Prodrug of hexahydro-β-acid compound, its feed composition and its use

Abstract

The present invention relates to a prodrug of a hexahydro-β-acid compound, a feed composition thereof, and its use, as well as a compound of formula (I) [C25] TIFF2023548235000031.tif46170 (wherein R1 is a substituted or unsubstituted C1-C2 alkyl, and each of R2 and R3 is independently selected from H and a linear or branched C2-C4 carbonyl, wherein the C2-C4 carbonyl is substituted or unsubstituted) This disclosure discloses a prodrug of a hexahydro-beta acid compound, or a solvate thereof, or a feed-acceptable salt thereof. It has been found herein that the prodrug of a hexahydro-beta acid compound obtained by esterification with an aliphatic acid exhibits excellent stability at high temperatures, overcoming problems caused by the decomposition of the hexahydro-beta acid compound in high-temperature pelleting processes. Furthermore, it has been found herein that both propionate and butyrate prodrugs of a hexahydro-beta acid compound obtained by esterification with an aliphatic acid, as well as their feed-acceptable salts and solvates, are stable in high-temperature feed processing and achieve substantially equivalent efficacy to the hexahydro-beta acid compound in farm feeding.

Description

Technical Field

[0001] The present invention relates to the field of additives for animal feed, and particularly to prodrugs of hexahydro-β-acid compounds, their feed compositions and their use.

Background Art

[0002] Hop plants produce organic acids known as hop acids, which include α - acids and β - acids and are used to replace antibiotics in animal feed to control the biological performance of sterilization, antibacterial activity, or metabolites. Among hop acids, β - acids have stronger antibacterial activity. Due to poor stability and solubility, hop acids are usually mixed into animal feed after grinding, or sprayed, encapsulated, or mixed with / into animal feed as a 1% aqueous solution of their potassium salts. The above - mentioned uses of hop acids were inconvenient in animal breeding. Derivatives of di - hydrogenated, tetra - hydrogenated, or hexa - hydrogenated hop acids have been proposed to exhibit changes in activity, stability, solubility, or other properties. However, unfortunately, hexa - hydrogenated β - acid and its metal salts (referred to as hexahydro - β - acid) have soon become known to be unstable to heat. Furthermore, hexahydro - β - acid stored at room temperature and mixed into feed rapidly decomposes, resulting in a decrease in the hexahydro - β - acid content in the feed. The rapid decomposition of hexahydro - β - acid in feed at room temperature could not meet the requirements of feed additives. The inventors have found that the main components of hexahydro - β - acid are hexahydro - lupulone, hexahydro - colupulone, and hexahydro - adlupulone, and that the instability of hexahydro - β - acid in feed at room temperature is due to the instability of hexahydro - lupulone, resulting in a decrease in the content of hexahydro - β - acid. The inventors have further found that a combination of hexahydro - colupulone or hexahydro - colupulone and hexahydro - adlupulone in a premix achieves an effect similar to or even better than that of hexahydro - β - acid on animal productivity. However, due to the decrease in the content of hexahydro - colupulone and / or hexahydro - adlupulone in feed during storage, their use in the breeding industry is restricted. Summary of the Invention Problems to be Solved by the Invention

[0003] In view of the above, the present invention is proposed.

[0004] The objectives provided herein include providing a prodrug of a hexahydro-β-acid compound.

[0005] The objectives provided herein also include providing a feed composition comprising a prodrug of a hexahydro-β-acid compound.

[0006] The objectives provided herein also include providing the use of a prodrug of a hexahydro-β-acid compound or a feed composition thereof in the preparation of an additive for animal feed.

[0007] The objectives provided herein also include providing the use of a prodrug of a hexahydro-β-acid compound or a feed composition thereof in the preparation of animal feed.

[0008] The objectives provided herein also include providing a method for improving the productivity of animals.

Means for Solving the Problems

[0009] To achieve at least one of the objectives provided herein, the following technical solutions are proposed.

[0010] In one aspect, a prodrug of a hexahydro-β-acid compound of formula (I)

Chemical Formula

[0011] In another aspect, a feed composition is provided herein, which comprises an optional feed-acceptable adjuvant and a prodrug of formula (I) or a solvate thereof or a feed-acceptable salt thereof.

[0012] In another aspect, provided herein is the use of a prodrug of formula (I), a solvate thereof, a feed acceptable salt thereof, and a feed composition in the preparation of an additive for animal feed, the feed composition comprising a prodrug of formula (I) or a solvate thereof or a feed acceptable salt thereof.

[0013] In another aspect, provided herein is the use of a prodrug of formula (I), a solvate thereof, a feed acceptable salt thereof, and a feed composition in the preparation of animal feed, the feed composition comprising a prodrug of formula (I) or a solvate thereof or a feed acceptable salt thereof.

[0014] In another aspect, a method for improving animal productivity is provided, feeding an animal with a prodrug provided herein, or a solvate thereof, or a feed acceptable salt thereof, or feeding an animal with a feed composition provided herein, or feeding an animal with a feed comprising a feed composition provided herein is provided herein.

[0015] Compared with the prior art, the technical effects provided herein are as follows: Prodrugs of hexahydro-β-acid compounds from esterification with aliphatic acids are found herein to exhibit excellent stability at high temperatures and overcome problems caused by the decomposition of hexahydro-β-acid compounds in the high-temperature pellet forming process. Further, both propionate and butyrate, prodrugs of hexahydro-β-acid compounds from esterification with aliphatic acids, and feed acceptable salts and solvates thereof are found herein to be stable in high-temperature feed processing and achieve substantially the same effects as hexahydro-β-acid compounds in farm breeding.

[0016] Any embodiment of any aspect provided herein can be combined with other embodiments, provided there is no contradiction between them.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The foregoing described herein merely outlines the specific aspects provided herein but is not limited to these aspects. The above aspects and other aspects will be described in more detail and completely as follows.

[0018] Specific embodiments provided herein are described in detail and illustrated by the accompanying structures and formulas. This disclosure is intended to cover all alternative forms, modifications, and equivalents within the scope of this disclosure as defined by the appended claims. Further, for clarity, specific technical features disclosed herein that are separately described in multiple independent embodiments can also be provided in individual embodiments or in any suitable partial combination.

[0019] Compound The compounds related to this specification are prodrugs of hexahydro-β-acid compounds of formula (I)

Chemical formula

[0020] R1 is a linear or branched alkyl, which may be substituted or unsubstituted; each of R2 and R3 is independently selected from H and a linear or branched aliphatic carbonyl, and the aliphatic carbonyl may be substituted or unsubstituted.

[0021] Furthermore, R1 is selected from substituted or unsubstituted C1-C2 alkyl; each of R2 and R3 is independently selected from H and a linear or branched C3-C4 carbonyl, and the C3-C4 carbonyl may be substituted or unsubstituted.

[0022] The "hexahydro-β-acid compound" related to this specification refers to the main components of hexahydro-β-acid, namely hexahydro-coproic acid (I1-1), hexahydro-adipic acid (I1-2), and hexahydro-lupic acid (I1-3), and its formula is as follows.

Chemical formula

[0023] Generally, the term "substituted" means that one or more replaceable hydrogen atoms in a given formula are replaced by a specific group, one substituent can be replaced by a group at each of its respective replaceable positions, and when there are multiple positions substituted by one or more specific groups in a given formula, the groups can be the same or different.

[0024] The term "C a ~C b alkyl" herein refers to a linear or branched saturated alkyl group having a to b carbon atoms, such as methyl, ethyl, propyl, isopropyl, etc.; for example, the term "C3-C4 alkyl" represents a linear or branched saturated alkyl group having 3 to 4 carbon atoms. The term "C a ~C b carbonyl" refers to a linear or branched aliphatic carbonyl group having a to b carbon atoms, such as C(=O)CH2CH3, C(=O)(CH2)2CH3, C(=O)CH2(CH3)2, etc.

[0025] In some embodiments, in the prodrug of formula (I), R1 is CH3, each of R2 and R3 is independently selected from H and linear or branched C3-C4 carbonyl, and the C3-C4 carbonyl is either substituted or unsubstituted.

[0026] Furthermore, R2 and R3 are each independently selected from H and unsubstituted linear C3-C4 carbonyl, and preferably not both are H.

[0027] In some examples, R3 is H and R2 is an unsubstituted linear C3-C4 carbonyl.

[0028] In some other examples, R2 and R3 are each independently selected from unsubstituted linear C3-C4 carbonyls and are preferably the same.

[0029] In some embodiments, in the prodrug of formula (I), R1 is CH2CH3, and each of R2 and R3 is independently selected from H and linear or branched C3-C4 carbonyls, and the C2-C4 carbonyls are either substituted or unsubstituted.

[0030] Furthermore, R2 and R3 are each independently selected from H and unsubstituted linear C3-C4 carbonyls, and preferably not both are H.

[0031] In some examples, R3 is H and R2 is an unsubstituted linear C3-C4 carbonyl.

[0032] In some other examples, R2 and R3 are each independently selected from unsubstituted linear C3-C4 carbonyls and are preferably the same.

[0033] In some other specific examples, the prodrugs of the hexahydro-β-acid compounds described herein are

Chemical formula

[0034] Preparation and purification of compounds The prodrugs of the hexahydro-β-acid compounds related to this specification can be prepared using the following procedures. (1) Extract the commercially available hop extract with an organic solvent as a raw material to obtain β-acid. (2) Hydrogenate β-acid to obtain hexahydro-β-acid. (3) Recrystallize or subject the hexahydro-β acid to preparative chromatography to provide a hexahydro-β acid compound, where the compound is known as hexahydro-corpolone (I1-1), hexahydro-adolpropiolactone (I1-2), and hexahydro-lupetidine (I1-3). (4) Esterify the hexahydro-β acid compound with one or two stoichiometric linear or branched fatty acids to provide a prodrug of the hexahydro-β acid compound, where the fatty acid is substituted or unsubstituted.

[0035] Hexahydro-β acid compounds having an asymmetric center are mesomers, racemic compounds, stereoisomers, geometric isomers, tautomers, a single enantiomer, a single diastereomer, or a diastereomeric mixture; it should be noted that prodrugs of the isomeric forms via step (4) above are included herein. The hexahydro-β acid compound can be commercially available or prepared by semi-synthesis from plant-derived raw materials or total synthesis by skilled chemists.

[0036] In some embodiments, the procedure for preparing the prodrug of the hexahydro-β acid compound provided herein also involves a work-up step known as isolation, purification, or recrystallization of the product. The product can be obtained as a crude product from the reaction system by removing the solvent. To obtain a solid substance with higher chemical purity and lower impurity content, the crude product can be dissolved, crystallized, precipitated, or recrystallized in an alcohol solvent, an alcohol-water mixed solvent, or other organic solvents that can be used for recrystallization of the product under appropriate temperature, light, and mechanical vibration conditions to provide a prodrug of the hexahydro-β acid compound in a specific crystal form. The prodrug of the hexahydro-β acid compound in a specific crystal form refers to the prodrug or its solvate. The solvate can be selected from the hydrate of the prodrug and the prodrug having ethanol.

[0037] As used herein, the term "solvate" refers to a co-crystalline association formed by contacting a compound provided herein with a stoichiometric or non-stoichiometric solvent via non-covalent intermolecular forces due to external and internal conditions. Solvents that form solvates include, but are not limited to, water, acetone, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, isopropanol, and the like. The term "hydrate" refers to a complex or crystal having water, i.e., a compound having stoichiometric or non-stoichiometric water molecules via non-covalent intermolecular forces.

[0038] To obtain a purer solid material with a lower content of impurities, the preparation procedure of the prodrug provided herein may also involve a salting-out step. The salting-out step results in and precipitates a pharmaceutically acceptable salt of the prodrug of the hexahydro-β-acid compound with a corresponding organic base, inorganic base, organic acid, or inorganic acid under the principles of acid-base neutralization, acid-base coordination, or acid-base chelation. Here, inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, or combinations thereof. Here, organic bases include, but are not limited to, ammonia or triethylamine. Here, inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide.

[0039] A pharmaceutically acceptable salt refers to a salt formed by the prodrug of the hexahydro-β-acid compound provided herein and an organic base, inorganic base, organic acid, or inorganic acid, and the base or acid is non-toxic to animals. The term "pharmaceutically acceptable" refers to a substance or composition that is chemically or toxicologically suitable and relevant for the feed or livestock thus obtained.

[0040] In some embodiments, the post-treatment step of the prodrug of the hexahydro-β-acid compound provided herein also involves a salting-out process that forms an acidic-basic salt and / or an acidic-basic chelate salt with an inorganic acid or an organic acid. Here, the organic acids include, but are not limited to, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, malic acid, 2-hydroxypropionic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, glucuronic acid, galactonic acid, citric acid, tartaric acid, aspartic acid, glutamic acid, benzoic acid, p-toluic acid, cinnamic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, or combinations thereof.

[0041] Use of the compound The prodrug of the hexahydro-β-acid compound provided herein, its solvate or its pharmaceutically acceptable salt can be used in the preparation of additives for animal feed.

[0042] As used herein, "animal" refers to a human or a domesticated animal that cannot convert inorganic substances into organic substances and can only use organic substances as food for life activities such as ingestion, digestion, absorption, respiration, circulation, excretion, sensation, movement, and reproduction. "Livestock" includes legally captured poultry, livestock, aquatic animals, and other animals, including pets such as cats and dogs. The term "livestock" refers to, for example, any one of pigs, cows, horses, goats, sheep, deer, and any species of various useful rodents. The term "poultry" includes, for example, chickens, ducks, geese, quails, pigeons, etc. The term "aquatic animals" includes, for example, fish, shrimps, turtles, frogs, etc.

[0043] The use of the prodrug of the hexahydro-β-acid compound provided herein, its solvate or its pharmaceutically acceptable salt is used in the preparation of non-nutritive feed additives for improving the productivity of animals at all growth stages, and the animals can be selected from livestock, poultry, aquaculture animals or pet animals at various growth stages.

[0044] In further embodiments, livestock includes, but is not limited to, pigs, cows, sheep, horses, rabbits, donkeys and camels; poultry includes, but is not limited to, chickens, turkeys, ducks, geese, quails or pigeons; aquaculture animals includes, but is not limited to, fish, shrimps, turtles, crabs, soft-shell turtles, bullfrogs, eels and loaches; and pet animals includes, but is not limited to, various subspecies of dogs or cats.

[0045] In one embodiment, the use of a prodrug of a hexahydro-β-acid compound provided herein, a solvate thereof or a feed acceptable salt thereof is in the preparation of an additive for a feed for improving the productivity of pigs, which has an improving effect on feed intake, average daily weight gain and feed efficiency.

[0046] In another embodiment, an additive for a feed prepared from a prodrug of a hexahydro-β-acid compound provided herein, a solvate thereof or a feed acceptable salt thereof can significantly improve the productivity of broilers or laying hens.

[0047] In another embodiment, the use of a prodrug of a hexahydro-β-acid compound provided herein, a solvate thereof or a feed acceptable salt thereof is used in the preparation of an additive for a feed, and the feed can improve the productivity of fish.

[0048] The feed composition of the present invention Provided herein is a stable feed composition comprising a prodrug of formula (I), a solvate thereof or a feed acceptable salt thereof and an optional feed acceptable adjuvant, wherein the feed acceptable adjuvant is a carrier, an excipient, an additive and a solvent or a combination thereof.

[0049] "Composition", as used herein, refers to a series of compounds including one or more compounds as active ingredients.

[0050] As used herein, the terms "comprising", "comprised of", "containing", "includes", "include", "having", and variations thereof are open-ended expressions that include only what is specified herein and do not exclude other aspects. However, it should be noted that the feed compositions provided herein exclude hexahydro-γ-butyrolactone or its salts or esters. In one or more embodiments, except for the prodrugs of formula (I), the feed compositions provided herein do not contain other hexahydro-β-acid compounds or their salts and esters (except for amounts of other hexahydro-β-acid compounds as unavoidable impurities).

[0051] As used herein, a "stable feed composition" refers to a composition for consumption by an animal that is sufficiently stable upon preparation and can maintain the integrity of the compounds for a sufficient period of time for the purposes described in detail herein.

[0052] As used herein, a "carrier" refers to an ingestible substance that exhibits suitable chemical stability and absorbency characteristics and can carry the active ingredient, improving the dispersibility of the components. The carrier is an organic or inorganic carrier. Organic carriers are fiber-rich materials including, but not limited to, corn flour, corn cob flour, wheat bran, rice husk powder, defatted rice bran, by-products of rice polishers, corn stalk powder, peanut shell powder, etc. Inorganic carriers are minerals mainly classified into calcium salts and silicon oxides and are used for the preparation of trace element premixes including, but not limited to, calcium carbonate, silicate, vermiculite, zeolite, sepiolite, etc.

[0053] "Excipient", as used herein, refers to a substance that evenly distributes starting additives in a material and dilutes a high concentration of starting additives into a low-concentration premix, which separates trace components from each other and reduces the interaction between active ingredients, increasing the stability of the active ingredients without affecting the physicochemical properties of the substances involved. Excipients are either organic excipients or inorganic excipients. Organic excipients include, but are not limited to, corn flour, corn flour without germ, dextrose (glucose), sucrose, semolina with bran, fried soybean powder in oil, secondary flour, corn gluten meal, etc. Inorganic excipients include, but are not limited to, limestone, calcium dihydrogen phosphate, shell powder, kaolin (china clay), sodium chloride, and sodium sulfate.

[0054] Additives are selected from the group consisting of wetting agents, adhesives, disintegrants, retention aids, anti-adhesives, and combinations thereof. Here, a wetting agent is a drug that can cause the inherent viscosity of a substance, an adhesive is a drug that can bind other drugs together, a disintegrant is a drug that decomposes the entire sheet of a substance into many small particles, a retention aid is a drug that reduces the friction between particles, and an anti-adhesive is a drug that prevents the adhesion of materials, including, but not limited to, magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, starch slurry, water, inorganic salts, dextrin, powdered sugar, etc.

[0055] "Solvent", as used herein, refers to a solvent required to dissolve or disperse a solid, including, but not limited to, water, glycerin, ethanol, etc.

[0056] In some embodiments, the prodrug contained in the feed composition is a prodrug of hexahydro-coprone or a solvate thereof or a feed-acceptable salt thereof.

[0057] In one embodiment, the prodrug contained in the feed composition is hexahydro-copron monopropionate of formula (I2-1) or a solvate thereof or a feed acceptable salt thereof.

[0058] In one embodiment, the prodrug contained in the feed composition is hexahydro-copron monobutyrate of formula (I2-2) or a solvate thereof or a feed acceptable salt thereof.

[0059] In one embodiment, the prodrug contained in the feed composition is hexahydro-copron dipropionate of formula (I2-5) or a solvate thereof or a feed acceptable salt thereof.

[0060] In one embodiment, the prodrug contained in the feed composition is hexahydro-copron dibutyrate of formula (I2-6) or a solvate thereof or a feed acceptable salt thereof.

[0061] In some embodiments, the prodrug contained in the feed composition is a prodrug of hexahydro-adolpropion or a solvate thereof or a feed acceptable salt thereof.

[0062] In one embodiment, the prodrug contained in the feed composition is hexahydro-adolpropion monopropionate of formula (I2-3) or a solvate thereof or a feed acceptable salt thereof.

[0063] In one embodiment, the prodrug contained in the feed composition is hexahydro-adolpropion monobutyrate of formula (I2-4) or a solvate thereof or a feed acceptable salt thereof.

[0064] In one embodiment, the prodrug contained in the feed composition is hexahydro-adolpropion dipropionate of formula (I2-7) or a solvate thereof or a feed acceptable salt thereof.

[0065] In one embodiment, the prodrug contained in the feed composition is hexahydro-adrenalone dibutyrate of formula (I2-8), or a solvate thereof, or a feed acceptable salt thereof.

[0066] In some embodiments, the prodrug contained in the feed composition is a combination of hexahydro-corpolone, a solvate thereof or a feed acceptable one, and a prodrug of hexahydro-adrenalone, a solvate thereof or a feed acceptable one.

[0067] Specifically, the combinations of the prodrug of hexahydro-corpolone and the prodrug of hexahydro-adrenalone include, but are not limited to, the combination of hexahydro-corpolone monopropionate and hexahydro-adrenalone monopropionate, the combination of hexahydro-corpolone monobutyrate and hexahydro-adrenalone monobutyrate, the combination of hexahydro-corpolone dipropionate and hexahydro-adrenalone mono- or diester, and the combination of hexahydro-corpolone dibutyrate and hexahydro-adrenalone dibutyrate.

[0068] In some embodiments, the prodrug contained in the feed composition is a combination of a prodrug of hexahydro-corpolone, a solvate thereof or a feed acceptable salt, and a prodrug of hexahydro-adrenalone, a solvate thereof or a feed acceptable salt, the weight of the prodrug of hexahydro-corpolone is regarded as 1 unit, and the weight of the prodrug of hexahydro-adrenalone is 0.5 unit or less and 0.01 unit or more.

[0069] In some embodiments, the prodrug contained in the feed composition is a combination of a prodrug of hexahydro-coprostanol, its solvate or its feed-acceptable salt and a prodrug of hexahydro-adrenosterone, its solvate or its feed-acceptable salt. The weight of the prodrug of hexahydro-coprostanol is regarded as 1 unit, and the weight of the prodrug of hexahydro-adrenosterone is 0.5 unit.

[0070] In some embodiments, the prodrug contained in the feed composition is a combination of a prodrug of hexahydro-coprostanol, its solvate or its feed-acceptable salt and a prodrug of hexahydro-adrenosterone, its solvate or its feed-acceptable salt. The weight of the prodrug of hexahydro-coprostanol is regarded as 1 unit, and the weight of the prodrug of hexahydro-adrenosterone is 0.25 unit.

[0071] In some embodiments, the above feed composition further comprises additional feed additives and / or animal feed components for animals.

[0072] Feed additives for animals are nutritional additives, general feed additives or pharmaceutical additives for feed.

[0073] Nutritional additives refer to small or trace amounts of products added to compound feeds that meet the requirements of specific nutrients, improve the utilization of feeds, or achieve a direct nutritional effect on animals, including but not limited to amino acids, amino acid salts and their analogs, vitamins and vitamin-like substances, trace elements and their complexes (chelates), microbial enzyme preparations or non-protein nitrogen.

[0074] Common feed additives, also known as non-nutritive additives, refer to non-nutritive products added to feed to improve feed utilization, achieve effects on feed quality and characteristics, and achieve good effects on animal health or metabolism, including but not limited to growth promoters, insect repellents, flavors, attractants, regulators, preparations for feed, preservatives and antioxidants for feed, and traditional Chinese medicine additives.

[0075] In some embodiments, the additional feed additives included in the feed composition are selected from the group consisting of nutritive additives, non-nutritive additives, medicated feed additives, and combinations thereof.

[0076] More specifically, the non-nutritive additives include, but are not limited to, growth promoters such as butyric acid, calcium butyrate, sodium butyrate, tannic acid, p-thymol, p-thymol ester, p-thymol salt, 2-hydroxybenzoic acid, benzoic acid or calcium benzoate, zinc oxide, zinc sulfate, and zinc chloride.

[0077] In one embodiment, the non-nutritive additive is calcium butyrate.

[0078] In another embodiment, the non-nutritive additive is tannic acid.

[0079] More specifically, the pharmaceutical additives for feed include, but are not limited to, premixes of veterinary drugs with carriers or excipients, which are used in feed for a long time to prevent animal diseases and achieve good effects on animal growth.

[0080] More specifically, the pharmaceutical additives for feed are antibiotics for feed, including but not limited to polymyxin, salinomycin, avilamycin, bacitracin, virginiamycin, nosiheptide, flavomycin, enramycin, kitasamycin, olaquindox, oxytetracycline, or chlortetracycline.

[0081] In some embodiments, the animal feed components are grains, oilseeds, legumes, tubers / roots, other seeds, forages / stover, other plants / algae and their processed products, as well as dairy products, products of terrestrial animals, products of fish and other aquatic organisms and their by-products, as well as trace elements, microbial fermentation products and their by-products and other feed components.

[0082] Use of the feed composition The use of the stable feed composition described above is provided herein, and the feed composition comprises an optional feed-acceptable adjuvant and a prodrug of a hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salts.

[0083] In some embodiments, the stable feed composition described above is used in the preparation of a feed additive for animals, and the feed composition comprises an optional feed-acceptable adjuvant and a prodrug of a hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salts.

[0084] Furthermore, the feed additives for animals are additives used to increase the productivity of animals, including but not limited to feed additives for livestock, poultry, aquatic animals and pets.

[0085] Specifically, the stable feed composition described above is used in the preparation of feed additives for livestock including but not limited to pigs, cows, sheep, horses, rabbits, minks, etc. at various growth stages, and the feed composition comprises an optional feed-acceptable adjuvant and a prodrug of a hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salts.

[0086] Specifically, the above-mentioned stable feed composition is used in the preparation of feed additives for poultry including, but not limited to, chickens, ducks, geese, pigeons, etc. at various growth stages. The feed composition comprises an adjuvant acceptable as an optional feed, a prodrug of the hexahydro-β-acid compound of formula (I), a solvate thereof, and a salt thereof acceptable as a feed.

[0087] Specifically, the above-mentioned stable feed composition is used in the preparation of feed additives for aquatic animals including, but not limited to, fish, shrimps, crabs, turtles, eels, etc. at various growth stages. The feed composition comprises an adjuvant acceptable as an optional feed, a prodrug of the hexahydro-β-acid compound of formula (I), a solvate thereof, and a salt thereof acceptable as a feed.

[0088] Specifically, the above-mentioned stable feed composition is used in the preparation of feed additives for pets including, but not limited to, artificially raised dogs or cats. The feed composition comprises an adjuvant acceptable as an optional feed, a prodrug of the hexahydro-β-acid compound of formula (I), a solvate thereof, and a salt thereof acceptable as a feed.

[0089] In some embodiments, the animal feed additive prepared from the above-mentioned stable feed composition is a premix, a multi-premix, an aqueous solution or a granule. The feed composition comprises an adjuvant acceptable as an optional feed, a prodrug of the hexahydro-β-acid compound of formula (I), a solvate thereof, and a salt thereof acceptable as a feed.

[0090] In some embodiments, the above-mentioned stable feed composition is used in the preparation of animal feed. The feed composition comprises an adjuvant acceptable as an optional feed, a prodrug of the hexahydro-β-acid compound of formula (I), a solvate thereof, and a salt thereof acceptable as a feed.

[0091] The feed provided herein refers to a product processed and produced by industrialization for animal consumption.

[0092] Animal feed prepared from the above-mentioned stable feed composition containing an adjuvant acceptable as an optional feed and a prodrug of the hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salt is feed for livestock, poultry, aquatic animals, pets, etc.

[0093] Specifically, the above-mentioned stable feed composition is used in the preparation of feed for livestock, and the feed composition contains an adjuvant acceptable as an optional feed and a prodrug of the hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salt. Livestock includes, but is not limited to, pigs, cows, sheep, horses, rabbits, minks, etc. at various growth stages.

[0094] Specifically, the above-mentioned stable feed composition is used in the preparation of feed for poultry, and poultry includes, but is not limited to, chickens, ducks, geese, pigeons, etc. at various growth stages. The feed composition contains an adjuvant acceptable as an optional feed and a prodrug of the hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salt.

[0095] Specifically, the above-mentioned stable feed composition is used in the preparation of feed for aquatic animals, and aquatic animals includes, but is not limited to, fish, shrimps, crabs, turtles, eels, etc. at various growth stages. The feed composition contains an adjuvant acceptable as an optional feed and a prodrug of the hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salt.

[0096] Specifically, the above-mentioned stable feed composition is used in the preparation of feed for pets, and pets includes, but is not limited to, dogs or cats raised on farms. The feed composition contains an adjuvant acceptable as an optional feed and a prodrug of the hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salt.

[0097] In some embodiments, the animal feed prepared from the above stable feed composition is a single feed, a concentrated feed, a compound feed, a multi-premix or a concentrated supplement, and the feed composition comprises an adjuvant acceptable as an optional feed, a prodrug of the hexahydro-β-acid compound of formula (I), a solvate thereof and a salt thereof acceptable as a feed.

[0098] Specifically, the compound feed is a complete compound feed.

[0099] Method for improving the productivity of farmed animals In some feeding embodiments, the above stable feed composition and the additives for the feed prepared from the feed composition are administered to animals together with the feed by farmers, greatly increasing the productivity of the animals, and the feed composition comprises an adjuvant acceptable as an optional feed, a prodrug of the hexahydro-β-acid compound of formula (I), a solvate thereof and a salt thereof acceptable as a feed.

[0100] Optionally, the feed composition is a premix of additives for the feed, a multi-premix of additives for the feed, a granule or an aqueous solution, and is administered to animals together with the feed.

[0101] In one embodiment, the feed composition is a premix of additives for the feed.

[0102] In one embodiment, the feed composition is a multi-premix of additives for the feed.

[0103] In some embodiments, the additives for the feed are a premix, a multi-premix, a granule or an aqueous solution, and are mixed with the animal feed for the animals to ingest.

[0104] The animals are livestock, poultry, aquatic animals or pets.

[0105] Specifically, livestock includes, but is not limited to, pigs, cows, sheep, horses, rabbits, minks, etc. at various growth stages; poultry includes, but is not limited to, chickens, ducks, geese, pigeons, etc. at various growth stages; aquatic animals includes, but is not limited to, fish, shrimps, crabs, turtles, eels, etc. at various growth stages; pets includes, but is not limited to, artificially bred dogs or cats.

[0106] In one embodiment, the additive for feed is administered to piglets weaned from milk together with feed by farmers, significantly increasing the average daily weight gain and feed efficiency of the weaned piglets. The additive includes a prodrug of the hexahydro-β-acid compound of formula (I), its solvate, and its feed-acceptable salt.

[0107] In one embodiment, the additive for feed prepared from the above-mentioned stable feed composition and feed composition is administered to broilers together with feed by farmers, significantly reducing the feed requirement rate and increasing the feed efficiency of the broilers. The feed composition includes an optional feed-acceptable adjuvant and a prodrug of the hexahydro-β-acid compound of formula (I), its solvate, and its feed-acceptable salt.

[0108] In one embodiment, the additive for feed prepared from the above-mentioned stable feed composition and feed composition is administered to fish together with feed. The feed composition includes an optional feed-acceptable adjuvant and a prodrug of the hexahydro-β-acid compound of formula (I), its solvate, and its feed-acceptable salt.

[0109] In one embodiment, the additive for feed prepared from the above-mentioned stable feed composition and feed composition is administered to young dogs together with feed. The feed composition includes an optional feed-acceptable adjuvant and a prodrug of the hexahydro-β-acid compound of formula (I), its solvate, and its feed-acceptable salt.

[0110] In some other feeding embodiments, the animal feed prepared from the stable feed composition described above is administered to the animals together with the feed by the farmer, significantly increasing the productivity of the animals, and the composition comprises an optional adjuvant acceptable as a feed, a prodrug of the hexahydro-β-acid compound of formula (I), its solvate and its feed-acceptable salts.

[0111] Optionally, the feed composition is a concentrated feed, a compound feed, a multi-premix or a concentrated supplement and is administered directly to the animals as animal feed.

[0112] The premix of additives for the feed, as used herein, refers to a homogeneous mixture prepared by mixing the prodrug of the hexahydro-β-acid compound provided herein, other additives for the feed, carriers and / or excipients, and the combination mainly comprises two or more nutritional additives for the feed, etc. at a specific ratio, and the nutritional additives are mineral trace elements, vitamins, microorganisms, amino acids, etc. in a content sufficient to meet the basic nutrient requirements of the animals to which they are applied at a specific physiological stage, and are added to the compound feed, concentrated supplement or drinking water for the animals in a content of 0.1% or more and 10% or less.

[0113] The concentrated feed, as used herein, refers to a feed mainly prepared by mixing proteins, minerals, feed additives, etc. at a specific ratio.

[0114] The compound feed, as used herein, refers to a feed prepared by mixing a plurality of feed components for the animals, additives for the feed, etc. at a specific ratio that meets the nutrient requirements of the animals being raised.

[0115] The concentrated supplement, as used herein, refers to a feed prepared by mixing a plurality of feed components for the animals, additives for the feed, etc. at a specific ratio that achieves the effect on the supplement for the nutrients of herbivores.

[0116] In one embodiment, the feed composition is a complete feed.

[0117] The embodiments provided herein will be described in detail below together with examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. In the examples, if specific conditions are not indicated, they shall be carried out under normal conditions or conditions recommended by the manufacturer. Here, the reagents or equipment involved are presented without the manufacturer's name, and they are all ordinary products and can be commercially purchased.

Examples

[0118] Example A: Semi-synthesis of prodrugs of hexahydro-β-acid compounds Those skilled in the art will understand that all other preparation methods of the hexahydro-β-acid compounds provided herein are considered to be within the scope of the present disclosure as defined by the appended claims. For example, the non-exemplary synthesis of the hexahydro-β-acid compounds provided herein can be carried out by those skilled in the art with modified methods, such as appropriate protection of other groups, use of other reagents, normal modification of reaction conditions, etc.

[0119] A1: Preparation of β-acid 1 kg of hop extract, 3 L of pure water and 1 L of ethanol were sequentially added to a 5 L beaker with stirring to dissolve the hop extract. 0.5 L of KOH solution was added dropwise to the reaction mixture to adjust the pH to 13, allowed to stand for a while, then filtered to remove insoluble substances. CO2 gas was pumped into the filtrate to obtain a pH of 8.5, cooled, allowed to stand for 2 hours, and then filtered to collect the crude product.

[0120] The above crude product was dissolved in 200 mL of n-hexane, and the thus obtained organic solution was washed with water (150 mL × 3), then concentrated to obtain a paste. Subsequently, the paste was dissolved in 300 mL of KOH solution at pH 12.5. The thus obtained mixture was washed with n-hexane (200 mL × 3), and the organic phase was discarded. Acid was added to the thus obtained aqueous phase to adjust the pH to 8.5, and extraction was performed with n-hexane (200 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated by vacuum evaporation to obtain 400 g of β-acid crystals. HPLC analysis of the results showed that the β-acid crystals mainly contained coprosterone, adrosterone, and lupron.

[0121] A2: Preparation of hexahydro-β-acid 50 g of β-acid crystals were dissolved in 300 mL of 95% ethanol solution, and subsequently 1.7 g of 10% Pd / C was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by HPLC until the endpoint. The reaction solution was filtered, and the filtrate was concentrated to obtain 46 g of hexahydro-β-acid as crystals.

[0122] A3: Separation and purification of the main components of hexahydro-β-acid A3.1 Preparation of hexahydro-coprosterone

Chemical formula

[0123] A3.2: Preparation of hexahydro-lupron

Chemical formula

[0124] A3.3: Preparation of Hexahydro-adolprom

Chemical formula

[0125] A4: Preparation of Prodrug of Hexahydro-β-acid Compound A4.1: Preparation of Hexahydro-corpromonoacetate

Chemical formula

[0126] A4.2: Preparation of hexahydro-corpion monopropionate

Chemical formula

[0127] A4.3: Preparation of hexahydro-corpion monobutyrate

Chemical formula

[0128] A4.4: Preparation of hexahydro-coprone dipropionate

Chemical formula

[0129] A4.5: Preparation of hexahydro-coprone dibutyrate

Chemical formula

[0130] A4.6: Preparation of hexahydro-adolpropone monopropionate

Chemical formula

[0131] A4.7: Preparation of hexahydro-adolpropone monobutyrate [Chemistry] Dissolve 2.5 g (5.94 mmol, 1.0 equivalent) of hexahydro - adrenalone in 15 mL of dichloromethane, and then add 0.72 g (7.13 mmol, 1.2 equivalents) of triethylamine; cool the mixture to -5 °C to 0 °C while stirring. Dissolve 0.76 g (7.13 mmol, 1.2 equivalents) of butyryl chloride in 8 mL of dichloromethane and slowly add dropwise to the reaction system. Warm the thus - obtained reaction system to room temperature and monitor the reaction by thin - layer chromatography until the endpoint. Add 6 mL of pure water to the reaction system, separate the organic phase after stirring, wash with water (30 mL×3), dry over anhydrous sodium sulfate, concentrate by vacuum evaporation to remove the organic solvent, and obtain 1.45 g of an oily product in a yield of 49.6%.

[0132] A4.8: Preparation of hexahydro - adrenalone dipropionate [Chemistry] Place 2.5 g (5.94 mmol, 1.0 equivalent) of hexahydro - adrenalone in a 50 - mL dry reaction flask. Release oxygen and moisture with nitrogen, and sequentially add 25 mL of n - heptane and 0.15 g (0.82 mmol, 0.14 equivalent) of 4 - dimethylaminopyridine to the container. Cool the reaction system to 0 °C, and then sequentially add dropwise 1.32 g (14.26 mmol, 2.4 equivalents) of propionyl chloride and 1.44 g (14.26 mmol, 2.4 equivalents) of triethylamine to the reaction system. Stir the thus - obtained reaction system and monitor the reaction by thin - layer chromatography until the endpoint. Filter the thus - obtained reaction solution to remove triethylamine hydrochloride, then concentrate by vacuum evaporation to remove the solvent and obtain a yellow oily crude product. Subject the crude product to silica gel column chromatography (dichloromethane / methanol (w / w)=10 / 1) to obtain 1.42 g of hexahydro - adrenalone dipropionate in a yield of 44.9%.

[0133] A4.9: Preparation of Hexahydro-adelproterone Dibutyrate

Chem.

[0134] A4.10: Preparation of Hexahydro-corpterone Monodecanoate

Chem.

[0135] A4.11: Preparation of Hexahydro-corpionmonolaurate

Chem.

[0136] Example B: Preparation of a Feed Composition of a Prodrug of a Hexahydro-β-Acid Compound In the feed composition provided herein, the content of the prodrug of the hexahydro-β-acid compound is 0.00001% or more, and can be adjusted by the necessity of animals for nutrients at various growth stages or the usefulness of the characteristics of products in the feed industry (for example, additives for feeds, components for feed additives, components for feeds), and can also be adjusted by the weight ratio of other nutrients and non-nutrients in different feed formulations to meet the requirements of the feed formulation. The feed composition herein will be further described below with a basic granule premix as an example. However, the components of the formulation or any replacement or addition of any similar formulation are considered to be in line with the objectives of the present invention, and the components of the formulation are used to achieve a non-synergistic effect on each other.

[0137] Method for preparing the feed composition: The components and adjuvants were evenly mixed in a mixer. The mixture thus obtained in a ratio of 100:35 and an aqueous solution of 1.3 (wt)% hydroxypropyl methylcellulose were put into a pellet mill, and the mixing and cutter process were carried out for 3 to 5 minutes. After pellet forming was completed, the product was dried in a fluidized bed for 30 minutes and then passed through a 16-mesh sieve. Component: Prodrug of the hexahydro-β-acid compound prepared in Example A Adjuvant (carrier): Corn starch Formulation: As shown in Table 1

[0138]

Table 1

[0139] Example C: Study on the thermal stability and photostability of the prodrug of the hexahydro-β-acid compound 1: Materials Equipment and reagents: Drug stability test chamber; High-performance liquid chromatography (HPLC); Methanol (chromatography grade); Phosphoric acid (for analysis). Components for the test: hexahydro-coprone; hexahydro-coprone monoacetate; hexahydro-coprone monopropionate; hexahydro-coprone monobutyrate.

[0140] 2: Experiment 2.1: Preparation of samples and experimental methods Preparation of 1% premix samples of 1 component: 1 g of each 1 component was weighed out and evenly mixed with 99 g of corn cob meal in a mixer to obtain a 1% premix of 1 component for the test samples.

[0141] Thermal stability test at 60 °C: Samples of 1 component and its 1% premix were each spread on a Petri dish to form a thin layer of ≤5 mm and held at 60 °C. Two replicates for each sample were carried out in parallel on the 5th and 10th days for HPLC analysis. The results are shown in Table 2.

[0142] Photo-stability test: Samples of 1 component and its 1% premix were each spread on a Petri dish to form a thin layer of ≤5 mm and held under illumination of 4500 Lx. Sampling was carried out in parallel on the 5th and 10th days for HPLC analysis for three replicates of each sample. The results are shown in Table 2.

[0143] 2.2: Preparation of standard solutions 25.0 mg of 1 component was accurately weighed out and dissolved in an appropriate amount of methanol by sonication. Then the solution was transferred to a volumetric flask and diluted to 25 mL with methanol to obtain a stock solution. Samples from the stock solution were diluted with methanol to the concentrations of 100 ppm, 500 ppm and 1000 ppm working solutions respectively, and then the working solutions were filtered through a 0.22 μm organic membrane. Linearity was adjusted, detected between the concentration of the sample and the response value of its HPLC peak area to obtain a standard curve.

[0144] 2.3: Preparation of sample solutions Samples of 25.0 mg of the single component and 2.0000 g of its 1% premix were accurately weighed out and dissolved in 25 mL of methanol by sonication for 10 minutes. The solutions thus obtained were filtered through an organic membrane and then analyzed by HPLC.

[0145] 2.4: Test Conditions for HPLC Column: Symmetry C 18 Column (Waters; 250 mm * × 4.6 mm, 5 μm). Mobile phase: 0.02% phosphoric acid: methanol = 5:95 (v:v). Wavelength: 235 nm. Column temperature: 25 °C. Injection volume: 10 μL. Flow rate: 1 mL / min.

[0146] 3: Results As shown in Table 2, the change in hexahydro-coprone as the active ingredient of the 1% premix was more than 5% during the 10-day test period of the thermal stability test at 60 °C and more than 15% on the 10th day of the photo-stability test. Regardless of whether it was as the single component or as the active ingredient in the premix, the change in each of hexahydro-coprone monoacetate, monopropionate and monobutyrate was 5% or less in both the thermal stability test and the photo-stability test. The short-chain aliphatic acid ester derivatives were shown to achieve the effects of thermal stability and photo-stability and meet the requirements for additives for feed.

[0147] [Table 2]

[0148] Example D: Study on the Long-Term Stability of the Prodrug of Hexahydro-β-Acid Compound in Feed 1: Materials Equipment and Reagents: Drug Stability Test Chamber; High Performance Liquid Chromatography (HPLC); Methanol (Chromatography Grade); Phosphoric Acid (for Analysis); n-Hexane (Chromatography Grade); Isopropanol (Chromatography Grade).

[0149] Components for the Test: Hexahydro-coprone; Hexahydro-coprone monoacetate; Hexahydro-coprone monopropionate; Hexahydro-coprone monobutyrate; Hexahydro-coprone monopentaenoate (provided by the Chemical Department of Guangzhou Insighter Biotechnology Co., Ltd); Hexahydro-coprone monohexanoate (provided by the Chemical Department of Guangzhou Insighter Biotechnology Co., Ltd); Hexahydro-coprone monolaurate; Disodium salt of hexahydro-coprone monophosphate (provided by the Chemical Department of Guangzhou Insighter Biotechnology Co., Ltd); Diethyl ester of hexahydro-coprone monophosphate (provided by the Chemical Department of Guangzhou Insighter Biotechnology Co., Ltd).

[0150] Feeds: Premixed feed of ZUSF (a mixture of ground Feed A and ground Feed B at a weight ratio of 2:1, where Feed A is a multi-premixed feed for piglets from ZUSF's Hao-Ru-Zhen-Jing, and B is a multi-premixed feed for piglets from ZUSF's Hao-Ru-Zhen-Jing at 2.67%); Starter feed for piglets from CP FEED; Feed of INSIGHTER for broilers; 4% Premixed feed from GUANGDONG CO-POWER.

[0151] 2: Experiment 2.1: Sample Preparation and Experimental Method Preparation of 1% premix samples of the components: Weighed out 1 g of each of the 1 component and mixed it evenly with 99 g of corn cob meal in a mixer to obtain a 1% premix sample of the 1 component.

[0152] Preparation of 500 ppm feed samples of the 1 component: The 1% premix sample of the 1 component was serially diluted to 5000 ppm and 500 ppm using the pre-mixed feed of ZUSF to obtain a 500 ppm feed sample of the 1 component for subsequent tests.

[0153] Preparation of 100 ppm feed samples of the 1 component: The 1% premix sample of the 1 component was serially diluted to 1000 ppm and then 100 ppm using the feeding feed for piglets from CP FEED to obtain a 100 ppm feed sample of the 1 component for subsequent tests.

[0154] Preparation of 100 ppm feed samples of the 1 component: The 1% premix sample of the 1 component was serially diluted to 1000 ppm and 100 ppm using the feed of INSIGHTER for broilers to obtain a 100 ppm feed sample of the 1 component for subsequent tests.

[0155] Preparation of 2000 ppm feed samples of the 1 component: The 1% premix sample of the 1 component was serially diluted to 5000 ppm and 2000 ppm using the 4% pre-mixed feed from GUANGDONG CO-POWER to obtain a 2000 ppm feed sample of the 1 component for subsequent tests.

[0156] Method: Each feed sample was replicated 3 times under the conditions of 25°C ± 2°C and RH 60% ± 10%. For each replication of each feed sample, sampling was carried out in parallel on the 5th, 10th, 15th, 30th, 60th, and 90th days for HPLC analysis. The results are shown in Table 3.

[0157] 2.2: Preparation of the standard solution The 25.0 mg component was accurately weighed and dissolved in an appropriate amount of methanol or n-hexane by sonication. Then, the solution was transferred to a volumetric flask and diluted to 50 mL to obtain a stock solution of 500 ppm (wt). Samples from the stock solution were each diluted with methanol or n-hexane to working solutions with concentrations of 10 ppm, 25 ppm, 50 ppm, 100 ppm, and 250 ppm. Subsequently, the working solutions were filtered through a 0.22 μm organic membrane. Linearity was adjusted, detected, and a standard curve was obtained between the concentration of the sample and the response value of its HPLC peak area.

[0158] 2.3: Preparation of Sample Solution 5.0000 g of the samples sampled at different time intervals were each accurately weighed and dissolved in 25 mL of methanol or n-hexane by sonication for 10 minutes. The solutions thus obtained were filtered through an organic membrane and then analyzed by HPLC.

[0159] 2.4: Test Conditions for HPLC Reverse-Phase Chromatography: Equipment: Waters e2695 with a PDA detector. Mobile Phase: 0.02% Phosphoric Acid: Methanol = 5:95 (v:v). Column: Symmetry C 18 Column (Waters; 250 mm × 4.6 mm, 5 μm). Wavelength: 235 nm. Column Temperature: 25 °C. Injection Volume: 10 μL. Flow Rate: 1 mL / min.

[0160] Normal-Phase Chromatography: Equipment: Shimadzu LC-14C / SPD-15C. Column: SuperSil NH2 Column (5 μm; 250 mm × 4.6 mm). Mobile Phase: n-Hexane: Isopropanol = 60:40 (v:v). Wavelength: 235 nm. Column Temperature: 25 °C. Injection Volume: 20 μL. Flow rate: 1 mL / min.

[0161] 3: Results As shown in Table 3, during the test period, the content of hexahydro-coprostanone in the feed for 30 days decreased substantially, and the content of the phosphate derivative of hexahydro-coprostanone in the feed decreased substantially at the beginning of the test. The aliphatic esterified derivatives of hexahydro-coprostanone maintained good stability at room temperature, and the stabilities of hexahydro-coprostanone monoacetate, monopentanoate, and monohexanoate were relatively poor in some of the feeds.

[0162] [Table 3]

[0163] Example E: Effect of the prodrug of the hexahydro-β-acid compound on the productivity of pigs 480 67-day-old Duroc × Landrace × Yorkshire crossbred bacon-type piglets with similar body weights were randomly divided into 16 groups, with 3 replicates for each group, 10 piglets for each replicate, and the same number of males and females. The pigsty and tools were sterilized before the experiment. In the experiment, the piglets were kept in separate areas of the same pigsty under the same feeding and management conditions, given feed and water freely, and fed twice a day. The groups were known as the control group (Group 1) and test groups 2 - 16. The piglets in the control group were given only the basic formulated feed, while the piglets in test groups 2 - 16 were given the basic formulated feed mixed with different additives, and the active ingredient of the additive was the hexahydro-β-acid compound or the prodrug of the hexahydro-β-acid compound provided in this specification. As shown in Table 4, its content in the feed was 5 ppm or 25 ppm.

[0164] The experiment lasted for 14 days. During the experiment, no other antioxidants or growth promoters were given to each test group. On the 14th day, each test group was not given feed other than water for 12 hours, and each piglet in each replicate of the experiment was weighed to calculate the average daily feed intake (ADFI, g / d per piglet), average daily weight gain (ADG, g / d per piglet), and feed conversion ratio (FCR). Average daily feed intake = (total weight of feed provided - weight of remaining feed) / (number of days of experiment × number of piglets in each replicate) Average daily weight gain = (final average weight - initial average weight) / number of days of experiment Feed conversion ratio = average daily feed intake / average daily weight gain The results are shown in Table 4.

[0165]

Table 4

[0166] As shown in Table 4, the effects of the test samples on the productivity of piglets were evaluated in terms of three factors: feed intake, weight gain, and feed efficiency. The feed intake of piglets in the group of ester derivatives of hexahydro-corpolone or hexahydro-adrenalone increased compared to that of piglets in the control group, hexahydro-corpolone group, or hexahydro-adrenalone group. At the same content in the feed, the monoacetate derivatives, monopropionate derivatives, and monobutyrate derivatives of hexahydro-corpolone or hexahydro-adrenalone achieved substantially the same or better effects on the feed conversion ratio of piglets compared to that of piglets in the hexahydro-corpolone or hexahydro-adrenalone group. However, the effects of the monohexanoate, monodecanoate, and monolaurate of hexahydro-corpolone on the ability of piglets were probably not as significant as those of its monoacetate and monobutyrate due to the incomplete or slow hydrolysis of these ester compounds in the intestinal tract of animals.

[0167] Example F: Effect of prodrugs of hexahydro-β-acid compounds on the productivity of broilers Experiments were conducted using a single factor. 540 one-day-old yellow broilers with a similar average weight of 50 g were randomly divided into 6 groups, with 6 replicates for each group. There were the same number of males and females, and 15 yellow broilers for each replicate. The chicken coop and tools were sterilized before the experiment. During the experiment, the broilers were kept in separate areas of the same chicken coop under the same feeding and management conditions. During the experiment, each test group was given a basic formulated feed consisting of corn and soybean, and no other antioxidants or growth promoters were given. The groups were known as the control group (Group 1) and test groups 2 - 6. As shown in Table 5, the control group was given only the basic formulated feed, while test groups 2 - 6 were given the basic formulated feed mixed with hexahydro-corpion, hexahydro-corpion monoacetate, or hexahydro-corpion monobutyrate, respectively.

[0168] The experiment lasted for 30 days. The broilers were given feed and water freely and fed twice a day. To calculate the average daily feed intake (ADFI, g / d per broiler), average daily weight gain (ADG, g / d per broiler), and feed conversion ratio (FCR), the 31-day-old broilers of each replicate were weighed as a single unit (12 hours without feed other than water), and the amount of feed consumed was counted accordingly. Feed conversion ratio (FCR) = average daily feed intake / average daily weight gain The results were as shown in Table 5.

[0169]

Table 5

[0170] As shown in Table 5, the effects of the test samples on broiler productivity were evaluated in terms of three factors: feed intake, weight gain, and feed efficiency. The effects of hexahydro-corpion monoacetate and monobutyrate on broiler productivity achieved were equal to those of hexahydro-corpion.

[0171] Industrial applicability The prodrugs of hexahydro-coprone and / or hexahydro-adolprone provided herein have achieved an effect on animal productivity that is substantially the same as that of hexahydro-coprone and / or hexahydro-adolprone. Using the prodrugs of hexahydro-coprone and / or hexahydro-adolprone provided herein as an active ingredient in a feed composition not only avoids problems of hexahydro-β-acid compounds, such as poor thermal stability during the feed pellet forming process and poor stability during long-term storage, but also achieves an effect on productivity that is substantially equal to that of the hexahydro-β-acid compounds.

Claims

1. A prodrug of a hexahydro-β-acid compound or a solvate thereof or a pharmaceutically acceptable salt thereof, represented by formula (I): 【Chemical Formula 1】 (In the formula, R ３ is selected from H, R １ is selected from methyl, R ２ is selected from C(=O)CH ２ CH3) A prodrug of a hexahydro-β-acid compound or a solvate thereof or a pharmaceutically acceptable salt thereof.

2. A feed composition comprising an optional pharmaceutically acceptable adjuvant and the prodrug according to claim 1 or a solvate thereof or a pharmaceutically acceptable salt thereof.

3. The feed composition according to claim 2, further comprising additional additives for animal feed and / or animal feed ingredients.

4. The feed composition according to claim 3, wherein the additional additives are nutritional additives, non-nutritional additives, pharmaceutical additives for feed or combinations thereof.

5. Use of the prodrug according to claim 1 or the feed composition according to any one of claims 2 to 4 in the preparation of additives for animal feed.

6. Use of the prodrug according to claim 1 or the feed composition according to any one of claims 2 to 4 in the preparation of animal feed.

7. A method for increasing the productivity of an animal, comprising feeding the animal with the feed composition according to any one of claims 2 to 4 or feeding the animal with a feed comprising the feed composition according to any one of claims 2 to 4.

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