WO2008152081A2

WO2008152081A2 - Anthelmintic benzo[d]isoxazolyl benzamide derivatives

Info

Publication number: WO2008152081A2
Application number: PCT/EP2008/057348
Authority: WO
Inventors: Jan Heeres; Paulus Joannes Lewi
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2007-06-15
Filing date: 2008-06-12
Publication date: 2008-12-18
Also published as: WO2008152081A3; AR066980A1; TW200916100A; CL2008001765A1; PA8783901A1

Abstract

The present invention is concerned with novel anthelmintic N-benzo[d]isoxazol-6-yl-benzamide derivatives and the pharmaceutically acceptable acid addition salts thereof, compositions comprising said novel Compounds, processes for preparing said Compounds and compositions, and the use thereof as a medicine, in particular in treatment, control and prevention of endo- and ectoparasite infections in warm-blooded animals.

Description

ANTHELMINTIC BENZO[D]ISOXAZOLYL BENZAMIDE DERIVATIVES

The present invention is concerned with novel anthelmintic 7V-benzo[d]isoxazol-6-yl- benzamide derivatives and the pharmaceutically acceptable acid addition salts thereof, compositions comprising said novel compounds, processes for preparing said compounds and compositions, and the use thereof as a medicine, in particular in treatment, control and prevention of endo- and ectoparasite infections in warm-blooded animals.

Anthelmintic salicylanilide derivatives are known from GB- 1,537, 929.

The present invention relates to a compound of formula (I)

including any stereochemical^ isomeric form thereof, wherein each of R¹, R², R³, R⁴, and R⁵ is independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, trifluoromethyl, trifluoromethyloxy, Ci-₄alkylcarbonyl, C^alkyloxycarbonyl, cyano, nitro, and amino;

R⁶ is hydrogen, halo, C^alkyl, C^alkyloxy, trifluoromethyl, or trifluoromethyloxy; and R⁷ is hydrogen, halo, C^alkyl, C^alkyloxy, trifluoromethyl, or trifluoromethyloxy; or a pharmaceutically acceptable acid addition salt thereof, or a solvate thereof.

As used in the foregoing definitions :

- halo is generic to fluoro, chloro, bromo and iodo;

- Ci-₄alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methyl- ethyl, 2-methylpropyl and the like;

- Ci^alkyl is meant to include Ci^alkyl and the higher homologues thereof having

5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl and the like; The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.

The absolute stereochemical configuration of the compounds of formula (I) and of the intermediates used in their preparation may easily be determined by those skilled in the art while using well-known methods such as, for example, X-ray diffraction.

Furthermore, some compounds of formula (I) and some of the intermediates used in their preparation may exhibit polymorphism. It is to be understood that the present invention encompasses any polymorphic forms possessing properties useful in the treatment of the conditions noted hereinabove.

The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, /^-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of formula (I) may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular association comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol. The term 'hydrate' is used when said solvent is water. In an embodiment, the present invention relates those compounds of formula (I) wherein one or more of the following restrictions apply : a) R¹ is hydrogen, halo, C^alkyl or cyano; or b) R² is hydrogen, or halo; or c) R³ is hydrogen, halo, C^alkyl, polyhaloC^alkyl, polyhaloC^alkyloxy, or cyano; or d) R⁴ is hydrogen, or halo; or e) R⁵ is hydrogen, halo, C^alkyl or cyano; or f) R⁶ is Ci.galkyl, in particular R⁶ is methyl; or g) R⁷ is hydrogen.

In another embodiment, the present invention relates to those compounds of formula (I) including any stereochemically isomeric forms thereof, wherein R¹ is hydrogen, halo, C^alkyl or cyano; R² is hydrogen, or halo; R³ is hydrogen, halo, C^alkyl, polyhaloC^alkyl, polyhaloC^alkyloxy, or cyano; R⁴ is hydrogen, or halo; R⁵ is hydrogen, halo, C^alkyl or cyano; R⁶ is Cμgalkyl; or R⁷ is hydrogen.

In yet another embodiment the present invention relates to compounds of formula (I) including any stereochemically isomeric forms thereof, wherein R¹ is hydrogen or halo, R² is hydrogen, R³ is halo, R⁴ is hydrogen, R⁵ is hydrogen or halo, R⁶ is methyl, and R⁷ is hydrogen.

Compounds of formula (I) can be prepared by reacting intermediate (II) with 2-hydroxy-3,5-diiodo-benzoyl chloride (III), in a reaction-inert solvent such as dioxane or dichloromethane optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate, dimethylformamide or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.

Intermediates of formula (II) can be prepared as outlined below in Scheme 1. An intermediate of formula (IV) is reacted with an intermediate of formula (V) in the presence of a strong base such as potassium te/t-butoxide, followed by addition of hydrogen peroxide and bubbling of air through the reaction-mixture, thereby yielding an intermediate of formula (VI). The intermediate (VI) was then reacted with hydroxylamine hydrochloride and after crystallisation of the reaction product, the obtained intermediate (VII) was cyclized using sodium hydroxide thereby yielding intermediate (VIII). Intermediate (VIII) was then reduced using iron or zinc in the presence of ammonium chloride in order to obtain intermediates of formula (II).

Scheme 1

reduction

Starting intermediates (IV) and (V) are commercially available products.

The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. Those compounds of formula (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifϊcally . Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The compounds of formula (I), the pharmaceutically acceptable salts and stereo- isomeric forms thereof possess favorable anthelmintic activity. Therefore the present compounds of formula (I) are useful as a medicine in treatment, control and prevention of endo- and ectoparasite infections in warm-blooded animals.

Endo- and ectoparasites include amongst others Nemathelminthes such as Amidostomum, Ancylostoma, Angiostrongylus, Anisakis, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Dictyocaulus (lungworm), Dipetalonema, Dirofϊlaria (heartworm), Dracunculus, Elaeophora, Gaigeria, Globocephalus urosubulatu, Haemonchus, Heterakis, Hyostrongylus, Metastrongylus (lungworm), Muellerius (lungworm), Necator americanus, Nematodirus, Neoascaris, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris, Parascaris, Protostrongylus (lungworm), Setaria, Stephanofilaria, Strongyloides, Strongylus, Syngamus, Teladorsagia, Toxascaris, Toxocara, Trichinella, Trichostrongylus, Trichuris, Uncinaria stenocephala, and Wuchereria bancrofti.

Warm-blooded animals as used throughout this text include both human and non- human animals such as farm animals (e.g. sheep, cattle, swine, goats or horses), domestic animals (e.g. dogs, cats, or cavias) as well as wild animals held in captivity and birds (e.g. poultry).

In view of the utility of the compounds of formula (I), it follows that the present invention also provides a method of treating, controlling and preventing endo- and ecto-parasite infections in warm-blooded animals. This method comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of a compound of formula (I). The term "therapeutically effective amount of a compound of formula (I)" as used herein, means that amount of compound of formula (I) that elicits the biological or medicinal response in the warm-blooded animal that is being sought by the physician or veterinarian, which includes alleviation of the symptoms of the condition being treated. The therapeutically effective amount can be determined using routine optimization techniques and is dependent upon the particular condition to be treated, the condition of the warm-blooded animal, the route of administration, the formulation, and the judgment of the practitioner and other factors evident to those skilled in the art. A therapeutically effective amount may be achieved by multiple dosing.

Additionally the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

For use in warm-blooded animals, including humans, the compounds of formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutically or veterinary acceptable diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally, including sublingually, in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. The compounds of formula (I) could be incorporated into capsules, tablets or boluses for targeting the colon or duodenum via delayed dissolution of said capsules, tablets or boluses for a particular time following oral administration. The compounds of formula (I) can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution or suspension that may contain other substances, for example, enough salt or glucose to make the solution isotonic with blood. The compounds of formula (I) can be administered topically, in the form of sterile creams, gels, pour-on or spot-on formulations, suspensions, lotions, ointments, dusting powders, sprays, drug- incorporated dressings or via a skin patch. For example the compounds of formula (I) can be incorporated into a cream consisting of an aqueous or oily emulsion of polyethylene glycols or liquid paraffin, or they can be incorporated into an ointment consisting of a white wax soft paraffin base, or as hydrogel with cellulose or polyacrylate derivatives or other viscosity modifiers, or as a dry powder or liquid spray or aerosol with butane/propane, HFA or CFC propellants, or as a drug-incorporated dressing either as a tulle dressing, with white soft paraffin or polyethylene glycols impregnated gauze dressings or with hydrogel, hydrocolloid, alginate or film dressings. The compounds of formula (I) could also be administered intra-ocularly as an eye drop with appropriate buffers, viscosity modifiers (e.g. cellulose derivatives), preservatives (e.g. benzalkonium chloride (BZK)) and agents to adjust tenicity (e.g. sodium chloride). Such formulation techniques are well-known in the art. All such formulations may also contain appropriate stabilizers and preservatives.

For veterinary use, compounds can be administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinarian will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.

For topical application dip, spray, powder, dust, pour- on, spot-on, emulsifiable concentrate, jetting fluid, shampoos, collar, tag or harness may be used. Such formulations are prepared in a conventional manner in accordance with standard veterinary and pharmaceutical practice. Thus capsules, boluses or tablets may be prepared by mixing the active ingredient with a suitable finely divided diluent or carrier, additionally containing a disintegrating agent and/or binder such as starch, lactose, talc, or magnesium stearate. A drench formulation may be prepared by dispersing the active ingredients in an aqueous solution together with dispersing or wetting agents and injectable formulations may be prepared in the form of a sterile solution or emulsion. Pour-on or spot-on formulations may be prepared by dissolving the active ingredients in an acceptable liquid carrier vehicle, such as butyl digol, liquid paraffin or non- volatile ester with or without addition of a volatile component such as isopropanol.

Alternatively, pour-on, spot-on or spray formulations can be prepared by encapsulation to leave a residue of active agent on the surface of the animal. These formulations will vary with regard to the weight of active compound depending on the species of host animal to be treated, the severity and type of infection and type and body weight of the host. The formulations comprising a compound of formula (I) may be administered continuously, particularly for prophylaxis by known methods.

As an alternative the combinations may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed. For human use the compounds of formula (I) are administered as a pharmaceutically acceptable formulation in accordance with normal medical practice.

The compounds of formula (I) may be used in conjunction with other anthelmintic or antiparasitic agents so as to widen the spectrum of action or to prevent the buildup of resistance. Other anthelmintic agents are e.g. avermectines and milbemycines such as abamectin, doramectin, eprinomectin, ivermectin, milbemycin, milbemycin oxime, moxidectin, selamectin, and the like; benzimidazoles such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, parbendazole, oxibendazole and cyclobendazole; pro-benzimidazoles such as febantel, thiophanate and netobimin; closantel, praziquantel, and pyrantel.

Those skilled in the treatment of helminthiasis will easily determine the therapeutically effective amount of a compound of formula (I) from the test results presented hereinafter. In general it is contemplated that a therapeutically effective dose will be from about 0.1 mg/kg to about 20 mg/kg of body weight, more preferably from about 1 mg/kg to about 10 mg/kg of body weight of the warm-blooded animal to be treated. It may be appropriate to administer the therapeutically effective dose in the form of two or more sub-doses at appropriate intervals throughout the day.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular warmblooded animal as well as the other medication (including the above-mentioned additional anthelmintic or antiparasitic agents), the warm-blooded may be taking, as is well known to those skilled in the art. Furthermore, said effective daily amount may be lowered or increased depending on the response of the treated animal and/or depending on the evaluation of the physician or veterinarian prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.

Experimental part

In the procedures described hereinafter the following abbreviations were used: 'DCM' stands for dichloromethane; 'DMF' stands for N,Λ/-dimethylformamide; 7-BuOK' stands for potassium te/t-butoxide; 'Na2SO4'stands for sodium sulfate;

'KHSO4' stands for potassium hydrogensulfate; 'DIPE' stands for diisopropylether, 'NaHCOs' stands for sodium hydrogen carbonate. A. Synthesis of the intermediates Example A.1

a) Preparation of intermediate (1)

A solution of 4-chloro-2-fluorobenzeneacetonitrile (0.059 mol) in anhydrous DMF (150 ml) was chilled on an ice-bath. t-BuOK (0.118 mol) was added under nitrogen and the resulting mixture was stirred for 30 minutes. l,2-Dichloro-4-methyl-5- nitrobenzene (0.059 mol) was added and the reaction mixture was stirred for 1 hour at 0⁰C. The mixture was allowed to warm to room temperature for 1 hour and then cooled to 0⁰C. A solution of hydrogen peroxide in water (30%) (17.8 ml) was added and air was bubbled through the solution overnight. The obtained mixture was slowly added dropwise to IN HCl (750 ml) and after stirring in ice-cold DIPE, the resulting precipitate was filtered off, yielding 5.83 g of intermediate (1).

b) Preparation of intermediate (2)

Intermediate (1) (0.018 mol) and hydroxylamine hydrochloride (0.035mol) was stirred in ethanol (125 ml) with pyridine (0.088 mol) at 60⁰C. The mixture was stirred overnight and extra hydroxylamine hydrochloride (0.018 mol) and pyridine (0.044 mol) were added. The reaction mixture was stirred for 3 days at 60⁰C and ethyl acetate (500 ml) was added. The resulting mixture was washed with KHSO₄ (0.5M) (3 x 250 ml), dried (brine and Na₂SO₄), filtered off and concentrated. The residue was crystallised from methanol, yielding 2.37 g of intermediate (2).

c) Preparation of intermediate (3)

Intermediate (2) (0.0013 mol) and sodium hydroxide (pearls) (0.0025 mol) were stirred for 1 hour at room temperature in anhydrous DMF (10 ml). The reaction mixture was poured out into water. The obtained solid was filtered off, washed with water and dried at low pressure, yielding 0.390 g of intermediate (3). d) Preparation of intermediate (4)

A mixture of ammonium chloride (0.0065 mol) in water (10 ml) was added to a solution of intermediate (3) (0.0013 mol) and iron (0.0065 mol) in methanol (20 ml) and THF (10 ml). The reaction mixture was stirred for 1 hour at 70⁰C and then cooled to room temperature. Water (100 ml) was added and the organic solvents were evaporated. The aqueous concentrate was stirred in ethyl acetate (3 x 100 ml) and the organic layer was decanted each time. The organic layers were combined, dried (brine and Na₂SO₄), filtered off and then the solvent was evaporated and co-evaporated with DCM, yielding 0.353 g of intermediate (4).

Example A.2

a) Preparation of 1 J |l JL intermediate (5)

Cl

1 ,2-dichloro-4-methyl-5 -nitrobenzene (1 g) and 3,4-dichlorobenzeneacetonitrile (903 mg, 1 equivalents) were dissolved in anhydrous DMF (25 ml). Sodium hydroxide (pearls) (485 mg, 2.5 equivalents) were added at once. After 3 hours, TLC showed complete conversion and air was bubbled through the solution. After 2 days the reaction was complete (TLC). The reaction mixture was dropped onto hydrochloric acid (IN) (100 ml). Diethyl ether (100 ml) was added. The mixture was stirred for 1 hour and the organic fraction was washed with a saturated solution of sodium hydrogen carbonate in water (3x), dried (brine and Na₂SO₄) and evaporated. The residue was sonicated in DIPE and filtered off. The solid was dissolved in ethyl acetate and filtered over silica, yielding 1.27 g of intermediate (5).

b) Preparation of intermediate (6)

Intermediate (5) (1.25 g), hydroxylamine hydrochloride (756 mg, 3 equivalents) and pyridine (2.2 ml, 7.5 equivalents) were refluxed in ethanol (40 ml) over 2 nights. Extra hydroxylamine hydrochloride (1.5 equivalent) and pyridine (3.5 equivalents) were added. Heating was continued overnight. After that, ethyl acetate (200 ml) was added and the mixture was washed with KHSO₄ (0.5 N) (3x). The ethyl acetate was dried (brine, Na₂SO₄) and evaporated, yielding 1.30 g of intermediate (6).

c) Preparation of intermediate (7)

Intermediate (6) (600 mg) was dissolved in dry DMF (15 ml) and sodium hydroxide (pearls) (133 mg, 2 equivalents) were added. The mixture was stirred at room temperature. After 1 hour, water (250 ml) was added to the reaction mixture and this was extracted with ethyl acetate (3x). The combined organic extracts were washed with water and dried (brine and Na₂SO₄) and evaporated. The residue was stirred in DIPE and filtered off, yielding 112 mg of intermediate (7).

d) Preparation of intermediate (8)

Intermediate (7) (112 mg), iron (97 mg, 5 equivalents) and ammonium chloride (93 mg, 5 equivalents) were heated in a mixture of methanol/THF/water 2/1/1 (16 ml) at 70⁰C for 2.5 hours. Then water (100 ml) was added and THF/methanol was evaporated. The product was extracted with ethyl acetate. The ethyl acetate was dried (brine and Na₂SO₄) and evaporated, yielding 91 mg of intermediate (8).

The following compounds were prepared analogously as Example A.2 but starting from 2-methyl-benzeneacetonitrile, 4-bromo-benzeneacetonitrile, 2,4-dimethyl-benzene- acetonitrile, 4-(trifluoromethoxy)-benzeneacetonitrile, 2-fluoro-benzeneacetonitrile, or 2,4-dichloro-benzeneacetonitrile respectively.

intermediate (9) intermediate (12)

intermediate (10) intermediate (13)

Example A.3 a) Preparation of

intermediate (15)

Potassium cyanide (1.1 equivalents, 23.2 g) was dissolved in water (250 ml) and added to a solution of intermediate (15) (0.32 mol) and tetrabutylammonium hydrogensulfate (0.05 equivalents, 5.5 g) in DCM (250 ml). The mixture was stirred at 40⁰C for 6 hours. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water (2 x 250 ml), dried (brine and Na₂SO₄) filtered and concentrated. The residual oil was washed twice with heptane to remove impurities, yielding intermediate (15).

b) Preparation of intermediate (16)

Intermediate (15) (0.05 mol) was dissolved in anhydrous DMF (150ml) and chilled in an ice-bath. Under nitrogen₂- atmosphere, t-BuOK (2.0 equivalents) was added at once and this mixture was stirred for 30 minutes. 1 ,2-Dichloro-4-methyl-5 -nitrobenzene (12.17 g) was added at once and the reaction mixture was stirred at O⁰C for 1 hour. The mixture was allowed to warm up to room temperature for 1 hour and cooled to 0⁰C. Hydrogen peroxide (30%) (3.25 equivalents) was added at once and air was bubbled through the solution overnight. The reaction mixture was slowly dropped in IN HCl (750 ml). A yellow precipitate was filtered off. Stirred in ice-cold DIPE and filtered again, yielding intermediate (16).

c) Preparation of intermediate (17)

A mixture of intermediate (16) (0.0176 mol) and hydroxylamine hydrochloride (2 equivalents, 2.46 g) was stirred in ethanol (125 ml) with pyridine (5.0 equivalents, 7.1 ml) at 60⁰C. After stirring one night, hydroxylamine hydrochloride (1.0 equivalent, 1.23 g) and pyridine (3.55 ml) were added. The reaction mixture was stirred for 3 days at 60⁰C and ethyl acetate (500 ml) was added. The mixture was washed with KHSO₄ (0.5M) (3 x 250ml), filtered and concentrated. The residue was crystallized in methanol, yielding intermediate (17).

d) Preparation of intermediate (18)

Intermediate (17) (1.25 mmol) and sodium hydroxide (pearls) (2.0 equivalents, 100 ml) were stirred in anhydrous DMF (20 ml) at room temperature for 2 hours. The reaction mixture was poured into water and the beige solid was filtered, washed with water and dried at low pressure, yielding intermediate (18).

e) Preparation of intermediate (19)

Intermediate (18) (1 mmol) and zinc (5.0 equivalents) were dissolved / suspended in methanol (20 ml) and THF (10 ml). Ammonium chloride (5 equivalents) in water (10 ml) was added. This mixture was stirred for 1 hour at 70⁰C and cooled to room temperature. Water (100 ml) was added and the organic layer was decanted. The combined organic layers were dried (brine and Na₂SO₄), filtered, concentrated and co- evaporated with DCM, yielding intermediate (19).

The following compounds were prepared analogously as Example A.3 but starting from methylbenzene, 2,6-dichloro-l -methyl-benzene, 4-cyano-l -methyl-benzene, 4-chloro- 1 -methyl-benzene, 4-bromo-2-fluoro- 1 -methyl-benzene, 4-trifluoromethyl- 1 -methyl- benzene, or 2-cyano-l -methyl-benzene respectively.

Example A.4

Preparation of intermediate (27)

Commercially available 3,5-diiodosalysilic acid (20 g) was dissolved in DCM (150 ml). Oxalyl chloride (1.2 equivalents) and anhydrous DMF (3 drops) were added. The reaction mixture was stirred at room temperature for 3 hours, evaporated and co- evaporated with DCM, yielding 17.80 g of intermediate (27).

B. Synthesis of the final compounds Example B.I

Preparation of compound (1)

A mixture of intermediate (4) (0.005 mol) and intermediate (27) (0.006 mol) in anhydrous dioxane (125 ml) was stirred overnight (the reaction vessel was protected from daylight by aluminium foil). The reaction mixture was diluted with ethyl acetate (500 ml) and washed with a saturated NaHCOs solution (2 x 250 ml). The organic layer was separated, dried (brine and Na₂SO₄), filtered off and the solvent was evaporated. The obtained residue was triturated under ethanol (40 ml), then under DIPE/ethanol (1/1; 250 ml) and filtered, yielding 1.60 g of compound (1); mp. 241- 248°C).

Example B .2

Preparation of compound (10)

Intermediate (19) (0.5 mmol) and intermediate (27) ( 1.2 equivalents) were stirred in hydrous dioxane (125 ml) overnight. The reaction vessel was protected from daylight by aluminum foil. The reaction mixture was diluted with ethyl acetate (500 ml) and washed with a saturated NaHCO₃ solution (2 x 200 ml), dried (brine and Na₂SO₄), filtered and concentrated. The product was triturated with ethanol (40 ml), subsequently with DIPE/ethanol 1 : 1 (250 ml), and filtered off, yielding compound (10).

Table F-I lists the compounds that were prepared according to one of the above Examples.

Table F-I

C. Pharmacological examples

Cl. Efficacy study of anthelmintics in in vivo H. contortus /jirds model The anthelmintic efficacy of the compounds of the present invention was evaluated in an in vivo model using unmedicated jirds (Meriones unguiculatus) , inoculated three times with approximately 300 exsheated infective larvae of Haemonchus contortus (multi-resistant strain), treated orally with a test compound 11 days after their first infection with H. contortus larvae, and necropsied on day 14 to count the number of recovered H. contortus worms. The anthelmintic efficacy of the art known compounds (A) and (B) was also evaluated using the same model.

Animals

Female CRW jirds aged between 28 and 35 days and weighing 30-35 g (Charles River, Sulzfeld, Germany) were used. Three jirds each were assigned randomly upon arrival to translucent polysulfone individually ventilated cages (48 x 37.5 x 21 cm) containing wood shavings. Commercial rodent chow and water were given ad libitum. Following a four-day acclimation period, the jirds were artificially infected.

Parasite A poly-resistant strain of Haemonchus contortus ( the 'Nooitgedacht strain' BZ/FSM/02/Pl/HcN isolated in South Africa) was used. This strain has been maintained in artificially infected male donor lambs. Individual feces containing Haemonchus eggs were collected in fecal bags. The fecal pellets were broken, mixed with charcoal, moistened and put in an incubator for embryonation at 28°C and 95 % relative humidity. Seven days later this mixture was placed in Baermann funnels and third stage ensheathed larvae were collected after 12 hours. These larvae were rinsed with water for cleaning and disinfected with a 2 % formalin solution. Such larvae can be used immediately for artificial infection or can be stored in the fridge at about 8°C for a maximum duration of 6 months. Infective larvae (< 6 months old) were exsheated by rinsing with a 3.3 vol% commercial sodium hypochlorite solution during 10 minutes, filtered through a Buchner funnel, rinsed with water, concentrated in a Baermann funnel, and collected after 2 hours. Exsheated larvae prepared in this manner can be used for subsequent infection of jirds or laid in a supply for extended periods by cooling in the gas over liquid nitrogen during 1 hour and storing in liquid nitrogen.

Infections

All jirds were inoculated orally with approximately 300 exsheated infective larvae of H. contortus per dose on three consecutive days. Inoculations were administered using a blunted 18 G dosing needle fitted to a 1 ml syringe.

Treatments

Eleven days after their first infection jirds were treated with test compounds, suspended or dissolved in 0.4 ml DMSO, and the dose to be tested was administered in a volume of 0.1 ml / 50 g bodyweight via a blunted 18 G dosing needle fitted to a 1 ml syringe. Control animals, included in each experiment, remained untreated. Levamisole hydrochloride, mebendazole, ivermectin and closantel were used in different dosage titration experiments to validate the model.

Necropsy

All jirds were starved 20 hours before necropsy and killed on day 14 past first infection by CO₂ inhalation. For worm recovery their stomachs were removed, opened longitudinally, and incubated in a beaker with 20 ml digestion fluid (1O g pepsin + 30 ml concentrated hydrochloric acid) at 37°C for 3 hours. Following digestion, the stomach content was passed through a tea-strainer, the passage fluid was catched in a sieve (32 μm) and the worms were recovered with tap water. The beakers were stored in the fridge for subsequent counting.

Examination and percentage efficacy The content of each beaker was mixed, poured over in a 6-well plate in 6 aliquots, and the worms were counted under an inverted microscope. The percentage efficacy for each test compound was determined and the results are summarized in Table 1 below. Table 1 : efficacy data in clearing the poly-resistant Haemonchus contortus strain from jirds after oral treatment with a test compound

(*) : 7.5 mg test concentration

Percentage efficacy = ({(mean number of worms recovered from control group) -

(mean number of worms recovered from treated group)} divided by (mean number of worms recovered from control group)) x 100

Claims

1. Compound of formula (I)

including any stereochemically isomeric form thereof, wherein each of R¹, R², R³, R⁴, and R⁵ is independently from another selected from hydrogen, halo, hydroxy, Cμgalkyl, Cμgalkyloxy, trifluoromethyl, trifluoromethyloxy, Ci^alkylcarbonyl, C^alkyloxycarbonyl, cyano, nitro, and amino; R⁶ is hydrogen, halo, C^alkyl, Cμgalkyloxy, trifluoromethyl, or trifluoromethyloxy; and

R⁷ is hydrogen, halo, C^alkyl, Cμgalkyloxy, trifluoromethyl, or trifluoromethyloxy; or a pharmaceutically acceptable acid addition salt thereof, or a solvate thereof.

2. A compound as claimed in claim 1 wherein R¹ is hydrogen, halo, C^alkyl or cyano; R² is hydrogen, or halo; R³ is hydrogen, halo, C^alkyl, polyhaloC^alkyl, polyhaloC^alkyloxy, or cyano; R⁴ is hydrogen, or halo; R⁵ is hydrogen, halo,

C^alkyl or cyano; R⁶ is C^alkyl; or R⁷ is hydrogen.

3. A compound as claimed in claim 1 wherein R⁶ is methyl and R⁷ is hydrogen.

4. A compound as claimed in claim 3 wherein R¹ is hydrogen or halo, R² is hydrogen, R³ is halo, R⁴ is hydrogen and R⁵ is hydrogen or halo.

5. A compound as claimed in claim 1 wherein the compound is N-[3-(4-chloro-2- fluoro-phenyl)-5-methyl-benzo[d]isoxazol-6-yl]-2-hydroxy-3,5-diiodo-benzamide

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in any of claims 1 to

5.

7. A process for preparing a pharmaceutical composition as claimed in claim 6 wherein a therapeutically active amount of a compound as claimed in any of claims 1 to 5 is intimately mixed with a pharmaceutically acceptable carrier.

8. A compound as claimed in any of claims 1 to 5 for use as a medicine.

9. Use of a compound as claimed in any of claims 1 to 5 for the manufacture of a medicament for the treatment, control and prevention of endo- and ectoparasite infections.

10. A process for preparing a compound of formula (I) wherein an intermediate of formula (II) is reacted with 2-hydroxy-3,5-diiodo-benzoyl chloride (III) in a suitable reaction-inert solvent

or if desired; a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof.