,2,3,3,4-hexafluorocyclobutyl, 1,2,2,3,3,4,4,5,5-nonafluorocyclopentyl, 1,2,2,3,3,4,5,5-octafluorocyclopentyl, 2,2,3,3,4,4,5,5-octafluorocyclopentyl, 1,2,2,3,3,4,4,5,5,6,6-undecafluorocyclohexyl, 1,2,2,3,3,4,4,5,5,6-decafluorocyclohexyl, and 1,2,2,3,3,4,5,5,6,6-decafluorocyclohexyl. While all of the compounds described above are potent ectoparasiticides, certain compounds are preferred. Preferred compounds of the present invention are those wherein R¹ is a C₂-C₄ alkyl group in which hydrogen atoms have been replaced by fluorine atoms. Especially preferred compounds of the present invention are those wherein R¹ is a C₂-C₃ alkyl group in which hydrogen atoms have been replaced by fluorine atoms. Particularly preferred compounds are 1-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl)-1,3-propanedione and 1-(3,5-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione, and the sodium, potassium and lithium salts thereof. Preferred compounds for use in the method for controlling ectoparasites of this invention are those wherein R¹ is a C₂-C₄ alkyl group in which hydrogen atoms have been replaced by fluorine atoms. Especially preferred compounds for use in the method of the present invention are those wherein R¹ is a C₂-C₃ alkyl group in which hydrogen atoms have been replaced by fluorine atoms. Particularly preferred compounds in the method of the present invention are 1-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl)-1,3-propanedione, 1-(3,5-dichlorophenyl)-3-(1,1,2,2,2-pentafluoroethyl)-1,3-propanedione, and 1-(3,5-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione, and the sodium, potassium and lithium salts thereof. Use of any of the above compounds, especially the most preferred compounds enumerated above, in the form of their salts, especially the sodium salt, is particularly preferred in the method for controlling ectoparasites of this invention. While the compounds of the present invention are consistently named as 1,3-propanediones in the present document, it will be understood that it is quite possible if not probable that one of the carbonyl groups will actually be in the enol form. That is to say, the compound will exist in a form described as follows: R-CO-CH=C(OH)-R¹ Indeed, it is most probable that the compounds exist in an equilibrium form containing some of the diketone and some of the enol at all times. A careful study of the equilibrium has not been carried out, and so the compounds will be described here as diketones in all cases. It will be understood by the skilled reader that the principles and function of the present invention remain the same, whether carried out with the diketone, with pure enol, or with an equilibrium mixture of the diketone and the corresponding enol. It is believed that the nature of the compounds used in the present invention has been made entirely clear. However, to assure that the reader fully comprehends the invention, a group of exemplary compounds will be mentioned here. 1-(3,5-dichlorophenyl)-3-(1,1,2,2,2-pentafluoroethyl)-1,3-propanedione 1-(3,5-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione 1-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl)-1,3-propanedione 1-(3,5-dichlorophenyl)-3-(1,1,2,3,3,3-hexafluoropropyl)-1,3-propanedione 1-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)-1,3-propanedione 1-(3,5-dichlorophenyl)-3-(1,1,2,2,3,4,4,4-octafluorobutyl)-1,3-propanedione 1-(3,5-dichlorophenyl)-3-(2-trifluoromethyl)-1,1,3,3,3-pentafluoropropyl)-1,3-propanedione 1-(3,5-dichlorophenyl)-3-(1,2,2,3,3-pentafluorocyclopropyl)-1,3-propanedione 1-(3,5-dichlorophenyl)-3-(1,2,3,3,4,4-hexafluorocyclobutyl)-1,3-propanedione According to one aspect of the invention there is provided a method for preparing the novel compounds of the invention which have the formula wherein R¹ is as defined above, which comprises reacting a compound of the formula with an activated form of the acid of formula R¹CO₂H (II) in the presence of a base sufficiently strong enough to generate the anion of the compound of formula (I). The activated form of the acid will normally be a C₁-C₄ alkyl ester of the formula R¹CO₂R³, where R³ is C₁-C₄ alkyl, preferably ethyl. However, acid halides or acid anhydrides can also be used. As stated above, the reaction should be carried out in the presence of a base strong enough to generate the anion of the compound of formula (I). Suitable bases which may be mentioned are alkali metal hydrides, such as sodium hydride, alkali metal hydroxides, such as sodium methoxide or sodium ethoxide, alkyllithium compounds, such as n -butyl lithium, or alkali metal amides, such as lithium diisopropyl amide. The present reaction should be effected at a temperature within the range of from about 0°C to about 100°C, preferably from about 0°C to about room temperature (22°C), in an inert organic solvent such as toluene or diethyl ether. When a compound containing a cycloalkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms is to be made, a preferred synthesis proceeds through a compound containing an alkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms, preferably trifluoromethyl, said compound being in the alkali metal salt form. That compound is contacted with a strong base, such as sodium hydride, to form an anion, which is then reacted with the acid fluoride of the desired fluorinated cycloalkyl carboxylic acid. The reaction is readily carried out at ambient or moderately elevated (up to about 100°C) temperatures. Thus, during the above described reaction, the anion is generated, wherein R⁴ represents a C₁-C₄ fluorinated alkyl group, preferably trifluoromethyl. This anion then reacts with an acid fluoride of the formula R¹COF, where R¹ represents a C₃-C₆ fluorinated cycloalkyl group, to form a compound of the formula Hydrolysis of this product with an aqueous mineral acid such as hydrochloric acid yields a compound of the formula in which R¹ is a C₃-C₆ fluorinated cycloalkyl group. The compounds of the present invention are highly acidic in nature and readily form alkali metal salts. Therefore, the products of the above-described processes are routinely obtained in the salt form. If the free acid form is desired, however, it is only necessary to take the product through an acidic step as the reaction mixture is being worked up. For example, a brief wash with a dilute strong acid, such as dilute hydrochloric acid, readily converts a salt to the free acid. The following preparative Examples are given to assure that the reader can obtain any desired compound of the present invention. The Examples are not intended to limit the scope of the invention in any respect and should not be so construed. Example 1 1-(3,5-Dichlorophenyl)-3-(1,1,2,2-3,3,3-heptafluoropropyl)-1,3-propanedione, sodium salt Sodium ethoxide was prepared by reacting 3.6 g of 50% sodium hydride (75.0 mmol of sodium hydride) and 3.5 g (76.0 mmol) of ethanol in 100 ml of diethyl ether. The solution was cooled to about 5° and 9.0 g (37.0 mmol) of ethyl 2,2,3,3,4,4,4-heptafluorobutyrate were added. Then 7.0 g (37.0 mmol) of 3,5-dichloroacetophenone were added and the mixture stirred for two hours. The mixture was poured onto ice along with 50 ml of a 10% disodium hydrogen phosphate solution. The organic layer was separated, washed with brine, dried over magnesium sulphate, and concentrated under vacuum. The residue was recrystallized from diethyl ether:hexane to provide approximately 10 g of the desired product. Its n.m.r. spectrum on a 250 mHz instrument showed singlets at δ = 6.35, 7.75, and 7.85, respectively. Analysis calc. for C₁₂H₄Cl₂F₇O₂Na Theory: C, 35.41; H, 0.99 Found: C, 35.68; H, 1.26 In an analogous manner to that described in Example 1, the following compounds were prepared: Example 2 1-(3,5-Dichlorophenyl)-3-(1,1,2,2,2-pentafluoroethyl)-1,3-propanedione, sodium salt. Ethyl 2,2,3,3,3-pentafluoropropionate (30.0 g, 156.0 mmol) and 3,5-dichloroacetophenone (23.2 g, 123.0 mmol) were reacted to provide the title compound. The compound's n.m.r. spectrum on a 250 mHz instrument showed a singlet at δ = 6.35 and a broad singlet at δ = 7.8-7.9. Analysis calc. for C₁₁H₄Cl₂F₅O₂Na Theory: C, 37.00; H, 1.13 Found: C, 36.93; H, 1.40 Example 3 1-(3,5-Dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione, sodium salt 2,2,3,3-Tetrafluoropropionyl chloride (5.5 g, 33.0 mmol) and 3,5-dichloroacetophenone (5.6 g, 29.6 mmol) were reacted to provide the title compound, which was then recrystallized from hexane to provide an off white solid. The compound's n.m.r. spectrum on a 250 mHz instrument showed a singlet at δ = 6.30 (1H): a triplet of triplets at δ = 6.65 (1H); a singlet at δ = 7.80 (1H); and a singlet at δ = 7.85 (2H). Mass spectrum analysis established that this compound exists as a dimer and a trimer, containing from one to three sodium cations. Analysis calc. for a trimer of the formula C₃₃H₁₆Cl₆F₁₂O₆Na₂ Theory: C, 39.83; H, 1.62 Found: C, 39.81; H, 1.92 Representative compounds of the present invention have been tested both in vitro and in vivo to determine the scope of their activity. The following tests are illustrative. Single Dose - Cattle Systemic Test Representative compounds were tested in cattle using a single intraruminal injection of the desired dose of the compound dissolved in 10 ml of polyethylene glycol. The cattle were calves weighing at least 165 kg, housed in environmentally controlled pens. Two calves were used for each compound tested. The calves were fed on a conventional mixed feed which provided adequate nutrients and energy. Feed and water were available to the calves at all times. Each day, a sample of blood was obtained from the jugular vein of each calf. The blood samples were centrifuged to obtain serum, and the serum was exposed to insects as described below. Thus, the tests evaluated the systemic activity of the compounds, and also the length of time during which the compound persisted in the animal's system. In one in vitro method used to evaluate compound activity, dental wicks were saturated with the above blood serum and then placed in Petri dishes containing adult stable flies and in test tubes containing blow fly larvae. After 24 hours, the insects were examined and the number of dead counted. A compound was considered to be active, for purposes of the present disclosure, on any day in which at least 50% of the insects were killed upon exposure to the saturated wick. Certain compounds were further tested by exposing dental wicks saturated with blood serum, per the method described above, to insects for 48 hours rather than 24 hours. After 48 hours, the insects were examined and the number of dead counted. Again, a compound was considered to be active, for purposes of the present disclosure, on any day in which at least 50% of the insects were killed upon exposure to the saturated wick. The following table reports test results of representative compounds of the present invention. The compounds are identified by their Example numbers above. Insecticidal results are reported in terms of "days of insecticidal activity", indicating the specific test days on which at least 50% of the insects were killed upon exposure to a serum saturated dental wick for either a 24 or 48 hour period. Insecticidal Activity Following 24 and 48 Hour In Vitro Exposure of Insects to Cattle Sera Compound of Ex. Number Dose (mg/kg) Test Days Days of Insecticidal Activity 24 Hours 48 Hours L A L A 1 5.0 10 2-4 2-4 1-6 1-8, 10 1 5.0 10 2-3 2-4 1-6 1-10 2 5.0 10 0 2-3 3-4 3-5 2 5.0 10 0 0 3-4 3-6 3 5.0 10 0 0 0+ 0+ 3 5.0 10 0 0 0+ 0+ L = Blow Fly Larvae A = Adult Stable Fly NT = Not Tested Multiple Dose - Cattle Systemic Test Representative compounds of the invention were also tested in cattle using multiple intraruminal injections of the desired dose of the compound. The multiple injections consisted of daily administration of a single intraruminal injection for a period ranging from 10 to 18 days. The cattle tested were similar in size to those described for the single dose test detailed above. Two calves were used for each compound and dose tested. The calves were also fed and watered as previously described. The daily dose of compound to be tested was prepared using one of two methods. In one method the desired dose was prepared, daily, prior to administration, by dissolving the required daily amount of test compound in 5 ml of polyethylene glycol. In an alternative method the entire amount of compound required for the test was dissolved in a sufficient amount of polyethylene glycol such that the resulting solution contained approximately 5 ml of polyethylene glycol for each day of testing. The total volume of material thus prepared was then placed in a capped serum bottle which was suitable for metering out the desired daily dose. Approximately 24 hours after the previous day's intraruminal dose had been administered, and just before the current day's dose was to be admiinistered, a sample of blood was obtained from the jugular vein of each calf tested. The blood samples were centrifuged to obtain serum and the serum exposed to adult stable flies and blow fly larvae per the 24 and 48 hour in vitro test system described previously. In addition, certain representative compounds of the present invention were also tested using an in vivo test system comprising placing a chamber containing six starved adult stable flies on the back of the test animal on each test day. The flies were collected daily and the number of dead flies counted. A compound was considered to be active, for purposes of the present discussion, on any day in which at least 50% of the flies had died prior to collection. The calves were given daily intraruminal injections for periods ranging from 10 to 18 days and then the injections were stopped. Both in vitro and in vivo testing was continued for several days beyond the administration period, preferably until no further insecticidal activity was observed. Thus, the tests evaluated the systemic activity of the compounds, and also the length of time during which the compound persisted in the animal's system. Tables II and III report test results of representative compounds. The compounds are identified by their Example numbers above. Table II reports insecticidal activity in the 24 and 48 hour in vitro test system. Table III reports insecticidal activity against adult stable flies in the in vivo test system. Insecticidal results, in both tables, are reported in terms of "days of insecticidal activity". The term "days of insecticidal activity" in Table II is used in the same manner as in Table I above. The same term, in Table III, refers to the specific test days in which at least 50% of the adult stable flies had died prior to collection. Insecticidal Activity Following 24 and 48 Hour In Vitro Exposure of Insects to Cattle Sera Compound of Ex. Number Daily Dose (mg/kg) Dose Time Days Test Days Days of Insecticidal Activity 24 Hours 48 Hours L A L A 1 1.00 18 26 6-26 3-26 NT NT 1 1.00 18 21 5-21 3-21 NT NT 1 0.50 17 25 0 10-11 7-16 18-19 4, 6-21 1 0.50 17 25 0 12 8-15 4, 6-19 1 0.35 17 25 0 0 0 7, 9-18 1 0.35 17 25 0 0 0 6, 8-18 1 0.20 17 25 0 0 0 0 1 0.20 17 25 0 0 0 0 2 1.50 10 19 4-18 2, 4-19 2-19 2-19 2 1.50 10 19 4-16 3-19 2-18 2-19 2 1.00 18 26 5-23 3-25 NT NT 2 1.00 18 26 5-22 3-25 NT NT 2 0.75 10 19 6-11 5, 8-14 4-13 3-17 2 0.75 10 19 7-10 9-11 4-13 4-17 2 0.50 10 19 0 10-11 6-12 4, 6-18 2 0.50 10 19 0 10-12 6-12 4,6-16,18 2 0.30 17 25 0 0 0 4,9,12 2 0.30 17 25 0 0 0 4, 8, 10-11,16 3 1.00 18 26 0 4,6-9, 11,17 0 3-18 3 1.00 18 26 0 6,8,9, 11,17 0 5-18 L = Blow Fly Larvae A = Adult Stable Fly NT = Not Tested In Vivo Insecticidal Activity Compound of Ex. Number Dose (mg/kg/day) Dose Time (Days) Test Days Days of Insecticidal Activity 1 1.00 18 26 4-13,15-22,25-26 1 1.00 18 21 1,6-12,15-21 2 1.00 18 26 4-8,10-13,15-26 2 1.00 18 26 5-13, 15-26 Tick Test The activity of the compounds of the invention against Lone Star ticks, Amblyomma americanum, was determined as follows. Two calves were given a daily 1 mg/kg intraruminal injection of a solution consisting of the required amount of the compound of Example 2 dissolved in 5 ml of polyethylene glycol. Two other calves were given a daily 1 mg/kg intraruminal injection of a solution consisting of the required amount of the compound of Example 3 dissolved in 5 ml of polyethylene glycol. Finally, two other calves were used as control calves, with one calf given 5 ml of polyethylene glycol each day while the other calf was left untreated. All treatments continued for a total of 18 days. Forty (20 female and 20 male) adult Lone Star ticks were placed on each calf seven days after the treatments described above were started. In addition, 30 Lone Star tick nymphs were placed on each test animal at this same point in time. Eleven days later the calves were examined to assess the compounds' efficacy on adult and nymph tick viability. The results of this test are presented in Table IV below. Compound Efficacy Against Adult and Nymph Ticks Calf Treatment Tick Viability After 11 Days Exposure 1 mg/kg/day of Compound of Example 2 in 5 ml of polyethylene glycol All nymphs dead; No adult ticks repleted; All female adult ticks dead. 1 mg/kg/day of Compound of Example 3 in 5 ml of polyethylene glycol All nymphs dead; No adult ticks repleted; All female adult ticks dead. 5 ml/day of polyethylene glycol 16/30 nymphs alive; All adult ticks repleted; All female adult ticks alive and normal in egg production. No treatment 18/30 nymphs alive; All adult ticks repleted; All female adult ticks alive and normal in egg production. Methods of Use The method of the present invention is carried out by administering a compound of the invention to a host animal to control insect and acarina parasites. Administration to the animal may be by the oral or percutaneous routes. Parasitic insects and acarina include species that are bloodsucking as well as flesh eating and are parasitic during all of their life cycle or only part of their life cycle, such as only the larval or only the adult stage. Representative species include the following: horse fly Tabanus spp. stable fly Stomoxys calcitrans black fly Simulium spp. horse sucking louse Haematopinus asini mange mite Sarcoptes scabiei scab mite Psoroptes equi horn fly Haematobia irritans cattle biting louse Bovicola bovis shortnosed cattle louse Haematopinus eurysternus longnosed cattle louse Linognathus vituli tsetse fly Glossina spp. cattle follicle mite Demodex bovis cattle tick Boophilus microplus and B . decoloratus Gulf Coast tick Amblyomma maculatum Lone Star tick Amblyomma americanum ear tick Otobius megnini Rocky Mountain wood tick Dermacentor andersoni screwworm fly Cochliomyia hominivorax assassin bug Reduvius spp. mosquito Culiseta inornata brown ear tick Rhipicephalus appendiculatus African red tick Rhipicephalus evertsi bont tick Amblyomma sp. bont legged tick Hyalomma sp.. hog louse Haematopinus suis chigoe Tunga penetrans body louse Haematopinus ovillus foot louse Linognathus pedalis sheep ked Melophagus ovinus sheep scab mite Psoroptes ovis greenbottle fly Phaenicia sericata black blow fly Phormia regina secondary screw-worm Cochliomyia macellaria sheep blow fly Phaenicia cuprina bed bug Cimex lectularius Southern chicken flea Echidnophaga gallinacea fowl tick Argas persicus chicken mite Dermanyssus gallinae scalyleg mite Knemidokoptes mutans depluming mite Knemidokoptes gallinae dog follicle mite Demodex canis dog flea Ctenocephalis canis American dog tick Dermacentor variabilis brown dog tick Rhipicephalus sanguineus The method of the invention may be used to protect economic and companion animals from ectoparasites. For example, the compounds may beneficially be administered to horses, cattle, sheep, pigs, goats, dogs, cats and the like, as well as to exotic animals such as camels, llamas, deer and other species which are commonly referred to as wild animals. The compounds may also beneficially be administered to poultry and other birds, such as turkeys, chickens, ducks and the like. Preferably, the method is applied to economic animals, and most preferably to cattle and sheep. The claimed compounds display systemic ectoparasiticidal activity. The compounds have the ability to permeate the tissues of a host animal to which one of the compounds has been administered. Insect parasites which then consume blood or other living tissues of the host animal are thereby killed. Hence, the term "controlling", as defined for purposes of the present disclosure, entails the destruction of an insect population by killing the undesired insects after thay have consumed blood or other living tissue from the host animal. The compounds can be administered by oral or percutaneous routes, and are preferably formulated prior to administration. Percutaneous administration is conveniently accomplished by intraperitoneal, intraruminal and intravenous injection of an injectable formulation. Oral administration is a particularly preferred route of administration. The rate, timing, and manner of effective administration will vary widely with the identity of the parasite, the degree of parasiticidal attack, and other factors. Administration can be made periodically over the entire lifespan of the host, or for only a peak season of parasitic attack. In general, effective parasite control is achieved at administration rates of from about 5 to about 100 mg/kg. Oral administration may be performed by mixing the compound in the animals' feed or drinking water, or by administering dosage forms such as tablets, capsules, boluses, or implants. Since ectoparasitic attack generally takes place during a substantial portion of the host animal's lifespan, it is preferred to orally administer the compounds of the present invention in a dosage form capable of providing sustained release over a period of time. Conventional procedures include the use of a matrix which physically inhibits dissolution, where the matrix is a waxy semisolid, such as a vegetable wax, a high molecular weight polyethylene glycol, or a copolymeric matrix such as that described in Nevin, U.S. Patent 4,273,920. A good way to administer the compounds is by means of a sustained-action bolus, such as those of Laby, U.S. Patent 4,251,506, Davis et al ., U.S. Patent 4,649,042 and Simpson, British Patent 2,059,767. Sustained release of the compounds of the present invention can also be achieved by the use of an implant such as from a silicone-containing rubber. Usually, the compounds are formulated into ectoparasiticidal compositions which comprise a compound of the present invention and a physiologically-acceptable carrier. Such formulations are well known to those skilled in the art, for example by dissolving or dispersing the compound in one of many physiologically acceptable adjuvants or diluents. The compounds can be formulated for oral administration in the usual forms, such as drenches, tablets, or capsules. Such compositions, of course, require orally-acceptable inert carriers. The compounds can also be formulated as an injectable solution or suspension, for intraperitoneal, intraruminal or intravenous injection. In some applications, the compounds are conveniently formulated as one component of a standard animal feed. In this embodiment, it is usual to formulate the compound first as a premix in which the compound is dispersed in a liquid or particulate solid carrier. The premix can contain from about 2 to 250 grams of compound per pound. The premix is then, in turn, formulated into the ultimate feed by conventional mixing. The following exemplary compositions illustrate the sort of formulations used to practice the present invention. Feed Premix Compound of Example 1 10% Rice hulls 85 Light mineral oil 5 Feed Premix Compound of Example 2 25% Alfalfa meal 60 Powdered clay 5 Molasses 10 Drip-On Solution Compound of Example 3 20% Nonionic surf actant 0.8 Propylene glycol 15 Water 64.2 Injectable Solution Compound of Example 2 15% Propylene glycol 85 Injectable Solution Compound of Example 1 5% Polyethylene glycol 95 Injectable Suspension Compound of Example 2 25% Propylene glycol 15 Water 60 Injectable Suspension Compound of Example 3 30% Polyvinylpyrrolidone 2 Water 68

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, GR, IT, LI, NL, SE A compound of the formula wherein R¹ is a C₂-C₄ alkyl or a C₃-C₆ cycloalkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms but excluding a 1,1,2,2,2-pentafluoroethyl group, or a sodium, potassium or lithium salt thereof. A compound of Claim 1 wherein R¹ is a C₂-C₄ alkyl group in which hydrogen atoms have been replaced by fluorine atoms, or a sodium, potassium or lithium salt thereof. A compound of Claim 2 wherein R¹ is a C₂-C₃ alkyl group in which hydrogen atoms have been replaced by fluorine atoms, or a sodium, potassium or lithium salt thereof. A compound of Claim 3, said compound being 1-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl)-1,3-propanedione or a sodium, potassium or lithium salt thereof. A compound of Claim 3, said compound being 1-(3,5-dichloro phenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione or a sodium, potassium or lithium salt thereof. A method of controlling a population of insect or acarina ectoparasites which consume the blood of a host animal which comprises administering to the host animal an effective amount of a compound of the formula wherein R¹ is a C₂-C₄ alkyl or a C₃-C₆ cycloalkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms, or a sodium, potassium or lithium salt thereof. A method of Claim 6, wherein the compound used is 1-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl)-1,3-propanedione or a sodium, potassium, or lithium salt thereof. A method of Claim 6 wherein the compound is 1-(3,5-dichlorophenyl)-3-(1,1,2,2,2-pentafluoroethyl)-1,3-propanedione or a sodium, potassium, or lithium salt thereof. A method of Claim 6 wherein the compound is 1-(3,5-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione or a sodium, potassium, or lithium salt thereof. An ectoparasiticidal composition comprising a physiologically-acceptable inert carrier and a compound of the formula wherein R¹ is as defined in Claim 6, or a sodium, potassium or lithium salt thereof. A process for preparing a compound of the formula wherein R¹ is as defined in Claim 1, which comprises: A) reacting a compound of formula (I) with an activated form of the acid of formula (II) R¹CO₂H (II) in the presence of a base sufficiently strong enough to generate the anion of the compound of formula (I); or B) hydrolyzing a compound of the formula wherein R¹ is a C₃-C₆ cycloalkyl group and R⁴ is a C₁-C₄ alkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms. Claims for the following Contracting State : ES A process for preparing a compound of the formula wherein R¹ is a C₂₋₄ alkyl or a C₃-C₆ cycloalkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms but excluding a 1,1,2,2,2-pentafluoroethyl group, or a sodium potassium or lithium salt thereof, which comprises: A) reacting a compound of formula (I) with an activated form of the acid of formula (II) R¹CO₂H (II) in the presence of a base sufficiently strong enough to generate the anion of the compound of formula (I); or B) hydrolyzing a compound of the formula wherein R¹ is a C₃-C₆ cycloalkyl group and R⁴ is a C₁-C₄ alkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms. A process of Claim 1 wherein R¹ is a C₂-C₄ alkyl group in which hydrogen atoms have been replaced by fluorine atoms, or a sodium, potassium or lithium salt thereof. A process of Claim 2 wherein R¹ is a C₂-C₃ alkyl group in which hydrogen atoms have been replaced by fluorine atoms, or a sodium, potassium or lithium salt thereof. A process of Claim 3, said compound being 1-(3,5-dichloro phenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl)-1,3-propanedione or a sodium, potassium or lithium salt thereof. A process of Claim 3, said compound being 1-(3,5-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione or a sodium, potassium or lithium salt thereof. A method of controlling a population of insect or acarina ectoparasites which consume the blood of a host animal which comprises administering to the host animal an effective amount of a compound of the formula wherein R¹ is a C₂-C₄ alkyl or a C₃-C₆ cycloalkyl group in which all or all but one of the hydrogen atoms have been replaced by fluorine atoms, or a sodium, potassium or lithium salt thereof. A method of Claim 6, wherein the compound used is 1-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl)-1,3-propanedione or a sodium, potassium, or lithium salt thereof. A method of Claim 6 wherein the compound is 1-(3,5-dichlorophenyl)-3-(1,1,2,2,2-pentafluoroethyl)-1,3-propanedione or a sodium, potassium, or lithium salt thereof. A method of Claim 6 wherein the compound is 1-(3,5-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione or a sodium, potassium, or lithium salt thereof. An ectoparasiticidal composition comprising a physiologically-acceptable inert carrier and a compound of the formula wherein R¹ is as defined in Claim 6, or a sodium, potassium or lithium salt thereof.

Inventors: BOISVENUE RUDOLF JOSEPH, CROUSE GARY DEAN, BOISVENUE, RUDOLF JOSEPH, CROUSE, GARY DEAN
Applicants: BRITISH TECH GROUP USA, BRITISH TECHNOLOGY GROUP USA INC.
Application year: 1988
Main classification: C07C49
IPC codes: C07C49, A61P33, C07C45, A61K31, C07C67, A01N35