MXPA99004767A - Pirazo - Google Patents

Abstract

The present invention relates to: The compounds of formula (IA) and (IB) :( See Formula) and the salts and solvates thereof are useful as antiparasitic agents.

Description

PIRAZOLES DESCRIPTIVE MEMORY This invention relates to pyrazole derivatives, specifically 4-carbocyclyl-1-aryl pyrazoles having parasiticidal properties. International Patent Application Publication No. WO98 / 24767 discloses certain antiparasitic 1-aryl-4-cyclopropylpyrazole substances. International Patent Application Publication No. WO97 / 07102 describes, among others, certain 1-aryl-4- (cyclohex-1-enyl) -pyrazoles as antiparasitic agents. In accordance with the present invention, the compounds of formula (IA) and (IB) are provided.

(IB) (IA) wherein R1 is H, halogen, NH2, CONH2, CN, C6 alkyl optionally substituted with one or more substituents independently selected from halogen and OH, C2-6 alkanoyl optionally substituted with one or more halogen or C2-6 alkenyl optionally substituted with one or more halogens. R2 is H, C1-6 alkyl, NH2 or halogen. Y is an unbranched C0-4 alkylene optionally carrying substituents independently selected from halogen and C1-6 alkyl. R5, R6, R7, R8, R9 and R10 are each independently H or halogen or R7 and R8 can be linked to form an oxo or radical = CR12R13 where R12 and R13 are each independently H or halogen. R11 is H, C4-4 alkyl optionally substituted with one or more halogens, or C1-4 alkoxy optionally substituted with one or more halogen, R3 is halogen, R4 is C-alkyl optionally substituted with one or more halogens, C1-6 alkoxy 4 optionally substituted with one or more halogens, S (O) n (C? -4 alkyl optionally substituted with one or more halogens), halogen or SF5, m is-0, 1, 2, 3, or 4, n is 0.1? 2, X is N or CR14, wherein R14 is halogen, or a pharmaceutically, agriculturally or veterinarily acceptable salt thereof or solvate of any of said compounds or salts (hereinafter referred to as "the substances of the invention"). The alkyl and alkenyl groups may be straight or branched chain, where the number of carbon atoms allows the S (O) nalkyl, alkanoyl and alkoxy groups to incorporate said alkyl radicals. "Halogen" means fluorine, chlorine, bromine or iodine. Pharmaceutically, agriculturally or veterinarily acceptable salts are well known in the art and include, for example, those mentioned by Berge et al., In J. Pharm. Sci .. 66. 1-19 (1977). Suitable acid addition salts are formed from the acids that form non-toxic salts and include the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, gluconate, lactate, salicylate, citrate, tartrate salts , ascorbate, succinate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate. Suitable basic acid addition salts are those formed from the bases, which form non-toxic salts and include salts of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine. Solvates are generally well known in the technique. Preferably R1 is CN or C6-6 alkyl optionally substituted with one or more halogens. More preferably R1 is CN, CH3 or CF3. Preferably R2 is H, NH2 or Cl.

More preferably R2 is H or NH2. Preferably R3 is Cl. Preferably R4 is CF3, OCF3 or SF5. Preferably Y is a C0-4 unbranched alkylene. Preferably X is N or C-Cl. Preferably R5 is H, Cl or F. Preferably R6 is H, Cl or F. Preferably R7 when considered by itself is H, Cl or F. Preferably R8 when considered by itself is H, Cl or F. Preferably R7 and R8 when considered by themselves are oxo, CH2 or CBr2. Preferably R9 is H. Preferably R10 is H. Preferably R11 is H, CH3 or CF3. Preferably substituent 4 on pyrazole is a group selected from 2,2-dichloro-3-oxocyclobutyl, 2-chloro-2,3,3-trifluorocyclobutyl, 3-chloro-2,3,3-trifluoro-cyclobutyl, 3- oxocyclobutyl, 3,3-difluorocyclobutyl, 3-methylenecyclobutyl, cyclobutyl, cyclopent-2-enyl, cyclohepty-2-enyl, 3-dibromomethylene-cyclobutyl and cyclopen-tyl. More preferably, the substituent 4 on the pyrazole is a group selected from 2-chloro-2,3,3-trifluorocyclobutyl, 3-chloro-2,3,3-trifluorocyclobutyl, 3-oxocyclobutyl, 3,3-difluorocyclobutyl, 3- methylenecyclobutyl, cyclobutyl, cyclopent-2-enyl, cycloheptyl-2-enyl and cyclopentyl.

The preferred specific substances are those of the following examples and the salts and solvates thereof. The compounds of formula (IA) and (IB) may possess one or more asymmetric centers and thus exist in two or more stereomeric forms. The present invention includes all individual stereoisomers of the compounds of formula (IA) and (IB), slaes, solvates and mixtures thereof. The separation of the diastereomers can be carried out by conventional techniques, for example, by fractional crystallization, chromatography or HPLC of a stereoisomeric mixture of a compound of formula (IA) or (IB) or an appropriate salt or derivative thereof. An individual enantiomer of a compound of formula (IA) or (IB) can also be prepared from the corresponding optically pure intermediate or by resolution, such as by HPLC of the corresponding racemate using an appropriate chiral support or by fractional crystallization of the diastereomeric salts formed by the reaction of the corresponding racemate with an appropriate optically active acid or base. The compounds of the following examples and preparations can be prepared by various methods, such as the procedures outlined above and appropriate adaptation thereof. Unless otherwise specified, the substituents mentioned in the following procedures are as defined above for the compounds of formulas (IA) and (IB).

PROCEDURE 1 (A) The compounds of formula (IA) wherein m is 0, R7 and R8 are attached and are an oxo radical and R9 and R10 are chloro, ie, compounds of formulas (IA (i)) below, which can be made by reaction of a compound of formula (II) with an appropriate reactive system, such as zinc / trichloroacetic chloride / phosphorus oxychloride in an appropriate solvent, such as diethyl ether, as described in example 1 below.

The compounds of formulas (II) above are available by the methods described in International Patent Application Number WO97 / 07102 and an appropriate adaptation thereof.

PROCEDURE 1 (B) The α, α-dichloroketone compounds of formula (IA (i)) and homologues thereof of formula (IA) wherein m is 1, 2.3 or 4, R7 and R8 are joined as oxo and R9 and R10 are chloro, they can be transformed into the one corresponding to, unsubstituted a-ketone by appropriate reduction with various systems, such as those described by J. March in "Advanced Organic Chemistry" (3rd or later editions), Wiley Interscience, in the section of reaction 0-77 and references thereto, incorporated herein by reference. An example of this type of reaction is described below in example 3.

PROCEDURE KC) The compounds of formula (IA), in which m is 0, R5, R6 and R11 are all H and R7, R8, R9 and R10 are all halogen, can be prepared by reaction of the compound of formula (II) above, where R5, R6 and R11 are all H, with an olefin of formula R7R8C = CR9R10, where R7, R8, R9 and R10 are all halogen. An appropriate procedure is to heat the reactants to high temperatures under reduced pressure, such as in a steel "canister". The procedure is exemplified later in example 2.

PROCEDURE 2 Compounds of formula (IA), wherein R7 and R8 are joined as oxo (see procedure 1 above) can be transformed into compounds of formula (IA), wherein R7 and R8 are joined as CR12R13 by a reaction Wittig-appropriate or similar reaction with an appropriate phosphorus ylide reagent such as a phosphonium salt such as "CR12R13-triphenylphosphonium bromide" with an appropriate base in an appropriate solvent. Said reactions are generally described in J. March. in "Advanced Organic Company" (3rd edition or later), Wiley Interscience in reaction section 6-47 and references herein, incorporated herein by reference. Examples of this type of reaction are described below in examples 5 and 12.

PROCEDURE 3 Compounds of formula (IA), in which R7 and R8 join as oxo (see process 1 above) can be transformed into compounds of formula (IA) or (IB) gem-dihalide, wherein R7 and R8 are considered separately and both are halogen by an appropriate reaction of the type described in J. March in "Advanced Organic Chemistry" (3rd edition or later), Wiley Interscience, in reaction section 6-25 and references herein, incorporated here as a reference Examples of this type of reaction are described below in example 4.

PROCEDURE 4 Certain compounds of formula (I A) and (IB) wherein R 11 is H can be prepared for example by the transformation exemplified in example 6.

The 4-iodopyrazoles of formulas (IV) are available by known methods and can be reacted with an appropriate lithiating agent, such as n-butyllithium under appropriate conditions, such as in tetrahydrofuran at reduced temperatures giving the corresponding 4-lithiated species. This can then be reacted with a ketone of formula (Va) or (Vb) giving the alocholic species (Via) or (Vlb) respectively as shown above. Alcohols (Via) or (Vlb) can be reduced by various forms, for example, using the triethylsilane / boron trifluoride etherate system described in Example 6 below. Ketones of formulas (Va) and (Vb) are available either commercially or through published procedures.

PROCEDURE 5 (A) The compounds of formula (IA) and (IB), wherein R2 is H, can be prepared from the corresponding compounds of formula (IA) or (IB) respectively, wherein R2 is NH2 by reaction with an alkyl nitrile, such as t-butyl nitrite in N, N-dimethylformamide or tetrahydrofuran. This type of reaction is described in J. March in "Advanced Organic Chemistry" (3rd edition or later), Wiley Interscience in reaction section 4-23 and references herein, incorporated herein by reference. An example of this type of reaction is described below in example 8.

PROCEDURE 5 (B) The compounds of formula (IA) and (IB), wherein R 2 is halogen, can be prepared from the corresponding compounds of formula (IA) or (IB) respectively, wherein R 2 is NH 2 by reaction with an alkyl nitrite, such as t-butyl nitrite and a halide source. This type of reaction is described among others, in J. March in "Advanced Organic Chemistry" (3rd edition or later), Wiley Interscience in reaction sections 3-24, 3-25 and 4-24 and references herein, as reference. An example of this type of reaction is described later in example 9.

PROCEDURE 5 (C) The compounds of formula (IA) and (IB), wherein R 2 is C 1 -C 16 alkyl can be prepared from the corresponding compounds of formula (IA) or (IB) respectively, wherein R 2 is NH 2 by reaction with a nitrite of alkyl, such as t-butyl nitrite and a reagent such as tetra (Ci-β) alkyl tin. This type of reaction is described among others, in "Advanced Organic Chemistry" (3rd edition or later), Wiley Interscience, in reaction section 4-29 and references herein, incorporated herein by reference.

PROCEDURE 6 The compounds of formula (IB) wherein R7 and R9 are H can be prepared from the compounds of formula (IV) (see process 4 above) by a palladium catalyzed coupling reaction, with a reagent of formula (VII) : (vp) This type of reaction is exemplified later in Example 7. Certain compounds of the invention can be transformed into certain other compounds of the invention by interconversions of functional groups, etc. by methods generally known in the art. It will be apparent that all compounds of the invention are available by methods known in the art and the methods set forth herein and the proper adaptation thereof using methods known in the art. The expert chemist will make use of his knowledge and criteria to carry out any necessary adaptation, for example, when choosing reagents, conditions, compatibility of starting materials and reagents with the desired reaction, reaction order, protection / deprotection, additional reactions, etc. It will be apparent to those skilled in the art that it will be necessary for the sensitive functional groups to be protected or deprotected during the synthesis of substances of the invention. This can be achieved by conventional techniques, for example, as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons Inc, 1991. Compounds of formula (I) and salts and solvates they can be separated and purified by conventional methods. The substances of the invention are useful because they possess parasiticidal activity in humans, animals and plants. They are particularly useful in the treatment of ectoparasites. As regards the use of substances of the invention in humans, there is provided: a) a pharmaceutical formulation comprising a substance of the invention mixed with a pharmaceutically acceptable adjuvant, diluent or vehicle, which can be adapted for topical administration; b) a substance of the invention, for use as a medicament; c) the use of a substance of the invention in the manufacture of a parasiticidal medicament; and d) a method for treating a parasitic infection in a patient, which comprises administering an effective amount of a substance of the invention to the patient. As regards the use of substances of the invention in non-animal humans, the substances can be administered alone or in a suitable formulation for the specific intended use and for the particular species of host animal to be treated and parasite involved. The methods by which the substances can be administered include oral administration by capsules, large pill, tablets, potion or as pourable or drop formulations, or alternatively, they can be administered by injection (eg, subcutaneously, intramuscularly). or intravenous), disinfectant bath, spray, foam, shampoo, powder or as an implant. Such formulations are prepared in a conventional manner in accordance with conventional veterinary practice. Thus, capsules, large pills or tablets may be prepared by mixing the compound / active substance with an appropriate finely divided diluent or vehicle containing a disintegrating and / or binder agent, such as starch, lactose, talc, magnesium stearate, etc. Oral potions are prepared by dissolving or suspending the active ingredient in an appropriate medium. The injectable formulations may be prepared in the form of a sterile solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with the blood. Liquid pharmaceutically acceptable carriers include vegetable oils such as sesame oil and the like, glycerides, such as triacetin and the like, esters, such as benzyl benzoate, isopropyl myristate and propylene glycol fatty acid derivatives and the like, as well as organic solvents such such as pyrrolidone, glycerol formal and the like. The formulations are prepared by dissolving or suspending the active ingredient in the liquid vehicle, such that the final formulation contains from 0.01 to 10% by weight of the active ingredient. These formulations will vary as to the weight of the active substance contained herein depending on the species of the host animal to be treated, the severity and type of infection and the body weight of the host. For parenteral, topical administration (for example, using a pourable or droplet formulation, potion, spray, foam, shampoo, powder to disperse the compound) and oral administration, the typical dosage ranges of the active ingredient are 0.01 and 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg. As an alternative to the substances of the invention they can be administered with the animal's food and for this purpose a concentrated additive can be prepared to the food or premix to be mixed with the normal animal feed.

The substances of the invention have utility in the control of arthropod pests, plant nematodes, helminths or protozoa. The substances of the invention can be used, in particular, in the field of veterinary medicine, agriculture and livestock and in the maintenance of public health against arthropods, helminths and protozoa, which are internal or external parasites of vertebrates, particularly vertebrates of hot blood, for example, men or domestic animals, for example, cows, sheep, goats, horses, pigs, birds, dogs, cats and fish, for example mites, including ticks (for example, Ixodes, sp., Boophilus spp. example Boophilus microplus, Ambiyomma spp., Hyalomma spp., Rhipicephalus spp., for example, Rhipicephalus appendiculatus, Haemaphysalis sp., Dermacentor spp., Ornithodorus spp. (eg, Ornithodorus moubata and mites (eg Damalinia spp., Dermahyssus gallinae, Sarcoptes spp., For example, Sarcoptes scabiei, Psoroptes spp., Chorioptes spp., Demodex spp., Eutrombicula spp.,), Diptera (e.g., Aedes spp., Anopheles spp., Musca spp., Hgypoderma sp. p., Gastrophilus spp., Simulium spp.); Hemiptera (for example, Triatoma spp.); Ftirápteros (for example, Damalinia spp., Linoqnathus spp.) Sofonápteros (for example, Damalinia spp., Linoqnathus spp.) Dictriptera (for example Períplaneta spp., Blatella spp.); for example against gastrointestinal tract infections caused by worms nematode pests, for example, members of the family Tríchostrongylidae, Nippostronylus brasiliensis, Trichinella spiralis, Haemonchus contrortus, Trichochostronylus colubriformis, Nematodirus battus, Ostertagia circumcincta, Trichhostrongylus axi, Cooperia spp. and Hymenolepsis nana in the control and treatment of protozoa diseases caused for example, by Eimeria spp. for example Eimeria tenella, Elmeria acervulina, Eimeria brunetti, Eimeria maximus, Eimeria necatrix, Eimeria bovis, Eimeria zuerni and Eimeria ovinoidalis; Trypanosoma cruzi; Leishmania spp., Plasmodium spp., Babesia spp., Trichomonadidae spp., Histomonas spp., Giardia spp., Toxoplasma spp., Entamoeba histolytica and Theileria spp .; in the protection of stored products, for example cereals, including grains and flour, peanuts, animal feed, construction timber and household goods, for example, carpets and textiles, against the attack of arthropods, more especially beetles, including weevils, moths and mites, for example, Ephestia spp. (flour moths), Anthrenus spp. (carpet beetles), Tríbolium spp. (flour beetles), Sitophilus spp. (grain weevils) and Acarus spp. (mites) in the control of cockroaches, ants and termites and pests of similar arthropods in infected domestic and industrial premises and in the control of mosquito larvae in waterways, wells, reservoirs and other locations of running or stagnant water, for the treatment of foundations, structure and soil in the prevention of the attack of buildings by termites, for example, Reticulitermes spp., Heterotermes spp., Coptoterms app.,; in agriculture, against adults, larvae and eggs of Lepidoptera (butterflies and moths); for example Heliothis spp. such as Heliothis virscens (twister of the tobacco bud), Heliothis armioera and Heliothis zea, Spodoptera spp., such as S. Exempta, S. Littoralis (Egyptian cotton worm), S. Erídania (gardama), Mamestra configurata (gardama); Earías spp. for example, E. insulana (spiny caterpillar of the capsules), Pectinophora spp. for example, Pectinophora gossypiella (cotton bollworm), Ostrinia spp., such as O. Nubilalis (corn cob), Trichopulsia ni (false meter), Pieris spp (cabbage butterfly), Laphyma spp. (gardama), Agrotis and Amathes spp. (cutworm), Wiseana spp. (porina moth), Chilo spp. (noctuid rice), Tryporyza spp. and Diatrea spp. (sugar cane miner worm, rice sweeper), Sparganothis pillerina (cluster moth), Cydia pomonella (apple moth), Archips spp. (caterpillar of the skin of the fruit trees), Plutella xylostella (small moth of the cabbage); against adults and larvae of coleoptera (beetles) for example, Hypothenemus hampei (palm weevil), Hylesinus spp. (barrenillos), Anthonomus grandis (cotton boll weevil), Acalymma spp. (Cucumber beetle), Lema spp., Psylliodes spp., Leptinotarsa decemilineata (potato beetle), Diabrotica spp. (corn rootworms), Gonocephalum spp. (false wireworm), Agriots spp (wire worms), Dermolepida and Heteronychus spp. (white worms), Phaedon cochleariae (mustard beetle), Lissorhoptrus oryzophilus (rice weevil), Melioethes spp. (pollen beetles), Ceutorhynchus spp., Rhynchophorus and Cosmopolitas spp. (weevils of the roots); against Hemiptera for example Psylla spp., Bemisia spp., Trialeurodes spp., aphis spp., Myzus spp., Megoura viciae, Phylloxera spp., Adelges spp., Phorodon humuli (hopper aphid), Aeneolamia spp., Nephotettrix spp. (rice cicadas), Impoasca spp., Nilaparvata spp., Perkinsiella spp., Pyrilla spp., aonidiella spp. (red scale insects), Coccus spp., Pseucoccus spp., Helopeltis spp. (mosquito bugs), Lygus spp., dysdercus spp., Oxzycarenus spp. and Cephus spp. (saw flies), Atta spp. (cutting ants); Diptera, for example, Hylemya spp. (flies of the roots), atherigona spp. and Chlorops spp. (shoot flies), Phytomyza spp. (Leafminers), Ceratitis spp. (vinegar fly); Thysanoptera, such as Thrips tabaci; Orthoptera, such as Locusta and Schistocerca spp. (lobster) and crickets for example, Gryllus spp. and acehta spp .; Collembola, for example Sminthurus spp. and Onychiurus spp. (brincacolas), Isoptera, for example Odontotermes spp. (termites), Dermápteros for example Forfícula spp. (earwigs) and also other arthropods of agricultural significance, such as Acary Bi (mites), for example Tetranychus spp., Panonychus spp. ryobia spp. (spider mites), Eríophyes spp. (Eriophids), Scutigerella spp. (syphilids), Oniscus spp. (wood lice) and Tríops spp. (crustaceans); nematodes that attack plants and trees of importance for agriculture, forestry and horticulture or directly or by expansion of bacterial, viral, mycoplasmic or fungal diseases of plants, nematodes of root knots, such as Meliodogyna spp. (for example M. incognito, cysts by nematodes, with Globodera sp. (for example G. Rostochiensis), Heterodera spp. (for example H. Avenae), Radopholus spp. (for example R. Similis), lesions by nematodes, such as Pratylenchus spp. (for example P. pratensis), Belonoiiamus spp. (for example B. gracilis), Tylenchulus spp. (for example T. semipenetrans), Rotylenchulus spp. (for example R. reniformis), Rotylenchulus spp. R. Robustus), Helicotylenchus spp. (for example H. Multicinctus), Hemicycliophora spp. (for example H. Gracilis), Criconemoides spp. (for example C. Similis), Trichodorus spp. (for example T. primitivus); nematodes, such as Xiphinema spp. (for example X. Diversicaudatum), Longidorus spp. (for example L: elongatus), Hoplolaimus spp. (for example H. Coronatus), Aphelenchoides spp. (for example A. Ritzemabosi, A. Besseyi ), nematodes of stems and bulbs, such as Ditylenchus spp. (eg D. Dipsaci) .The substances of the invention also they may have utility in the control of arthropod pests or plant nematodes. The active substance is generally applied at the site where the infestation with the arthropod or the nematode must be controlled, at a dose of approximately 0.005 kg to approximately 25 kg of active compound per hectare of site to be treated, preferably from 0.02 to 2 kg / ha. Under ideal conditions, depending on the pest to be controlled, the lower dose may offer adequate protection. On the other hand, adverse weather conditions, pest resistance and other factors may make it necessary to use the active ingredient in higher proportions. For foliar application, a percentage of 0.01 to 1 kg / ha can be used. When the pest is spread on the ground, the formulation containing the active substance is evenly distributed over the area to be treated conveniently. The application can be made, if desired, generally in the growing area of the crop or near the seed or the plant to be protected from attack. The active substance can be left to the natural action of rain. During or after the application, the formulation can, if desired, be mechanically distributed in the soil, for example by plowing or plowing with discs. The application can be prior to planting, during planting, germination or after it, after planting, but before germination has occurred or subsequent to it. The substances of the invention can be applied in solid or liquid compositions to the soil mainly to control those nematodes that live in the same but also to the foliage mainly for the control of those nematodes that attack the parts of the plants (for example, Aphelenchoides spp. and Ditylenchus spp., cited above). The substances of the invention are valuable for the control of pests that feed on the parts of plants located far from the point of application, for example, the insects that feed on the leaves are destroyed by the object substances applied to the roots. In addition, the substances can reduce the attack on the plant by means of the antialimentation or repellent effect. The substances of the invention are of particular value in the protection of agricultural crops, fodder crops, plantations, greenhouse crops, fruit trees, vineyards or ornamental and plantation trees and forests, for example, cereals (such as corn, wheat, rice, sorghum), cotton, tobacco, horticultural plants (such as beans, cabbages, squash, lettuce, onions, tomatoes and peppers), agricultural crops (such as potato, sugar beet, peanuts, soybeans, rapeseed oil), cane sugar , pastures and fodder crops (such as corn, sorghum, alfalfa), plantations (such as tea, coffee, cocoa, bananas, palm oil, coconuts, rubber, spices), fruit trees and other trees (such as stone fruit trees) and pipe, citrus, kiwis, avocados, mango, olives, and nuts), vineyards, plants, ornamental flowers and greenhouse shrubs and in gardens and parks, forests (deciduous and perennial) in forests, plantations and nurseries. They are also valuable for the protection of woods for construction (permanent, felled, converted, stored or structural) from the attack of sawflies (for example, Urocerus) or beetles (for example, scolitids, platypid, lithic, bostrid, cerambic, anobiids) or termites, for example, Reticulitermes spp., Heterotermes spp., Coptotermes spp. They have applications in the protection of stored products, such as grains, fruits, nuts, spices and tobacco, or whole, ground or included in products, the attack of moths, beetles and mites. Also protected are preserved animal products such as fur, hair, wool and feathers in natural or converted form (for example, as rugs or fabrics), from the attack of moths and beetles; also preserved meat and fish from the attack of beetles, mites and flies. The substances of the invention are valuable for the control of arthropods, helminths or protozoa, which are harmful and propagate or act as vectors of diseases in man and other animals, for example, domestic animals, such as those mentioned herein above. and more especially for the control of ticks, mites, lice, fleas, mosquitoes and flies that bite, bother and cause myiasis. The substances of the invention are also useful for the control of arthropods, helminths or protozoa that are present, for example, in domestic host animals or that feed on the skin or that suck the blood of the animal, for which, they can be Administer orally, parenterally, percutaneously or topically. According to another aspect of the invention, there is provided a parasiticidal formulation comprising a substance of the invention, in admixture with a compatible adjuvant, diluent or carrier. Preferably, the formulation is adapted for topical administration. The invention further provides a substance of the invention for use as a parasiticide and a method for treating a parasitic infestation in a location, comprising treating the site with an effective amount of a substance of the invention. Preferably, the site is the skin or fur of an animal, or a surface of the plant or soil around the plant to be treated. The invention further provides: the process described herein for the preparation of the compounds of formula (I) and the salts and solvates thereof; pharmaceutical, veterinary or agricultural parasiticidal formulations comprising a compound of formula (IA) or (IB), or a pharmaceutically, agriculturally or veterinarily acceptable salt and / or solvate thereof, mixed with a compatible adjuvant, diluent or carrier, a compound of formula (IA) or (IB) and the salts and / or solvates and pharmaceutically or veterinarily acceptable formulations thereof, for use as a medicament; A method for treating a parasitic infestation in a location, comprising treating this site with the effective amount of a compound of formula (IA) or (IB) or a salt or solvate of any entity or formulation thereof: use of a compound of formula (IA) or (IB) or a pharmaceutically or veterinarily acceptable salt thereof or formulation thereof, in the manufacture of a medicament for the treatment of a parasitic infestation; a procedure to destroy or damage a parasite in one place; and any of the new intermediates described herein. It should also be noted that with regard to treatment, this includes prophylaxis, as well as relief of established symptoms in a disorder, such as a parasitic infestation.

Insecticide activity test Adult flies are collected (Stomoxys calcitrans) and anesthetized using CO2. 1 μl of an acetone solution containing the test compound is applied directly on the thorax of the fly. The flies are then carefully placed in a 50 ml tube covered with a wetted grease to collect the CO2. The negative controls are administered 1 μl of acetone. The mortality is determined 24 hours after the administration of the dose. The following table illustrates the in vivo activity of a selection of the substances of the invention against flies. The dosages required to produce 100% mortality are expressed in μg / fly.

Assay of acaricidal activity A dose of 10 μg / cm2 is prepared by uniformly pipetting 0.5 ml of a 1 mg / ml solution of the test compound in an appropriate solvent, such as acetone or ethanol on a Whatman # 1 filter paper ( trademark) cut into a size of 8 x 6.25 cm. When it dries, the paper is folded in half, closed on two sides using a beading device and placed in a Kilner jar containing a cotton pad moistened with water. The jar is then closed and placed for 24 h at 25 ° C. Then, about 50 larvae of Boophilus microplus are introduced into the treated paper envelope, which is flanged along the third side so that the closure is complete. The paper envelope is put back in the Kilner jar, which is closed and placed another 48 hours at 25 ° C. The papers are then removed and mortality determined. Negative controls are provided by treating an appropriately cut filter paper with 0.5 ml of a solvent and following the same procedure. Activity is obtained with other doses by varying the concentration of the test solution. The following table illustrates the in vivo activity of a selection of compounds of the invention against the larvae of Boophilus microplus. The dosages are expressed in μg / cm2.

The invention is illustrated by the following examples. In the examples and preparations, the melting points were determined using an apparatus for the determination of the Galienkam melting point and are given uncorrected. Nuclear magnetic resonance (NMR) data were obtained using a Bruker AC300 or AM300 and are given in parts per million using a solvent or tetramethylsilane as reference. The mass spectrum (MS) data were obtained in a Finnigan Mat. TSQ 7000 or a Fisons Instruments Trio 1000. The calculated and observed ions quoted refer to the lower mass isotopic composition. The purification by HPLC was carried out on an ODS Dynamax inverted phase column of 21x250 mm eluted at a rate of 10 ml / minute with mixtures of acetonitrile: water: methanol. The fractions were processed by evaporation of the non-aqueous components followed by the partition between ether and a saturated aqueous solution of sodium bicarbonate. The organic layer was then separated, dried and evaporated.

EXAMPLES EXAMPLE 1 3-cyano-4- (2,2-dichloro-3-oxocyclobutyl) -1 - (2,6-dichloro-4-trifluoromethylphenyl) pyrazole 3-Cyano-1- (2,2-dichloro-4-trifluoromethylphenyl) -4-vinylpyrazole was dissolved (5.00 g, 15.06 mmol, WO97 / 07-102-AI) in anhydrous diethyl ether (50 ml) in a nitrogen purged flask. Activated zinc (2.97 g, 45.8 mmol) was added and the suspension was stirred vigorously. A mixture of trichloroacetyl chloride (3.57 ml, 37.65 mmol) and phosphorus oxychloride (4.1 ml, 37.65 mmol) in diethyl ether (20 ml) was added dropwise at room temperature by means of a pressure equalizing dropping funnel over a period of time. of 30 minutes, controlling the resulting exotherm by the rate of addition. When the addition was complete, the mixture was heated to reflux for 4 h and then cooled to room temperature. The mixture was filtered and poured into 200 ml of crushed ice before extracting with diethyl ether (3 x 100 ml). The combined organic extracts were washed successively with a saturated aqueous solution of NaCHO3 and brine before drying over MgSO4, filtering and evaporating the ether in vacuo leaving a black oil. This was purified by chromatography on silica (eluting with 10% diethyl ether / hexane) to give 3.80 g of the title compound as a white solid, m.p. 1 18.2-120.1 ° C. 1 H-NMR d (CDCl 3): 3.70 (ddd, 2H), 4.35 (t, 1 H), 7.70 (s, 1 H), 7.80 (s, 2H). MS (thermospray) M / Z 492.9; C15H6C14F3N3O + CH3OH + NH4 requires 493.13.

EXAMPLE 2 fp 4- (2-Choro-2,3,3-trifluorocilobutil) -3-cyano-1 - (2,6-dichloro-4-trifluoromethylphenylazole and (II) 4- (3-chloro-2,2,3-trifluorocyclobutyl) -iano-1 - (2-, 6- dichloro-4-trifluoromethylphenyl) pyrazole 3-Cyano-1- (2,2-dichloro-4-trifluoromethylphenyl) -4-vinylpyrazole (500 mg, 1.51 mmol, WO97 / 07-102-AI) was dissolved in methylene chloride (20 ml) in a cylinder of steel. The cylinder was cooled in Cardice and an excess of chlorotrifluoroethylene condensed in the cylinder, which was closed and heated to 130 ° C for 48 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by chromatography on silica (eluting with dichloromethane: hexane 1: 1) followed by HPLC (Microsorb C18 eluting with acetonitrile / methanol / water 57:10:33 v / v) to give 120 mg of the title compounds as a mixture of isomers (1.4: 1). p.f. 1 12.7-1 14.2 ° C. 1 H-NMR d (CDCl 3): major isomer: 2.65-2.80 (m, 1 H), 3.00-3.20 (m, 1 H), 4.05-4.20 (m, 1 H), 7.65 (s, 1 H), 7.75 (s, 2H); minor isomer: 2.85-2.95 (m, 1 H), 3.25-3.45 (m, 1 H), 3.95-4.05 (m, 1 H), 7.70 (s, 1 H), 7.75 (s, 2H). MS (thermospray): M / Z 467.0; C-i5H6Cl3F6 + NH4 requires 466.62.

EXAMPLE 3 3-Cyano-4- (3-oxocylcobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole 3-Cyano-4- (3-oxocylcobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (3.00 g, 6.77 mmol, Example 1) was dissolved in dry toluene (60 ml) in a flask purged with nitrogen and cooled to 2 ° C. 2,2'-azobisisobutyronitrile (134 mg, 0.81 mmol) was added all at once followed by the dropwise addition of tributyltin hydride (4.73 ml, 17.60 mmol) in dry toluene (10 ml). The mixture was allowed to slowly warm to room temperature and was stirred for 18 h. The toluene was removed in vacuo and the residue was dissolved in acetonitrile (50 ml). This solution was washed with hexane (4x50 ml) to remove the organotin residues. The combined haxane fractions were extracted with acetonitrile (50 ml). The acetonitrile phases were combined and the solvent was removed in vacuo to give a yellow oil. This was purified by chromatography on silica gel (eluting with 10% diethyl ether / hexane) to give 2.07 g of the title compound as a white solid, m.p. 127 ° C. 1 H-NMR d (CDCl 3): 2.25-2.40 (m, 1 H), 2.65-2.80 (m, 3 H), 7.55 (s, 1 H); 7-80 (s, 2H). MS (thermospray): M / Z 392.0 Ci 5 H 8 F 3 N 3 O + NH 4 requires 392.19.

EXAMPLE 4 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (3,3-difluorocyclobutyl) pyrazole 3-Cyano-4- (3-oxocyclobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (200 mg, 0.53 mmol, example 3) was dissolved in dry dichloromethane (DCM) (5 ml) in a flask purged with nitrogen and cooled to 0 ° C. Diethylaminosulfide trifluoride (0.14 ml, 0.53 mmol) was added dropwise. The reaction mixture gradually acquired a pale yellow color and was allowed to warm to room temperature after stirring for 15 minutes at 0 ° C. After 4 hours, the mixture was diluted with DCM (50 ml) and washed successively with water (30 ml) and brine (30 ml). The organic phase was dried (MgSO 4), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica (eluent with DCM / 33% hexane). The product was recrystallized from hexane to give 62 mg of the title compound as white plates. p.f. 127.9-129.0 ° C. 1 H-NMR d (CDCl 3): 2.60-2.80 (m, 2H), 3.05-3.30 (m, 2H); 3.55 (quin, 1 H); 7.55 (s, 1 H), 7.80 (s, 2H).

MS (APCI): M / Z 396.2: C15H8C12F5N3 requires 396.15.

EXAMPLE 5 3-cyano-1-f2.6-dichloro-4-trifluoromer-phenyl) -4- (3-methexyl-butyl) pyrazole Methyltriphenylphosphonium bromide (304 mg, 0.85 mmol) in dry diethyl ether (5 ml) was suspended in a nitrogen purged flask and cooled to -5 ° C. N-Butyllithium (.34 ml, 2.5 M in hexanes) was added dropwise to produce a yellow odor. The mixture was warmed to room temperature before heating to reflux for 1 hour. The homogeneous amber solution thus obtained was cooled to -78 ° C and 3-iano-4- (3-oxocyclobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (300 mg, 0.80 mmol, example) was dissolved. 3), dissolved in dry diethyl ether (5 ml), added dropwise keeping the internal temperature to about -70 °. The mixture was allowed to warm slowly to room temperature before refluxing it for 1 hour. The mixture was then cooled, poured into water (20 ml) and extracted with diethyl ether (3x10 ml). The combined organic phases were washed with brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica (eluting with 20% DCM / hexane) yielding 40 mg of a white solid. This was further purified by HPLC chromatography (Microsorb 18 eluting with acetonitrile / methanol / water 6: 1: 3 v / v) to give 18 mg of the title compound, m.p. 1 10.3-1 1 1.7 ° C. 1 H-NMR d (CDCl 3): 2.80-2.95 (m, 2H); 3.20-3.35 (m, 2H), 3.65 (quin, 1 H); 4.90 (dd, 2H); 7.50 (s, 1 H); 7.75 (s, 2H); MS (thermospray): M / Z 390.1: C16H10Cl2F3N3 + NH4 requires 390.22.

EXAMPLE 6 3-cyano-4-cyclobutyl-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (3-methylenylbutyl-pyrazole) 3-Cyano-4- (1-hydroxycyclobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (80 mg, 0.48 mmol, preparation 1) was dissolved in dry DCM (10 ml) in a dry flask and dried. purged with nitrogen and cooled to -78 ° C. Diethyl boron trifluoride etherate (0.24 ml, 1.92 mmol) was added dropwise, followed by triethylsilane (0.31 ml, 1.92 mmol) keeping the internal temperature at about -72 ° C. the reaction mixture was stirred while cooling for 1 hour, then allowed to warm slowly to room temperature and stirred for another 18 hours. The reaction mixture was poured into water (20 ml) and extracted with DCM (2 × 20 ml). The organic phases were washed (brine), dried (Mg2SO4), filtered and the solvent was removed in vacuo to give a yellow oil. This was purified by chromatography on silica (eluting with 33% DCM / hexane) to give the product as a white solid. This was recrystallized from hexane to give 80 mg of the title compound, m.p. 124.6-125.7 ° C. 1 H-NMR d (CDCl 3): 1.95 (m, 1 H); 2.10 (q, 1 H); 2.20 (m, 2H); 2.40-2.55 (m, 2H); 3.65 (m; 1 H); 7.45 (s, 1 H); 7.75 (s, 1 H). MS (thermospray) M / Z 378.3: C15H? OCl2F3N3 + NH4 requires 378.20.

EXAMPLE 7 5-amino-3-cyano-4- (iclopent-2-enyl) -1 - (2, β-dichloro-4-trifluoromethylphenyl) pyrazole To 5-amino-3-cyano-4-iodo-1 - (2,6-dichloro-4-trifluoro-methylphenyl) pyrazole (2.23 g, 5 mmol, WO97 / 07102) and cyclopentene (1 g, 15 mmol) in dry N, N-dimethoxyformamide (DMF) (25 ml) under nitrogen atmosphere, bis (trifeniifostin) palladium dichloride (175 mg, 0.25 mmol), cuprous iodide (100 mg) and triethylamine (2 ml) were added. The mixture was heated to 70 ° C for 4 hours. An additional 1 g of cyclopentene was added and the mixture was heated at 70 ° C for 8 h. The cooled mixture was partitioned between DCM (75 ml) and water (75 ml), the organic phase was washed with water (2x75 ml) and dried (MgSO 4). After filtration, the solvent was removed in vacuo leaving a brown oil. This was purified by chromatography on silica (eluting with DCM). The resulting creamy solid recrystallized from cyclohexane to give 564 mg of the title compound as a creamy solid. p.f. 143-146 ° C. 1 H-NMR d (CDCl 3): 1.80 (m, 1 H), 2.45-2.65 (m, 3 H), 3.60 (s, 2 H), 4.00 (m, 1 H), 5.80 (m, 1 H), 6.10 ( m, 1 H), 7.80 (s, 2H).

EM (thermospray) M / Z 387.2: C16H11CI2F3N4 + H requires 387. 2.

EXAMPLE 8 3-Cyano-4- (cyclopent-2-enyl) -1 - (2,6-dichloro-4-trifluoromethylphenyl) pyrazole To 5-amino-3-cyano-4- (cyclopent-2-enyl) -1 - (2,6-dichloro-4-trifluoromethyiphenyl) -p-maleol (300 mg, 0.77 mmol, example 7) in dry tetrahydrofuran ( THF) (8 ml) heated at 65 ° C tere-butyl nitrite (239 mg, 2.3 mmol) in dry THF (2 ml) was added dropwise over 30 minutes. The solution was heated for another 3 hours at 65-70 ° C. The solvent was removed in vacuo and the resulting brown oil was purified by chromatography on silica (eluting with DCM) to give 170 mg of the title compound as a white solid, m.p. 76-80 ° C. 1 H-NMR d (CDCl 3): 1.80 (m, 1 H), 2.40-2.60 (m, 3 H), 4.05 (m, 1 H), . 80 (m, 1 H), 6.00 (m, 1 H), 7.39 (s, 1 H), 7.80 (s, 2H). MS (thermospray) M / Z 372.0: C-16H10Cl2F3N3 + H requires 372.18.

EXAMPLE 9 5-Chloro-3-cyano- - (cyclopent-2-enyl) -1- (2,6-dichloro-4-trifluoromethyl-phenylezole) To 5-amino-3-cyano-4- (cyclopent-2-enyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) -pyrazol (500 mg, 1.3 mmol, example 8) and cupric chloride (520 mg , 3.9 mmol) in dry acetonitrile (10 ml) at room temperature tere-butyl nitrite (239 mg, 2.3 mmol) in dry THF (5 ml) was added dropwise over 10 minutes. The solution was stirred for another 2 hours. The solvent was removed in vacuo and the resulting solid was triturated with diethyl ether (25 ml) followed by DCM (20 ml). The combined organic phases were evaporated to dryness and triturated again with diethyl ether. The mixture was filtered and the filtrate was evaporated to dryness. The solid was partitioned between water (15 ml) and diethyl ether (25 ml). The organic phase was separated and washed with water (10 ml) followed by brine (10 ml). The organic phase was dried (MgSO4), filtered and the solvent was removed in vacuo to give a brown solid. The material was purified by chromatography on silica (eluting with 10% diethyl ether in hexane) to give 200 mg of the title compound as a white solid. This crystallized from isopropanol. p.f. 118-121 ° C. 1 H-NMR d (CDCl 3): 1.85 (m, 1 H), 2.40-2.60 (m, 2 H), 2.65 (m, 1 H), 4. 05 (m, 1 H), 5.75 (m, 1 H), 6.10 (m, 1 H), 7.80 (s, 2H).

EM (thermospray) M / Z 423.0: C16H9CI3F3N3 + NH4 requires 423. 01.

EXAMPLE 10 5-Amino-3-cyano-4- (cyclohepty-2-enyl) -1- (2,6-dichloro-4-trifluoromethylphenol) To 5-amino-3-cyano-4-iodo-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (2.23 mg, 5 mmol, WO97 / 07102) and cycloheptene (3 ml) in dry DMF (25 ml). ml), under a nitrogen atmosphere, bis (triphenylphosphine) palladium dichloride (100 mg, 0.13 mmol), cupric iodide (100 mg) and triethylamine (2 ml) were added. The mixture was heated at 65 ° C for 18 hours. Another 3 ml of cycloheptene was added and the mixture was heated at 70 ° C for 82 hours. The cooled mixture was poured into water (500 ml) and extracted with DCM (2 x 100 ml), the organic phase was dried (MgSO4), filtered and the solvent was removed in vacuo leaving a brown oil. This was purified by chromatography on silica (eluting with hexane / diethyl ether 1/1 v / v). The resulting creamy solid was further purified by chromatography on silica (eluting with hexane, hexane / diethyl ether 19/1, hexane / diethyl ether 9/1 and finally hexane / diethyl ether 3/1) to give 564 mg of the title compound as a creamy solid, mp 158-159 ° C. 1 H-NMR d (CDCl 3): 1.45 (m, 1 H), 1.80-2.40 (m, 6H), 2.25-2.85 (m, 2H), 3.50 (a, 1.33H), 3.61 (a, 0.66H), 5.8-6.02 (m, 2H), 7.77 (s, 2H).

EM (thermospray) M / Z 415.0: C18H15CI2F3N4 + H requires 415. 25 EXAMPLE 11 3-Cyano-4- (cyclohepty-2-eniP-1 ^ 2,6-dichloro-4-trifluoromethylpheniP-pyrazole To 5-amino-3-cyano-4-iodo-1- (2,6-dichloro-4-trifluoromethylphenyl) -pyrazol (208 mg, 0.5 mmol, example 10) in dry THF (8 ml) warmed to 65 ° C tere-butyl nitrite (160 mg) was added dropwise., 1.5 mmol) in dry THF (2 ml) for 30 minutes. The solution was heated for a further 2 hours at 65-70 ° C. The solvent was removed in vacuo and the resulting brown oil was purified by chromatography on silica (eluting with hexane, hexane / diethyl ether 19/1, hexane / diethyl ether 9/1, hexane / diethyl ether 4/1, hexane / diethyl ether 1/1, finally diethyl ether). The resulting orange solid recrystallized from hexane to give 80 mg of the title compound as a creamy solid, m.p. 106-107 ° C. 1 H-NMR d (CDCl 3): 1.55 (m, 1 H), 1.70-2.00 (m, 3 H), 2.15-2.30 (m, 3 H), 2.40-2.60 (m, 1.5 H), 3.0 (m, 0.75 H) ), 3.80 (m, 0.25H), 5.82 (m, 1 H), 5.90 (m, 1 H), 7.44 (2 xs, 1 H), 7.75 (s, 2H). MS (thermospray) M / Z 417.0: C16H 3CI2F3N4 + H requires 417. 26 EXAMPLE 12 3-Cyano-4- (3-dibromomethylene-cyclobutiP-1- (2,6-dichloro-4-trifluoromethylpyr-pyrazole Triphenylphosphine (560 mg, 2.14 mmol) was dissolved in 2 ml of anhydrous DCM and cooled to 10 ° C. Carbon tetrabromide (355 mg, 1.07 mmol in 2 ml of DCM) was added dropwise to the cooled solution, an amber color was produced, 3-cyano-4- (3-oxocyclobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (200 mg, 0.53 mmol, example 3) in DCM (2M) was added dropwise. ml), the reaction mixture becoming brown, the reaction mixture was warmed to room temperature, After 0.5 hours the mixture was poured into water (20 ml) and extracted with DCM (3x20 ml). washed (brine), dried (Na 2 S 4), filtered and the solvent was removed in vacuo to give a brown solid, which was purified by chromatography on silica (eluting with 50% DCM / hexane) to give 230 mg of the title as a white solid, mp 139.9-141.1 ° C. 1 H-NMR d (CDCl 3): 2.70-2.85 (m, 2H), 3.15-3.30 (m, 2H), 3.65 (quin; 1 H). 0 (s, 1 H), 7.75 (s, 2H). * EM (thermospray) M / Z 548.2: requires 548. 01.

EXAMPLE 13 5-Amino-3-cyano-4-cyclopentyl-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole -Amio-3-cyano-4- (cyclopent-2-enyl) -1 - (2,6-dichloro-4-trifluoromethylphen!) Pyrazole (200 mg, 0.5 mmol, example 7) was hydrogenated in ethanol (10 ml. ) at room temperature and 3.45 kPa (50 psi) on 10% palladium on carbon for 9 hours. The catalyst removed by filtration was washed with ethanol and the combined filtrates were concentrated in vacuo to give an oil. The residue was puirified by HPLC (Microsorb ™ C18 eluting with acetonitrile / methanol / water 5: 1: 4 v / v) to give 35 mg of the title compound as a white solid. p.f. 160 ° C. 1 H-NMR d (CDCl 3): 1.70-1.90 (m, 6H), 2.10 (m, 2H), 2.90 (m, 1 H), 3.45 (a, 2H), 7.78 (s, 2H). MS (thermospray) M / Z 389.3: C16H13Cl2F3N4 + H requires 389.05.

PREPARATIONS PREPARATION 1 3-Cyano-4- (1-hydroxycyclobutyP-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole 3-Cyano-1- (2,2-dichloro-4-trifluoromethylphenyl) -4-iodopyrazole (500 mg, 1.16 mmol, WO9707102) was dissolved in THF in a dry flask purged with nitrogen and cooled to -78 ° C. 0.46 ml, 2.5 M in hexanes) n-butyllithium was added dropwise over a period of 30 minutes, maintaining the internal temperature to about -72 ° C. The reaction mixture was stirred at -78 ° C for 20 minutes, then cyclobutanone (0.10 ml, 1.28 mmol) dissolved in THF (4 ml) was added dropwise and the mixture was stirred for 1 hour at -78 ° C. before heating to -20 ° C. After 2 hours, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into aqueous ammonium chloride (20 ml) and extracted with diethyl ether (2x20 ml). The combined organic phases were washed (brine), dried (Na 2 SO 4), filtered and the solvents were removed in vacuo leaving a yellow oil. This was purified by chromatography on silica (eluting with a solvent gradient of DCM to 3% methanol / DCM) to give 256 mg as a clear gum. 1 H-NMR d (CDCl 3): 1.75-1.95 (m, 1 H), 2.0-2.15 (m, 1 H), 2.40-2.55 (m, 2H), 2.60-2.75 (m, 2H), 7.65 (s, 1 H), 7.75 (s, 2H). MS (thermospray) M / Z 394.1: C-15H10Cl2F3N3O + H requires 394.20.

PREPARATION 2 3-Cyano-4- (2,2-dichloro-3-hydroxycyclobutyP-1 - (2,6-dichloro-4-trifluoromethylphenyleprazole Cerium chloride (III) heptahydrate (665 mg, 2.0 mmol) was added to 3-cyano-4- (2,2-dichloro-3-oxocyclobutyl) -1 - (2,6-dichloro-4-trifluoromethyl). lphenyl) pyrazole (890 mg, 2.0 mmol, example 1) dissolved in ethanol (15 ml) and DCM (10 ml) and the mixture was cooled to -10 ° C. Sodium borohydride (531 mg, 14.0 mmol) was added at once. The reaction mixture was stirred cooled for 2 hours before heating to room temperature and pouring into crushed ice (75 ml). It was extracted with DCM (2x50 ml). The combined organic phases were washed (brine), dried (Na 2 SO 4), filtered and the solvent was removed in vacuo. The residue was purified by chromatography on silica (eluting with 1% methanol / DCM) to give 168 mg of the title compound as a gum. 1 H-NMR d (CDCl 3): 2.20 (q, 1 H), 2.75 (d, 1 H), 2.85-2.95 (m, 1 H), 3. 85 (dd, 1 H), 4.60 (q, 1 H), 7.65 (s, 1 H), 7.80 (s, 2H).

PREPARATION 3 3-Cyano-4- (2,2-dichloro-3-toluenesulfonyl-cyclobutiP-1- (2,6-dichloro-4-trifluoromethyl-phenylezole 3-Cyano-4- (2,2-dichloro-3-hydroxycyclobutyl) -1 - (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (628 mg, 1.41 mmol, preparation 2) was dissolved in anhydrous DCM and cooled up to 0 ° C. Triethylamine (0.27 ml, 1.98 mmol) was added dropwise followed by p-toluenesulfonyl chloride (297 mg, 1.56 mmol). The cooling bath was removed and the reaction mixture was stirred 18 h at room temperature. The reaction mixture was poured into an equal volume of water and extracted with DCM (2x30 ml). The combined organic fractions were washed successively with saturated sodium bicarbonate, brine, then dried (Na 2 SO 4), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica (eluting with DCMK / 33% hexane) to give 131 mg of the title compound as a grayish solid. 1 H-NMR d (CDCl 3): 2.45 (s, 3 H), 2.85-2.95 (m, 1 H), 3.85 (q, 1 H), 5.20 (t, 1 H), 7.40 (d, 2 H), 7.60 ( s, 1H), 7.80 (s, 2H), 7.90 (d, 2H).

Claims (22)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula (IA) or (IB), (IA) (IB) wherein R1 is H, halogen, NH2, CONH2, CN, C6-6 alkyl optionally substituted with one or more substituents independently selected from halogen and OH, C2-6 alkanoyl optionally substituted with one or more halogen or C 2-6 alkenyl optionally substituted with one or more halogens, R 2 is H, C 1-6 alkyl, NH 2 or halogen, Y is an unbranched Co-4 alkylene optionally carrying substituents independently selected from halogen and d-6 alkyl, R5, R6, R7, R8, R9 and R10 are each independently H or halogen or R7 and R8 can be linked to form an oxo or a radical = CR12R13 where R12 and R13 are each independently H or halogen, R 11 is H, C 1-4 alkyl optionally substituted with one or more halogens, or C 1-4 alkoxy optionally substituted with one or more halogens, R 3 is halogen, R 4 is C 1 alkyl optionally substituted with one or more halogen, C 1-4 alkoxy optionally substituted with one or more halogens , S (O) n (C? -4 alkyl optionally substituted with one or more halogens), halogens or SF5, m is 0, 1, 2, 3 or 4, n is 0, 1 or 2, X is N or CR14 , wherein R14 is halogen, or a pharmaceutically, agriculturally or veterinarily acceptable salt thereof or solvates of any such compound or salt.

2. A compound, salt or solvate according to claim 1, wherein R1 is CN, CH3 or CF3.

3. A compound, salt or solvate according to any of the preceding claims wherein R2 is H, NH2 or Cl.

4. A compound, salt or solvate according to any of the preceding claims wherein R3 is Cl.

5. A compound, salt or solvate according to any of the preceding claims wherein R 4 is CF 3, OCF 3 or SF 5.

6. A compound, salt or solvate according to any of the preceding claims wherein Y is an unbranched alkylene Co-4.

7. A compound, salt or solvate according to any of the preceding claims wherein X is N or C-Cl.

8. - A compound, salt or solvate according to any of the preceding claims wherein R5 is H, Cl or F.

9. A compound, salt or solvate according to any of the preceding claims wherein R6 is H, Cl or F.

10. A compound, salt or solvate according to any of the preceding claims wherein R7 when considered by itself is H, Cl or F.

11.- A compound, salt or solvate in accordance with any of the preceding claims wherein R8 when considered by itself is H, Cl or F.

12. A compound, salt or solvate according to any of claims 1 to 9 wherein R7 and R8 when considered together they are oxo, CH2 or CBr2.

13. A compound, salt or solvate according to any of the preceding claims wherein R9 is H.

14. A compound, salt or solvate according to any of the preceding claims wherein R10 is H.

15. - A compound, salt or solvate according to any of the preceding claims wherein R11 is H, CH3 or CF3.

16. A compound, salt or solvate according to the claim 1, wherein the substituent 4 on the pyrazole is a group selected from 2,2-dichloro-3-oxocyclobutyl, 2-chloro-2,3,3-trifluorocyclobutyl, 3-chloro-2,2,3-trifluorocyclobutyl, 3-oxocyclobutyl, 3,3-difluorocyclobutyl, 3-methylenecyclobutyl, cyclobutyl, cyclopent-2-enyl, cyclohepty-2-enyl, 3-dibromomethylene-cyclobutyl and cyclopentyl.

17. A compound, salt or solvate according to the claim 16 wherein the substituent 4 on pyrazole is a group selected from 2-chloro-2,3,3-trifluorocyclobutyl, 3-chloro-2,2,3-trifluorocyclobutyl, 3-oxocyclobutyl, 3,3-difluorocyclobutyl, 3-methylenecyclobutyl, cyclobutyl, cyclopent-2-enyl, cyclohepty-2-enyl and cyclopentyl.

18. A compound, salt or solvate according to claim 1, selected from: 3-cyano-4- (2,2-dichloro-3-oxocyclobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 4- (2-Chloro-2,3,3-trifluorocyclobutyl) -3-cyano-1- (2,6-dichloro-4-trifluoromethylphenol) p -razole; 4- (3-chloro-2,2,3-trylfuorocyclobutyl) -3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 3-cyano-4- (3-oxocyclobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (3,3-difluorocyclobutyl) pyrazole; 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (3-methylenecyclobutyl) pyrazole; 3-cyano-4-cyclobutyl-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 5-amino-3-cyano-4- (cyclopent-2-enyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 3-cyano-4- (cyclopent-2-enyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 5-chloro-3-cyano-4- (cyclopent-2-enyl) -1- (2,6-dichloro-4-trifluoromethyl-phenyl) pyrazole; 5-amino-3-cyano-4- (cyclopent-2-enyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 3-cyano-4- (cyclopent-2-enyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) -pyrazol; 3-cyano-4- (3-dibromomethylenecyclobutyl) -1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 5-amino-3-cyano-4-cyclopent-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole and the salts and solvates thereof.

19. - A pharmaceutical or veterinary formulation comprising a substance according to any of the preceding claims mixed with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle.

20. A formulation according to claim 19, which is adapted for topical administration.

21. The use of a compound according to any of claims 1 to 18 in the manufacture of a medicament for treating the parasitic infection in a site, for example in an animal.

22. The use of a compound according to any of claims 1 to 18 in the manufacture of a medicament for killing or damaging a parasite at a site in an animal.