Use of N-carbamoyl aspartate compounds for the preparation of a medicament for the treatment of animal coccidiosis

Abstract

This invention discloses the use of N-carbamoyl aspartic acid compounds, as shown in structural formula (I), or their racemic, stereoisomer, geometric isomer, tautomer, solvate, pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the prevention and / or treatment of coccidiosis infection in animals: (I), wherein Y and X are each independently selected from H, or straight-chain or branched C1-C 18 Alkyl group. The N-carbamoyl aspartic acid compound of the present invention, or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising thereof, exhibits inhibitory activity against coccidia and shows a significant dose-response effect.

Description

Technical Field

[0001] This invention relates to the use of N-carbamoyl aspartic acid compounds or their racemates, stereoisomers, geometric isomers, tautomers, solvates, or pharmaceutically acceptable salts thereof, or compositions comprising thereof, in the preparation of medicaments for the prevention and / or treatment of coccidiosis in animals; it also relates to pharmaceutical compositions comprising N-carbamoyl aspartic acid compounds or their racemates, stereoisomers, geometric isomers, tautomers, solvates, or pharmaceutically acceptable salts thereof as an anticoccidial active substance; and it further relates to methods for the prevention and / or treatment of coccidiosis in animals using N-carbamoyl aspartic acid compounds or their racemates, stereoisomers, geometric isomers, tautomers, solvates, or pharmaceutically acceptable salts thereof, or compositions comprising thereof. Background Technology

[0002] Coccidiosis is a common and widespread disease caused by protozoan parasites of the genus *Eimeria*. Among poultry coccidiosis, the most important are those caused by the following coccidia: E. maxima , E. pile of piles , E. tenella , E.necatrix , E. brunetti , E. early and E. mild In turkeys, E. turkeys and E. adenoids It is also the causative microorganism of coccidiosis. Besides chicken coccidiosis, which has long existed and is widely recognized, the incidence of coccidiosis in pigs and dairy cows has been increasing year by year in recent years, becoming a major cause of diarrhea and death in suckling and weaned piglets. Eimeria coccidia is a direct-life-cycle parasitic protozoan, and its biological characteristics make it difficult to eradicate. As long as there is intensive farming of pigs and chickens, coccidiosis infection and epidemics are inevitable. The serious consequences of this disease include poor weight gain, reduced feed efficiency, and high mortality, making it a serious animal disease that severely harms livestock production. Chicken coccidiosis alone causes billions of dollars in losses worldwide annually. Currently, the control of animal coccidiosis mainly relies on anticoccidial drugs, but the long-term and widespread use of these drugs has led to drug resistance. Therefore, successful control of coccidiosis is of great significance. Summary of the Invention

[0003] In view of this, the present invention provides the use of an N-carbamoyl aspartic acid compound in the preparation of a medicament for the prevention and / or treatment of coccidiosis in animals.

[0004] The present invention also provides pharmaceutical compositions comprising N-carbamoyl aspartic acid compounds.

[0005] This invention also provides a method for preventing or treating coccidiosis in animals.

[0006] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:

[0007] This invention provides the use of N-carbamoyl aspartic acid compounds with the structure shown in formula (I), or their racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the prevention and / or treatment of coccidiosis in animals: (I)

[0008] Wherein: X and Y are independently selected from H, or straight-chain or branched C1-C. 18 alkyl.

[0009] In some embodiments, X and Y are each independently selected from H, or straight-chain or branched C1-C4 alkyl groups.

[0010] The acceptable salts for the drug in question are salts formed with an alkali metal or a divalent metal when X and Y are each independently selected from H. The alkali metal salt is preferably a sodium or potassium salt, and the divalent metal salt is preferably a calcium, zinc, or copper salt.

[0011] The animals involved are farmed animals susceptible to coccidiosis, including poultry, livestock, and pets. Poultry include chickens, turkeys, ducks, geese, and quails; livestock include pigs, cattle, sheep, and rabbits; and pets include cats and dogs.

[0012] The coccidiosis involved is a disease caused by the following coccidia:

[0013] Including Eimeria giantiformis ( E. maxima ), Eimeria coccidia ( E. mild ), Eimeria tenella ( E. tenella ), poisonous Eimeria coccidia ( E. necatrix ), Eimeria tenella ( E. acervulina ), Eimeria aureus ( E. auburnensis Eimeria coccidia ( E. ox ), Eimeria churni ( E. zuernii ), Eimeria demersalina ( E. debliecki ), Eimeria stearothermia ( E. stiedai E. perforans, E. canis ( E. dog ), or Eimeria brunetti, preferably Eimeria giantiformis ( E. maxima ), Eimeria coccidia ( E. mild ), Eimeria tenella ( E. acervulina ), Eimeria brunetti.

[0014] The present invention also provides a pharmaceutical composition comprising an N-carbamoyl aspartic acid compound of formula (I) or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] Furthermore, the pharmaceutical composition also contains an additional anticoccidial drug.

[0016] Furthermore, the pharmaceutical composition is in the form of a water-dispersible powder.

[0017] Furthermore, the pharmaceutical composition is in the form of an aqueous solution.

[0018] The present invention also provides the formula (I) shown N -Carbamoyl aspartic acid compounds or their racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, are used for the prevention or treatment of coccidiosis in animals.

[0019] The present invention also provides a method for preventing or treating coccidiosis in animals, the method comprising administering to an animal susceptible to coccidiosis a therapeutically effective amount of an N-carbamoyl aspartic acid compound of formula (I) or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0020] The effective therapeutic dose involved is 100-2000 ppm.

[0021] The administration of the N-carbamoyl aspartic acid compound of formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof includes administration as a pharmaceutical composition to animals susceptible to coccidiosis by mixing with feed or drinking water.

[0022] The present invention also provides N-carbamoyl aspartic acid compound of formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising thereof for the prevention or treatment of coccidiosis infection in animals.

[0023] The present invention also provides the use of the N-carbamoyl aspartic acid compound of formula (I) or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof as a medicament. In some embodiments, the aforementioned N-carbamoyl aspartic acid compound or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof is used in a method for treating or preventing coccidiosis in animals, the method comprising administering to an animal a therapeutically effective amount of the N-carbamoyl aspartic acid compound or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0024] The beneficial effects of this invention are:

[0025] The N-carbamoyl aspartic acid compound or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof involved in this invention exhibits significant inhibitory activity against coccidia and shows a clear dose-response effect. In some embodiments, at a therapeutically effective dose of 100-500 ppm, the N-carbamoyl aspartic acid compound or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof exhibits low-potency anticoccidial efficacy; in some embodiments, at a therapeutically effective dose of 1000 ppm, the N-carbamoyl aspartic acid compound or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof exhibits medium-potency anticoccidial efficacy; and in some embodiments, at a therapeutically effective dose of 2000-5000 ppm, the N-carbamoyl aspartic acid compound or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof exhibits high-potency anticoccidial efficacy.

[0026] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. The foregoing and other aspects will be described in more detail below.

[0027] Detailed description of the invention:

[0028] The following detailed description is intended to enable those skilled in the art to implement different embodiments. The description of specific devices, techniques, or applications is merely illustrative. The invention is intended to encompass all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Furthermore, certain technical features of the invention are clearly visible and are described separately in multiple independent embodiments, but may also be provided in combination or in any suitable sub-combination in a single embodiment.

[0029] compound

[0030] This invention provides an N-carbamoyl aspartic acid compound with the structure shown in formula (I), or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof: (I)

[0031] Wherein, Y and X are independently selected from H, or straight-chain or branched C1-C 18 Alkyl group; the acceptable salts of the drug are alkali metal salts or divalent metal salts.

[0032] The term "drug-acceptable" means that the substance or composition must be chemically or toxicologically appropriate in relation to the composition of the drug.

[0033] The N-carbamoyl aspartic acid compound with the structure shown in formula (I) involved in this invention is prepared by the preparation method disclosed in CN110225706A or a variation thereof, which is obtained by racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0034] In this invention, the N-carbamoyl aspartic acid compound includes N-carbamoyl aspartic acid (NCA), and / or its alkyl ester, and / or its alkali metal salt, and / or its divalent metal salt.

[0035] In this invention, "C" a -C b "Alkyl" refers to a straight-chain or branched saturated alkyl group containing a to b carbon atoms, such as methyl, ethyl, propyl, isopropyl, ..., while "C1-C5 alkyl" refers to a straight-chain or branched saturated alkyl group containing 1 to 5 carbon atoms.

[0036] The N-carbamoyl aspartic acid compound involved in this invention is a compound having a chiral center and includes different stereoisomers, wherein the stereoisomers are selected from the levorotatory L-(-)-N-carbamoyl aspartic acid compound (structure as shown in formula (II)), the dextrorotatory D-(+)-N-carbamoyl aspartic acid compound (structure as shown in formula (III)) or the racemic DL-(±)N-carbamoyl aspartic acid compound; ; Equation (II) Equation (III)

[0037] In some embodiments, the chiral stereoisomers of the N-carbamoyl aspartic acid compound can undergo stereoconfiguration inversion under suitable conditions. For example, conformational tautomerism of the N-carbamoyl aspartic acid compound can result in the coexistence of two tautomers. The tautomerism process is illustrated in the following scheme:

[0038] The aforementioned stereoisomers and tautomers are also included within the scope of this invention.

[0039] The "stereoisomers" involved in this invention refer to compounds with the same chemical structure but different spatial arrangements of atoms or groups, including enantiomers, diastereomers, conformational isomers, geometric isomers, and transisomers. "Enantiomers" are two non-overlapping but mirror-image isomers of a compound. "Diastereomers" are stereoisomers with two or more chiral centers whose molecules are not mirror images of each other, possessing different physical properties such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical operations such as electrophoresis or chromatography; "tautomers" are structural isomers with different energies that can interconvert through low energy barriers.

[0040] In some technical solutions, when X and Y are each independently H, the N-carbamoyl aspartic acid compound provided by the present invention is N-carbamoyl aspartic acid.

[0041] In some technical solutions, X and Y are each independently C1-C chains, either straight or branched. 18 When alkyl is involved, the N-carbamoyl aspartic acid compound provided by the present invention is an N-carbamoyl aspartic acid alkyl ester obtained by converting N-carbamoyl aspartic acid under esterification reaction conditions.

[0042] In one specific embodiment, the N-carbamoyl aspartic acid alkyl ester is formed in the presence of an inorganic acid by reacting N-carbamoyl aspartic acid with a straight-chain or branched C1-C2 bond. 18 Alkyl alcohols are produced through esterification.

[0043] In some specific embodiments, the N-carbamoyl aspartic acid compound is an N-carbamoyl aspartic acid alkyl ester in which X and Y are each independently a straight-chain or branched C1-C4 alkyl group; X and Y are each independently preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

[0044] More preferably, the N-carbamoyl aspartic acid compound is N-carbamoyl aspartic acid propyl ester (NCA propyl ester), in which X and Y are each independently propyl.

[0045] In some technical solutions, when X and Y are independently H, the pharmaceutically acceptable salt of the N-carbamoyl aspartic acid compound provided by the present invention is the N-carbamoyl aspartic acid alkali metal salt converted into an N-carbamoyl aspartic acid alkali metal salt by contacting an alkali metal hydroxide, bicarbonate or carbonate in an aqueous solution.

[0046] In some specific embodiments, the hydroxide, bicarbonate or carbonate of the alkali metal is preferably potassium hydroxide, sodium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate, and the alkali metal salt of N-carbamoyl aspartate is specifically sodium N-carbamoyl aspartate (1:2) (abbreviated as "NCA-Na") or potassium N-carbamoyl aspartate (1:2) (abbreviated as "NCA-K").

[0047] In some technical solutions, when X and Y are independently H, the pharmaceutically acceptable salt of the N-carbamoyl aspartic acid compound provided by the present invention is the N-carbamoyl aspartic acid in an aqueous solution that is contacted with a divalent metal hydroxide, bicarbonate or carbonate to convert the N-carbamoyl aspartic acid into a divalent metal salt (1:1) or a divalent metal salt (2:1).

[0048] In some specific embodiments, the hydroxide, bicarbonate, or carbonate of the divalent metal is preferably a hydroxide, bicarbonate, or carbonate of calcium, magnesium, zinc, copper, or iron. Specifically, the divalent metal salt of N-carbamoyl aspartic acid is N-carbamoyl aspartic acid calcium salt (1:1) (hereinafter referred to as "NCA-Ca(1:1)") or N-carbamoyl aspartic acid calcium salt (2:1) (hereinafter referred to as "NCA-Ca(2:1)"), N-carbamoyl aspartic acid magnesium salt (1:1) (hereinafter referred to as "NCA-Mg(1:1)") or N-carbamoyl aspartic acid magnesium salt (2:1) (hereinafter referred to as "NCA-Mg(2:1)"). N-carbamoyl aspartic acid copper salt (1:1) (abbreviated as "NCA-Cu(1:1)") or N-carbamoyl aspartic acid copper salt (2:1) (abbreviated as "(NCA-Cu(2:1)")), N-carbamoyl aspartic acid zinc salt (1:1) (abbreviated as "(NCA-Zn(1:1)") or N-carbamoyl aspartic acid zinc salt (2:1) (abbreviated as "(NCA-Zn(2:1)")), N-carbamoyl aspartic acid iron salt (1:1) (abbreviated as "(NCA-Fe(1:1)") or N-carbamoyl aspartic acid iron salt (2:1) (abbreviated as "(NCA-Fe(2:1))").

[0049] In some technical solutions, the N-carbamoyl aspartic acid compound provided by the present invention is a pharmaceutically acceptable salt of N-carbamoyl aspartic acid, which is a non-toxic acid addition salt formed by the basic amino substituent of N-carbamoyl aspartic acid, including organic acid salts and inorganic acid salts.

[0050] In some embodiments, the pharmaceutically acceptable salts of the N-carbamoyl aspartic acid compounds provided by the present invention are salts formed with organic acids, including but not limited to, acetates, maleates, succinates, mandelates, fumarates, malonates, malates, 2-hydroxypropionates, pyruvates, oxalates, glycolates, salicylates, glucurons, galacturons, citrates, tartrates, aspartates, glutamates, benzoates, p-methylbenzoates, cinnamates, p-toluenesulfonates, benzenesulfonates, methanesulfonates, ethanesulfonates, trifluoromethanesulfonates, or combinations thereof.

[0051] In some embodiments, the pharmaceutically acceptable salt of the N-carbamoyl aspartic acid compound provided by the present invention is a salt formed with an inorganic acid, including but not limited to, hydrochloride, hydrobromide, phosphate, sulfate, nitrate, or combinations thereof.

[0052] The N-carbamoyl aspartic acid compound represented by formula (I) above, or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, has shown inhibitory activity against coccidia, especially intestinal coccidia, in coccidia inhibition studies. Furthermore, the inhibitory activity against coccidia increases with increasing dosage, exhibiting a clear dose-response effect. The intestinal coccidia include, but are not limited to, *Eimeria gianti* (…). E. maxima ), Eimeria coccidia ( E. gentle ), Eimeria tenella ( E. tenella ), poisonous Eimeria coccidia ( E. necatrix ), Eimeria tenella ( E. acervulina ), Eimeria aureus ( E. auburnensis Eimeria coccidia ( E. ox ), Eimeria churni ( E. zuernii ), Eimeria demersalina ( E. debliecki ), Eimeria stearothermia ( E. stiedai Eimeria perforans, Eimeria canis E. dog ), or Eimeria brunetti, preferably Eimeria giantiformis ( E. maxima ), Eimeria coccidia ( E. mild ), Eimeria tenella ( E. acervulina ), Eimeria brunetti.

[0053] In this invention, "inhibition" and "inhibitory" mean a relative reduction in a specific response of a designated activity, such as coccidia motility, in the presence of the N-carbamoyl aspartic acid compound of formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof. Inhibition of coccidia motility can be determined by the assays described in this invention.

[0054] N-carbamoyl aspartic acid compounds with the structure shown in formula (I), or their racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salts thereof, have the efficacy of inhibiting coccidia activity and can be used as drugs for the treatment, prevention or improvement of symptoms in farmed animals susceptible to coccidiosis, for the treatment, prevention or improvement of all diseases, disorders or symptoms related to coccidiosis.

[0055] The term "treatment" in this invention refers to the complete or partial relief of an obstacle, disease, or condition, or one or more symptoms associated with the obstacle, disease, or condition, or the slowing or cessation of the further development or worsening of these symptoms, or the reduction or elimination of one or more causes of the obstacle, disease, or condition itself. In a specific embodiment, the obstacle, disease, or condition refers to coccidiosis or coccidiosis infection.

[0056] In some embodiments, treatment refers to administering a therapeutically effective amount of the animal drug of the present invention to a sick animal to improve the disease or symptom (i.e., slow down, stop, or alleviate the development of the disease or at least one of its clinical symptoms); in other embodiments, treatment refers to administering a therapeutically effective amount of the animal drug of the present invention to a sick animal to alleviate or improve at least one bodily parameter, including bodily parameters that may not be perceived by the patient; in still other embodiments, treatment refers to administering a therapeutically effective amount of the animal drug of the present invention to a sick animal to regulate the disease or symptom physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both; in still other embodiments, treatment refers to administering a therapeutically effective amount of the animal drug of the present invention to a sick animal to prevent or delay the onset, occurrence, or worsening of the disease or symptom.

[0057] The "prevention" involved in this invention refers to delaying and / or preventing the complete or partial onset, recurrence, or spread of an obstacle, disease, or symptom; preventing farmed animals from suffering from an obstacle, disease, or symptom; or methods for reducing the risk of an obstacle, disease, or symptom in farmed animals. In a specific embodiment, the obstacle, disease, or symptom refers to coccidiosis or coccidiosis infection.

[0058] The "coccidiosis infection" involved in this invention refers to an infection caused by coccidia. Coccidiosis in farmed animals refers to the infection of a part of their body with coccidia. The term "coccidiosis" specifically refers to an infection caused by coccidia.

[0059] The "animals" involved in this invention refer to domesticated animals that cannot convert inorganic matter into organic matter, can only consume organic matter as food, and whose life activities include feeding, digestion, absorption, respiration, circulation, excretion, sensation, movement, and reproduction. These domesticated animals can be selected from livestock, poultry, or other legally captured animals at various growth stages, including pets.

[0060] Furthermore: the livestock include, but are not limited to, pigs, cattle, sheep, horses, rabbits, minks or donkeys, preferably pigs, cattle, sheep and rabbits; the poultry include, but are not limited to, chickens, turkeys, ducks, geese or quails, preferably broilers, laying hens, ducks, geese and quails; the pets include, but are not limited to, various subspecies of cats or dogs.

[0061] This invention provides a method for treating diseases caused by coccidiosis.

[0062] In some embodiments, the present invention relates to the use of N-carbamoyl aspartic acid compounds of formula (I) or their racemates, stereoisomers, geometric isomers, tautomers, solvates, or pharmaceutically acceptable salts thereof in veterinary medicine for farmed animals, particularly in the treatment of coccidiosis or coccidioidosis infection. In some embodiments, the method comprises administering an N-carbamoyl aspartic acid compound of formula (I) or its racemates, stereoisomers, geometric isomers, tautomers, solvates, or pharmaceutically acceptable salts thereof to animals suffering from or susceptible to coccidiosis to prevent or treat coccidiosis. The aforementioned N-carbamoyl aspartic acid compound or its racemates, stereoisomers, geometric isomers, tautomers, solvates, or pharmaceutically acceptable salts thereof are administered to farmed animals by mixing with feed or drinking water. A therapeutically effective dose of 100-2000 ppm is sufficient to satisfactorily control coccidiosis or coccidioidosis infection in relation to the total amount of feed or fluid intake consumed by the farmed animals.

[0063] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a sick animal, and this amount can vary depending on the compound, the disease and its severity, as well as the condition, age, weight, and sex of the animal being treated.

[0064] In one embodiment, the present invention provides a method for treating or preventing coccidiosis infection and coccidiosis, the method comprising administering to an animal a therapeutically effective amount of an N-carbamoyl aspartic acid compound of formula (I) or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0065] In one embodiment, the present invention provides a method for treating or preventing coccidiosis and coccidiosis, comprising administering to a subject a therapeutically effective amount of a combination of two or more anticoccidial agents, said combination of anticoccidial agents being a combination of an N-carbamoyl aspartic acid compound of formula (I) or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof with one or more additional anticoccidial agents. In one embodiment, the treatment of coccidiosis or coccidiosis infection involves the administration of a combination of anticoccidial agents, said additional anticoccidial agents including amprolium, nicarbazin, glycinamide, 3,5-dinitrobenzamide, and 2-methyl-3,5-dinitrobenzamide.

[0066] The present invention also provides pharmaceutical compositions comprising an N-carbamoyl aspartic acid compound having the structure shown in formula (I) or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0067] The pharmaceutical composition provided by this invention serves as an effective anticoccidial agent. The N-carbamoyl aspartic acid compound of formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof is tightly dispersed in or mixed with a suitable pharmaceutically acceptable excipient. The effective amount of the N-carbamoyl aspartic acid compound or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt in the pharmaceutical composition can be at a level that will exert the desired effect. The amount of the pharmaceutical composition used industrially per tonne of feed depends on the desired final level of use.

[0068] In this invention, "comprising" and "including" are used interchangeably and should be interpreted as specifying the presence of the stated features or components mentioned, but not excluding the presence or addition of one or more other features or components, intended to include instances covered by "composed of". "Composed of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the features or components of its stated composition, and can also be understood to exclude any other features or components from any subsequently set forth scope, except those not essential to the desired technical effect.

[0069] The "or" used in this invention should be understood as inclusive "or," meaning any one or any combination. Therefore, "A, B, or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition only occur when combinations of elements, functions, steps, or actions are inherently mutually exclusive in some way.

[0070] The pharmaceutical composition refers to a group or collection of compounds comprising one or more compounds. This pharmaceutical composition can be used to prepare a drug for the prevention or treatment of coccidiosis in animals, or to be added to animal feed for the prevention or treatment of coccidiosis in animals or for the preparation of anticoccidial animal feed.

[0071] The pharmaceutical composition is a formulation that can be prepared using conventional pharmaceutically acceptable excipients and common formulation methods.

[0072] The excipients used in these pharmaceutical compositions should be mediators in which the anticoccidial agent is stable, compatible with feed, and safe for administration to animals. These pharmaceutical compositions contain a higher concentration of the anticoccidial agent, which is mixed with or incorporated into the feed. To assume uniform distribution of the coccidioidin inhibitor in the feed, an intermediate dilution step is typically employed, in which the pharmaceutical composition is mixed with a portion of the feed, and then this "intermediate mixture" is added to the remaining feed and thoroughly mixed.

[0073] Pharmaceutically acceptable excipients are selected from one or more of the following: pharmaceutically acceptable carriers, diluents, excipients, binders, disintegrants, wetting agents, flavoring agents, preservatives, stabilizers, suspending agents, dispersants, solubilizers, buffers, copolymers, base waxes, and solvents.

[0074] The carrier refers to a pharmaceutically acceptable substance that can carry active ingredients, improve their dispersibility, and has good chemical stability and adsorption properties, including but not limited to: different carriers that can be used in pharmaceutically acceptable formulations and their known preparation methods.

[0075] The diluent refers to a substance that evenly distributes additive raw materials in the material, dilutes high-concentration additive raw materials into low-concentration premixes or premixes, separates trace components from each other, reduces mutual reactions between active ingredients, and increases the stability of active ingredients without affecting the physicochemical properties of related substances.

[0076] The excipient is selected from one or more of the following: wetting agents that induce the inherent viscosity of the substance; adhesives that bind substances together; disintegrants that break down a whole sheet of substance into many fine particles; retention aids that reduce interparticle friction; and anti-adhesion agents that prevent material adhesion. These include, but are not limited to: cellulose, calcium carbonate, mannitol, sorbitol, magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, starch paste, water, inorganic salts, dextrin, or powdered sugar.

[0077] The solvent refers to the solvent required to dissolve or disperse the solid, including but not limited to: water, glycerol, and ethanol.

[0078] The adhesive is selected from cellulose, methylcellulose, hydroxymethylcellulose, polypropylene pyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch.

[0079] The disintegrant is selected from starch, hydroxymethyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, ammonium bicarbonate, calcium phosphate, or calcium citrate.

[0080] The wetting agent is selected from magnesium stearate, light anhydrous silica, talc, or sodium dodecyl sulfate.

[0081] The flavoring agents include citric acid, menthol, glycine, or wheat starch.

[0082] The preservatives include sodium benzoate, sodium bisulfite, methylparaben, or propylparaben.

[0083] The stabilizer includes citric acid, sodium citrate, or acetic acid.

[0084] The suspending agent includes methylcellulose, polyvinylpyrrolidone, or aluminum stearate.

[0085] The dispersant may be hydroxypropyl methylcellulose.

[0086] The co-solvent can be propylene glycol or tetrahydrofuran polyethylene glycol ether.

[0087] Specifically, the pharmaceutically acceptable excipients mentioned above include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, sodium dihydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicates, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyoxyethylene-polyoxypropylene-block polymers, lanolin; sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, etc. Vitamins and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginate; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solutions, and other non-toxic and suitable lubricants such as sodium laurate and magnesium stearate; colorants, release agents, coating materials, sweeteners, flavorings, fragrances, preservatives, and antioxidants.

[0088] Furthermore, excipients commonly used in these pharmaceutical compositions can be solid, orally administered animal feed additives, such as distillers' grains, corn flour, citrus powder, fermentation residues, ground oyster shells, wheat bran, wheat short fiber, molasses-solubles, corn cob meal, corn gluten feed, corn germ meal, edible plant matter, soybean meal, hulled soybean meal, milled soybean feed, antibiotic mycelium, crushed limestone, soybean grits, etc. Preferably, although not essential, the excipients are nutritious.

[0089] Furthermore, the pharmaceutical composition may further comprise at least one additional anticoccidial agent that is primarily effective against coccidia and / or nematodes, and in many cases, the efficacy of such a combination is better than that expected from the activity of the anticoccidial agent alone. The additional anticoccidial agent includes, but is not limited to, amprolium, nicarbazin, glycinamide, 3,5-dinitrobenzamide, and 2-methyl-3,5-dinitrobenzamide.

[0090] The specific formulations of typical pharmaceutical compositions containing N-carbamoyl aspartic acid compounds of formula (I) or their racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salts thereof are as follows:

[0091] Formula 1: Distillers' grains, N-carbamoyl aspartic acid.

[0092] Formula 2: Corn protein feed, N-carbamoyl aspartic acid calcium salt.

[0093] Formula 3: Soybean flour, sodium N-carbamoyl aspartate.

[0094] Formula 4: Wheat residue, N-carbamoyl aspartic acid propyl ester.

[0095] A typical pharmaceutical composition containing an N-carbamoyl aspartic acid compound of formula (I) of the present invention, or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, is an aqueous dispersible powder, specifically formulated as an N-carbamoyl aspartic acid compound, or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, tightly dispersed in glucose or sucrose at a concentration of about 0.3% to about 25% by weight.

[0096] A typical pharmaceutical composition containing an N-carbamoyl aspartic acid compound of formula (I) of the present invention, or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, is an aqueous solution composition specifically formulated as an N-carbamoyl aspartic acid compound, or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, uniformly dispersed in an aqueous solution of glucose or sucrose at a concentration of about 0.3% to about 25% by weight.

[0097] The method of using the veterinary drug of the present invention will be described below. The method of use for treating diarrhea in animals involves administering to a sick animal a pharmaceutical composition containing a therapeutically effective amount of an N-carbamoyl aspartic acid compound of formula (I) or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the present invention can be manufactured according to conventional methods disclosed in the art. The pharmaceutical compositions are specific target dosage forms suitable for therapeutic purposes. The N-carbamoyl aspartic acid compound or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or a pharmaceutically acceptable salt thereof is mixed with a suitable pharmaceutical diluent, excipient, or carrier selected according to the form of administration and conventional pharmaceutical practice, for example, administered via a suitable carrier in an oral dosage form.

[0098] The pharmaceutical compositions of the present invention are formulated into dosage units to maintain consistency in dosage and administration. Each unit dose of a suitable formulation may contain 1 mg to 100 mg of an N-carbamoyl aspartic acid compound of formula (I) or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof. In these dosage forms, the active ingredient generally constitutes 0.5% to 95% of the total weight of the composition.

[0099] The aforementioned "unit dose" refers to the physical dispersion unit of the drug required for an organism to receive appropriate treatment.

[0100] The pharmaceutical composition is used to treat diarrhea in animals. The oral dosage forms include, but are not limited to, enteric-coated tablets, pills or capsules. Farmers or veterinarians administer the oral dosage form containing the pharmaceutical composition of the present invention to the sick animals by gavage or by mixing it with feed.

[0101] The dosing regimen of the pharmaceutical compositions of the present invention will vary depending on various known factors, such as the pharmacokinetic characteristics and patterns of the specific agent and the route of administration; the species, age, and weight of the diseased animal; the nature and severity of the symptoms; the types of concurrent treatments; the frequency of therapeutic administration; the route of administration; and the desired therapeutic effect. A veterinarian can make a decision and prescribe an effective amount of the drug to prevent, stop, alleviate, or slow the development of disease symptoms.

[0102] The preferred dose levels of the N-carbamoyl aspartic acid compound of formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof required for the prevention and / or treatment of coccidiosis in animals will vary to some extent depending on the specific compound used, the type and severity of the coccidiosis infection, and the animal's weight, and may be determined by a veterinarian or livestock technician based on the specific circumstances.

[0103] In any case, the amount of the N-carbamoyl aspartic acid compound of formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof applied also depends on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0104] In some technical solutions, the therapeutically effective amount of the N-carbamoyl aspartic acid compound represented by formula (I) or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof is 100-500 ppm, exhibiting the efficacy of a low-efficiency anticoccidial drug.

[0105] In some technical solutions, the N-carbamoyl aspartic acid compound represented by formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof exhibits the efficacy of a moderately effective anticoccidial drug when the therapeutically effective amount is 1000 ppm.

[0106] In some technical solutions, the N-carbamoyl aspartic acid compound represented by formula (I) or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof exhibits highly effective anticoccidial efficacy when the therapeutically effective amount is 2000-5000 ppm.

[0107] The N-carbamoyl aspartic acid compound includes N-carbamoyl aspartic acid, and / or its alkyl esters, and / or its alkali metal salts, and / or its divalent metal salts. In the application of inhibiting coccidia growth, the appropriate type of N-carbamoyl aspartic acid compound and its pharmaceutically acceptable salt can be selected according to the method of use and the type of animal.

[0108] For example, using N-carbamoyl aspartic acid, poultry can be well controlled for coccidiosis by administering feed containing approximately 100 ppm to 5000 ppm of N-carbamoyl aspartic acid by weight. However, for optimal results, it is preferable to administer N-carbamoyl aspartic acid at a level of 1000 ppm to 5000 ppm. Those skilled in the art will understand that, in most cases, the lowest level consistent with complete and adequate control of coccidiosis and the development of immunity will be used to minimize the risk of potential side effects induced by prolonged feeding of unnecessarily high doses of the drug. The term "feed" refers to an industrially processed, manufactured product for animal consumption. Unless otherwise stated, "feed" or "animal feed" comprises animal feed ingredients and one or more animal feed additives, including carbohydrates, proteins, fats, vitamins, minerals, and other nutrients commonly used in commercial animal husbandry.

[0109] For example, in anticoccidial testing protocols for poultry, similar control of coccidioidomycetic infection is achieved by administering the same dosage of the N-carbamoyl aspartic acid compound of formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof to poultry. Furthermore, the N-carbamoyl aspartic acid compound includes N-carbamoyl aspartic acid, and / or its alkyl esters, and / or its alkali metal salts, and / or its divalent metal salts. Pharmaceutically acceptable salts of the N-carbamoyl aspartic acid compound also include salts formed by the N-carbamoyl aspartic acid compound with organic or inorganic acids.

[0110] When administered via drinking water to infected animals, the N-carbamoyl aspartic acid compound of formula (I) of this invention, or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, can also be used as an anticoccidial agent. Preferred dosage levels in drinking water are generally slightly lower than those used in solid feed. For example, poultry drink approximately twice as much water as they consume feed; when these compounds are used for therapeutic purposes, it is advantageous to add these anticoccidial compounds to drinking water. These compounds can be prepared as water-dispersible powders, tightly dispersed at a concentration of about 0.3% to about 25% by weight in a suitable carrier such as glucose or sucrose, allowing animal owners to easily add these powders to drinking water.

[0111] Biological Example:

[0112] To make the objectives, technical solutions, and advantages of this invention clearer, the compounds, compositions, and applications of this invention are further described in detail below through examples. It should be understood that the specific examples described herein are for illustrative purposes only and are not intended to limit the scope of this invention.

[0113] Example 1: Study on the inhibitory effect of N-carbamoyl aspartic acid compound on Eimeria tenella in chickens.

[0114] One-day-old fast-growing yellow-feathered broilers were raised in a coccidiotropic environment. At 18 days of age, microscopic examination of feces revealed the absence of coccidial oocysts, and the chickens were then divided into groups for the experiment. Thin or overweight chicks were culled, and healthy chickens with an individual weight difference within 20g were selected and divided into 10 groups of 10 chickens each. Groups 1 and 2 were the control group (no medication, no treatment) and the control group (infected with coccidia, no medication), respectively. Groups 3-8 were the experimental groups treated with the test drug. On the day of the experiment, different test drugs were added to the feed according to Table 2. Chickens had free access to feed and water during the experiment. Except for Group 1, each chicken in each experimental group was administered 7.5 × 10⁶ sporulated oocysts of *Eimeria tenella* via crop gavage 24 hours after the start of the experiment. 4 The experiment ended on day 8 post-infection. Bloody stools were scored for each experimental group on day 5 post-infection. During the experiment, the chickens' mental state, appetite, water intake, defecation, morbidity, and mortality were observed and recorded daily. From day 4 post-infection until the end of the experiment, the number of bloody stools was counted every 12 hours. On day 8 post-infection, all experimental chickens were weighed and necropsies were performed. Cecal lesions were observed, cecal contents were collected, the number of oocysts in the cecum was counted, and the anticoccidial index (ACI) was calculated.

[0115] Efficacy assessment criteria: Based on the anticoccidial index (ACI), an ACI above 180 indicates high efficacy, between 160 and 180 indicates moderate efficacy, and between 120 and 160 indicates low efficacy. The ACI is calculated as follows: ACI = (Survival rate + Relative weight gain rate) - (Lesion value + Oocyst value).

[0116] (1) Survival rate (%): (Total number of chickens in the experimental group - number of chickens that died from coccidiosis during the experiment) / Total number of chickens in the experimental group × 100%.

[0117] (2) Relative weight gain rate (%): (average weight gain of chickens in the drug-treated group or the infected but not drug-treated group ÷ average weight gain of chickens in the uninfected but not drug-treated group) × 100%. The relative weight gain rate of chickens in the uninfected but not drug-treated group is 100%.

[0118] (3) Score for bloody stool: 0 points, no bloody stool; 1 point, less than 25% of the stool contains blood; 2 points, 25-50% of the stool contains blood; 3 points, 50-75% of the stool contains blood; 4 points, more than 75% of the stool contains blood.

[0119] (4) Lesion scoring: The severity of the lesion is represented by a scale of 0 to 5, where 0 represents no lesion and 5 represents the most severe lesion.

[0120] (5) Lesion value: the average lesion score of each group × 10.

[0121] (6) Average number of oocysts per chicken: After scraping the contents of the cecum and digesting them with 10% sodium hypochlorite for 15 minutes, the oocysts were counted using the hemocytometer method, and the number of oocysts in the cecum was calculated.

[0122] (7) Oocyte count: The conversion relationship between the number of ovocytes and the ovocyte count is shown in Table 1.

[0123] Table 1. Conversion between number of ovules and ovule value

[0124] The test results show that:

[0125] Positive control group: On the 3rd day after infection, chickens showed decreased feed intake and lethargy. On the 4th day, they developed bloody stools, and a total of 3 chickens died. Autopsy of the dead chickens revealed severe edema of the cecum, filled with blood clots, and numerous hemorrhages on the intestinal mucosa. The surviving chickens had ruffled feathers, drooping wings, and a few had their necks retracted and eyes closed.

[0126] Negative control group: Chickens had normal appetite and no abnormalities such as bloody stools were observed.

[0127] Drug experimental groups: All drug experimental groups showed that N-carbamoyl aspartic acid compound had significant inhibitory activity against Eimeria tenella in chickens, and exhibited a clear dose-response effect.

[0128] Table 2 Results of the anticoccidial effect studies in each experimental group

[0129] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. The use of N-carbamoyl aspartic acid compounds, or their racemates, stereoisomers, geometric isomers, tautomers, solvates, or pharmaceutically acceptable salts thereof, as shown in formula (I), in the preparation of medicaments for the prevention and / or treatment of coccidiosis in animals: （I） in: X and Y are independently selected from H, or from C1-C of either straight or branched chains. 18 alkyl.

2. The application according to claim 1, characterized in that, The acceptable salts for the drug are alkali metal salts or divalent metal salts, preferably sodium, potassium, calcium, zinc, or copper salts.

3. The application according to claim 1, characterized in that, The animals described are farmed animals susceptible to coccidiosis.

4. The application according to claim 1, characterized in that, The animals mentioned are poultry susceptible to coccidiosis, preferably chickens, turkeys, ducks, geese, or quails.

5. The application according to claim 1, characterized in that, The animals mentioned are livestock susceptible to coccidiosis, preferably pigs, cattle, sheep or rabbits.

6. The application according to claim 1, characterized in that, The animal in question is a pet susceptible to coccidiosis, preferably a cat or dog.

7. The application according to claim 1, characterized in that, The coccidiosis described above is a disease caused by the following coccidia: E. maxima, E. mitis , E. tenella , E. necatrix , E. acervulina , E. auburnensis, E. bovis, E. zuernii, E.debliecki, E. stiedai, E. perforans, E. canis, or E. brunetti Preferred E. maxima, E. mitis, E. acervulina, or E. brunetti .

8. A pharmaceutical composition, characterized in that, It comprises an N-carbamoyl aspartic acid compound or its racemate, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, as shown in formula (I), and pharmaceutically acceptable excipients: （I） in: X and Y are independently selected from H, or from C1-C of either straight or branched chains. 18 alkyl; The acceptable salts for the drug are alkali metal salts or divalent metal salts, preferably sodium, potassium, calcium, zinc, or copper salts.

9. The pharmaceutical composition according to claim 8, characterized in that, The pharmaceutical composition is in the form of a water-dispersible powder.

10. The pharmaceutical composition according to claim 8, characterized in that, The pharmaceutical composition is in the form of an aqueous solution.

11. The pharmaceutical composition according to claim 8, characterized in that, The composition also contains an additional anticoccidial drug.

12. A method for preventing or treating coccidiosis in animals, comprising administering to a susceptible animal a therapeutically effective amount of an N-carbamoyl aspartic acid compound of the structure shown in formula (I), or a racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof: （I） in: X and Y are independently selected from H, or from C1-C of either straight or branched chains. 18 alkyl; The acceptable salts for the drug are alkali metal salts or divalent metal salts, preferably sodium, potassium, calcium, zinc, or copper salts.

13. The method according to claim 12, characterized in that, The effective therapeutic dose is 100-2000 ppm.

14. The method according to claim 12, characterized in that, The N-carbamoyl aspartic acid compound with the structure shown in Formula (I) or its racemic, stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof is administered by mixing or drinking water in the form of a pharmaceutical composition according to any one of claims 8-11.

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