MXPA98009089A - Compounds of acrylic urea for the treatment of coccidioidomycosis in animals of sangre calie - Google Patents

Abstract

The use of acyl urea compounds for the treatment or prophylaxis of Coccidiodes immitis infections in warm-blooded animals, preferably the treatment or prophylaxis of coccidiodomycosis in dogs or cats, is described by the use of an effective therapeutic amount of a acyl represented by the following formula: (wherein formula (I)) wherein: R1 is phenyl, niftyl, pyridyl, pyridazinyl, pyrimidinyl, or unsubstituted or substituted pyrazinyl, R2 is hydrogen or alkyl of 1 to 6 carbon atoms, R3 is: (See formula) R4 R5 are each independently hydrogen, halogen alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, or thioalkyl 1 to 6 of carbon; R9 is hydrogen or alkyl 1 to 6 carbon atoms, and X + is an inorganic and organic cation pharmaceutically or agronomically acceptable, and salts pharmaceutically or agronomically ac eptable of them. Also described are compounds for the treatment or prophylaxis of infections by C, immitis, and their use for the preparation of pharamaceutical compositions against infections by Coccidioides immit

Description

COMPOUNDS OF UREA ACRILIGA FOR THE TREATMENT OF COCCIDIOIDQMICOSIS IN HOT BLOOD ANIMALS This invention relates to the use of acrylic urea compounds for the treatment or prophylaxis of Coccidioides immi tis infections in warm-blooded animals. The invention has a particular application in the treatment, prophylaxis, or reduction of coccidioidomycosis. Acrylic ureas, including processes for their preparation, are known in the art, and are described, for example, in U.S. Patent Number 5,420,163. The class of acrylic urea compounds disclosed in U.S. Patent No. 5,420,163 are described as parasiticides. Endoparasites and ectoparasites such as fleas, scabies mites, and helminths are among the illustrative parasites. There is no reference to activity against fungi, such as Coccidioides immi ti s, or diseases such e- or coccidioidomycosis. The coccidioides immi tis (C. immi tis) is a geophilic dimorphic fungus that is endemic to the southeastern United States, including parts of California, Nevada, Utah, Arizona, New Mexico, and Texas. C. immi tis is also widespread in parts of Mexico and in Central and South America, and in other parts of the world. It is more commonly referred to as "Cocci" or "Valley Fever." The active growth of the mycelial phase that lives freely of C. iirapitis, on the earth, follows the winter rains, and produces arthroconidia. Infection of warm-blooded animals may occur at any time but more likely in summer, when dry conditions favor inhalation of C. immi tis arthroconidia spread by the wind or by physical alteration of the infected soil. In certain years, the infection may occur with a higher incidence also in the fall. The buds are then associated with the seasons of heavy rain. When the small arthropods of the fungus come to settle in the air, either blown by the wind or stirred by the excavation, they can be inhaled and enter the lungs, where they become the second phase - the tissue phase of the fungus. Once inside the host animal of warm blood, the arthroconidia of C. immi tis conform to the parasitic spherical phase. These large spherules (20 to 100 microns) grow, mature, and divide internally to produce endospores. When released, endospores spread C. immi tis infection locally or to distant sites through the lymphatic system or blood. In dogs, approximately one third of infections affect the lungs. However, if the infection extends into the host through the lymphatic or circulatory systems, Valley Fever can cause bone disease, or other forms of dissemination. Acute primary pulmonary coccidioidomycosis usually occurs within 1 to 3 weeks following infection with C. immi tis. Early clinical signs may be absent, or may include a mild nonproductive cough, reduced grade fever, partial anorexia, and weight loss. This form of disease is often self-limiting, but may progress to a disseminated infection. Pulmonary disseminated coccidioidomycosis causes a more severe producing cough due to extensive lung involvement and tracheobronchial lymphadenopathy. Systemic signs include a fluctuating fever that does not respond to the antibiotic, depression, weakness, anorexia, and weight loss. As noted above, C. immi tis can extend beyond the pulmonary tree, to affect any organ or system of the body through the lymphatic system or blood. The average age of incidence for coccidioidomycosis in dogs, for example, has been reported in 1.5 to 4.0 years; males are more likely to be affected. Sporting dogs (hunting), Boxers, and Doberrnan pinschers, may be particularly susceptible to the development of coccidioidomycosis. Confirmed Fiebre del Valle classes have been found in dogs, cats, horses, cattle, sheep, and other species, including marine mammals. Dogs seem to develop clinical disease at higher incidences than cats or other species mentioned. Approximately 60 percent of human beings who live in endemic areas can also get minor cases of the disease. In the human being, the Fever of the Valley resembles a cold or a cold. Only about 5 percent of affected humans become sick enough to require treatment. Fortunately, the tissue phase of the fungus in general is not transmitted from the infected person or animal directly to other people or animals. Currently, there are no vaccines or preventive treatments available for veterinarians. So far, vaccines have not been effective for prevention. The treatments available for coccidioidomycosis in warm-blooded animals include systemic antifungal chemotherapy. For example, imidazoles, such as ketoconazole and itraconazole, are used for the treatment of coccidioidomycosis in dogs and cats. In addition, it has been shown that amphotericin B encapsulated in liposome is safe and effective in the treatment of coccidioidomycosis in dogs that can not tolerate oral imidazole therapy. However, C. immi tis is more resistant to amphotericin B than to the other systemic fungal agents. In view of the problems of patient tolerance and drug resistance occurring from time to time during the currently available treatments, there continues to be a need for new chemotherapeutic agents and methods for the treatment of C. immiitis infections in animals of hot blood, and related diseases implicated by these infections, including coccidioidomycosis. Surprisingly, it has now been discovered that certain compounds of the acrylic urea class are useful for the treatment or prophylaxis of Coccidioides immiis infections in warm-blooded animals, as well as for treatment, prophylaxis, or reduction of conditions, diseases or syndromes involved in these infections. These compounds are excellent for their safety and their systemic action mode in warm-blooded animals. The method of the invention comprises administering to a warm-blooded animal in need of the treatment or prophylaxis of a C. immiis infection, an effective antifungal amount of a compound represented by the formula: R2 I Rx N COR3 (I) Where Rx, 1 ^, and R3 are as defined hereinafter. As indicated above, the present invention relates to a method for the treatment or prophylaxis of C. immiis infections in warm-blooded animals. The invention also relates to the acyl ureas of the formula (I), or preferably (II), presented below, or pharmaceutically or agronomically acceptable salts thereof, for the treatment or prophylaxis of C. immi tis infections. in warm-blooded animals. A further preferred aspect of the present invention relates to the acyl ureas of the formula (I), or preferably (II) presented below, or pharmaceutically or agronomically acceptable salts thereof, for the treatment or prophylaxis of coccidioidomycosis in dogs and cats. An important aspect of the present invention is the preparation of a pharmaceutical composition comprising, as an active inient, at least one of the acyl ureas of the formula (I) or preferably (II), for the treatment or prophylaxis of said infections Suitable acyl urea compounds for use in the method of the present invention include the following compounds of the formula (I): R N COR3 (I) where: R? is phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, or unsubstituted or substituted pyrazinyl; R2 is hydrogen or alkyl of 1 to 6 carbon atoms; R3 is: R4 to R8 are each independently hydrogen, halogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 * carbon atoms; R9 is hydrogen or alkyl of 1 to 6 carbon atoms; and X + is an inorganic or organic cation pharmaceutically or agronomically acceptable. In the compounds of the formula (I), suitable inorganic (X +) cations are, for example, alkali metal and alkaline earth metal cations; and suitable organic (X +) cations are, for example, characterized by the group: RlT in which formulas, R :, to R are each independently hydrogen, alkyl of 1 to 20 carbon atoms, benzyl, or phenyl; and R <4> is hydrogen or alkyl of 1 to 20 carbon atoms, for example H? T-,: CH;) N +, (C: HS) ÍN +, (n-C_K-,) .N +, (i-C3H7) 4N + , (nC.Hs) 4N +, CH3- (CH2); N (CH 3 -) 3 where n is a value of 8 to 15. Other pharmaceutically or agronomically acceptable salts of the acyl ureas of the formula (I) are also contemplated. For example, compounds of the formula (I) having a basic center can form acid addition salts, especially pharmaceutically acceptable salts, for example, inorganic acids, such as mineral acids, are formed. for example sulfuric acid, a phosphoric or halohydric acid, or with organic carboxylic acids, such as alkane acids (of 1 to 4 carbon atoms) -carboxylic acids, which are, for example, unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic, or terephthalic acids, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric acids , or citric, such as amino acids, for example aspartic or glutamic acid, benzoic acid, or with organic sulfonic acids, such as alkane acids (from 1 to 4 carbon atoms) carbon) - or aryl sulphonics which are unsubstituted or substituted, for example, by halogen, for example methan- or toluene sulfonic acid. Particularly preferred compounds for use in the present method sor. the benzoyl urea compounds represented by the formula: where Hai is independently chlorine; bromine; or fluorine; R3 is hydrogen, chlorine, bromine, fluorine, methyl, trifluoromethyl, tri-luoro-ethoxyl, 2-clcrc-1, 1, 2-tri-chloroethoxy, 2-bromo-1, 1,2-trifluoroethoxy, 1.2. , 2-tetrafluoroethoxy, or 1, 1,2,3,3,3-hexafluoroprop-l-oxyl; Rb is hydrogen or chlorine; and Rc is hydrogen, chloro, 5-trifluoromethylpyrid-2-yloxy, or 3-chloro-5-trifluoromethylpyrid-2-yloxy; at least one of Ra and Rc are different from hydrogen; and pharmaceutically or agronomically acceptable salts thereof. The preferred subgroups are those where Hai is fluorine, and one of Ra and Rb is an ether group. Accordingly, a preferred first subgroup is the benzoyl ureas of the formula (II), wherein Ra is hydrogen, methyl, or chloro; R ° is hydrogen; and R ° is 5-trifluoromethylpyrid-2-yloxy or 3-chloro-5-trifluoromethylpyrid-2-yloxy. A second preferred subgroup are the benzoyl ureas of the formula (II), wherein Ra is 2-chloro-l, 1,2-trifluoromethoxy, 2-bromo-1,2,2-trifluoromethoxy, 1,1,2,2 -tetrafluoroethoxy, or 1, 1, 2, 3, 3, 3-hexafluoroprop-1-oxyl; Rb is chlorine; and Rc is chloro, ie, an N- (2,6-difluorobenzoyl) -N '- (3,6-dichloro-4-Ra-phenyl) urea or N- (2,6-difluorobenzoyl) -N' - (3, 5-dichloro-4-Ra-phenyl) urea. Representative examples of the particularly preferred individual compounds are: N- (2,6-difluorobenzoyl) -N1 - [3- (3-chloro-5-trifluoromethyl-pyrid-2-yloxy) -4-bromo-phenyl] -urea, N- (2,6-difluorobenzoyl) -N '- [3- (3-chloro-5-trifluoromethyl-pyrid-2-yloxy) -4-methylphenyl] urea, N- (2,6-difluorobenzoyl) -N' - [ 3- (3-chloro-5-trifluoromethyl-pyrid-2-yloxy) -4-chlorophenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (3-chloro-5-trifluoromethyl-pyrid -2-yloxy) -4-fluorophenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (5-trifluoromethylpyrid-2-yloxy) -4-bromo-phenyl] -urea, N- (2, 6 -difluorobenzoyl) -N '- [3- (5-trifluoromethylpyrid-2-yloxy) -4-methylphenyl] urea, N- (2,6-difluorobenzoyl) -N' - [3- (5-trifluoromethylpyrid-2-yloxy ) -4-chlorophenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (5-trifluoromethylpyrid-2-yloxy) -4-fluorophenyl] urea, N- (2,6-difluorobenzoyl) - N '- [3,5-dichloro-4- (2-chloro-1,1,2-trifluoro-l-ethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N' - [3,6] -gave chloro-4- (2-chloro-1,1,2-trifluoro-1-ethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,5-dichloro-4- (1, 1,2,3, -3, 3-hexafluoroprop-2-oxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,5-dichloro-4- (1,1,2, 3, -3, 3-hexafluoroprop-1-oxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,6-dichloro-4- (1,1,2,3, -3 , 3-hexafluoroprop-l-oxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,5-dichloro-4- (2-bromo-1,1,2-trifluoroethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,6-dichloro-4- (2-bromo-1, 1,2-trifluoroethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,5-dichloro-4- (1,1,2,2-tetrafluoroethoxy) phenyl] urea, and N- (2,6-difluorobenzoyl) -N'- [3,6-dichloro-4] - (1,1,2,2-tetrafluoroethoxy) phenyl] urea. In accordance with the present invention, the administration of at least one acyl urea compound to the warm blood host animal is achieved with various forms of application, for example, by administration of an orally formulated active ingredient. In this case the term "formulated" means in the form of a powder, a tablet, a granulate, a capsule, an emulsion, a foam, and the like. The preparation does not necessarily have to be administered to the animal directly; It may be convenient to mix it with the animal's food. The method of the present invention also contemplates the treatment or prophylaxis of C. immiis infections in warm-blooded animals, by administering at least one acyl urea together with one or more known antifungal or fungal agents. Suitable mixing partners include the imidazoles, such as ketoconazole and itraconazole, as well as the amphotericin B compound. Representative warm-blooded host animals that can be treated according to the method of the present invention include humans and domestic animals. , such as cattle, horses, sheep, goats, poultry, pigs, dogs, cats, and zoo animals. Time, the manner, and the concentrations at which the acyl urea compounds of formulas (I) or (II) are effectively administered, for the prophylaxis or treatment of C. immi tis infections in a host warm-blooded animal, They can vary over a wide range. Therapeutically effective amounts of the acyl urea compounds can be administered to the host animals, in concentrations of about 0.01 to about 1,000 milligrams / kilogram of body weight of the animal. The best concentration for a given animal should be determined individually, but in general it is found that, in most cases, the optimum concentration is within the range of about 0.25 to about 100 milligrams / kilogram of body weight of the host animal. The optimal concentration for a given instance depends, for example, on factors such as the activity of the specific compound or acyl urea compounds, the level of C. immi tis infection, if a prophylactic regimen is being followed, the method of administration , and the health of the host animal that is being treated. The doses are usefully repeated in a regular manner at daily, weekly, biweekly, and monthly intervals. The most appropriate interval for administration should be determined on a case-by-case basis.

For the treatment of a specific disease, such as coccidioidomycosis, it is generally found that the optimum dosage concentration of the acyl ureas (I) or (II) is within the range of about 1 to about 20 milligrams per kilogram of body weight. body of the host animal per day, more particularly from about 2.5 to about 12 milligrams / kilogram per day. The treatment may continue for a period of several weeks or months, depending on the severity of the clinical symptoms. In one embodiment, the acyl ureas of formulas (I) or (II) are conveniently applied in a dose of about 0.01 to 800, preferably about 0.5 to 200, more preferably 1 to 30, and most preferably 2.5 to 12 milligrams / kilogram of body weight, based on the host animal, oral administration being preferred. A good dose for a regular administration is generally in the range of 1 to 100 milligrams / kilogram of the body weight of the host animal. The total dose of the acyclic ureas in the formulas (I) and (II) can vary from one genus of animal to the other, and can even vary within the same genus, since this dose depends, among other things, on the weight and constitution of the animal, the degree of severity of infection by C. immi tis, and of the seasonal period for the prophylaxis of C. immi tis.

According to the method of the invention, prophylaxis or treatment of C. immitis infections in a warm-blooded host animal is achieved by the oral, percutaneous, or parenteral administration in another manner, of at least one acyl urea compound of the formula (I) to the warm-blooded host animal. Management is also contemplated by means of a suppository. The oral application may be in the form of tablets, capsules, troches, bolus, water to drink, or granules. Parenteral administration can be performed by injection, implantation, or transdermal application. In addition to containing adjuvants conventionally employed in the art of formulation, the compositions to be administered orally, of course, may contain other additives that encourage voluntary ingestion by the animal, for example, suitable flavors or aromas. Due to its simplicity, oral application is one of the preferred objects of the present invention. A further mode of application is parenteral application, for example by subcutaneous, intravenous, or intramuscular injection, or by means of a sustained action preparation in the form of an implant or other reservoir formulation. Oral application methods include, but are not limited to, compounds previously mixed in the food of the dog and cat, given in biscuits or cakes, more icables tablets, capsules or tablets that can be dissolved in water, water soluble compounds applied with a dropper in water, or materials applied in any way to the dog's food. The implants include any device applied to the animal to release the acyl urea compounds in order to control Coccidinides immi tis infections. Percutaneous administration is conveniently carried out by subcutaneous, dermal, intramuscular, and even intravenous application of the injectable formulation. Conventional needle type injection devices, as well as needleless air jet injection devices, can be used. It is possible to delay or sustain the permeation of the active ingredient through the living tissues of the animal by an appropriate formulation. For example, a very insoluble compound can be used. In this case, the slight solubility of the compound causes a sustained action, because the body fluids of the animal can dissolve only a small amount of the compound at any time. Sustained action of the active ingredient can also be obtained by formulating the compound in a matrix that physically inhibits the solution. The formulated matrix is injected into the body, where it remains as a reservoir, from where the compound slowly dissolves.

Matrix formulations, now known in the art, are formulated in waxy semi-solids, such as vegetable waxes and high molecular weight polyethylene glycols. A very effective sustained action is obtained by introducing into the animal the implant containing one of the active ingredients. These implants are well known in the veterinary art, and are usually made of a rubber containing silicone. The active ingredient is dispersed through a solid rubber implant, and is contained within a hollow implant. Care must be taken to choose an active ingredient that is soluble in the rubber form in which the implant is made, since it is dispersed by first dissolving it in the rubber, and then leaching out of the rubber, into the bodily fluids of the treated animal. The speed at which the active ingredient is released from an implant, and therefore the length of time the implant remains effective, is controlled with good precision by appropriate adjustment of the concentration of the compound in the implant, external area of the implant, and the polymer formulation from which the implant is made. The administration of the active ingredient by means of an implant is a particularly useful additional modality. This administration is highly economical and effective, because an appropriately designed implant maintains a concentration constant composition of the compound in the tissues of the host animal. An implant can be designed to deliver the compound for several months, and is easily inserted into the animal. No additional handling of the animal is needed, nor worry about the dosage, after the insertion of the implant. The formulation of veterinary additives in animal feed is an extremely well-known technique. It is usual to formulate a compound first as a premix in which the active ingredient is dispersed in a liquid or particulate solid carrier. The premix may conveniently contain from about 1 to 800 grams of the compound per kilogram, depending on the desired concentration in the food. As is known in the art, many active ingredients can be hydrolyzed or degraded by the animal's food constituents. These compounds are formulated routinely in protective matrices, such as gelatin, before being added to the premix. In the method of the present invention, acyl urea is not normally applied in a pure form, but preferably in the form of a composition which, in addition to containing the active ingredient, contains application promoters that are tolerated by the animal. Guest. However, these additional measures are not absolutely necessary. The composition to be applied in the method of this invention usually contains from 0.1 to 99 weight percent, preferably from 0.1 to 95 weight percent of benzoylurea, and from 99.9 to 1 weight percent of preferably from 0.1 to 25 weight percent of a non-toxic solid or liquid auxiliary, including 0 to 25 weight percent, preferably 0.1 to 25 weight percent of a non-toxic surfactant. Although commercial products are preferably formulated as concentrates, the end user will usually employ diluted formulations. The compositions may also contain other ingredients, such as stabilizers, defoamers, viscosity regulators, binders, viscosifiers, as well as other active ingredients to obtain special effects. Known materials of veterinary practice as suitable for oral administration, parenterally, or by implant, can be used as formulation aids. A number of examples are cited below. Suitable carriers are especially fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates., for example calcium triphosphate or calcium phosphate, also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, tragacanth, methyl cellulose and / or, if desired, disintegrants, such as the aforementioned starches, also carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. Auxiliaries are especially flow regulators and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores can be provided with suitable coatings that may be resistant to gastric juices, for example concentrated sugar solutions that may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, or hairspray. suitable organic solvents or mixtures of solvents, or, for the production of coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. Dyes, flavors, or pigments may be added to tablets or dragee coatings, for example, for identification purposes or to indicate different doses of the active ingredient. Other preparations that can be administered orally are dry-filled capsules consisting of gelatin, and also sealed soft capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The dry filled capsules may contain the active ingredient in the form of a granulate, for example mixed with fillers, such as lactose, binders, such as starches, and / or brighteners, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil, or liquid polyethylene glycols, it also being possible to add stabilizers. Preferred are, inter alia, capsules that can be easily bitten or swallowed without chewing. Particularly suitable for parenteral administration are aqueous solutions of an active ingredient in a water-soluble form, for example a water-soluble salt, also suspensions of the active ingredient, such as the corresponding oily suspensions for injection, for example lipophilic solvents or vehicles. suitable, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides, or aqueous suspensions for injection containing viscosity-increasing substances, for example sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also stabilizers. The preparations of the present invention can be manufactured in a manner known per se, for example by means of conventional mixing, granulating, making, dissolving, or lyophilizing processes. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granulate, if desired or necessary, after the addition of suitable auxiliaries, to form tablets or dragee cores. The following examples illustrate the invention described hereinabove, but do not limit its scope in any way. In these examples, the active ingredient can include any of: N- (2,6-difluorobenzoyl) -N '- [3- (3-chloro-5-trifluoromethyl-pyrid-2-yloxy) -4-bromophenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (3-chloro-5-trifluoromethyl-pyrid-2-yloxy) -4-methylphenyl] urea, N- (2,6-difluorobenzoyl) -N' - [3- (3-chloro-5-trifluorome-tilpyrid-2-yloxy) -4-chlorophenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (3-chloro-5-trifluoromethyl-pyrid-2-yloxy) -4-fluorophenyl] urea, • N- (2,6-difluorobenzoyl) - N '- [3- (5-trifluoromethylpyrid-2-yloxy) -4-bromophenyl] urea, N- (2,6-difluorobenzoyl) -N' - [3- (5-trifluoromethylpyrid-2-yloxy) -4- methylphenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (5-trifluoromethylpyrid-2-yloxy) -4-chlorophenyl] urea, N- (2,6-difluorobenzoyl) -N' - [ 3- (5-trifluoromethylpyrid-2-yloxy) -4-fluorophenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,5-dichloro-4- (2-chloro-1,1,2 -trifluoroethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,6-dichloro-4- (2-chloro-1,1,2-trifluoroethoxy) phenyl] urea, N- (2 , 6-difluorobenzoyl) -N '- [3, 5-dichloro-4- (1,1,2,3, -3, 3-hexafluoroprop-2-oxy) phenyl] urea, N- (2,6-difluorobenzoyl) ) -N '- [3,6-dichloro-4- (1,1,2,3, -3,3-hexafluoroprop-1-oxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N' - [3,5-dichloro-4- (2-bromo-1,1,2-trifluoroethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,6-d icloro-4- (2-bromo-1,1,2-trifluoroethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,5-dichloro-4- (1,1,2, 2-tetrafluoroethoxy) phenyl] urea, and N- (2,6-difluorobenzoyl) -N '- [3,6-dichloro-4- (1,1,2,2-tetrafluoroethoxy) phenyl] urea.

EXAMPLE 1 Tablets containing 25 milliliters of active ingredient can be manufactured as follows: Constituents (for 1000 tablets) active ingredient 25. 0 g. lactose 100 7 g. wheat starch 7.5 g. polyethylene glycol (molecular weight: 6,000) 5.0 g. Talc 5.0 g. magnesium stearate 1.8 g. demineralized water q.s.

Manufacturing All solid ingredients are first forced through a sieve having a mesh size of 0.6 millimeters. Then the active ingredient, lactose, and talc, magnesium stearate, and half of the starch are mixed. The other half of the starch is suspended in 40 milliliters of water, and this suspension is added to a boiling solution of polyethylene glycol in 100 milliliters of water. The resulting starch paste is added to the main batch, and the mixture, if necessary with the addition of water, is granulated. The granulate is dried overnight at 35 ° C, forced through a sieve having a mesh width of 1.2 millimeters, and compressed to form tablets having a diameter of about 6 millimeters that are concave on both sides.

EXAMPLE 2 Tablets containing 0.02 grams of active ingredient are manufactured as follows: Composition Active ingredient 200.00 g. lactose 290.80 g. potato starch 24.70 g. stearic acid 10.00 g. Talc 200.00 g. magnesium stearate 2.50 g. colloidal silica 32.00 g. ethanol c.s. A mixture of the active ingredient, lactose, and 194. 70 grams of potato starch, moistened with an ethanolic solution of stearic acid, and granulated through a sieve. After drying, the rest of the potato starch, talc, magnesium, and colloidal silica are mixed, and the mixture is compressed to form 0.1 gram tablets, which, if desired, can be provided with slots to break, for a finer adjustment of the dosage.

EXAMPLE 3 Capsules containing 0.025 grams of the active ingredient can be manufactured as follows: Composition (for 1,000 capsules). active ingredient 25.00 g. lactose 249.00 g. gelatin 2.00 g. corn starch 10.00 g. talcum 15.00 g water c.s. The active ingredient is mixed with the lactose, and the mixture is moistened uniformly with an aqueous solution of the gelatin, and is granulated through a sieve having a mesh width of 1.2 to 1.5 millimeters. The granulate is mixed with dry corn starch, and the talc is introduced in portions of 300 milligrams in hard gelatin capsules (size 1).

EXAMPLE 4 Premix (Food Additive): 0.25 parts by weight of active ingredient and 4. 75 parts of secondary calcium phosphate, or porcelain, aerosol or carbonate clay, are mixed homogeneously with 95 parts of an animal feed.

EXAMPLE 5 Solution for injection 8 parts by weight of active ingredient 3.6 parts of acetic acid 88.4 parts of water for injection Acetic acid and water are added to the active ingredient, and the mixture is stirred until all is dissolved. Then the solution is filtered and sterilized by a suitable method. pH of the solution: 5.0.

EXAMPLE 6 Emulsifiable concentrate: 20 parts of the active ingredient are mixed with 20 parts of emulsifier, for example, a mixture of alkylaryl polyglycol ether with alkylaryl sulfonate, and 60 parts of solvent, until the solution is completely homogeneous. By diluting this concentrate with water, it is possible to obtain an emulsion of the desired concentration.

EXAMPLE 7 Solutions (To Dilute With Water To Drink): 15 percent active ingredient in 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane 10 percent active ingredient in diethylene glycol monoethyl ether 10 percent active ingredient in polyethylene glycol (molecular weight: 300) 5 percent active ingredient in glycerol EXAMPLE 8 Soluble powder: 25 parts of active ingredient 1 part of lauryl sodium sulfate 3 parts of colloidal silica 71 parts of urea The constituents are mixed, and the mixture is finely ground in a suitable mill. Other ingredients or biocidal active agents which are inert to the active ingredients and acceptable to the animals to be treated, or mineral salts or vitamins, can be mixed with the compositions described. In a manner analogous to that described in formulation examples 1 to 9, it is possible to manufacture corresponding preparations containing a compound of the formulas (I) or (II) above.

EXAMPLE 10 Treatment of C. immi tis infections through oral administration of an active ingredient: The clinical diagnosis of coccidioidomycosis in the dog is generally based on clinical findings of persistent fever, itching, rough cough, inappetence, more abnormal sounds of the lung. Frequently, radiographic opacities are identified in the area of the lymphatic node, or foci in the fields of the lung, or both. The clinical diagnosis is also substantiated by the use of serological laboratory test. A specific precipitin antibody which is a type of antibody derived from IgM is tested by agar gel immunodiffusion (AGID). Since IgM is considered to be the first antibody response in most infectious diseases, its presence in a dog suggests an early or acute infection. The presence of IgG antibodies is also identified by agar gel immunodiffusion. The level of IgG antibody is then quantified by an assay of complement fixation antibody (CF) with standard microtiter. The titration is quantified starting at serum dilutions of 1: 4, then 1: 8, 1:16, 1:32, to 1: 256 or greater. It is known that the level of titration in humans reflects in direct proportion the severity of the coccidioidal disease present. The same general principle is true in dogs. Dogs, in the early lung stages of infection, generally have titration levels of 1:32 or lower.

Case Studies: Dogs were identified with positive precipitin reactions, and low to moderate complement fixation titers, from laboratory results. Contact was made with the veterinarians who handled the cases, to verify the acute and pulmonary nature suspected of the infection. The dogs were treated for 20 weeks with N- (2,6-difluorobenzoyl) -N '- ([3,6-dichloro-4- (1, 1, 2, 3, 3, 3-hexafluo-roprop-1- oxy) phenyl] urea (lufenurone) according to the protocol summarized in the following Tables A and B: TABLE A. Race, sex, and treatment regimen of the animals used in the trial.

TABLE B * X-rays were given a visual rating of 0 (no injuries) to 3 (severe injuries) A review of the above data reveals that dogs infected with C. immi tis that had clinically observable coccidioidomycosis had substantially normal clinical signs after receiving the treatment according to the method of the present invention. This positive result suggests that certain compounds of the acylurea class, preferably those of the formula (I) or (II), more preferably the representatives named herein specifically as examples of particularly preferred individual compounds, have a promising future as a Successful treatment for the Valley Fever.

Claims (19)

1. A method for the treatment or prophylaxis of C. immiis infections in warm-blooded animals, which comprises administering to an animal in need of this treatment, an effective therapeutic amount of an acyl urea represented by the following formula: i R. N C0R3 C) wherein: R: is phenyl, naphthyl, pyridyl, pyridazir.yl, pyrimidinyl, or unsubstituted or substituted pyrazinyl; R is hydrogen or alkyl of 1 to 6 carbon atoms; R3 is: R4 to R are each independently hydrogen, halogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, mole,: -: ilc of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 atemos ee carrero, or ticaiquilo of 1 to 6 carbon atoms; R9 is hydrogen or alkyl of 1 to 6 carbon atoms; and X * is an inorganic or organic cation pharmaceutically or agronomically acceptable; and pharmaceutically or agronomically acceptable salts thereof.

2. The method according to claim 1, wherein the acyl urea is a benzoyl urea compound represented by the formula: where Hai is independently chlorine; bromine; or fluorine; R3 is hydrogen, chlorine, bromine, fluorine, methyl, trifluorotr.ecilc, trifluoro-ethoxy, 2-chloro-l, 1,2-trifluoroethoxy, 2-thromc-1, 1,2-trifluoroethoxy, 1, 2, 2 -tetrafluoroethoxy, or 1,1,2,3, -3,3-hexafluoroprop-1-oxyl, -R "is hydrogen or chloro, and: 3 is hydrogen, chloro, 5-trifluoromethylpyrid-2-ylcxyl, or Chloro-5-trifluoromethylpyrid-2-yloxyio, at least one of Ra and R to which is different from hydrogen, and pharmaceutically or agronomically acceptable salts thereof

3. The method according to claim 2, wherein the benzoyl urea is N- (2,6-thiifluorobenzoyl) -N'-3,6-dichloro-4-Ra-phenyl) urea, in which Ra is 2-chloro-1,2,1-trichloroethoxy 2-bromo-1, 1, 2-trifluoroethoxy, 1,1, 2,2-tetrafluoroethoxy, or 1, 1,2,3,3,3-hexafluoroprop-1-oxyl

4. The method according to claim 3, wherein the benzoyl urea is N- (2,6-difluorobenzoyl) -N '- (3,5-dichloro-4-Ra-phenyl) urea, wherein Ra is 2-chloro-l, 1, 2 -trifluoroethoxy; 2-brom o-1, 1,2-trifluoroethoxy; 1, 1, 2, 2-tetrafluoroethoxy; or 1, 1,2,3,3,3-hexafluoroprop-1-oxyl; The method according to claim 1, wherein the acyl urea is administered orally, parenterally, or through implantation. 6. The method according to claim 5, wherein the amount of the acyl urea administered is from 0.01 to about 1,000 milligrams per kilogram of body weight. The method according to claim 6, wherein the amount of the acyl urea administered is from 1 to about 30 milligrams per kilogram of body weight. The method according to claim 6, wherein the amount of the acyl urea administered is from 0.5 to about 200 milligrams per kilogram of body weight. The method according to claim 5, wherein the benzoyl urea is selected from the group of benzoyl ureas consisting of: N- (2,6-difluorobenzoyl) -N 1 - [3,5-dichloro-4 - (2-chloro-1, 1,2-trifluoro-1-ethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N'- [3,6-dichloro-4- (2-chloro-1, 1,2-trifluoro-1-ethoxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N'- [3,5-dichloro-4- (1,1,2,3,3,3- hexafluoroprop-l-oxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N'- [3,6-dichloro-4- (1,1,2,3,3,3-hexafluoroprop-1 oxy) phenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3,5-dichloro-4- (2-bromo-1,1,2-trifluoro-1-ethoxy) phenyl] urea; N- (2,6-difluorobenzoyl) -N '- [3,6-dichloro-4- (2-bromo-1,2-trifluoroethoxy) phenyl] urea; N- (2,6-difluorobenzoyl) -N * - [3,5-dichloro-4- (1,1,2,2-tetrafluoroethoxy) phenyl] urea; and N- (2,6-difluorobenzoyl) -W - [3,6-dichloro-4- (1,1,2,2-tetrafluoroethoxy) phenyl] urea; The method according to claim 5, wherein the benzoyl urea is selected from the group of benzoyl ureas consisting of: N- (2, 6-difluorobenzoyl) -N '- [3- (3-chloro-5-trifluoromethyl-pyrid-2-yloxy) -4-bromo-phenyl] -urea, N- (2,6-difluorobenzoyl) -N' - [3- (3-chloro-5-trifluorome-tilpyrid-2-yloxy) -4-methylphenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (3-chloro-5-trifluoromethylpyrid-2-yloxy ) -4-chlorophenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (3-chloro-5-trifluoromethyl-pyrid-2-yloxy) -4-fluorophenyl] urea, N- (2 , 6-difluorobenzoyl) -N'- [3- (5-trifluoromethylpyrid-2-yloxy) -4-bromophenyl] urea, N- (2,6-difluorobenzoyl) -N '- [3- (5-trifluoromethylpyrid-2 -iloxy) -4-methylphenyl] urea, N- (2,6-difluorobenzoyl) -N1- [3,5-dichloro-4- (1,1,2,3,3,3-hexafluoroprop-2-oxy) ) phenyl] urea, N- (2,6-difluorobenzoyl) -N1- [3- (5-trifluoromethylpyrid-2-yloxy) -4-chlorophenyl] urea, and N- (2,6-difluorobenzoyl) -N '- [3- (5-trifluoromethylpyrid-2-yloxy) -4-fluorophenyl] urea, 11. A method for the treatment or prophylaxis of coccidioidomycosis in a host dog or cat, comprises administering to a dog or cat which treatment is required, an effective therapeutic amount of an acyl urea as defined in claim 1, or a pharmaceutically or agronomically acceptable salt thereof. 12. A method according to claim 11, wherein the acyl urea is defined as in any of claims 2 to 4. The method according to claim 11, wherein the acyl urea is administered orally, parenterally, or through implantation. The method according to claim 13, wherein the amount of the acyl urea administered is from 0.01 to about 1,000 milligrams per kilogram of body weight. The method according to claim 13, wherein the acyl urea is N- (2,6-difluorobenzoyl) -N 1 - [3,6-dichloro-4- (1,1,2,3,3,3) hexafluoroprop-1-oxy) phenyl] -urea. 16. An acyl urea as defined in any one of claims 1 to 4, or 9 to 10, or a pharmaceutically or agronomically acceptable salt thereof, for the treatment or prophylaxis of C. immiis infections in blood animals. hot. 17. The use of an acyl urea as defined in claims 1 to 4, or 9 to 10, or a pharmaceutically or agronomically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment or prophylaxis of C. immi tis infections in warm-blooded animals. 18. An acyl urea as defined in claims 1 to 4, or 9 to 10, or a pharmaceutically or agronomically acceptable salt thereof, for the treatment or prophylaxis of coccidioidomycosis in a host dog or cat. 19. The use of an acyl urea as defined in claims 1 to 4, or 9 to 10, or a pharmaceutically or agronomically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment or prophylaxis of coccidioidomycosis in a host dog or cat. SUMMARY The use of acyl urea compounds is described for the treatment or prophylaxis of Coccidi infections and is not in warm-blooded animals, preferably the treatment or prophylaxis of coccidioidomycosis in dogs or cats, by the use of an amount effective treatment of an acyl urea represented by the following formula: R, I R. N COR,. (I) wherein: R x is phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, or unsubstituted or substituted pyrazinyl; R2 is hydrogen or alkyl of 1 to 6 carbon atoms; R3 is: R4 to R are each independently hydrogen, halogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, or thioalkyl from 1 to 6 carbon atoms; R9 is hydrogen or alkyl of 1 to 6 carbon atoms; and X + is an inorganic or organic cation pharmaceutical or agronomically acceptable; and pharmaceutically or agronomically acceptable salts thereof. Also described are compounds for the treatment or prophylaxis of C. immi tis infections, and their use for the preparation of pharmaceutical compositions against Coccidioides immi tis infections. * *