WO2022022752A1 - 六氢-β-酸组分化合物的前体化合物、饲用组合物及其应用 - Google Patents

六氢-β-酸组分化合物的前体化合物、饲用组合物及其应用 Download PDF

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WO2022022752A1
WO2022022752A1 PCT/CN2021/120638 CN2021120638W WO2022022752A1 WO 2022022752 A1 WO2022022752 A1 WO 2022022752A1 CN 2021120638 W CN2021120638 W CN 2021120638W WO 2022022752 A1 WO2022022752 A1 WO 2022022752A1
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Prior art keywords
feed
hexahydro
compound
acid component
hexahydrolupulone
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PCT/CN2021/120638
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English (en)
French (fr)
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彭险峰
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源至技术有限公司
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Priority to CA3198485A priority Critical patent/CA3198485A1/en
Priority to MX2023005630A priority patent/MX2023005630A/es
Priority to KR1020237015891A priority patent/KR20230084296A/ko
Priority to EP21848769.2A priority patent/EP4209481A1/en
Priority to JP2023527418A priority patent/JP2023548235A/ja
Priority to AU2021317552A priority patent/AU2021317552A1/en
Priority to IL302682A priority patent/IL302682A/en
Publication of WO2022022752A1 publication Critical patent/WO2022022752A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/16—Acetic acid esters of dihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/28—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with dihydroxylic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/60—Feeding-stuffs specially adapted for particular animals for weanlings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/80—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present application relates to the field of animal feed additives, in particular to a precursor compound of a hexahydro-beta-acid component compound and a feed composition comprising the precursor compound of the hexahydro-beta-acid component compound and its application.
  • Hop acid is an organic acid derived from hops, including ⁇ -acid and ⁇ -acid, which has the biological effect of bactericidal, bacteriostatic or changing metabolites, and can be used as a substitute for antibiotics in animal feed in the field of animal breeding. Among them, ⁇ -acid has stronger antibacterial activity. Hop acid has poor stability and solubility. In the past, it was usually added to animal feed for mixing, or prepared into a 1% concentration of potassium salt solution, sprayed and wrapped in feed or mixed for use. These forms of use are in It is extremely inconvenient to use in animal breeding and production.
  • hexahydrogenated ⁇ -acid and its metal salt referred to as hexahydro- ⁇ -acid
  • hexahydro- ⁇ -acid hexahydrogenated ⁇ -acid and its metal salt
  • the instability is due to the destabilization of hexahydrolupulone resulting in a decrease in the content of hexahydro-beta-acid in the feed.
  • the inventors have further found that the direct application of hexahydrolupulone or the composition of hexahydrolupulone and hexahydrolupulone is used as a mixture in aquaculture. Excellent efficacy in improving animal performance.
  • the content of active ingredients decreases during storage, which affects the use of products in aquaculture.
  • Objects of the present application include providing a precursor compound of a hexahydro-beta-acid component compound.
  • the object of the present application also includes providing a feed composition comprising a precursor compound of the hexahydro-beta-acid component compound.
  • the purpose of the present application also includes providing the precursor compound of the hexahydro-beta-acid component compound and the application of the feed composition thereof in the preparation of animal feed additives.
  • the purpose of the present application also includes the provision of precursor compounds of the hexahydro-beta-acid component compounds and the application of the feed compositions thereof in the preparation of animal feed.
  • the present application also aims to provide a method for improving animal production performance.
  • the present application provides a precursor compound of a hexahydro-beta-acid component compound whose structure is shown in formula (I), or a solvate thereof and a feed-acceptable salt thereof, wherein R in formula (I) 1 is substituted or unsubstituted linear or branched alkyl; R 2 or R 3 is independently selected from H or substituted or unsubstituted linear or branched aliphatic carbonyl.
  • the present application also provides a feed composition
  • a feed composition comprising a precursor compound of a hexahydro- ⁇ -acid component compound whose structure is represented by formula (I), or a solvate thereof At least one of salts acceptable to food and feedstuffs and optional feedstuffs.
  • the present application also provides a precursor compound of a hexahydro- ⁇ -acid component compound whose structure is shown in formula (I), or a solvate thereof and a feed-acceptable salt thereof, and a compound having a structure such as formula ( The application of the precursor compound of the hexahydro- ⁇ -acid component compound shown in I), or the solvate thereof and the feed composition of the feed acceptable salt, in the preparation of animal feed additive.
  • the present application also provides a precursor compound of a hexahydro- ⁇ -acid component compound whose structure is shown in formula (I), or a solvate thereof and a feed-acceptable salt thereof, and a compound having a structure such as formula ( The application of the precursor compound of the hexahydro- ⁇ -acid component compound shown in I), or the solvate thereof and the feed composition of the feed-acceptable salt, in the preparation of animal feed.
  • the present application also provides a method for improving animal production performance, comprising: carrying out the process with the precursor compound of the hexahydro-beta-acid component compound of the present application, or a solvate thereof and a feed-acceptable salt thereof.
  • Animal feeding alternatively, animal feeding is carried out with the feed composition of the present application; alternatively, animal feeding is carried out with the feed comprising the feeding composition of the present application.
  • the fatty acid esterified precursor compound of the hexahydro-beta-acid component compound has good stability under high temperature conditions, which overcomes the fact that the hexahydro-beta-acid component compound undergoes high temperature granulation in the feed processing process The problem of degradation of active ingredients caused by time.
  • the present invention also found the hexahydro-beta-acid component compound propionate or butyrate in the fatty acid esterification precursor compound of the hexahydro-beta-acid component compound and a feed-acceptable salt thereof Or the solvate can not only withstand the high temperature history of feed processing, but also has basically the same effect as the hexahydro-beta-acid component compound when applied in aquaculture.
  • the compound involved in the present invention is a precursor compound of a hexahydro-beta-acid component compound whose structure is represented by formula (I).
  • R 1 is a substituted or unsubstituted linear or branched alkyl
  • R 2 and R 3 are independently selected from H and substituted or unsubstituted linear or branched aliphatic carbonyl.
  • R 1 is selected from substituted or unsubstituted C 1 -C 2 alkyl
  • R 2 and R 3 are independently selected from H and substituted or unsubstituted linear or branched C 3 -C 4 carbonyl.
  • hexahydro-beta-acid component compound involved in the present invention refers to the main components contained in the hexahydro-beta-acid, specifically hexahydrolupulone (I1-1), hexahydrolupulone (I1-1), hexahydrolupulone ( I1-2) and hexahydrolupulone (I1-3), the specific structure is shown in the following formula:
  • substituted means that one or more substitutable hydrogen atoms in a given structure are replaced by a specific substituent, and a substituted group may have a substituent at each substitutable position of the group. , when more than one position in a given formula can be substituted by one or more substituents of a particular group, the substituents may be substituted identically or differently at each position.
  • C a -C b alkyl represents a straight-chain or branched saturated alkyl group containing a to b carbon atoms, such as methyl, ethyl, propyl, isopropyl, ... , such as "C 3 -C 4 alkyl” is a linear or branched saturated alkyl group containing 3 to 4 carbon atoms.
  • R 1 in the precursor compound of the hexahydro- ⁇ -acid component compound represented by formula (I) is CH 3
  • R 2 and R 3 are independently selected from H and substituted or non- Substituted straight or branched C 3 -C 4 carbonyl.
  • R 2 and R 3 are independently selected from H or unsubstituted linear C 3 -C 4 carbonyl, preferably not H at the same time.
  • the R 3 is H, and R 2 is an unsubstituted linear C 3 -C 4 carbonyl group.
  • said R 2 and R 3 are independently selected from unsubstituted linear C 3 -C 4 carbonyl, preferably R 2 and R 3 are selected from the same unsubstituted linear C 3 -C 4 carbonyl.
  • R 1 in the precursor compound of the hexahydro- ⁇ -acid component compound represented by formula (I) is CH 2 CH 3
  • R 2 and R 3 are independently selected from H and substituted or unsubstituted straight or branched C 3 -C 4 carbonyl.
  • R 2 and R 3 are independently selected from H or unsubstituted linear C 3 -C 4 carbonyl, preferably not H at the same time.
  • the R 3 is H, and R 2 is an unsubstituted linear C 3 -C 4 carbonyl group.
  • said R 2 and R 3 are independently selected from unsubstituted linear C 3 -C 4 carbonyl, preferably R 2 and R 3 are selected from the same unsubstituted linear C 3 -C 4 carbonyl.
  • the precursor compounds of the hexahydro-beta-acid component compounds of the present invention include:
  • the preparation of the precursor compound of the hexahydro- ⁇ -acid component compound represented by the formula (I) involved in the present invention includes the following process:
  • the hexahydro- ⁇ -acid is prepared by recrystallization method or chromatographic separation method to obtain different hexahydro- ⁇ -acid component compounds, and the hexahydro- ⁇ -acid component compound is specifically six Hydrolupulone (I1-1), Hexahydrolupulone (I1-2) and Hexahydrolupulone (I1-3);
  • the hexahydro- ⁇ -acid component compound is combined with a substituted or unsubstituted linear or branched fatty acid to undergo an esterification reaction to obtain a precursor compound of the hexahydro- ⁇ -acid component compound, and the esterification reaction includes Combined with one stoichiometric or two stoichiometric substituted or unsubstituted linear or branched fatty acids.
  • Hexahydro-beta-acid component compounds have asymmetric centers and can be racemates, racemates, stereoisomers, geometric isomers, tautomers, single enantiomers, single diastereomers It exists in the form of isomers and diastereomers, and it is clear that the forms of the precursor compounds of the hexahydro- ⁇ -acid component compounds obtained by these isomers through the above step (4) are included in the present application.
  • the hexahydro- ⁇ -acid component compound can be obtained through commercial channels in addition to semi-synthetic preparation or total synthesis by chemists with ordinary skills by extracting raw materials from plants.
  • the present invention provides processes for the preparation of precursor compounds of the hexahydro-beta-acid component compounds that also involve isolation, purification, or recrystallization of the reaction product.
  • the reaction product can be obtained as a crude product from the reaction system by desolventizing method.
  • the crude product is dissolved and analyzed in alcohol solvent, alcohol-water mixed solvent or other organic solvent that can be used for product recrystallization under suitable temperature, light, mechanical vibration and other conditions. Crystallization or precipitation or recrystallization and separation to obtain the precursor compound of the hexahydro-beta-acid component compound having a certain crystal state.
  • the precursor compound of the hexahydro-beta-acid component compound having a certain crystal state is the precursor compound of the hexahydro-beta-acid component compound or the precursor compound of the hexahydro-beta-acid component compound Solvate.
  • the solvate of the precursor compound of the hexahydro-beta-acid component compound can be selected from the hydrate of the precursor compound of the hexahydro-beta-acid component compound or the hydrate of the hexahydro-beta-acid component compound. Ethanolates of precursor compounds.
  • solvate refers to the formation of the compound of the present invention in the process of contacting solvent molecules, external conditions and internal conditions, resulting in the combination of stoichiometric or non-stoichiometric solvent molecules through non-covalent intermolecular forces. of co-crystal associates.
  • Solvates that form solvates include, but are not limited to, water, acetone, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, isopropanol, and the like.
  • Hydrophilicity refers to an association or crystal formed by the solvent molecule being water, that is, a compound that binds a stoichiometric or non-stoichiometric amount of water through non-covalent intermolecular forces.
  • the preparation of the precursor compound of the hexahydro- ⁇ -acid component compound provided by the present invention can also be processed by a salting-out method in order to obtain a solid substance with higher chemical purity and lower impurity content.
  • the described salting-out method is a process in which the acid-base neutralization method, the acid-base coordination method or the acid-base chelation method are used to make the amino acid derivatives and the corresponding organic bases, inorganic bases, organic acids or inorganic acids to form salts and precipitate.
  • the inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid or their combination;
  • the organic bases include but are not limited to ammonia or triethylamine.
  • the inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide.
  • Feed-acceptable salts are salts of precursor compounds of the hexahydro-beta-acid component compounds of the present invention with organic bases, inorganic bases, organic acids or inorganic acids that are nontoxic to animals.
  • feed acceptable is meant that the substance or composition must be chemically or toxicologically suitable in relation to the composition of the feed or the farmed animal for consumption.
  • the post-treatment of the precursor compounds of the hexahydro-beta-acid component compounds of the present invention also involves the formation of acid-base complex salts and/or acid-base chelates with inorganic or organic acids during salting-out precipitation Combined salts
  • 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, galacturonic acid, citric acid, tartaric acid, aspartic acid, glutamic acid, benzoic acid, p-toluic acid, cinnamic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethyl acetate sulfonic acid, trifluoromethanesulfonic acid
  • the precursor compounds of the hexahydro-beta-acid component compounds provided by the present invention and their solvates or feed-acceptable salts are used in the preparation of animal feed additives.
  • the "animal” involved in the present invention refers to a person or a breeder who cannot synthesize inorganic matter into organic matter, and can only use organic matter as food for life activities such as ingestion, digestion, absorption, respiration, circulation, excretion, sensation, movement and reproduction. animal.
  • "Farmed animals” include poultry, livestock, aquaculture animals, and other animals that are legally captured in captivity, including pets, such as cats and dogs.
  • livestock is, for example, any of pigs, cattle, horses, goats, sheep, deer and many useful rodents.
  • the term “poultry” is intended to include, for example, chickens, ducks, geese, quails, pigeons, and the like.
  • aquaculture animals includes, for example, fish, shrimp, turtles, soft-shelled turtles, and the like.
  • the precursor compounds of the hexahydro-beta-acid component compounds provided by the present invention and their solvates or feed-acceptable salts are prepared as non-nutritive additives for improving animal production performance of animals at various growth stages.
  • the animals may be selected from livestock, poultry, aquaculture animals or pets of various growth stages.
  • the livestock include but are not limited to pigs, cattle, sheep, horses, rabbits, minks or donkeys
  • the poultry includes but are not limited to chickens, turkeys, ducks, geese, quails or pigeons
  • the aquatic products Farmed animals include but are not limited to fish, shrimp, turtles, crabs, soft-shelled turtles, bullfrogs, eels or loaches
  • the pets include but are not limited to dogs or cats of various subspecies.
  • the precursor compound of the hexahydro-beta-acid component compound provided by the present invention and its solvate or feed-acceptable salt are used to prepare a feed additive for improving the production performance of hogs. improved feed intake, average daily gain or feed conversion ratio.
  • the feed additive prepared by using the precursor compound of the hexahydro-beta-acid component compound provided by the present invention and its solvate or feed-acceptable salt can significantly improve the production performance of broilers or laying hens .
  • the use of the precursor compounds of the hexahydro-beta-acid component compounds provided by the present invention and their solvates or feed-acceptable salts is a feed additive for improving the production performance of fish.
  • a kind of precursor compound comprising the hexahydro-beta-acid component compound represented by formula (I), or a solvate thereof, and at least one of feed-acceptable salts and optional feed adjuvants
  • the feed adjuvant is one or a combination of one or more selected from a feed carrier, a diluent, an excipient, and a vehicle.
  • composition refers to a compound collective comprising one or more than one compound constituting an active ingredient.
  • the feed composition provided in this application does not contain hexahydrolupulone or its salts and esters.
  • other hexahydro- ⁇ -acid component compounds or their salts and esters are not included (except for unavoidable small amounts of other hexahydro-beta-acid component compounds as impurities).
  • a “stable feedable composition” means one that is stable enough to allow production and maintains the integrity of the compound for a period of time sufficient to be available for consumption by animals for the purposes detailed herein. Compositions.
  • the “carrier” referred to in this application refers to a feedable substance that can carry the active ingredient, improve its dispersibility, and have good chemical stability and adsorption, and is an organic carrier and an inorganic carrier.
  • the organic carrier is a material containing a lot of crude fiber, including but not limited to corn flour, corncob flour, wheat bran, rice husk flour, defatted rice bran, traditional bran, corn stalk flour or peanut husk flour.
  • the inorganic carriers are minerals, which are mainly divided 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 or seafoam. stone.
  • the "diluent” referred to in this application refers to a substance that evenly distributes the additive raw material in the material, and dilutes the high-concentration additive raw material into a low-concentration premix or premix, which can separate the trace components from each other and reduce active ingredients. The interaction between them is to increase the stability of the active ingredients without affecting the physicochemical properties of the related substances, and is an organic diluent and an inorganic diluent.
  • Organic diluents include, but are not limited to, corn flour, degerminated corn flour, dextrose (glucose), sucrose, semolina with bran, sautéed soybean meal, sub-flour, corn gluten meal, etc.; inorganic diluents include, but are not limited to Limited to limestone, calcium dihydrogen phosphate, shell powder, kaolin (white clay), table salt or sodium sulfate.
  • Described excipient includes the wetting agent that is selected from the wetting agent that induces the inherent viscosity of the material itself, the adhesive that makes the material stick together, and the disintegrating agent that breaks the whole sheet of the material into many fine particles,
  • retention aids that reduce friction between particles and anti-sticking agents that prevent material sticking, including but not limited to magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, Starch slurry, water, inorganic salts, dextrin or powdered sugar.
  • vehicle refers to the solvent required to dissolve or disperse the solid, including but not limited to water, glycerol or ethanol.
  • the precursor compound of the hexahydro-beta-acid component compound contained in the feed composition is the precursor compound of hexahydrolupulone, or a solvate thereof, or a feed can Accepted salt.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is hexahydrolupulone monopropyl ester whose structure is shown in formula (I2-1), or a solvate thereof, or a feed-acceptable salt thereof.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is hexahydrolupulone monobutyl ester whose structure is shown in formula (I2-2), or a solvate thereof, or a feed-acceptable salt thereof.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is hexahydrolupulone dipropyl ester whose structure is shown in formula (I2-5), or a solvate thereof, or a feed-acceptable salt thereof.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is hexahydrolupulone dibutyl ester whose structure is shown in formula (I2-6), or a solvate thereof, or a feed-acceptable salt thereof.
  • the precursor compound of the hexahydro-beta-acid component compound contained in the feed composition is the precursor compound of hexahydrolupulone, or a solvate thereof, or a feed can Accepted salt.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is hexahydrolupulone monopropyl ester whose structure is shown in formula (I2-3), or a solvate thereof, or a feed-acceptable salt thereof.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is hexahydrolupulone monobutyl ester whose structure is shown in formula (I2-4), or a solvate thereof, or a feed-acceptable salt thereof.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is hexahydrolupulone dipropyl ester whose structure is shown in formula (I2-7), or a solvate thereof, or a feed-acceptable salt thereof.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is hexahydrolupulone dibutyl ester whose structure is shown in formula (I2-8), or a solvate thereof, or a feed-acceptable salt thereof.
  • the precursor compound of the hexahydro-beta-acid component compound contained in the feed composition is a hexahydrolupulone precursor compound, or a solvate thereof, or a feed-acceptable compound thereof. salt, in combination with a hexahydrolupulone precursor compound, or a solvate thereof, or a feed-acceptable salt thereof.
  • the combination of the hexahydrolupulone precursor compound and the hexahydrolupulone precursor compound includes but is not limited to hexahydrolupulone monopropyl ester and hexahydrolupulone monopropyl ester Combination, Hexahydrolupulone monobutyl ester combined with Hexahydrolupulone monobutyl ester, Hexahydrolupulone dipropyl ester combined with Hexahydrolupulone monobutylester and Hexahydrolupulone Dibutyl ester combined with hexahydrolupulone dibutyl ester.
  • the precursor compound of the hexahydro-beta-acid component compound contained in the feed composition is a hexahydrolupulone precursor compound, or a solvate thereof, or a feed-acceptable compound thereof.
  • the mass of the hexahydrolupulone precursor compound in the combination is 1 parts, and the mass of the hexahydrolupulone precursor compound is not more than 0.5 part and not less than 0.01 part.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is a hexahydrolupulone precursor compound, or a solvate thereof, or a feed acceptable compound thereof.
  • the mass of the hexahydrolupulone precursor compound in the combination is 1 parts, and the mass of the hexahydrolupulone precursor compound is 0.5 part.
  • the precursor compound of the hexahydro- ⁇ -acid component compound contained in the feed composition is a hexahydrolupulone precursor compound, or a solvate thereof, or a feed acceptable compound thereof.
  • the mass of the hexahydrolupulone precursor compound in the combination is 1 part, the mass of the hexahydrolupulone precursor compound is 0.25 part.
  • the above-described feed composition further comprises additional animal feed additives and/or animal feed ingredients.
  • the animal feed additives are nutritional feed additives, general feed additives or pharmaceutical feed additives.
  • the nutritional feed additive refers to a small or trace amount of substances that are added to compound feed to balance feed nutrients, improve feed utilization, and directly exert nutritional effects on animals, including but not limited to amino acids, amino acid salts and their analogs, vitamins. And vitamins, mineral elements and their complexes (chelates), microbial enzymes or non-protein nitrogen.
  • the general feed additives are also called non-nutritive additives, which refer to some non-nutritive substances added to the feed to improve feed utilization, ensure feed quality and quality, and be beneficial to animal health or metabolism, including but not limited to growth. Accelerators, insect repellent health care agents, flavoring and food attractants, feed conditioners, feed preparations, feed storage agents or Chinese herbal medicine additives.
  • the additional animal feed additives included in the above-mentioned feed compositions are one or more of nutritional feed additives, general feed additives, and medicated feed additives.
  • non-nutritive additives are growth promoters, including but not limited to butyric acid, calcium butyrate, sodium butyrate, tannin, p-thymol, p-thymol ester, p-thymol salt, 2 -Hydroxybenzoic acid, benzoic acid or calcium benzoate, zinc oxide, zinc sulfate or zinc chloride.
  • growth promoters including but not limited to butyric acid, calcium butyrate, sodium butyrate, tannin, p-thymol, p-thymol ester, p-thymol salt, 2 -Hydroxybenzoic acid, benzoic acid or calcium benzoate, zinc oxide, zinc sulfate or zinc chloride.
  • the non-nutritive additive is calcium butyrate.
  • the non-nutritive additive is tannin.
  • the pharmaceutical feed additives include, but are not limited to, veterinary drug premix substances that have the effects of preventing animal diseases and promoting animal growth and can be added to the feed for a long time and incorporated into a carrier or diluent.
  • the medicated feed additive is a feed antibiotic
  • the feed antibiotic includes but is not limited to polymyxin, salinomycin, avilamycin, bacitracin, virginiamycin, Nosiheptide, flavomycin, enramycin, beilimycin, olaquindox, oxytetracycline, or chlortetracycline.
  • the animal feed materials are grains and their processed products, oilseeds and their processed products, legume seeds and their processed products, tubers, roots and their processed products, other seeds, fruit products and Its processed products, forage grass, roughage and its processed products, other plants, algae and their processed products, dairy products and their by-products, terrestrial animal products and their by-products, fish, other aquatic organisms and their by-products, minerals, microbial fermentation Products and by-products, other feed materials and other feed substances.
  • the present application relates to the above-mentioned precursor compound comprising the hexahydro-beta-acid component compound represented by formula (I), or a solvate thereof, and at least one of the feed-acceptable salts and optionally for feed Use of excipients for stable feed compositions.
  • the above-mentioned precursor compound comprising the hexahydro-beta-acid component compound represented by formula (I), or a solvate thereof, and at least one and optional feed-acceptable salts
  • the stable feed compositions that can be used as feed excipients are used in the preparation of animal feed additives.
  • animal feed additives are feed additives for improving animal production performance, including but not limited to livestock feed additives, poultry feed additives, aquaculture animal feed additives or pet feed additives.
  • At least one of the above-mentioned precursor compounds comprising the hexahydro- ⁇ -acid component compound represented by the formula (I), or solvates thereof and feed-acceptable salts, and optionally feed
  • the stable feed composition of adjuvants is used to prepare feed additives for livestock, including but not limited to pigs, cattle, sheep, horses, rabbits, minks, etc. at various growth stages.
  • the above-mentioned precursor compound comprising the hexahydro- ⁇ -acid component compound represented by formula (I), or its solvate and at least one of the feed-acceptable salts and the feed adjuvant are used.
  • the stable feed composition is used to prepare feed additives for poultry including but not limited to chickens, ducks, geese, pigeons and the like at various growth stages.
  • At least one of the above-mentioned precursor compounds comprising the hexahydro- ⁇ -acid component compound represented by the formula (I), or solvates thereof and feed-acceptable salts, and optionally feed is prepared by using the stable feed composition of auxiliary materials, and the aquaculture animals include but are not limited to fish, shrimp, crab, soft-shelled turtle, eel and the like at various growth stages.
  • At least one of the above-mentioned precursor compounds comprising the hexahydro- ⁇ -acid component compound represented by the formula (I), or solvates thereof and feed-acceptable salts, and optionally feed
  • the stable feed composition of excipients is used to prepare pet feed additives, including but not limited to captive-bred dogs or cats.
  • the animal feed additives prepared from the stable feed compositions of feed excipients are premixes, compound premixes, water preparations or granules.
  • the above-mentioned precursor compound comprising the hexahydro-beta-acid component compound represented by formula (I), or a solvate thereof, and at least one and optional feed-acceptable salts
  • Stable feed compositions that can be used as feed excipients are used in the preparation of animal feed.
  • the feed referred to in this application refers to the industrially processed and produced products for animal consumption.
  • At least one of the above-mentioned precursor compounds comprising the hexahydro- ⁇ -acid component compound represented by the formula (I), or a solvate thereof and a feed acceptable salt, and optional feed
  • the animal feed prepared with the stabilized feed composition of excipients is livestock feed, poultry feed, aquaculture animal feed or pet feed.
  • At least one of the above-mentioned precursor compounds comprising the hexahydro- ⁇ -acid component compound represented by the formula (I), or solvates thereof and feed-acceptable salts, and optionally feed
  • the stable feed composition of excipients is used to prepare feed for livestock including but not limited to pigs, cattle, sheep, horses, rabbits, minks, etc. at various growth stages.
  • At least one of the above-mentioned precursor compounds comprising the hexahydro- ⁇ -acid component compound represented by the formula (I), or solvates thereof and feed-acceptable salts, and optionally feed
  • the stable feed composition of adjuvants is used to prepare feed for poultry including but not limited to chickens, ducks, geese, pigeons, etc. at various growth stages.
  • the stable feed composition of optional feed excipients is used to prepare feed for aquaculture animals, including but not limited to fish, shrimp, crab, soft-shelled turtle, eel and the like at various growth stages.
  • At least one of the above-mentioned precursor compounds comprising the hexahydro- ⁇ -acid component compound represented by the formula (I), or solvates thereof and feed-acceptable salts, and optionally feed
  • the stabilized feed composition of excipients is used to prepare pet feed, including but not limited to captive dogs or cats.
  • the above-mentioned precursor compound comprising the hexahydro-beta-acid component compound represented by formula (I), or a solvate thereof, and at least one and optional feed-acceptable salts
  • the feeds prepared from the stable feed compositions of feed excipients are single feeds, concentrated feeds, compound feeds, compound premixes or concentrate supplements.
  • the compound feed is full-price compound feed.
  • the farmer feeds at least one of the aforementioned precursor compounds comprising the hexahydro-beta-acid component compound of formula (I), or a solvate thereof, and a feed-acceptable salt
  • the stable feed composition of the species and optional feedable excipients or the animal feed additive prepared from the feed composition and administered to the animals along with the feed can significantly improve the production performance of the animals.
  • the feed composition is a feed additive premix, a composite feed additive premix, a granule or a water preparation, which is administered to the animals along with the feed.
  • the feed composition is a feed additive premix.
  • the feed composition is a feed additive compound premix.
  • the feed additive is a premix, a composite premix, a granule or a water preparation, which is mixed with the animal feed and eaten by the animals.
  • the animals are livestock, poultry, aquaculture animals or pets.
  • the livestock include but are not limited to pigs, cattle, sheep, horses, rabbits, minks, etc. in various growth stages;
  • the poultry includes but are not limited to chickens, ducks, geese, pigeons, etc. in various growth stages;
  • Said aquaculture animals include but are not limited to fish, shrimp, crabs, soft-shelled turtles, eels, etc. in various growth stages; and said pets include but are not limited to artificially raised dogs or cats.
  • a farmer mixes a feed additive comprising a precursor compound of the hexahydro- ⁇ -acid component compound represented by formula (I), or a solvate thereof and at least one of a feed-acceptable salt with the feed additive.
  • a feed additive comprising a precursor compound of the hexahydro- ⁇ -acid component compound represented by formula (I), or a solvate thereof and at least one of a feed-acceptable salt.
  • the farmer mixes at least one of the above-mentioned precursor compound comprising the hexahydro- ⁇ -acid component compound with the structure shown in formula (I), or a solvate thereof and a feed acceptable salt.
  • the stable feed composition that can be used as a feed excipient or the animal feed additive prepared from the feed composition is administered to broilers along with the feed, which significantly reduces the feed-to-meat ratio of the broiler and improves the feed conversion rate.
  • the farmer mixes at least one of the above-mentioned precursor compound comprising the hexahydro- ⁇ -acid component compound with the structure shown in formula (I), or a solvate thereof and a feed acceptable salt.
  • the stable feed composition of the feed excipient or the animal feed additive prepared from the feed composition is administered to the fish along with the feed.
  • the farmer mixes at least one of the above-mentioned precursor compound comprising the hexahydro-beta-acid component compound with the structure shown in formula (I), or a solvate thereof and a feed-acceptable salt.
  • the stable feed composition that can be used as a feed excipient or the animal feed additive prepared from the feed composition is administered to puppies along with the feed.
  • the farmer will feed at least the above-mentioned precursor compound comprising the hexahydro-beta-acid component compound of formula (I), or a solvate thereof and a feed-acceptable salt.
  • An animal feed prepared with a stable feed composition that can be used as an excipient can significantly improve the animal's production performance when administered to an animal.
  • the feed composition is a concentrated feed, a compound feed, a compound premix or a concentrate supplement, which is directly given to the animals as animal feed.
  • the feed additive premixed feed refers to any two or more types of nutritional feed additives in minerals, trace elements, vitamins, microorganisms, and amino acids, which are the same as the hexahydro- ⁇ -acid group provided in this application.
  • the addition amount in concentrate supplements or animal drinking water is not less than 0.1% and not more than 10%.
  • the said concentrated feed refers to the feed which mainly consists of protein, minerals and feed additives prepared according to a certain proportion.
  • the compound feed refers to a feed prepared by a variety of feed raw materials and feed additives according to a certain proportion according to the nutritional needs of the breeding animals.
  • the concentrate supplement refers to a feed prepared by a variety of feed raw materials and feed additives according to a certain proportion in order to supplement the nutrition of herbivorous animals.
  • the feed composition is a full-price compound feed.
  • hexahydro-beta-acid component compounds of the present application are considered to be within the scope of the present application.
  • the synthesis of non-exemplified hexahydro-beta-acid component compounds according to the present application can be successfully accomplished by those skilled in the art by modifying methods such as appropriate protection of interfering groups, by using other reagents or by changing the reaction conditions Make some general modifications.
  • Hexahydrolupulone 2.0g (4.92mmol, 1.0eq) was dissolved in 10mL of dichloromethane, 0.59g (5.90mmol, 1.2eq) of triethylamine was added, and the temperature was cooled to -5°C to 0°C with stirring.
  • 0.47g (5.90mmol, 1.2eq) of acetyl chloride was dissolved in 2mL of dichloromethane and slowly added dropwise to the reaction system. After dropping, the reaction system was warmed to room temperature. The reaction was monitored by thin-layer chromatography to the end point, and 5mL was added to the reaction system. pure water, and the organic phase was separated after stirring. The organic phase was washed with water (15 mL ⁇ 3), dried over sodium sulfate pentahydrate, and concentrated under reduced pressure to remove the organic solvent to obtain 1.35 g of an oily product with a yield of 61.3%.
  • Hexahydrolupulone 2.0g (4.92mmol, 1.0eq) was dissolved in 10mL of dichloromethane, 0.60g (5.90mmol, 1.2eq) of triethylamine was added, and the temperature was cooled to -5°C to 0°C with stirring.
  • 0.62 g (5.90 mmol, 1.2 eq) of butyryl chloride was dissolved in 3 mL of dichloromethane and slowly added dropwise to the reaction system. After dropping, the reaction system was warmed to room temperature, and the reaction was monitored by thin layer chromatography to the end point. 5 mL was added to the reaction system. pure water, and the organic phase was separated after stirring. The organic phase was washed with water (15 mL ⁇ 3), dried over sodium sulfate pentahydrate, and concentrated under reduced pressure to remove the organic solvent to obtain 1.29 g of an oily product with a yield of 55.1%.
  • Hexahydrolupulone 2.5g (6.15mmol, 1.0eq) was put into a 50mL dry reaction vessel, nitrogen was introduced for deoxygenation and dehumidification, and n-heptane 20mL and 4-lutidine 0.1g (0.82mmol, 0.1g) were added in turn. 0.13eq).
  • the reaction system was cooled to 0°C, and 1.37 g (14.76 mmol, 2.4 eq) of propionyl chloride and 1.49 g (14.76 mmol, 2.4 eq) of triethylamine were successively added dropwise.
  • Hexahydrolupulone 2.5g (6.15mmol, 1.0eq) was put into a 50mL dry reaction vessel, nitrogen was introduced for deoxygenation and dehumidification, and n-heptane 20mL and 4-lutidine 0.1g (0.82mmol, 0.1g) were added in turn. 0.13eq).
  • the reaction system was cooled to 0°C, and 1.57 g (14.76 mmol, 2.4 eq) of butyryl chloride and 1.49 g (14.76 mmol, 2.4 eq) of triethylamine were successively added dropwise.
  • Hexahydrolupulone 2.5g (6.15mmol, 1.0eq) was dissolved in 10mL of dichloromethane, 0.75g (7.38mmol, 1.2eq) of triethylamine was added, and the temperature was cooled to -5°C to 0°C with stirring. 1.41 g (7.38 mmol, 1.2 eq) of decanoyl chloride was dissolved in 8 mL of dichloromethane and slowly added dropwise to the reaction system. After dropping, the reaction system was warmed to room temperature, and the reaction was monitored by thin layer chromatography to the end point. pure water, and the organic phase was separated after stirring.
  • Hexahydrolupulone 2.5g (6.15mmol, 1.0eq) was dissolved in 10mL of dichloromethane, 0.75g (7.38mmol, 1.2eq) of triethylamine was added, and the temperature was cooled to -5°C to 0°C with stirring. 1.61 g (7.38 mmol, 1.2 eq) of lauroyl chloride was dissolved in 8 mL of dichloromethane and slowly added dropwise to the reaction system. After dropping, the reaction system was warmed to room temperature, and the reaction was monitored by thin layer chromatography to the end point. pure water, and the organic phase was separated after stirring.
  • the content of the precursor compound of the hexahydro- ⁇ -acid component compound in the feed composition involved in the present invention is greater than or equal to 0.00001%, which can be determined according to the different growth stages of different animals or the product characteristics of the feed industry (such as feed additives). , feed additive raw materials, feed raw materials, etc.) can be used to adjust the content, and can also be adjusted according to the proportion of other nutrients and non-nutrients in different feed formulas to meet the needs of the feed formula.
  • feed additive raw materials, feed raw materials, etc. can be used to adjust the content, and can also be adjusted according to the proportion of other nutrients and non-nutrients in different feed formulas to meet the needs of the feed formula.
  • the following only takes the basic granular premix as an example to explain the feed composition of the present invention. Any similar formula or the replacement or increase of the non-synergistic effect of the formula components is regarded as the purpose of the present invention. Consistent.
  • the preparation method of the feed composition put the raw materials and auxiliary materials into the mixing unit to mix evenly, and put them into the granulator according to the ratio of 100:35 with a mass fraction of 1.3% hydroxypropyl methylcellulose aqueous solution (binder), and start mixing. And the cutter runs for 3-5min, the material enters the fluidized bed for drying after granulation, and passes through a 16-mesh sieve after 30min.
  • Raw material the precursor compound of the hexahydro-beta-acid component compound prepared in Example A.
  • Excipients corn starch.
  • Tested products hexahydrolupulone raw material, hexahydrolupulone monoethyl ester raw material, hexahydrolupulone monopropyl ester raw material, hexahydrolupulone monobutyl ester raw material.
  • Preparation of the 1% premix sample of the test product Weigh 1g of the raw material of the test product, add 99g of corncob flour, and mix in a mixer to obtain a 1% sample of the test product premix, which is to be tested.
  • test results are shown in Table 2.
  • Test materials Hexahydrolupulone raw material, Hexahydrolupulone monoethyl ester raw material, Hexahydrolupulone monopropyl ester raw material, Hexahydrolupulone monobutyl ester raw material, Hexahydrolupulone monobutyl ester raw material Ketone monoamyl ester raw materials (provided by the Chemical Department of Guangzhou Inset Co., Ltd.), hexahydrolupulone monohexyl ester raw materials (provided by the Chemical Department of Guangzhou Inset Co., Ltd.), hexahydrolupulone monolaurate raw materials , Hexahydrolupulone monophosphate disodium salt (provided by the chemical department of Guangzhou Inset Co., Ltd.), hexahydrolupulone monophosphate diethyl ester (provided by the chemical department of Guangzhou Inset Co., Ltd.).
  • Preparation of the 1% premix sample of the test product Weigh 1g of the raw material of the test product, add 99g of corncob flour, and mix in a mixer to obtain a 1% sample of the test product premix.
  • the 1% premix sample of the test product is diluted to 5000 ppm and 500 ppm of the test product feed sample step by step with Master Zhu's pre-mixed feed, pending inspection.
  • Preparation of 100 ppm feed sample for test product Dilute the 1% premix sample of the test product with Chia Tai suckling pig teaching trough feed to 1000 ppm and 100 ppm for the test feed sample, to be tested.
  • Preparation of 100ppm feed sample of the test article The 1% premix sample of the test article was diluted step by step with the broiler feed provided by Nanxiong to 1000ppm and 100ppm of the test article feed sample, to be tested.
  • Preparation of 2000ppm feed sample of the test article Dilute the 1% premix sample of the test article with the Guangdong Kebang 4% premix feed gradually to 5000ppm and 2000ppm of the test article feed sample, pending inspection.
  • control group was only given the basal diet
  • experimental groups 2 to 16 were respectively given the hexahydro- ⁇ -acid component compound or the hexahydro- ⁇ -acid component compound in the form of mixing on the basis of the basal diet.
  • the diet of the precursor compound, and the concentration of the active ingredient of each additive in test groups 2 to 16 was 5 ppm or 25 ppm, as shown in Table 4.
  • each experimental group did not add other antioxidant components and growth-promoting agents.
  • the test period was 14 days, with each repetition as the unit, on the 14th day of the test, the animals were weighed after 12 hours of water and feed interruption, and the average daily feed intake (ADFI, g/d*head) and average daily increase of each test group were calculated. Weight (ADG, g/d*head) and feed to meat ratio (FCR). Calculated as follows:
  • Average daily feed intake (total amount of ingredients - amount of remaining feed) / (test days ⁇ number of pigs per replicate);
  • Average daily gain (average body weight at the end of the test - average body weight at the beginning of the test)/test days;
  • Feed to meat ratio average daily feed intake/average daily gain.
  • control group was only given the basal diet, and the experimental groups 2 to 6 were given hexahydrolupulone, hexahydrolupulone monoethyl ester and hexahydrolupulone on the basis of the basal diet.
  • the specific diet of monobutyl ester is shown in Table 5.
  • the experimental period was 30 days, and the chickens were free to drink water and feed, and were fed twice a day. Taking each repetition as a unit, weighed at the age of 31 (with feeding 12 hours and water without stopping), the feed consumption of the test chickens was counted, and the average daily feed intake of the test chickens in each group was calculated (ADFI, g/d* only) , Average daily gain (ADG, g/d* only) and feed to meat ratio (FCR), the calculation formula is as follows:
  • Feed to meat ratio (FCR) average daily feed intake/average daily gain.
  • the precursor compounds of the hexahydro-beta-acid component compound hexahydrolupulone and/or hexahydrolupulone have compounds with hexahydrolupulone and/or hexahydrolupulone
  • the effect of improving animal production performance is basically equivalent.
  • it can not only avoid the thermal stability of hexahydro- ⁇ -acid component compounds during the feed pelleting process and the stability of long-term storage At the same time, it can also have the effect of improving the production performance of the fed animals equivalent to the hexahydro-beta-acid component compounds.

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Abstract

本发明公开了六氢-β-酸组分化合物的前体化合物、饲用组合物及其应用。结构如式（I）所示的六氢-β-酸组分化合物的前体化合物，或其溶剂合物及饲料可接受的盐，其中，R 1选自取代或非取代的C 1-C 2烷基；R 2或R 3独立选自H，取代或非取代的直链或支链的C 2-C 4羰基。本发明发现六氢-β-酸组分化合物的脂肪酸酯化前体化合物在高温条件下具有很好的稳定性，克服了六氢-β-酸组分化合物在饲料加工过程经历高温制粒时导致的有效成分降解的问题。进一步的，本发明还发现在六氢-β-酸组分化合物的脂肪酸酯化前体化合物中的六氢-β-酸组分化合物丙酸酯或丁酸酯及其饲料可接受的盐或溶剂合物不但能承受饲料加工的高温历程在养殖中应用时具有与六氢-β-酸组分化合物基本等同的效果。

Description

六氢-β-酸组分化合物的前体化合物、饲用组合物及其应用 技术领域：
本申请涉及动物饲料添加剂领域，具体涉及一种六氢-β-酸组分化合物的前体化合物和包含六氢-β-酸组分化合物的前提化合物的饲用组合物及其应用。
背景技术：
酒花酸是源自啤酒花的有机酸，包括α-酸和β-酸，具有杀菌、抑菌或改变代谢产物的生物学效果，在动物养殖领域可作为动物饲料中的抗生素替代物使用。其中，β-酸具有更强的抗菌活性。酒花酸稳定性和溶解性差，过去通常是在磨碎后添加到动物饲料中进行混料使用，或制备成1％浓度的钾盐水溶液，喷雾包裹于饲料中或混料使用，这些使用形式在动物养殖生产中使用极为不方便。有研究提出酒花酸的二元氢化、四元氢化或六元氢化化合物可改变酒花酸的活性、稳定性、溶解性或其它物质特征。但是，很遗憾的是，不久就有研究报道六元氢化的β-酸及其金属盐(简称六氢-β-酸)对热不稳定，另外将其添加在饲料中常温下保存，饲料中的六氢-β-酸会迅速降解导致有效含量下降，不能满足做为饲料添加剂的要求。发明人在研究中发现六氢-β-酸中的主要成分为六氢蛇麻酮、六氢合蛇麻酮和六氢加蛇麻酮，其中导致六氢-β-酸在饲料中常温下不稳定是因为六氢蛇麻酮的不稳定导致六氢-β-酸在饲料中的含量下降。发明人还进一步发现，六氢合蛇麻酮或六氢合蛇麻酮与六氢加蛇麻酮的组合物直接应用在养殖中混料使用具有与六氢-β-酸等效相似甚至更优的改善动物生产性能的功效。但是，六氢合蛇麻酮和六氢加蛇麻酮应用在饲料成品中在存放过程中有效成分的含量下降从而影响产品在养殖业中的使用。
有鉴于此，特提出本申请。
发明内容：
本申请的目的包括提供一种六氢-β-酸组分化合物的前体化合物。
本申请的目的还包括提供一种包含六氢-β-酸组分化合物的前体化合物的饲用组合物。
本申请的目的还包括提供六氢-β-酸组分化合物的前体化合物及其饲用组合物在制备动物饲料添加剂中的应用。
本申请的目的还包括提供六氢-β-酸组分化合物的前体化合物及其饲用组合物在制备动物饲料中的应用。
本申请的目的还包括，提供一种改善动物生产性能的方法。
为了实现本申请的至少一个目的，特采用如下技术方案：
一方面，本申请提供了一种结构如式(I)所示的六氢-β-酸组分化合物的前体化合物，或其溶剂合物及饲料可接受的盐，式(I)中R 1是取代或非取代的直链或支链烷基；R 2或R 3独立选自H或取代或非取代的直链或支链的脂肪羰基。
Figure PCTCN2021120638-appb-000001
另一方面，本申请还提供了一种饲用组合物，所述饲用组合物包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐中的至少一种和任选的可饲用辅料。
另一方面，本申请还提供了结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐，及包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的饲用组合物在制备动物饲料添加剂中的应用。
另一方面，本申请还提供了结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐，及包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的饲用组合物在制备动物饲料中的应用。
另一方面，本申请还提供了一种改善动物生产性能的方法，包括：以本申请的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐进行动物饲喂；或者，以本申请的饲用组合物进行动物饲喂；或者，以包含本申请饲用组合物的饲料进行动物饲喂。
与已有技术相比，本申请的有益效果包括：
本发明发现六氢-β-酸组分化合物的脂肪酸酯化前体化合物在高温条件下具有很好的稳定性，克服了六氢-β-酸组分化合物在饲料加工过程经历高温制粒时导致的有效成分降解的问题。进一步的，本发明还发现在六氢-β-酸组分化合物的脂肪酸酯化前体化合物中的六氢-β-酸组分化合物丙酸酯或丁酸酯及其饲料可接受的盐或溶剂合物不但能承受饲料加工的高温历程在养殖中应用时具有与六氢-β-酸组分化合物基本等同的效果。
本申请的任一方面的任一实施方案可以与其他实施方案进行组合，只要它们之间不出现 矛盾。
具体实施方式
前面所述内容只是概述了本申请的某些方面，但不限于这些方面。上述涉及内容及其他方面的内容将在下面做更加具体完整的描述。
本申请的进一步详细描述。
现在详细描述本申请的某些实施方案，其实例由随附的结构式和化学式加以说明。本申请的意图涵盖所有的替代、修改和等同的技术方案，它们均包括在如权利要求定义的本申请的范围内。另外，本申请的某些技术特征为清楚可见，在多个独立的实施方案中分别进行描述，但也可以在单个实施例中以组合形式提供或以任意适合的子组合形式提供。
化合物
本发明涉及的化合物是一种结构如式(I)所示的六氢-β-酸组分化合物的前体化合物。
Figure PCTCN2021120638-appb-000002
其中，R 1是取代或非取代的直链或支链烷基；R 2和R 3独立选自H和取代或非取代的直链或支链的脂肪羰基。
进一步的，R 1选自取代或非取代C 1-C 2烷基；R 2和R 3独立选自H和取代或非取代的直链或支链的C 3-C 4羰基。
本发明涉及的“六氢-β-酸组分化合物”是指六氢-β-酸中含有的主要成分，具体为六氢合蛇麻酮(I1-1)、六氢加蛇麻酮(I1-2)和六氢蛇麻酮(I1-3)，具体结构如下式所示：
Figure PCTCN2021120638-appb-000003
一般的，“取代的”表示所给结构中的一个或多个可被取代的氢原子被具体取代基所取代，一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代，当所给出的结构式中 不只一个位置能被具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
在本发明中，“C a-C b烷基”表示含有a个至b个碳原子的直链或支链的饱和烷基，如甲基、乙基、丙基、异丙基、……，如“C 3-C 4烷基”是表示含有3个至4个碳原子的直链或支链的饱和烷基。“C a-C b羰基”表示含有a个至b个碳原子的直链或支链的脂肪羰基，如C(＝O)CH 2CH 3、C(＝O)(CH 2) 2CH 3、C(＝O)CH 2(CH 3) 2、……。
在一些实施方案中，所述的式(I)所示的六氢-β-酸组分化合物的前体化合物中的R 1是CH 3，R 2和R 3独立选自H和取代或非取代的直链或支链的C 3-C 4羰基。
进一步的，所述的R 2和R 3独立选自H或非取代的直链的C 3-C 4羰基，优选为不同时为H。
在一些实施例中，所述的R 3为H，R 2为非取代的直链的C 3-C 4羰基。
在另一些实施例中，所述的R 2和R 3独立选自非取代的直链的C 3-C 4羰基，优选为R 2和R 3选自相同的非取代的直链的C 3-C 4羰基。
在一些实施方案中，所述的式(I)所示的六氢-β-酸组分化合物的前体化合物中的R 1是CH 2CH 3，R 2和R 3独立选自H和取代或非取代的直链或支链的C 3-C 4羰基。
进一步的，所述的R 2和R 3独立选自H或非取代的直链的C 3-C 4羰基，优选为不同时为H。
在一些实施例中，所述的R 3为H，R 2为非取代的直链的C 3-C 4羰基。
在另一些实施例中，所述的R 2和R 3独立选自非取代的直链的C 3-C 4羰基，优选为R 2和R 3选自相同的非取代的直链的C 3-C 4羰基。
在一些具体的实施例中，本发明所述的六氢-β-酸组分化合物的前体化合物包括：
Figure PCTCN2021120638-appb-000004
Figure PCTCN2021120638-appb-000005
化合物的制备与纯化
制备本发明涉及的如式(I)所示的六氢-β-酸组分化合物的前体化合物包含如下过程：
(1)以商用啤酒花浸膏为原料，以有机溶剂提取分离法获得β-酸；
(2)所述的β-酸经过加氢还原制备六氢-β-酸；
(3)所述的六氢-β-酸经过重结晶法或色谱分离法分别制备得到不同的六氢-β-酸组分化合物，所述的六氢-β-酸组分化合物具体为六氢合蛇麻酮(I1-1)、六氢加蛇麻酮(I1-2)和六氢蛇麻酮(I1-3)；
(4)六氢-β-酸组分化合物与取代或非取代的直链或支链的脂肪酸结合发生酯化反应获得六氢-β-酸组分化合物的前体化合物，该酯化反应包括与一个化学当量或两个化学当量的取代或非取代的直链或支链的脂肪酸结合。
六氢-β-酸组分化合物具有不对称中心，可以消旋体、外消旋体、立体异构体、几何异构体、互变异构体、单个对映体、单个非对应异构体和非对映异构体的形式存在，要明确的是这些异构体经过上述步骤(4)获得的六氢-β-酸组分化合物的前体化合物的形式包括在本申请中。所述的六氢-β-酸组分化合物除了由具有普通技术的化学工作者从植物中提取原料经过半合成制备获得或通过全合成获得还可通过商业途径获得。
在一些实施方案中，本发明提供六氢-β-酸组分化合物的前体化合物的制备过程还涉及反应产物的分离、纯化或重结晶过程。反应产物可通过脱溶剂法从反应体系中获得粗品。为了获得化学纯度更高、杂质含量更低的固体物质，粗品经醇溶剂、醇水混合溶剂或其他可用于产品重结晶的有机溶剂中在合适的温度、光照以及机械振动等条件下溶解、析晶或沉淀或重结晶和分离得到具有一定晶型状态的六氢-β-酸组分化合物的前体化合物。所述具有一定晶型状态的六氢-β-酸组分化合物的前体化合物是六氢-β-酸组分化合物的前体化合物或六氢-β-酸组分化合物的前体化合物的溶剂合物。所述的六氢-β-酸组分化合物的前体化合物的溶剂合物可选自六氢-β-酸组分化合物的前体化合物的水合物或六氢-β-酸组分化合物的前体化合物的乙醇合物。
本发明涉及的“溶剂合物”是指本发明的化合物与溶剂分子接触的过程中，外部条件与内 部条件因素造成通过非共价分子间力而结合化学当量或非化学当量的溶剂分子而形成的共晶缔合物。形成溶剂合物的溶剂包括但是不限于水、丙酮、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、异丙醇等溶剂。“水合物”是指溶剂分子是水所形成的缔合物或结晶体，也就是通过非共价分子间力而结合化学当量或非化学当量的水的化合物。
本发明提供的六氢-β-酸组分化合物的前体化合物的制备为了获得化学纯度更高、杂质含量更低的固体物质还可通过盐析法后进行处理。所述的盐析法是利用酸碱中和法、酸碱配位法或酸碱螯合法的原理使氨基酸衍生物与相应的有机碱、无机碱、有机酸或无机酸成盐沉淀的过程，获得饲料可接受的盐；所述的无机酸包括但不限于盐酸、氢溴酸、磷酸、硫酸、硝酸或它们的组合；所述的有机碱包括但不限于氨或三乙胺。所述的无机碱包括但不限于氢氧化钠、氢氧化钾、氢氧化镁、或氢氧化钙。
饲料可接受的盐为本发明的六氢-β-酸组分化合物的前体化合物与对动物无毒的有机碱、无机碱、有机酸或无机酸形成的盐。所述的“饲料可接受的”是指物质或组合物必须是适合化学或毒理学的，与组成的饲料或食用的养殖动物有关。
在一些实施方案中，本发明的六氢-β-酸组分化合物的前体化合物的后处理还涉及盐析沉淀过程中，与无机酸或有机酸形成酸碱配位盐和或酸碱螯合盐，所述的有机酸包括但不限于乙酸、马来酸、琥珀酸、扁桃酸、延胡索酸、丙二酸、苹果酸、2-羟基丙酸、丙酮酸、草酸、乙醇酸、水杨酸、葡萄糖醛酸、半乳糖醇酸、柠檬酸、酒石酸、天冬氨酸、谷氨酸、苯甲酸、对甲基苯甲酸、肉桂酸、对甲苯磺酸、苯磺酸、甲磺酸、乙磺酸、三氟甲磺酸或它们的组合。
化合物的应用
本发明提供的六氢-β-酸组分化合物的前体化合物及其溶剂合物或饲料可接受的盐应用在制备动物饲料添加剂中。
本发明涉及的“动物”是指不能将无机物合成有机物，只能以有机物作为食料，以进行摄食、消化、吸收、呼吸、循环、排泄、感觉、运动和繁殖等为生命活动的人或养殖动物。“养殖动物”包括家禽、家畜、水产养殖动物以及人工饲养合法捕获的其他动物包括宠物，例如猫狗。术语“家畜”是，例如猪、牛、马、山羊、绵羊、鹿和许多有用的啮齿动物的任一种。术语“家禽”是包括，例如鸡、鸭、鹅、鹌鹑、鸽等。术语“水产养殖动物”包括，如鱼、虾、龟、鳖等。
应用本发明提供的六氢-β-酸组分化合物的前体化合物及其溶剂合物或饲料可接受的盐制备的是作为各个生长阶段的动物的改善动物生产性能的非营养性添加剂，所述动物可选自各个生长阶段的家畜、家禽、水产养殖动物或宠物。
进一步的，所述的家畜包括但不限于猪、牛、羊、马、兔、貂或驴，所述的家禽包括但不限于鸡、火鸡、鸭、鹅、鹌鹑或鸽，所述的水产养殖动物包括但不限于鱼、虾、龟、蟹、鳖、牛蛙、鳝或泥鳅，所述的宠物包括但不限于各个亚种的狗或猫。
在一实施例中，应用本发明提供的六氢-β-酸组分化合物的前体化合物及其溶剂合物或饲料可接受的盐制备的是改善肉猪生产性能的饲料添加剂，对肉猪的采食量、平均日增重或饲料转化率均具有改善效果。
在另一实施例中，应用本发明提供的六氢-β-酸组分化合物的前体化合物及其溶剂合物或饲料可接受的盐制备的饲料添加剂可显著改善肉鸡或蛋鸡的生产性能。
在另一实施例中，应用本发明提供的六氢-β-酸组分化合物的前体化合物及其溶剂合物或饲料可接受的盐制备的是改善鱼的生产性能的饲料添加剂。
本申请涉及的饲用组合物
一种包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物，所述的可饲用辅料为选自由可饲用的载体、稀释剂、赋形剂、和溶媒中的一种或几种的组合。
本申请涉及的“组合物”是指包含一种或一种以上的化合物组成有效成分的化合物集体。
本申请所述的“包含”为开放式表达，既包括本申请所明指的内容，但并不排除其他方面的内容。但需要注意的是，本申请所提供的饲用组合物中不包含六氢蛇麻酮或其盐、酯。在一种或多种实施方式中，除式(I)所示的六氢-β-酸组分化合物的前体化合物外，不包含其他六氢-β-酸组分化合物或其盐、酯(难以避免的、作为杂质的少量其他六氢-β-酸组分化合物除外)。
本申请所述的“稳定的可饲用组合物”是指具有足以允许生产的稳定性，且在足够长的一段时间内保持化合物的完整性以用于本申请详细描述的目的可供动物食用的组合物。
本申请涉及的“载体”是指能够承载活性成分，改善其分散性，并有良好的化学稳定性和吸附性的可饲用物质，为有机载体和无机载体。所述的有机载体是含粗纤维多的物料，包括但不限于玉米粉、玉米芯粉、麦麸、稻壳粉、脱脂米糠、统糠、玉米秸秆粉或花生壳粉。所述的无机载体是矿物质，主要分为钙盐类和硅的氧化物类，用于微量元素预混料的制作，包括但不限于碳酸钙、硅酸盐、蛭石、沸石或海泡石。
本申请涉及的“稀释剂”是指将添加剂原料均匀分布于物料中，将高浓度的添加剂原料稀释为低浓度的预混剂或预混料的物质，可将微量成分彼此分开，减少活性成分之间的相互反应，以增加活性成分的稳定性但不影响有关物质的物化性质，为有机稀释剂和无机稀释剂。有机稀释剂包括但不限于玉米粉、去胚玉米粉、右旋糖(葡萄糖)、蔗糖、带有麸皮的粗小麦粉、炒大豆粉、次粉、玉米蛋白粉等；无机稀释剂包括但不限于石灰石、磷酸二氢钙、贝壳粉、高岭土(白陶土)、食盐或硫酸钠。
所述的赋形剂包括选自由使物质本身固有的黏性诱发出来的润湿剂，使物质黏合起来的粘合剂，使物质整体的片状物裂碎为许多细小颗粒的崩解剂，降低颗粒间摩擦力的助留剂和防止物料黏着的抗黏剂所组成的组中的一种或几种，包括但不限于硬脂酸镁、滑石粉、植物油、月桂醇硫酸镁、淀粉、淀粉浆、水、无机盐、糊精或糖粉。
本申请涉及的“溶媒”是指溶解或分散固体所需的溶剂，包括但不限于水、甘油或乙醇。
在一些实施方案中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为六氢合蛇麻酮的前体化合物、或其溶剂合物、或其饲料可接受的盐。
在一实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为结构如式(I2-1)所示的六氢合蛇麻酮单丙酯、或其溶剂合物、或其饲料可接受的盐。
在一实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为结构如式 (I2-2)所示的六氢合蛇麻酮单丁酯、或其溶剂合物、或其饲料可接受的盐。
在一实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为结构如式(I2-5)所示的六氢合蛇麻酮双丙酯、或其溶剂合物、或其饲料可接受的盐。
在一实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为结构如式(I2-6)所示的六氢合蛇麻酮双丁酯、或其溶剂合物、或其饲料可接受的盐。
在一些实施方案中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为六氢加蛇麻酮的前体化合物、或其溶剂合物、或其饲料可接受的盐。
在一实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为结构如式(I2-3)所示的六氢加蛇麻酮单丙酯、或其溶剂合物、或其饲料可接受的盐。
在一实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为结构如式(I2-4)所示的六氢加蛇麻酮单丁酯、或其溶剂合物、或其饲料可接受的盐。
在一实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为结构如式(I2-7)所示的六氢加蛇麻酮双丙酯、或其溶剂合物、或其饲料可接受的盐。
在一实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为结构如式(I2-8)所示的六氢加蛇麻酮双丁酯、或其溶剂合物、或其饲料可接受的盐。
在一些实施方案中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为六氢合蛇麻酮前体化合物、或其溶剂合物、或其饲料可接受的盐，与六氢加蛇麻酮前体化合物、或其溶剂合物、或其饲料可接受的盐的组合。
具体的，所述的六氢合蛇麻酮前体化合物与六氢加蛇麻酮前体化合物的组合包括但不限于六氢合蛇麻酮单丙酯与六氢加蛇麻酮单丙酯组合、六氢合蛇麻酮单丁酯与六氢加蛇麻酮单丁酯组合、六氢合蛇麻酮双丙酯与六氢加蛇麻酮单双酯组合和六氢合蛇麻酮双丁酯与六氢加蛇麻酮双丁酯组合。
在一些实施方案中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为六氢合蛇麻酮前体化合物、或其溶剂合物、或其饲料可接受的盐，与六氢加蛇麻酮前体化合物、或其溶剂合物、或其饲料可接受的盐的组合时，所述的六氢合蛇麻酮前体化合物在组合中的质量为1份，所述的六氢加蛇麻酮前体化合物的质量为不超过0.5份及不少于0.01份。
在一些实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为六氢合蛇麻酮前体化合物、或其溶剂合物、或其饲料可接受的盐，与六氢加蛇麻酮前体化合物、或其溶剂合物、或其饲料可接受的盐的组合时，所述的六氢合蛇麻酮前体化合物在组合中的质量为1份，所述的六氢加蛇麻酮前体化合物的质量为0.5份。
在一些实施例中，所述的饲用组合物包含的六氢-β-酸组分化合物的前体化合物为六氢合蛇麻酮前体化合物、或其溶剂合物、或其饲料可接受的盐，与六氢加蛇麻酮前体化合物、或其溶剂合物、或其饲料可接受的盐的组合时，所述的六氢合蛇麻酮前体化合物在组合中的质量为1份，所述的六氢加蛇麻酮前体化合物的质量为0.25份。
在一些实施方案中，上述的饲用组合物进一步包含附加的动物饲料添加剂和/或动物饲料原料。
所述的动物饲料添加剂为营养性饲料添加剂、一般饲料添加剂或药物饲料添加剂。
所述的营养性饲料添加剂是指添加到配合饲料中，平衡饲料养分，提高饲料利用率，直接对动物发挥营养作用的少量或微量物质，包括但不限于氨基酸、氨基酸盐及其类似物、维生素及类维生素、矿物元素及其络(螯)合物、微生物酶制剂或非蛋白氮。
所述的一般饲料添加剂也叫非营养性添加剂，是指加入到饲料中用于改善饲料利用率、保证饲料质量和品质、有利于动物健康或代谢的一些非营养性物质，包括但不限于生长促进剂、驱虫保健剂、调味和诱食剂、饲料调质剂、饲料调制剂、饲料贮藏剂或中草药添加剂。
在一些实施方案中，上述饲用组合物包含的附加的动物饲料添加剂为营养性饲料添加剂、一般饲料添加剂和药物饲料添加剂中的一种或多种。
进一步具体地，所述的非营养性添加剂为生长促进剂，包括但不限于丁酸、丁酸钙、丁酸钠、单宁酸、对百里香酚、对百里香酚酯、对百里香酚盐、2-羟基苯甲酸、苯甲酸或苯甲酸钙、氧化锌、硫酸锌或氯化锌。
在一实施例中，所述的非营养性添加剂为丁酸钙。
在另一实施例中，所述的非营养性添加剂为单宁酸。
进一步具体地，所述的药物饲料添加剂包括但不限于具有预防动物疾病、促进动物生长作用并可在饲料中长期添加使用而掺入载体或稀释剂的兽药预混合物质。
进一步具体地，所述的药物饲料添加剂为饲用抗生素，所述的饲用抗生素包括但不限于多粘菌素、盐霉素、阿维拉霉素、杆菌肽、维吉尼亚霉素、那西肽、黄霉素、恩拉霉素、北里霉素、喹乙醇、土霉素或金霉素。
在一些实施方案中，所述的动物饲料原料为谷物及其加工产品，油料籽实及其加工产品，豆科作物籽实及其加工产品，块茎、块根及其加工产品，其它籽实、果实类产品及其加工产品，饲草、粗饲料及其加工产品，其它植物、藻类及其加工产品，乳制品及其副产品，陆生动物产品及其副产品，鱼、其它水生生物及其副产品，矿物质，微生物发酵产品及副产品，其它饲料原料等饲用物质。
饲用组合物的用途
本申请涉及上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物的应用。
在一些实施方案中，上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物应用于制备动物饲料添加剂中。
进一步的，所述的动物饲料添加剂为改善动物生产性能的饲料添加剂，包括但不限于家畜饲料添加剂、家禽饲料添加剂、水产养殖动物饲料添加剂或宠物饲料添加剂。
具体地，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备家畜饲料添加剂，所述的家畜包括但不限于各个生长阶段的猪、牛、羊、马、兔、貂等。
具体地，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂 合物及饲料可接受的盐的至少一种和可饲用辅料的稳定的饲用组合物制备家禽饲料添加剂，所述的家禽包括但不限于各个生长阶段的鸡、鸭、鹅、鸽等。
具体地，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备水产养殖动物饲料添加剂，所述的水产养殖动物包括但不限于各个生长阶段鱼、虾、蟹、鳖、鳝等。
具体地，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备宠物饲料添加剂，所述的宠物包括但不限于人工饲养的狗或猫。
在一些实施例中，以上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备的动物饲料添加剂为预混剂、复合预混剂、水剂或颗粒剂。
在一些实施方案中，上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物应用于制备动物饲料中。
本申请涉及的饲料是指经工业化加工、制作的供动物食用的产品。
进一步的，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备的动物饲料为家畜饲料、家禽饲料、水产养殖动物饲料或宠物饲料。
具体地，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备家畜饲料，所述的家畜包括但不限于各个生长阶段的猪、牛、羊、马、兔、貂等。
具体地，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备家禽饲料，所述的家禽包括但不限于各个生长阶段的鸡、鸭、鹅、鸽等。
具体地，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或所述前体化合物的溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备水产养殖动物饲料，所述的水产养殖动物包括但不限于各个生长阶段鱼、虾、蟹、鳖、鳝等。
具体地，应用上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备宠物饲料，所述的宠物包括但不限于人工饲养的狗或猫。
在一些实施方案中，上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物制备的饲料为单一饲料、浓缩饲料、配合饲料、复合预混料或精料补充料。
具体地，所述的配合饲料为全价配合饲料。
改善养殖动物生产性能的方法
在一些饲喂实施方案中，养殖户将上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和任选的可饲用辅料的稳定的饲用组合物或由所述饲用组合物制备的动物饲料添加剂与饲料伴服给与动物食用，可显著地改善动物的生产性能。
可选地，所述的饲用组合物是饲料添加剂预混剂、饲料添加剂复合预混剂、颗粒剂或水剂，与饲料伴服给与动物食用。
在一实施例中，所述的饲用组合物是饲料添加剂预混剂。
在一实施例中，所述的饲用组合物是饲料添加剂复合预混剂。
在一些实施例中，所述的饲料添加剂为预混剂、复合预混剂、颗粒剂或水剂，与动物饲料混匀后动物食用。
所述的动物为家畜、家禽、水产养殖动物或宠物。
具体地，所述的家畜包括但不限于各个生长阶段的猪、牛、羊、马、兔、貂等；所述的家禽包括但不限于各个生长阶段的鸡、鸭、鹅、鸽等；所述的水产养殖动物包括但不限于各个生长阶段鱼、虾、蟹、鳖、鳝等；所述的宠物包括但不限于人工饲养的狗或猫。
在一实施例中，养殖户将包含式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种的饲料添加剂与饲料伴服给与断奶猪食用，显著提高断奶猪的平均日增重的增重率和饲料转化率。
在一实施例中，养殖户将上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和可饲用辅料的稳定的饲用组合物或由所述饲用组合物制备的动物饲料添加剂与饲料伴服给与肉鸡食用，显著降低了肉鸡的料肉比提高饲料转化率。
在一实施例中，养殖户将上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和可饲用辅料的稳定的饲用组合物或由所述饲用组合物制备的动物饲料添加剂与饲料伴服给与鱼食用。
在一实施例中，养殖户将上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和可饲用辅料的稳定的饲用组合物或由所述饲用组合物制备的动物饲料添加剂与饲料伴服给与幼狗食用。
在另一些饲喂实施例中，养殖户将由上述包含结构如式(I)所示的六氢-β-酸组分化合物的前体化合物、或其溶剂合物及饲料可接受的盐的至少一种和可饲用辅料的稳定的饲用组合物制备的动物饲料给与动物食用，可显著地改善动物的生产性能。
可选地，所述的饲用组合物是浓缩饲料、配合饲料、复合预混料或精料补充料，直接作为动物饲粮给与动物食用。
所述的饲料添加剂预混合饲料，是指以矿物质微量元素、维生素、微生物、氨基酸中任何两类或两类以上的营养性饲料添加剂为主，与本申请提供的六氢-β-酸组分化合物的前体化合物或其他饲料添加剂、载体和(或)稀释剂按照一定比例配制的均匀混合物，其中营养性饲料添加剂的含量能够满足其适用动物特定生理阶段的基本营养需求，在配合饲料、精料补 充料或动物饮用水中的添加量不低于0.1％且不高于10％。
所述的浓缩饲料是指主要有蛋白质、矿物质和饲料添加剂按照一定比例配制的饲料。
所述的配合饲料是指根据养殖动物营养需要，将多种饲料原料和饲料添加剂按照一定比例配制的饲料。
所述的精料补充料是指为补充草食动物的营养，将多种饲料原料和饲料添加剂按照一定比例配制的饲料。
在一实施例中，所述的饲用组合物是全价配合饲料。
下面将结合实施例对本申请的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本申请，而不应视为限制本申请的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例A六氢-β-酸组分化合物的前提化合物的半合成制备法
所属领域的技术人员将认识到，用于制备本申请的六氢-β-酸组分化合物的其他方法都被认为是在本申请的范围之内。例如，根据本申请那些非例证的六氢-β-酸组分化合物的合成可以成功的被所述领域技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他试剂或将反应条件做一些常规修改。
A1β-酸的制备
在5L烧杯中依次加入1kg啤酒花浸膏、3L纯水和1L乙醇，搅拌使浸膏溶解，滴加KOH碱液0.5L调节溶液pH至13，静置，抽滤除去不溶物。向滤液通入CO 2气体调节滤液pH至8.5，冷却静置2h，抽滤得到粗产物。
将上述粗产物溶于200mL正己烷，水洗(150mL×3)，有机相浓缩得膏状物后加300mLKOH碱液调节pH至12.5使溶解，正己烷洗涤(200mL×3)，弃去有机相，水相加酸调节pH至8.5，再加正己烷萃取(200mL×3)，合并有机层并以五水硫酸钠干燥，减压浓缩除去有机层得400g结晶状β-酸。HPLC含量分析结果显示所述β-酸结晶的主要成分为合蛇麻酮、加蛇麻酮和蛇麻酮。
A2六氢-β-酸的制备
将50gβ-酸溶于300mL95％乙醇溶液中，加入1.7g 10％Pd/C，氢气置换，室温搅拌过夜。HPLC监控至反应终点。反应液过滤，滤液浓缩得46g六氢-β-酸结晶。
A3六氢-β-酸的主要成分分离纯化
A3.1六氢合蛇麻酮的制备
Figure PCTCN2021120638-appb-000006
六氢-β-酸经正己烷重结晶得六氢合蛇麻酮结晶，纯度为98.6％。 1HNMR(500MHz,DMSO-d6):δ(ppm)3.94-4.01(m,1H),2.39(t,2H),1.78-1.82(m,4H),1.47-1.51(m,1H),1.28-1.35(m,4H),1.11(q,6H),0.95-1.01(m,4H),0.91(d,18H)；LC-MS(ESI,pos.ion)m/z:407[M+H] +。
A3.2六氢蛇麻酮的制备
Figure PCTCN2021120638-appb-000007
六氢-β-酸通过制备色谱分离获得纯度为99.1％的六氢蛇麻酮。 1HNMR(500MHz,DMSO-d6):δ(ppm)3.86-3.90(m,1H),2.39(t,2H),1.80-1.83(m,4H),1.59-1.60(m,2H),1.47-1.52(m,5H),1.11(d,3H),0.90-0.96(m,7H),0.86(d,18H)；LC-MS(ESI,pos.ion)m/z:421[M+H] +。
A3.3六氢加蛇麻酮的制备
Figure PCTCN2021120638-appb-000008
六氢-β-酸通过制备色谱分离获得纯度为98.9％的六氢加蛇麻酮。 1HNMR(500MHz,DMSO-d6):δ(ppm)2.82-2.84(m,2H),2.37-2.40(m,2H),2.00-2.05(m,1H),1.80-1.88(m,4H),1.77-1.80(m,1H),1.34-1.51(q,2H),1.29-1.33(m,2H),0.90-0.96(m,4H),0.86-0.90(m,24H)；LC-MS(ESI,pos.ion)m/z:421[M+H] +。
A4六氢-β-酸组分化合物的前体化合物的制备
A4.1六氢合蛇麻酮单乙酯的制备
Figure PCTCN2021120638-appb-000009
六氢合蛇麻酮2.0g(4.92mmol,1.0eq)，溶于10mL二氯甲烷中，加三乙胺0.59g(5.90mmol,1.2eq)，搅拌降温至-5℃～0℃。将乙酰氯0.47g(5.90mmol,1.2eq)溶于2mL二氯甲烷中后缓慢滴加反应体系中，滴毕反应体系升温至室温，薄层层析法监控反应至终点，反应体系中加5mL纯水，搅拌后分离有机相。有机相经水洗(15mL×3)、五水硫酸钠干燥后减压浓缩除去有机溶剂得油状产物1.35g，收率为61.3％。
A4.2六氢合蛇麻酮单丙酯的制备
Figure PCTCN2021120638-appb-000010
六氢合蛇麻酮2.0g(4.92mmol,1.0eq)，溶于10mL二氯甲烷中，加三乙胺0.48g(5.90mmol,1.2eq)，搅拌降温至-5℃～0℃。将丙酰氯0.55g(5.90mmol,1.2eq)溶于3mL二氯甲烷中后缓慢滴加反应体系中，滴毕反应体系升温至室温，薄层层析法监控反应至终点，反应体系中加5mL纯水，搅拌后分离有机相。有机相经水洗(15mL×3)、五水硫酸钠干燥后减压浓缩除去有机溶剂得油状产物1.52g，收率为66.8％。
A4.3六氢合蛇麻酮单丁酯的制备
Figure PCTCN2021120638-appb-000011
六氢合蛇麻酮2.0g(4.92mmol,1.0eq)，溶于10mL二氯甲烷中，加三乙胺0.60g(5.90mmol,1.2eq)，搅拌降温至-5℃～0℃。将丁酰氯0.62g(5.90mmol,1.2eq)溶于3mL二氯甲烷中后缓慢 滴加反应体系中，滴毕反应体系升温至室温，薄层层析法监控反应至终点，反应体系中加5mL纯水，搅拌后分离有机相。有机相经水洗(15mL×3)、五水硫酸钠干燥后减压浓缩除去有机溶剂得油状产物1.29g，收率为55.1％。
A4.4六氢合蛇麻酮双丙酯的制备
Figure PCTCN2021120638-appb-000012
六氢合蛇麻酮2.5g(6.15mmol,1.0eq)，投入50mL干燥的反应容器中，通入氮气排氧除湿后依次加入正庚烷20mL和4-二甲基吡啶0.1g(0.82mmol,0.13eq)。反应体系降温至0℃，依次滴加丙酰氯1.37g(14.76mmol,2.4eq)和三乙胺1.49g(14.76mmol,2.4eq)，滴毕后，反应体系继续搅拌反应，薄层层析法监控反应至终点，反应液过滤除去三乙胺盐酸盐后减压浓缩除去溶剂得黄色油状粗产物，经硅胶柱层析(二氯甲烷/甲醇(w/w)＝10/1)分离得到六氢合蛇麻酮双丙酯1.39g，收率为43.7％。
A4.5六氢合蛇麻酮双丁酯的制备
Figure PCTCN2021120638-appb-000013
六氢合蛇麻酮2.5g(6.15mmol,1.0eq)，投入50mL干燥的反应容器中，通入氮气排氧除湿后依次加入正庚烷20mL和4-二甲基吡啶0.1g(0.82mmol,0.13eq)。反应体系降温至0℃，依次滴加丁酰氯1.57g(14.76mmol,2.4eq)和三乙胺1.49g(14.76mmol,2.4eq)，滴毕后，反应体系继续搅拌反应，薄层层析法监控反应至终点，反应液过滤除去三乙胺盐酸盐后减压浓缩除去溶剂得黄色油状粗产物，经硅胶柱层析(二氯甲烷/甲醇(w/w)＝10/1)分离得到六氢合蛇麻酮双丁酯1.59g，收率为47.2％。
A4.6六氢加蛇麻酮单丙酯的制备
Figure PCTCN2021120638-appb-000014
六氢加蛇麻酮2.5g(5.94mmol,1.0eq)，溶于15mL二氯甲烷中，加三乙胺0.72g(7.13mmol,1.2eq)，搅拌降温至-5℃～0℃。将丙酰氯0.66g(7.13mmol,1.2eq)溶于6mL二氯甲烷中后缓慢滴加反应体系中，滴毕反应体系升温至室温，薄层层析法监控反应至终点，反应体系中加5mL纯水，搅拌后分离有机相。有机相经水洗(20mL×3)、五水硫酸钠干燥后减压浓缩除去有机溶剂得油状产物1.66g，收率为58.5％。
A4.7六氢加蛇麻酮单丁酯的制备
Figure PCTCN2021120638-appb-000015
六氢加蛇麻酮2.5g(5.94mmol,1.0eq)，溶于15mL二氯甲烷中，加三乙胺0.72g(7.13mmol,1.2eq)，搅拌降温至-5℃～0℃。将丁酰氯0.76g(7.13mmol,1.2eq)溶于8mL二氯甲烷中后缓慢滴加反应体系中，滴毕反应体系升温至室温，薄层层析法监控反应至终点，反应体系中加6mL纯水，搅拌后分离有机相。有机相经水洗(30mL×3)、五水硫酸钠干燥后减压浓缩除去有机溶剂得油状产物1.45g，收率为49.6％。
A4.8六氢加蛇麻酮双丙酯的制备
Figure PCTCN2021120638-appb-000016
六氢加蛇麻酮2.5g(5.94mmol,1.0eq)，投入50mL干燥的反应容器中，通入氮气排氧除湿后依次加入正庚烷25mL和4-二甲基吡啶0.15g(0.82mmol,0.14eq)。反应体系降温至0℃，依 次滴加丙酰氯1.32g(14.26mmol,2.4eq)和三乙胺1.44g(14.26mmol,2.4eq)，滴毕后，反应体系继续搅拌反应，薄层层析法监控反应至终点，反应液过滤除去三乙胺盐酸盐后减压浓缩除去溶剂得黄色油状粗产物，经硅胶柱层析(二氯甲烷/甲醇(w/w)＝10/1)分离得到六加蛇麻酮双丙酯1.42，收率为44.9％。
A4.9六氢加蛇麻酮双丁酯的制备
Figure PCTCN2021120638-appb-000017
六氢加蛇麻酮2.5g(5.94mmol,1.0eq)，投入50mL干燥的反应容器中，通入氮气排氧除湿后依次加入正庚烷25mL和4-二甲基吡啶0.1g(0.82mmol,0.14eq)。反应体系降温至0℃，依次滴加丁酰氯1.52g(14.26mmol,2.4eq)和三乙胺1.44g(14.26mmol,2.4eq)，滴毕后，反应体系继续搅拌反应，薄层层析法监控反应至终点，反应液过滤除去三乙胺盐酸盐后减压浓缩除去溶剂得黄色油状粗产物，经硅胶柱层析(二氯甲烷/甲醇(w/w)＝10/1)分离得到六氢加蛇麻酮双丁酯1.72g，收率为51.7％。
A4.10六氢合蛇麻酮单癸酯的制备
Figure PCTCN2021120638-appb-000018
六氢合蛇麻酮2.5g(6.15mmol,1.0eq)，溶于10mL二氯甲烷中，加三乙胺0.75g(7.38mmol,1.2eq)，搅拌降温至-5℃～0℃。将癸酰氯1.41g(7.38mmol,1.2eq)溶于8mL二氯甲烷中后缓慢滴加反应体系中，滴毕反应体系升温至室温，薄层层析法监控反应至终点，反应体系中加5mL纯水，搅拌后分离有机相。有机相经水洗(15mL×3)、五水硫酸钠干燥、硅胶脱色后减压浓缩除去有机溶剂得油状产物1.87g，收率为54.2％。
A4.11六氢合蛇麻酮单月桂酸酯的制备
Figure PCTCN2021120638-appb-000019
六氢合蛇麻酮2.5g(6.15mmol,1.0eq)，溶于10mL二氯甲烷中，加三乙胺0.75g(7.38mmol,1.2eq)，搅拌降温至-5℃～0℃。将月桂酰氯1.61g(7.38mmol,1.2eq)溶于8mL二氯甲烷中后缓慢滴加反应体系中，滴毕反应体系升温至室温，薄层层析法监控反应至终点，反应体系中加5mL纯水，搅拌后分离有机相。有机相经水洗(15mL×3)、五水硫酸钠干燥后减压浓缩除去有机溶剂后所得粗产品经硅胶柱层析(二氯甲烷/甲醇(w/w)＝10/0.8)分离得到油状产物2.00g，收率为55.3％。
注：六氢合蛇麻酮单戊酯、六氢合蛇麻酮单己酯的制备方法与六氢合蛇麻酮单丁酯的相同。
实施例B六氢-β-酸组分化合物的前体化合物的饲用组合物的制备
本发明涉及的饲用组合物中六氢-β-酸组分化合物的前体化合物的含量为大于或等于0.00001％，可根据不同的动物的不同生长阶段或饲料工业的产品特性(如饲料添加剂、饲料添加剂原料、饲料原料等)的使用可行性进行含量调配，还可根据不同的饲料配方其他营养物质和非营养物质的比重进行含量调配以满足饲料配方的需要。下面仅以基础颗粒性预混剂为例对本发明所述的饲用组合物做个示例进行解释，任何的相似配方或配方组分的非协同效果的更换或增加都视为与本发明的宗旨一致。
饲用组合物的制备方法：将原料和辅料投入混合机组混合均匀，与质量分数1.3％羟丙基甲基纤维素水溶液(粘合剂)按照100:35的比例投入制粒机内，启动混合及切刀运行3-5min，物料制粒后进入流化床进行干燥，30min后过16目筛网。
原料：实施例A制备的六氢-β-酸组分化合物的前体化合物。
辅料(载体)：玉米淀粉。
产品配方：如表1所述。
表1混合型颗粒饲料添加剂的配方
Figure PCTCN2021120638-appb-000020
Figure PCTCN2021120638-appb-000021
实施例C六氢-β-酸组分化合物的前体化合物的热稳定性和光稳定性研究
1试验材料
实验仪器及试剂：药物稳定性试验箱、高效液相色谱仪(HPLC)；甲醇(色谱级)、磷酸(分析纯)。
供试品：六氢合蛇麻酮原料、六氢合蛇麻酮单乙酯原料、六氢合蛇麻酮单丙酯原料、六氢合蛇麻酮单丁酯原料。
2实验步骤
2.1样品的制备及实验方法
供试品1％预混剂样品的制备：称取1g供试品原料，加入99g玉米芯粉，在搅拌机中混匀，即得1％供试品预混剂样品，待检。
60℃下稳定性试验：供试品原料及其1％预混剂样品放置于培养皿中，摊成≤5mm的薄层，放置于60℃下，于第5天、10天取样进行HPLC检测，每种样品平行取样两次。检测结果如表2所示。
光照下稳定性试验：供试品及其1％预混剂样品放置于培养皿中，摊成≤5mm的薄层于4500Lx光照环境下，于第5天、10天时取样进行HPLC检测，每种样品平行取样三次。检测结果如表2所示。
2.2标准溶液的制备
准确称取25.0mg供试品，加入适量甲醇超声溶解，容量瓶中定容至25mL，制成工作储备液。取适量工作储备液，用甲醇分别稀释至浓度为100ppm、500ppm、1000ppm的工作液，经0.22μm有机滤膜过滤后，HPLC检测分析。检验样品浓度与HPLC峰面积响应值是否成线性，绘制标准曲线。
2.3供试品溶液的制备
准确称取放置于不同环境条件下的25.0mg供试品、2.0000g 1％供试品预混剂样品精密加入25mL甲醇超声溶解10min，经0.22μm有机滤膜过滤后，HPLC检测分析。
2.4 HPLC检测条件
色谱柱：waters Symmetry C18柱(250mm*4.6mm，5μm)柱；流动相：0.02％磷酸：甲醇＝5:95(v:v)；检测波长：235nm；柱温：25℃；进样量：10μL；流速：1ml/min。
3实验结果
从表2的结果可知，六氢合蛇麻酮的1％预混剂，在60℃高温稳定性试验的10天试验周期中，有效成分的变量超过5％；在光照稳定性试验试验中，第10天时有效成分的含量的变化量超过了15％；六氢合蛇麻酮的单乙酯、单丙酯和单丁酯在高温和光照试验中，无论是原料还是在预混剂中，有效成分的含量变化均未超过5％。由此可见，六氢合蛇麻酮的短链脂肪酸酯类衍生物具有符合饲料添加剂的要求的热稳定性和光稳定性。
表2六氢合蛇麻酮酯类衍生物及其1％预混剂的稳定性影响因素研究结果
Figure PCTCN2021120638-appb-000022
Figure PCTCN2021120638-appb-000023
实施例D六氢-β-酸组分化合物的前体化合物的在饲料中的长期稳定性研究
1试验材料
实验仪器及试剂：药物稳定性试验箱、高效液相色谱仪(HPLC)；甲醇(色谱级)、磷酸(分析纯)、正己烷(色谱级)、异丙醇(色谱级)。
供试品：六氢合蛇麻酮原料、六氢合蛇麻酮单乙酯原料、六氢合蛇麻酮单丙酯原料、六氢合蛇麻酮单丁酯原料、六氢合蛇麻酮单戊酯原料(广州英赛特有限公司化学部提供)、六氢合蛇麻酮单己酯原料(广州英赛特有限公司化学部提供)、六氢合蛇麻酮单月桂酸酯原料、六氢合蛇麻酮单磷酸酯二钠盐(广州英赛特有限公司化学部提供)、六氢合蛇麻酮单磷酸酯二乙酯(广州英赛特有限公司化学部提供)。
饲料：朱师傅预混合饲料(朱师傅好乳真经5.33％仔猪复合预混合饲料A：朱师傅好乳真经2.67％仔猪复合预混合饲料B＝2:1粉碎混匀)、正大乳猪教槽饲料、英赛特肉鸡饲料、广东科邦4％预混合饲料。
2实验步骤
2.1样品的制备及实验方法
供试品1％预混剂样品的制备：称取1g供试品原料，加入99g玉米芯粉，在搅拌机中混匀，即得1％供试品预混剂样品。
供试品500ppm饲料样品的制备：将供试品1％预混剂样品，用朱师傅预混合饲料逐级的 稀释至5000ppm、500ppm的供试品饲料样品，待检。
供试品100ppm饲料样品的制备：将供试品1％预混剂样品，用正大乳猪教槽饲料逐级的稀释至1000ppm、100ppm的供试品饲料样品，待检。
供试品100ppm饲料样品的制备：将供试品1％预混剂样品，用南雄提供的肉鸡饲料逐级的稀释至1000ppm、100ppm的供试品饲料样品，待检。
供试品2000ppm饲料样品的制备：将供试品1％预混剂样品，用广东科邦4％预混合饲料逐级的稀释至5000ppm、2000ppm的供试品饲料样品，待检。
实验方法：上述供试品饲料样品平行取三批样品在25℃±2℃、RH60％±10％条件进行试验，于第5天、10天、15天、30天、60天和90天取样进行HPLC检测。检测结果如表3所示。
2.2标准溶液的制备
准确称取25.0mg供试品原料，加入适量甲醇或正己烷超声溶解，容量瓶中定容至50mL，制成质量浓度为500ppm的工作储备液。取适量工作储备液，用甲醇或正己烷分别稀释至浓度为10ppm、25ppm、50ppm、100ppm、250ppm的工作液，经0.22μm有机滤膜过滤后，HPLC检测分析。检验样品浓度与HPLC峰面积响应值是否成线性，绘制标准曲线。
2.3供试品溶液的制备
准确称取不同取样时间的供试品饲料样品5.0000g，精确加入25mL甲醇或正己烷超声溶解10min，经0.22μm有机滤膜过滤后，HPLC检测分析。
2.4 HPLC检测条件
反相色谱：仪器：waters e2695 PDA检测器；流动相：0.02％磷酸：甲醇＝5:95(v:v)；色谱柱：waters Symmetry C18(250mm*4.6mm，5μm)柱；检测波长：235nm；柱温：25℃；进样量：10μL；流速：1ml/min。
正相色谱：仪器：岛津LC-14C/SPD-15C；色谱柱：SuperSil NH2柱，5μm 250mm×4.6mm；流动相：正己烷：异丙醇＝60:40(v:v)；检测波长：235nm；柱温：25℃；样量：20μL；流速：1ml/min。
3实验结果
从表3的结果可知，在试验周期中，六氢合蛇麻酮在饲料中30天后含量大幅度下降，六氢合蛇麻酮的磷酸酯系列化合物在饲料中的有效成分含量在试验初期急速大幅的下降，而六氢合蛇麻酮的脂肪酸酯类衍生物在饲料中的常温条件下可以保持较好的稳定性，其中，六氢合蛇麻酮单乙酯、六氢合蛇麻酮单戊酯和六氢合蛇麻酮单己酯在部分饲料中稳定性较差。
表3六氢合蛇麻酮酯类衍生物在饲料中的常温稳定性研究结果
Figure PCTCN2021120638-appb-000024
Figure PCTCN2021120638-appb-000025
实施例E六氢-β-酸组分化合物前体化合物对肉猪生产性能的影响
67日龄体重相近的“杜长大”三元杂交瘦肉型小猪480头，随机分成16个处理组，每组3个重复，每个重复10头，公母各半。试验前对猪圈及器具进行消毒。试验期在同一猪圈同一饲养管理条件下分栏圈养。试验期间，试验猪自由采食和饮水，日喂料2次。各试验组分别为对照组(1组)和试验2～16组。其中，对照组仅给予基础日粮，试验2～16组分别在基础日粮的基础上给与以混料方式添加六氢-β-酸组分化合物或六氢-β-酸组分化合物的前体化合物的日粮，并使得试验2～16组中各添加剂的有效成分的浓度为5ppm或25ppm，具体如表4所示。
整个饲养过程各试验组不额外添加其它抗氧化成分及促生长剂。试验周期14天，以每个重复为单位，于试验第14天不停水停料12h后称重，计算各试验组的平均日采食量(ADFI，g/d*头)、平均日增重(ADG，g/d*头)和料肉比(FCR)。计算公式如下：
平均日采食量＝(配料总量-剩料量)/(试验天数×每重复猪数)；
平均日增重＝(试验末平均体重-试验初平均体重)/试验天数；
料肉比＝平均日采食量/平均日增重。
试验结果如表4所示。
表4六氢-β-酸组分化合物及其前体化合物对肉猪的生产性能影响结果
Figure PCTCN2021120638-appb-000026
Figure PCTCN2021120638-appb-000027
从表4结果可知，本实验从采食量、增重和饲料转化率三方面对供试品对试验猪的生产性能的影响进行对比和考核，六氢合蛇麻酮或六氢加蛇麻酮的酯类衍生物对试验猪的采食量与空白组或六氢合蛇麻酮组或六氢加蛇麻酮组相比具有不同程度的提升，并且在相同使用剂量下六氢合蛇麻酮或六氢加蛇麻酮的单乙酯、单丙酯或单丁酯对试验猪的料肉比的影响分别与六氢合蛇麻酮或六氢加蛇麻酮相比具有等效或更优的改善效果，而六氢合蛇麻酮的单己酯、单癸酯和单月桂酸酯的作用效果不及单乙酯和单丁酯显著，可能原因在于这些酯类化合物进入动物肠道中水解不彻底或水解速度过慢。
实施例F六氢-β-酸组分化合物前体化合物对肉鸡生产性能的影响
试验采用单因子随机设计，选择1日龄、体重相近的平均体重为50g的三黄羽肉鸡540只，随机分为6个处理组，每组6个重复，公母各半，每个重复15只三黄羽肉鸡。试验前对鸡舍及器具进行消毒。试验期在同一鸡舍同一饲养管理条件下进行笼养。基础日粮以玉米-豆粕为主，整个饲养过程不额外添加其它抗氧化成分及促生长剂。各试验组分别为对照组(1组)和试验2～6组。其中，对照组仅给与基础日粮，试验2～6组分别在基础日粮的基础上给与添加六氢合蛇麻酮、六氢合蛇麻酮单乙酯和六氢合蛇麻酮单丁酯的日粮具体如表5所示。
试验期共30天，试验鸡自由饮水和采食，日喂料2次。以每个重复为单位，于31日龄称重(停料12h、不停水)，统计试验鸡耗料量，计算各组试验鸡的平均日采食量(ADFI，g/d*只)、平均日增重(ADG，g/d*只)和料肉比(FCR)，计算公式如下：
料肉比(FCR)＝平均日采食量/平均日增重。
试验结果如表5所示。
表5六氢-β-酸组分化合物前体化合物在肉鸡料中的应用效果研究
试验组 供试品 ADFI(g/d*只) ADG(g/d*只) FCR
1组 - 49.55 23.14 2.14
2组 六氢合蛇麻酮20ppm 49.68 25.19 1.97
3组 六氢合蛇麻酮单乙酯2ppm 49.13 25.67 2.02
4组 六氢合蛇麻酮单乙酯20ppm 50.06 27.36 1.95
5组 六氢合蛇麻酮单丁酯2ppm 48.32 24.65 1.96
6组 六氢合蛇麻酮单丁酯20ppm 49.95 25.88 1.93
从表5结果可知，本实验从采食量、增重和饲料转化率三方面对供试品对试验鸡的生产性能的影响进行对比和考核。六氢合蛇麻酮的单乙酯和单丁酯对肉鸡生产性能的改善效果与六氢合蛇麻酮的作用效果是等效的。
工业实用性
本申请中，以六氢-β-酸组分化合物六氢合蛇麻酮以及/或者六氢加蛇麻酮的前体化合物具有与六氢合蛇麻酮以及/或者六氢加蛇麻酮基本等效的改善动物生产性能的功效，作为饲用组合物的功能性成分使用，不仅能够避免六氢-β-酸组分化合物在饲料制粒过程中的热稳定性及长期存放的稳定性等问题，同时还能够起到比六氢-β-酸组分化合物等效的改善所饲喂动物生产性能的效果。

Claims (14)

  1. 结构如式(I)所示的六氢-β-酸组分化合物的前体化合物，或所述前体化合物的溶剂合物及饲料可接受的盐:
    Figure PCTCN2021120638-appb-100001
    其中，R 1选自取代或非取代的C 1-C 2烷基；R 2或R 3独立选自H，取代或非取代的直链或支链的C 2-C 4羰基。
  2. 根据权利要求1所述的六氢-β-酸组分化合物的前体化合物，其特征在于，所述的R 2或R 3独立选自H或C(＝O)CH 2CH 3，且不同时为H。
  3. 根据权利要求1所述的六氢-β-酸组分化合物的前体化合物，其特征在于，所述的R 2或R 3独立选自H或C(＝O)(CH 2) 2CH 3，且不同时为H。
  4. 根据权利要求1所述的六氢-β-酸组分化合物的前体化合物，其特征在于，所述的前体化合物具有如下结构之一：
    Figure PCTCN2021120638-appb-100002
    Figure PCTCN2021120638-appb-100003
  5. 一种饲用组合物，其特征在于，所述饲用组合物包含权利要求1-4任一项所述的六氢-β-酸组分化合物的前体化合物，或所述前体化合物的溶剂合物及饲料可接受的盐的至少一种，和任选的可饲用辅料。
  6. 根据权利要求5所述的饲用组合物，其特征在于，所述的六氢-β-酸组分化合物的前体化合物如式(I2-1)或式(I2-2)所示的任一化合物：
    Figure PCTCN2021120638-appb-100004
  7. 根据权利要求5所述的饲用组合物，其特征在于，所述的六氢-β-酸组分化合物的前体化合物为如式(I2-3)或式(I2-4)所示的任一化合物：
    Figure PCTCN2021120638-appb-100005
  8. 根据权利要求5所述的饲用组合物，其特征在于，所述的六氢-β-酸组分化合物的前体化合物为如式(I2-1)或式(I2-3)所示的任一化合物：
    Figure PCTCN2021120638-appb-100006
  9. 根据权利要求5所述的饲用组合物，其特征在于，所述的六氢-β-酸组分化合物的前体化合物为如式(I2-2)或式(I2-4)所示的任一化合物：
    Figure PCTCN2021120638-appb-100007
  10. 根据权利要求5所述的饲用组合物，其特征在于，所述饲用组合物还包含附加动物饲料添加剂和/或动物饲料原料。
  11. 根据权利要求10所述的饲用组合物，其特征在于，所述附加动物饲料添加剂包括选自由营养性饲料添加剂，非营养性添加剂和药物饲料添加剂所组成的组中的一种或几种。
  12. 权利要求1-4任一项所述的六氢-β-酸组分化合物的前体化合物或权利要求5-11任一项所述的饲用组合物在制备动物饲料添加剂中的应用。
  13. 权利要求1-4任一项所述的六氢-β-酸组分化合物的前体化合物或权利要求5-11任一项所述的饲用组合物在制备动物饲料中的应用。
  14. 一种改善动物生产性能的方法，其特征在于，所述方法包括：以权利要求5-11中任一项所述的饲用组合物进行动物饲喂；或者，以包含权利要求5-11中任一项所述的饲用组合物的饲料进行动物饲喂。
PCT/CN2021/120638 2020-11-20 2021-09-26 六氢-β-酸组分化合物的前体化合物、饲用组合物及其应用 WO2022022752A1 (zh)

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