WO2019223630A1 - N-乙酰甘氨酰谷氨酰胺在动物饲料添加剂中的应用 - Google Patents

N-乙酰甘氨酰谷氨酰胺在动物饲料添加剂中的应用 Download PDF

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Publication number
WO2019223630A1
WO2019223630A1 PCT/CN2019/087524 CN2019087524W WO2019223630A1 WO 2019223630 A1 WO2019223630 A1 WO 2019223630A1 CN 2019087524 W CN2019087524 W CN 2019087524W WO 2019223630 A1 WO2019223630 A1 WO 2019223630A1
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Prior art keywords
feed
glutamine
animal
acetylglycyl
test
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PCT/CN2019/087524
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English (en)
French (fr)
Inventor
彭险峰
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广州英赛特生物技术有限公司
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Publication of WO2019223630A1 publication Critical patent/WO2019223630A1/zh

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/20—Animal feeding-stuffs from material of animal origin
    • 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
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins

Definitions

  • the invention relates to the field of animal feed additives, in particular to N-acetylglycyl glutamine or a racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt thereof.
  • Glutamine is the most abundant amino acid in animal blood, intestinal mucosal epithelial cells, renal tubular cells, lymphocytes, macrophages and fibroblasts, and it is used to maintain the normal form and function of the intestine and immunity. It plays a very important role and is of great significance for protein nutrition balance in livestock and poultry. Glutamine has low solubility in water, is easily cyclized into toxic pyroglutamic acid and ammonia in solution, and is cleaved into glutamic acid and ammonia in heat and strong bases. It has a low absorption rate in the gastrointestinal system of animals, so it is limited Its application in intestinal nutrition and animal production.
  • Glycyl glutamine dipeptide is a dipeptide synthesized from glycine and glutamine. Its solubility in aqueous solution at room temperature reaches 154 g / L. Compared with glutamine, it is more stable in aqueous solution, heat and other storage conditions. It can be used in combination with a total parenteral nutrition solution to enter the animal in the form of a dipeptide and be hydrolyzed by aminopeptidase to release glycine and glutamine to provide glutamine to increase the plasma glutamine concentration and play a biological role.
  • the granulation process of compound feed is to mix the feed raw materials, feed additives and auxiliary materials in a mixer according to the proportion, and after the preparation in the feed granulator, it is granulated through the process of high-temperature puffing and granulation, and glutamine is in this process.
  • the content decreased significantly.
  • Further application of glycylglutamine to animal breeding when the dosage of glycylglutamine dipeptide exceeds 2500ppm, the feed intake of the test pigs decreased significantly, thereby reducing the daily gain of the test pigs.
  • the present invention provides a glutamine derivative with stable physicochemical properties and good palatability for animals, and the application of the glutamine derivative in the preparation of animal feed additives and animal breeding.
  • the glutamine derivative provided by the present invention is N-acetylglycylglutamine, including its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed. Acceptable salt.
  • the present invention provides the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feed-acceptable salts. Application in the preparation of animal feed additives.
  • the N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt are prepared by using the Animal feed additives are glutamine substitutes for animals.
  • the N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt are prepared by using the
  • the animal feed additive is a glycylglutamine substitute for animals.
  • the animal feed additive is applied to livestock breeding at various growth stages.
  • the animal feed additive is applied to livestock breeding at a young stage.
  • the animal feed additive is applied to poultry breeding at various growth stages.
  • the animal feed additive is applied in poultry farming at a young stage.
  • the animal feed additive is applied in the aquaculture of aquaculture animals.
  • the animal feed additive is applied in pet breeding.
  • the present invention provides a feed composition, said feed composition comprising N-acetylglycylglutamine and its racemate, stereoisomers, geometric isomers, interconversion Isomers, solvates or feed acceptable salts and feed supplements.
  • the feedable adjuvant is selected from a feedable carrier, a diluent, an excipient, a vehicle, or a combination thereof.
  • the feed composition further comprises an animal feed material.
  • the feed composition further comprises an additional animal feed additive.
  • the feed composition further comprises animal feed ingredients and additional animal feed additives.
  • the additional animal feed additive may be selected from nutritional feed additives and / or general feed additives and / or medicinal feed additives.
  • the present invention also provides a method for improving production performance of farmed animals.
  • the method comprises administering N-acetylglycylglutamine or a racemate, stereoisomer, geometric isomer, tautomer, solvent provided by the present invention to a farmed animal.
  • feed acceptable salts such as the addition of N-acetylglycyl glutamine or its racemates, stereoisomers, geometric isomers, tautomers, solvates, or Feed acceptable salt and then feed the animals.
  • the method includes administering to a farmed animal the present invention comprising N-acetylglycylglutamine or a racemate, stereoisomer, geometric isomer, A feed composition for a isomer, solvate or feed-acceptable salt.
  • the farm animals are livestock, poultry, aquaculture animals or pets at various growth stages.
  • the farmed animal is a livestock or poultry in a juvenile stage.
  • the livestock such as pigs
  • the acceptable dosage of the structure, solvate or feed salt is 1500-5000 ppm, and more preferably 1500-3000 ppm.
  • said poultry such as chicken, said adding N-acetylglycylglutamine or a racemate, stereoisomers, geometric isomers, intermutation to animal feed
  • the structure, solvate or feed-acceptable salt is added in an amount of 1000 to 2000 ppm.
  • the aquaculture animal such as grass carp
  • the present invention also provides the N-acetylglycylglutamine or its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable. Methods for the preparation, isolation and purification of salts.
  • the N-acetylglycylglutamine or its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt or premix provided by the present invention is used in feed
  • the additive has high stability under high temperature, high humidity, and light stability, as well as accelerated tests, long-term tests, and other conditions.
  • the stability of the content is not less than 95% during the stability inspection cycle, which has reached the level of feed additives. Temperature, humidity, light and storage stability requirements.
  • N-acetylglycyl glutamine or its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts are lower in animal breeding tests.
  • the effect of high-dose glutamine on animal performance can be reached at the dose.
  • the dosage is increased, the effect on the test animal's feed intake does not appear.
  • the animal feed of the high-dose glycylglutamine dipeptide does not appear. Rapid decline in palatability issues.
  • any embodiment of any aspect of the present invention may be combined with other embodiments as long as there is no contradiction between them.
  • any technical feature may be applied to the technical feature in other embodiments as long as there is no contradiction between them.
  • solvate refers to the formation of a combination of chemical or non-chemically equivalent solvent molecules through non-covalent intermolecular forces caused by external and internal conditions during the contact between the compound of the present invention and a solvent molecule. Eutectic association. Solvents that form solvates include, but are not limited to, solvents such as water, acetone, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, isopropanol, and the like. "Hydrate” refers to an association or crystal formed by water molecules, that is, a compound that binds chemically equivalent or non-chemically equivalent water through non-covalent intermolecular forces.
  • the feed-acceptable salt is a salt formed by the butyrylglutamic acid derivative of the present invention and an organic base, an inorganic base, an organic acid, or an inorganic acid which is non-toxic to animals.
  • feed acceptable means that the substance or composition must be chemically or toxicologically related to the composition of the feed or edible farm animal.
  • the "significant change" under the conditions of the influencing factor investigation test related to the present invention means "a change of more than 5% in the content of the test product is determined”.
  • the "animal” referred to in the present invention refers to a person or aquaculture who cannot use inorganic matter to synthesize organic matter, and can only use organic matter as food to feed, digest, absorb, breathe, circulate, excrete, feel, exercise and reproduce. animal.
  • “Farm animals” include poultry, livestock, aquaculture animals, and other animals legally captured by captives, 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” includes, for example, chicken, duck, goose, quail, pigeon, and the like.
  • aquaculture animals includes, for example, fish, shrimp, turtles, turtles and the like.
  • stereoisomers refer to compounds having the same chemical structure but different arrangements of atoms or groups in space.
  • feed additive refers to a small amount or a trace amount of substance added during the processing, production, and use of feed, and is divided into a nutritional feed additive and a general feed additive, also called a non-nutritive feed additive.
  • Nutritional feed additives refer to small or trace substances added to compound feed to balance feed nutrients, improve feed utilization, and directly exert nutritional effects on animals, including vitamins, trace elements, amino acids, small peptides, and non-protein nitrogen.
  • Non-nutritive additives refer to some non-nutritive substances added to feeds to improve feed utilization, ensure feed quality and quality, and be beneficial to animal health or metabolism, including growth promoters, deworming health Agents, feed conditioners, feed conditioners, feed storage agents and Chinese herbal medicine additives.
  • the feed related to the present invention refers to a product for animal consumption that has been industrially processed and produced.
  • composition refers to a collective of compounds containing one or more compounds as an active ingredient.
  • the "contain” in the present invention is an open expression, and includes both the content explicitly referred to in the present invention, but does not exclude other aspects.
  • N-acetylglycylglutamine structure provided by the present invention is shown by formula (I):
  • the N-acetylglycyl glutamine provided by the present invention is prepared by glutamic acid as a starting material through four steps of esterification of carboxylic acid, chloroacetylation of amino group, ammonolysis and acetylation.
  • the glutamic acid is a chiral compound
  • the glutamic acid according to the present invention is selected from the group consisting of L-(-)-glutamic acid (structure such as formula (II)), right D-(+)-glutamic acid (structure such as formula (III)) or racemic DL- ( ⁇ ) glutamic acid, N-acetylglycyl with chiral center can be obtained under relevant reaction conditions Stereoisomers or racemates of glutamine.
  • the chiral stereoisomers of glutamic acid and the stereoisomers of N-acetylglycylglutamine can undergo stereo configuration conversion under appropriate conditions, such as glutamine The conformation of acids or N-acetylglycyl glutamine and the intermediates for preparing the reaction are changed.
  • the glutamic acid undergoes four-step reaction such as esterification of carboxylic acid, chloroacetylation of amino group, ammonolysis and acetylation to form the corresponding N-acetylglycylglutamine with rigid structure
  • the reaction substrate Different geometric isomer products can be generated during the reaction.
  • the present invention provides a process for preparing N-acetylglycyl glutamine, which also involves the process of isolation, purification, or recrystallization of the reaction product.
  • the reaction product can be obtained from the reaction system by a solvent removal method.
  • the crude product is dissolved and analyzed in alcohol solvents, alcohol-water mixed solvents or other organic solvents that can be used for product recrystallization under appropriate temperature, light and mechanical vibration conditions. Crystal or precipitation or recrystallization and separation to obtain N-acetylglycylglutamine with a certain crystalline state.
  • the N-acetylglycyl glutamine having a certain crystalline state is a solvate of N-acetylglycyl glutamine crystals or N-acetylglycyl glutamine.
  • the solvate of N-acetylglycylglutamine can be selected from the hydrate of N-acetylglycylglutamine or N-acetylglycylglutamine ethanolate.
  • the preparation of N-acetylglycylglutamine provided by the present invention can also be processed after salting out.
  • the salting out method uses the principle of acid-base neutralization method, acid-base coordination method or acid-base chelation method to make N-acetylglycylglutamine and the corresponding organic base, inorganic base, organic acid or inorganic acid The process of salt precipitation to obtain acceptable salt for feed.
  • the N-acetylglycyl-L-glutamine raw material is placed in a suitable container under the conditions of the influencing factor investigation and test conditions, spread into a thin layer not exceeding 5mm thick, and the relevant indicators are sampled and tested at the corresponding time points. N-acetylglycyl-L-glutamine did not change significantly.
  • the conditions for examining the influencing factors are the conditions for examining high-temperature stability, and N-acetylglycyl-L-glutamine has not changed significantly.
  • the inspection conditions of the influencing factors are inspection conditions of high humidity stability, and the various detection indexes on the 5th day of the inspection period show N-acetylglycyl-L-glutamine and the control Compared with that, it decreased by about 5%, and the detection indicators in the remaining inspection cycles did not change significantly compared with the detection indicators on the fifth day.
  • the conditions for examining the influencing factors are conditions for examining the stability of light, and N-acetyl-glycyl-L-glutamine has not changed significantly.
  • the premix of N-acetylglycyl-L-glutamine is placed in a suitable container under the conditions of the influencing factor investigation test conditions, spread into a thin layer not exceeding 5mm thick, and sampled at the corresponding time point Related indicators were detected, and N-acetylglycyl-L-glutamine did not change significantly.
  • the conditions for examining the influencing factors are the conditions for examining high-temperature stability, and N-acetylglycyl-L-glutamine does not change significantly in the premix.
  • the conditions for examining the influencing factors are the conditions for examining high humidity stability, and N-acetylglycyl-L-glutamine does not change significantly in the premix.
  • the conditions for examining the influencing factors are the conditions for examining the stability of light, and N-acetylglycyl-L-glutamine has not changed significantly in the premix.
  • the invention relates to the use of N-acetylglycylglutamine.
  • N-acetylglycylglutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts thereof provided by the present invention are used for preparing animal feed additives in.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds acceptable to the present invention are applied.
  • the salt is prepared as a glutamine substitute as an in vitro source of glutamine for animals at various growth stages.
  • N-acetylglycyl glutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts prepared by using the present invention are prepared as each A glutamine substitute for an in vitro source of glutamine for an animal at a growth stage, which animal may be selected from livestock, poultry, aquaculture animals, or pets at various growth stages.
  • the domestic animals include, but are not limited to, pigs, cattle, sheep, horses, rabbits, marten or donkeys
  • the domestic fowls include, 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, turtle, crab, badger, bullfrog, tadpole or loach
  • the pets include but are not limited to dogs or cats of various subspecies.
  • N-acetylglycyl glutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable in the present invention are applied.
  • Salt is prepared as a glutamine substitute for in vitro sources of glutamine required for weaning pigs.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds provided by the present invention are acceptable.
  • the salt is prepared as a glutamine substitute for an in vitro source of glutamine required for medium pig nutrition.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds provided by the present invention are acceptable.
  • the salt is prepared as a glutamine substitute for the in vitro source of glutamine required by chicks.
  • N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds provided by the present invention may be applied.
  • the accepted salt is prepared as an in vitro source of glutamine required for fish.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds acceptable to the present invention are applied.
  • the salt is prepared as a glycylglutamine substitute as an in vitro source of glutamine for animals at various growth stages.
  • N-acetylglycyl glutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts prepared by using the present invention are prepared as each Glycyl glutamine substitutes for in vitro sources of glutamine for animals at growth stages, which animals may be selected from livestock, poultry, aquaculture animals or pets at various growth stages.
  • the domestic animals include, but are not limited to, pigs, cattle, sheep, horses, rabbits, marten or donkeys
  • the domestic fowls include, 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, turtle, crab, badger, bullfrog, tadpole or loach
  • the pets include but are not limited to dogs or cats of various subspecies.
  • the N-acetylglycyl glutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable in the present invention are applied.
  • the salt is prepared as a glycylglutamine substitute for in vitro sources of glutamine required for weaning pigs.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds provided by the present invention are acceptable.
  • the salt is prepared as a glycylglutamine substitute for an in vitro source of glutamine required for medium pig nutrition.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds provided by the present invention are acceptable.
  • the salt is prepared as a glycylglutamine substitute for in vitro sources of glutamine required by chicks.
  • N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds provided by the present invention may be applied.
  • the accepted salt prepares a glycylglutamine substitute as an in vitro source of glutamine required for fish.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds acceptable to the present invention are applied.
  • the salt is prepared as a glycylglutamine substitute as an in vitro source of amino acid dipeptide substances required for animal performance improvement at various growth stages.
  • N-acetylglycyl glutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts prepared by using the present invention are prepared as each Glycylglutamine substitutes for in vitro sources of amino acid dipeptide substances required for the improvement of production performance of animals at the growth stage can be selected from livestock, poultry, aquaculture animals or pets at various growth stages.
  • the domestic animals include, but are not limited to, pigs, cattle, sheep, horses, rabbits, marten or donkeys
  • the domestic fowls include, 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, turtle, crab, badger, bullfrog, tadpole or loach
  • the pets include but are not limited to dogs or cats of various subspecies.
  • the N-acetylglycyl glutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable in the present invention are applied.
  • the salt is prepared as an in vitro source of glycylglutamine as an amino acid dipeptide substance required for improved performance in weaned pigs.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds provided by the present invention are acceptable.
  • the salt is prepared as an in vitro source of glycylglutamine as a substitute for the amino acid dipeptide material required for improving pig performance.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds provided by the present invention are acceptable.
  • the salt is prepared as a glycylglutamine substitute in vitro as an amino acid dipeptide substance required for improving chick production performance.
  • N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds provided by the present invention may be applied.
  • the accepted salt is prepared as an in vitro source alternative to the amino acid dipeptide material required for improved fish performance.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds acceptable to the present invention are applied.
  • the salt is prepared as an in vitro source of amino acid dipeptide substances required for animal performance improvement at various growth stages.
  • N-acetylglycyl glutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts prepared by using the present invention are prepared as each
  • An in vitro source of amino acid tripeptide substances required for the improvement of animal production performance at a growth stage the animal may be selected from livestock, poultry, aquaculture animals or pets at various growth stages.
  • the domestic animals include, but are not limited to, pigs, cattle, sheep, horses, rabbits, marten or donkeys
  • the domestic fowls include, 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, turtle, crab, badger, bullfrog, tadpole or loach
  • the pets include but are not limited to dogs or cats of various subspecies.
  • the N-acetylglycyl glutamine and the racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable in the present invention are applied.
  • the salt is prepared as an in vitro source of amino acid tripeptide materials required for improved performance in weaned pigs.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds provided by the present invention are acceptable.
  • the salt is prepared as an in vitro source of amino acid tripeptide materials required for improving pig performance.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds provided by the present invention are acceptable.
  • the salt is prepared as an in vitro source of amino acid tripeptide substances required for improving chick production performance.
  • N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds provided by the present invention may be applied.
  • the accepted salt is prepared as an in vitro source alternative to the amino acid tripeptide material required for improved fish performance.
  • a feed composition using an adjunct, the feedable adjuvant is a feedable carrier, diluent, excipient, vehicle, or a combination thereof.
  • the “carrier” referred to in the present invention refers to an edible substance capable of carrying an active ingredient, improving its dispersibility, and having good chemical stability and adsorption, and is an organic carrier and an inorganic carrier.
  • the organic carrier is a material containing many coarse fibers, including but not limited to corn flour, corn cob flour, wheat bran, rice hull flour, defatted rice bran, system bran, corn stalk flour, peanut hull flour, and the like.
  • the inorganic carrier is a mineral, which is mainly divided into calcium salts and silicon oxides, and is used for the preparation of trace element premixes, including but not limited to calcium carbonate, silicate, vermiculite, zeolite, and sea foam. Stone etc.
  • the “diluent” referred to in the present invention refers to a material that uniformly distributes additive raw materials in a material and dilutes high-concentration additive raw materials into a low-concentration premix or premix, which can separate trace components from each other and reduce active ingredients They react with each other to increase the stability of the active ingredients without affecting the physical and chemical properties of the related substances. They are organic diluents and inorganic diluents.
  • Organic diluents include, but are not limited to, corn flour, degermed corn flour, dextrose (glucose), sucrose, bran semolina flour, fried soybean flour, secondary flour, corn protein flour, etc .; inorganic diluents include, but not Limited to limestone, calcium dihydrogen phosphate, shell powder, kaolin (white clay), table salt and sodium sulfate.
  • the adjuvant is a wetting agent induced by the inherent viscosity of the substance itself, a binder that binds the substance, a disintegrating agent that breaks the entire sheet of the substance into many fine particles, and reduces the inter-particle Friction retention aid or anti-sticking agent to prevent material sticking, including but not limited to magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, starch slurry, water, inorganic salt, dextrin, powdered sugar, etc. .
  • solvent refers to a solvent required to dissolve or disperse a solid, and includes, but is not limited to, water, ethanol, glycerin, and the like.
  • the feed composition further comprises additional animal feed additives and / or animal feed ingredients.
  • the animal feed additive is a nutritional feed additive, a general feed additive or a medicinal feed additive.
  • the nutritional feed additive refers to small or trace substances added to compound feed to balance feed nutrients, improve feed utilization, and directly exert nutritional effects on animals, and are amino acids, amino acid salts and the like, vitamins and vitamins. , Mineral elements and their complexes (chelates), microbial enzyme preparations 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 are beneficial to animal health or metabolism, including growth promoters, Insect repellent, flavoring and attractant, feed conditioner, feed conditioner, feed storage agent and Chinese herbal medicine additive.
  • the non-nutritive additive is a growth promoter, including, but not limited to, butyric acid, calcium butyrate, sodium butyrate, tannic acid, p-thymol, p-thymol ester, p-thymol salt, 2 -Hydroxybenzoic acid, ⁇ -acid, ⁇ -acid, ⁇ -acid, hexahydro ⁇ -acid, hexahydro ⁇ -acid, hexahydro ⁇ -acid, benzoic acid or calcium benzoate, zinc oxide, sulfuric acid Zinc and zinc chloride.
  • a growth promoter including, but not limited to, butyric acid, calcium butyrate, sodium butyrate, tannic acid, p-thymol, p-thymol ester, p-thymol salt, 2 -Hydroxybenzoic acid, ⁇ -acid, ⁇ -acid, ⁇ -acid, hexahydro ⁇ -acid,
  • the non-nutritive additive is calcium butyrate.
  • the non-nutritive additive is tannic acid.
  • the medicinal feed additive includes, but is not limited to, a veterinary drug premix which has the function of preventing animal diseases, promoting the growth of animals, and can be added to the feed for a long period of time and incorporated into a carrier or diluent.
  • the medicinal feed additive is a feed antibiotic
  • the feed antibiotic includes, but is not limited to, polymyxin, salinomycin, averamycin, bacitracin, and Virginiamycin , Naxipitin, flavomycin, enramycin, berimycin, quinethanol, oxytetracycline or chlortetracycline.
  • a composition comprising N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed-acceptable salts It also contains one or more of nutritional feed additives, general feed additives and medicinal feed additives.
  • the animal feed ingredients are cereals and processed products thereof, oilseeds and processed products thereof, legume crops and processed products, tubers, tubers and processed products thereof, other seeded and fruit products, and Its processed products, forage, roughage and processed products, other plants, algae and processed products, dairy products and by-products, terrestrial animal products and by-products, fish, other aquatic organisms and by-products, minerals, microbial fermentation Products and by-products, and other feed ingredients.
  • the present invention relates to the above-mentioned feed composition containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt.
  • the N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed-acceptable salts The feed composition is used in the preparation of animal feed additives.
  • the prepared animal feed additives are livestock feed additives, poultry feed additives, aquaculture animal feed additives or pet feed additives.
  • the feed containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is applied.
  • the composition is used to prepare a feed additive for livestock, and the livestock includes, but is not limited to, pigs, cattle, sheep, horses, rabbits, and minks at various growth stages.
  • the feed containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is applied.
  • the composition is used to prepare a poultry feed additive, and the poultry includes, but is not limited to, chickens, ducks, geese, pigeons and the like at various growth stages.
  • the feed containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is applied.
  • the composition is used to prepare aquaculture animal feed additives, and the aquaculture animals include, but are not limited to, fish, shrimp, crab, mandarin duck, maggot and the like at various growth stages.
  • the feed containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is applied.
  • the composition is used to prepare a pet feed additive, and the pet includes, but is not limited to, a dog or cat kept in captivity.
  • the N-acetylglycylglutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds are acceptable.
  • the animal feed additive prepared from the salt composition is a premix, a composite premix, a water or a granule.
  • the N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts are included.
  • the feed composition is used in the preparation of animal feed.
  • the prepared animal feed is livestock feed, poultry feed, aquaculture animal feed or pet feed.
  • the feed containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is applied.
  • the composition is used for preparing livestock feed, and the livestock includes, but is not limited to, pigs, cattle, sheep, horses, rabbits, marten and the like at various growth stages.
  • the feed containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is applied.
  • the composition is used to prepare poultry feed, including but not limited to chicken, duck, goose, pigeon, etc. at various growth stages.
  • the feed containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is applied.
  • the composition is used to prepare aquaculture animal feed, and the aquaculture animals include, but are not limited to, fish, shrimp, crab, mandarin duck, mandarin duck, and the like at various growth stages.
  • the feed containing N-acetylglycylglutamine and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is applied.
  • the composition is used to prepare pet feed, including, but not limited to, captive dogs or cats.
  • a feed comprising N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed-acceptable salts
  • the feed prepared by the composition is a single feed, a concentrated feed, a compound feed, a compound premix or a concentrate supplement.
  • the compound feed is a full-price compound feed.
  • farmers will include N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds that are acceptable
  • the salt feed additive and the accompanying feed for animal consumption can significantly improve the production performance of animals.
  • the feed additive is a premix, a composite premix, a granule, or a liquid, which is mixed with animal feed and consumed by animals.
  • the animals are livestock, poultry, aquaculture animals or pets.
  • the domestic animals include, but are not limited to, pigs, cattle, sheep, horses, rabbits, marten, etc. at various growth stages; the domestic birds include, but are not limited to, chickens, ducks, geese, pigeons, etc. at various growth stages; Said aquaculture animals include, but are not limited to, fish, shrimp, crab, magpies, magpies, etc. at various growth stages; said pets include but are not limited to dogs or cats raised in captivity.
  • the farmer will include N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts.
  • the feed additives and feed companions were given to weaned pigs for consumption, which significantly increased the average daily weight gain rate and feed conversion rate of weaned pigs.
  • the farmer will include N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts.
  • the feed additives and feed companion are given to broilers, which significantly reduces the feed-to-meat ratio of broilers and improves the feed conversion rate.
  • the farmer will include N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts. Feed additives and feed companions to fish.
  • the farmer will include N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts. Feed additives and companion feed for young dogs.
  • farmers will include N-acetylglycyl glutamine and its racemates, stereoisomers, geometric isomers, tautomers, solvates, or feeds.
  • the salt-containing feed composition for animal consumption can significantly improve animal performance.
  • the feed composition is a feed additive premix, a feed additive composite premix, a granule, or a water solution, and is fed to an animal for consumption with the feed.
  • the feed composition is a feed additive premix.
  • the feed composition is a feed additive composite premix.
  • the feed composition is a concentrated feed, a compound feed, a compound premix or a concentrate supplement, and is directly used as an animal feed for animals.
  • the feed composition is a full-price compound feed.
  • the reaction solution was suction filtered, and the filter cake was beaten with 200 mL of water for 4 hours.
  • the filter cake was dried at 45 ° C. to constant weight, and L-glutamic acid monoethyl ester was obtained as a white solid with a yield of 93.18 g and a yield of 49.76%.
  • Step 2 Preparation of chloroacetyl-L-glutamic acid monoethylamine amine salt (Compound 4)
  • TLC monitors the reaction to the end of the reaction.
  • the pH was adjusted to 2 with concentrated hydrochloric acid and the organic phase was separated.
  • the aqueous phase was extracted with ethyl acetate (500 mL * 2), and the ethyl acetate layers were combined.
  • the ethyl acetate layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow transparent oily liquid.
  • the yellow oily liquid was dissolved in 750 mL of absolute ethanol, and 150 mL of 28% ammonia water was added dropwise. With the addition of ammonia water, solids gradually precipitated.
  • chloroacetyl-L-glutamic acid monoethylamine amine salt was a white solid with a yield of 92.93 g and a yield of 60.62%.
  • Step 3 Preparation of glycyl-L-glutamine (compound 5)
  • the reaction was performed at 55 ° C for 1 h at constant temperature, and then the reaction was stirred at room temperature for 3 h.
  • the reaction solution was filtered with suction, and the filter cake was dried at 45 ° C to constant weight to obtain glycyl-L-glutamine as a white solid with a yield of 12.57 g and a yield of 83.08%.
  • Step 4 Preparation of N-acetylglycyl-L-glutamine (compound 6)
  • Drug stability incubator high performance liquid chromatography, etc.
  • Preparation of standard working solution Accurately weigh 0.0500g of the test product, add deionized water to make up to 25mL, and make a working stock solution. Take an appropriate amount of working stock solution and dilute it with water to a concentration of 250ppm, 500ppm, 1000ppm, 2000ppm, respectively, to be tested. Verify that the sample concentration is linearly related to the HPLC peak area response.
  • the 1% aqueous solution of glutathione and acetylglutathione were placed in a normal temperature environment, and samples were taken for HPLC detection on the 5th day, and each sample was taken three times in parallel (calculated with the main component content at 100% on day 0).
  • Chromatographic column C18 column (250mm * 4.6mm, 5 ⁇ m);
  • Injection volume 10 ⁇ L
  • the experimental data were analyzed by SPSS18 software. The data were first analyzed by single factor analysis of variance (ANOVA). If the differences between treatments were significant, multiple comparisons were performed using Duncan's method. The significance level was 0.05. The test results are expressed as "mean ⁇ standard error", as shown in Table 2.
  • Drug stability incubator high performance liquid chromatography, etc.
  • Preparation of 30% premixed sample to be tested accurately weigh 6g (accurate to 0.0001) acetylglycine dipeptide sample (Ac-Gly-Gln), 20g of corn cob powder, and mix in a blender.
  • Preparation of 1% feed test sample to be tested accurately weigh 1.5g (accurate to 0.0001) acetyl glutathione dipeptide sample, 150g of blank chicken broiler feed, mix in a mixer and mix well.
  • Preparation of the test solution of the raw materials Accurately weigh 0.05g (Ac-Gly-Gln) of acetylglycine dipeptide raw material (accurate to 0.0001) placed under different conditions, add deionized water to make up to 25mL, and make a working solution , To be tested.
  • Preparation of 1% feed test solution Accurately weigh 5g (accurate to 0.0001) of acetylgglutamine 1% feed at room temperature, add methanol to volume to 25mL, and make a working solution to be tested.
  • Chromatographic column C18 column (250mm * 4.6mm, 5 ⁇ m);
  • Injection volume 10 ⁇ L
  • the experimental data were analyzed by SPSS18 software. The data were first analyzed by single factor analysis of variance (ANOVA). If the differences between treatments were significant, multiple comparisons were performed using Duncan's method. The significance level was 0.05. The test results are expressed as "mean ⁇ standard error", as shown in Table 3.
  • N-acetylglycyl-L-glutamine raw material does not change significantly under the test conditions such as high temperature stability test at 60 °C, light stability test, accelerated long-term stability test at 40 °C, and constant temperature stability at 25 °C
  • the compound showed significant degradation on the 5th day of the test and the content decreased to 95%, and the change was not significant compared with the content on the 10th day of the test, indicating that N-acetylglycyl -L-glutamine compound shows stable physicochemical properties under high temperature, high humidity, and light conditions, and has storage stability.
  • N-acetylglycyl-L-glutamine at 60 °C high temperature stability test, 25 °C 95% RH high humidity stability test, light stability test, 40 °C accelerated long-term stability test, Within the test cycle range of the 25 ° C constant temperature stability test, N-acetylglycyl-L-glutamine showed significant degradation on the 5th day under high humidity conditions, reducing the content to about 97%. On the 10th day, a more significant degradation also occurred, reducing the content to 98%. N-acetylglycyl-L-glutamine showed significant stability in a 30% premix under the stability factor test.
  • N-acetylglycyl-L-glutamine 1% feed was subjected to constant temperature stability inspection at 25 ° C for one month in accordance with the requirements of feed storage stability.
  • N in 1% feed The content of -acetylglycyl-L-glutamine is reduced to 96.94% compared with the initial content, which does not exceed the 0 to 5% variation range allowed by feed processing or feed additive processing.
  • Each test component is a control group and a test group.
  • Group I was a control group, and piglets were fed a basic diet; experimental group II was fed with a basal diet based on 5000 ppm of glutamine (Gln); groups III and IV were fed a diet Add 2500ppm and 5000ppm Glycyl-Gln to the basic diet; add diets fed to piglets in groups V ⁇ X as basic diets and add 1000ppm, 1500ppm, and 2000ppm, respectively.
  • test pigs were weighed from 7:00 to 9:00 am at 0 and 14 days after the start of the test. During the test period, observe the piglets' feed intake and health status daily and weigh the remaining diets, record the feed consumption, the number of diarrhea in each group, and calculate the average daily feed intake (ADFI, g / d * only) and average daily weight gain. (ADG, g / d * only), feed to meat ratio (FCR) and diarrhea rate (DR). Calculated as follows:
  • Average daily feed intake (total ingredients-remaining amount) / (test days ⁇ number of repeat pigs);
  • Average daily weight gain (average weight at the end of the test-average weight at the beginning of the test) / days of the test;
  • Feed-meat ratio average daily feed intake / average daily weight gain
  • Diarrhea rate sum of daily diarrhea heads / (test days x number of pigs per repetition).
  • the experimental data were analyzed by SPSS18 software. The data were first analyzed by single factor analysis of variance (ANOVA). If the differences between treatments were significant, multiple comparisons were performed using Duncan's method. The significance level was 0.05. The test results are expressed as "mean ⁇ standard error”. The test results are shown in Table 4.
  • the test was designed using a single factor random design.
  • One hundred-day-old three-yellow feather broilers with a similar average body weight of 50 g were selected and 1200 randomly divided into 6 treatment groups, each group consisting of 6 replicates, male and female halves, each repeating 20 Three yellow feather broilers.
  • the houses and utensils were disinfected before the test.
  • cages were kept in the same house under the same feeding and management conditions.
  • the basic diet is mainly corn-soybean meal, and no other antioxidants and growth promoters are added during the entire feeding process.
  • Each test group was a control group and test groups I to VI. In the control group, only the basic diet was given.
  • experiment I 4000 ppm of glutamine (Gln) was added to the basic diet, and in test group II, 2000 ppm of glycyl-L-glutamine (Glycyl- Gln), and other experimental groups added N-acetylglycyl-L-glutamine (Ac-Glycyl-Gln) to the basic diet. See Table 5 for grouping.
  • the test period was 20 days in total. The test chickens were free to drink and feed, and fed twice a day.
  • Feed-to-meat ratio average daily feed intake / average daily gain.
  • the experimental data were analyzed by SPSS18 software. The data were first analyzed by single factor analysis of variance (ANOVA). If the differences between treatments were significant, multiple comparisons were performed using Duncan's method. The significance level was 0.05. The test results are expressed as "mean ⁇ SD”. The test results are shown in Table 5.
  • N-acetylglycyl-L-glutamine has similar effects to glutamine and glycyl-L-glutamine to improve broiler performance.
  • Test fish The test fish used was the healthy and lively grass carp species with the same specifications in the year. They were raised in large cages (4 ⁇ 2 ⁇ 1.5m 3 ) for 4 weeks before being used for formal breeding experiments.
  • the experimental system was floating small cages ( Size 1.1 ⁇ 1.1 ⁇ 1.1m 3 ). Each small net box is equipped with an inflatable head, which is inflated 24 hours a day. Both the small cage and the temporary cage are placed in a 3500m 2 pond in the test field. The depth of the pond is about 1.5m. The pond water is fully aerated.
  • Test feed The test feed was prepared according to the formula in Table 6, and different test groups were added with different contents of N-acetylglycyl-L-glutamine according to Table 7.
  • the feed material used is ultra-pulverized to make a floating puffed feed with a particle diameter of 3 mm through a Jiangsu Muyang puffing unit.
  • the mold temperature is 130 ° C.
  • soybean oil is sprayed from the outside of the fuel injection equipment. The cool place is sealed for future use.
  • Raw material composition content(%) Raw material composition content(%) Fish meal 9.0 Soybean oil 3.0 Casing powder 3.0 Phospholipid meal 9.0 Soybean meal 12.0 Gluten flour 4.0 Rapeseed meal 12.0 Blood cell powder 2.0 MSG protein 3.0 Vc-phosphate 0.1 Secondary powder 12.6 Calcium dihydrogen phosphate 1.8 flour 17.0 Choline chloride 0.2 Bentonite 0.70 Multidimensional 0.1 Rice bran 10.0 Micro-mine premix 0.5
  • Test management The experiment uses artificial restricted feeding. The feeding amount is adjusted once a week. The feeding level of each group (according to the initial weight) is completely the same. The feeding is performed twice a day (7:30 and 15:00). The total feeding amount It was 580 g / repeated test group. The trial lasted 8 weeks. The water quality was monitored regularly during the experiment. The water temperature during the whole breeding period was 26.88 ⁇ 3.08 ° C, DO> 5.0mg O L -1 , pH 7.8, ammonia nitrogen ⁇ 0.50mg N L -1 , and nitrite nitrogen ⁇ 0.05mg N L -1 .
  • Weight gain rate (WG,%) 100 ⁇ (average final weight-average initial weight) / average initial weight;
  • Feed coefficient (FCR) food intake / fish weight gain

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Abstract

一种N-乙酰甘氨酰谷氨酰胺在动物饲料添加剂中的应用，属于饲料添加剂领域。具体为一种物化性质稳定、动物适口性良好的谷氨酰胺衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐在制备动物饲料添加剂以及在动物养殖中的应用。所述谷氨酰胺衍生物是N-乙酰甘氨酰-谷氨酰胺，可作为谷氨酰胺供体来源的谷氨酰胺替代物或甘氨酰谷氨酰胺替代物或作为氨基酸二肽供体或氨基酸三肽应用在动物养殖中。

Description

N-乙酰甘氨酰谷氨酰胺在动物饲料添加剂中的应用 技术领域：
本发明涉及动物饲料添加剂领域，具体涉及N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐在制备动物饲料添加剂和动物养殖中的应用以及一种包含N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物。
背景技术：
谷氨酰胺是动物血液、肠道粘膜上皮细胞、肾小管细胞、淋巴细胞、巨噬细胞和成纤维细胞的等组织含量最丰富的一种氨基酸，在维持肠道和免疫的正常形态和功能上发挥非常重要的作用，对畜禽体内蛋白质营养平衡具有重要意义。谷氨酰胺在水中溶解度低，在溶液中易环化为有毒的焦谷氨酸和氨，在热和强碱中裂解为谷氨酸和氨，在动物胃肠道系统吸收率低，因此限制了它在肠内的营养和动物生产中的应用。
甘氨酰谷氨酰胺二肽是由甘氨酸和谷氨酰胺合成的二肽，常温下在水溶液中的溶解度达到154g/L，与谷氨酰胺相比在水溶液、热及其它存储条件下较为稳定，可与全胃肠道外营养液联合应用，以二肽形式进入动物体内被氨基肽酶水解释放出甘氨酸和谷氨酰胺提供谷氨酰胺从而提高血浆谷氨酰胺浓度而发挥生物学作用。但是，甘氨酰谷氨酰胺二肽在细胞营养液中保存时间延长或高温加热条件下则会出现环缩合反应形成具有比甘氨酰谷氨酰胺二肽更强差向异构化趋势的2,5-二酮哌嗪，所述哌嗪的生物学效应至今未明，则甘氨酰谷氨酰胺二肽做为动物营养的氨基酸来源存在不确定的生物学风险。另外，配合饲料的制粒过程是将饲料原料和饲料添加剂及辅料按比例在混合机中混合均匀，在饲料制粒机中调制后经过高温膨化制粒的过程出粒，谷氨酰胺在这个过程含量显著下降。进一步的将甘氨酰谷氨酰胺应用在动物养殖，当甘氨酰谷氨酰胺二肽的用量超过2500ppm的高剂量使用时试验猪出现采食量显著下降从而减少试验猪的日增重。
发明内容：
基于此，本发明提供一种物化性质稳定、动物适口性良好的谷氨酰胺衍生物以及该谷氨酰胺衍生物在制备动物饲料添加剂及动物养殖中的应用。
一方面，本发明提供的谷氨酰胺衍生物是N-乙酰甘氨酰谷氨酰胺，包括其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐。
另一方面，本发明提供了所述N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐在制备动物饲料添加剂中的应用。
在一些技术方案中，应用所述N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的动物饲料添加剂是动物用谷氨酰胺替代物。
在一些技术方案中，应用所述N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的动物饲料添加剂是动物用甘氨酰谷氨酰胺替代物。
在一些技术方案中，所述的动物饲料添加剂应用在各个生长阶段的家畜养殖中。
在一些技术方案中，所述的动物饲料添加剂应用在幼龄阶段的家畜养殖中。
在一些技术方案中，所述的动物饲料添加剂应用在各个生长阶段的家禽养殖中。
在一些技术方案中，所述的动物饲料添加剂应用在幼龄阶段的家禽养殖中。
在一些技术方案中，所述的动物饲料添加剂应用在全阶段水产养殖动物的养殖中。
在一些技术方案中，所述的动物饲料添加剂应用在宠物养殖中。
另一方面，本发明提供了一种饲用组合物，所述的饲用组合物包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐和可饲用辅料。
所述的可饲用辅料选自可饲用的载体、稀释剂、赋形剂、溶媒或它们的组合。
在一些技术方案中，所述的饲用组合物还包含动物饲料原料。
在一些技术方案中，所述的饲用组合物还包含附加的动物饲料添加剂。
在一些技术方案中，所述的饲用组合物还包含动物饲料原料和附加的动物饲料添加剂。
在一些技术方案中，所述的附加的动物饲料添加剂可选自营养性饲料添加剂和/或一般饲料添加剂和/或药物饲料添加剂。
另一方面，本发明还提供了一种改善养殖动物生产性能的方法。
在一些技术方案中，所述的方法包括给予养殖动物本发明提供的N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐，如在动物饲料中添加N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐，然后饲喂动物。
在一些技术方案中，所述的方法包括给予养殖动物本发明提供的包含本发明提供的包含N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物。
在一些技术方案中，所述的养殖动物为各个生长阶段的家畜、家禽、水产养殖动物或宠 物。
在一些技术方案中，所述的养殖动物为幼龄阶段的家畜或家禽。
在一些技术方案中，所述的家畜，例如猪，所述的在动物饲料中添加N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐，其添加剂量为1500～5000ppm，进一步优先为1500～3000ppm。
在一些技术方案中，所述的家禽，例如鸡，所述的在动物饲料中添加N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐，其添加剂量为1000～2000ppm。
在一些技术方案中，所述的水产养殖动物，例如草鱼，所述的在动物饲料中添加N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐，其添加剂量为100～3000ppm。
另一方面，本发明还提供了所述N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的制备、分离和纯化方法。
本发明的有益效果：
本发明提供的N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐或预混剂在饲料添加剂的高温、高湿、光照的稳定性等影响因素试验以及加速试验、长期试验等条件下具有很好的稳定性，在稳定性考察周期内含量变化不低于95％，达到了饲料添加剂对温度、湿度、光照以及储存的稳定性要求。
另外，在动物养殖试验中N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐在较低剂量下就可以达到高剂量谷氨酰胺对动物生产性能的影响水平，另外当使用剂量增加时对试验动物的采食量的影响未出现高剂量甘氨酰谷氨酰胺二肽的动物采食量急速下降的适口性问题。
本发明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。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们之间不会出现矛盾。
前面所述内容只是概述了本发明的某些方面，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。
本发明的进一步详细描述。
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式加以说明。本发明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发明 的范围内。另外，本发明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。
本发明涉及的定义和/或一般术语。
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。
饲料可接受的盐为本发明的丁酰谷氨酸衍生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。
本发明涉及的影响因素考察试验条件下的“显著变化”是指“供试品含量测定发生5％以上的变化”。
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。
本发明涉及的“立体异构体”是指具有相同化学构造，但原子或基团在空间上的排列方式不同的化合物。
本发明涉及的“饲料添加剂”是指在饲料加工、制作、使用过程中添加的少量或者微量物质，分为营养性饲料添加剂和一般饲料添加剂也叫非营养性饲料添加剂。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，包括维生素、微量元素、氨基酸与小肽和非蛋白氮。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，包括生长促进剂、驱虫保健剂、饲料调质剂、饲料调制剂、饲料贮藏剂和中草药添加剂。
本发明涉及的饲料是指经工业化加工、制作的供动物食用的产品。
本发明涉及的“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。
本发明所述的“包含”为开放式表达，既包括本发明所明指的内容，但并不排除其他方面的内容。
化合物。
本发明提供的N-乙酰甘氨酰谷氨酰胺结构如式(Ⅰ)所示：
Figure PCTCN2019087524-appb-000001
本发明提供的N-乙酰甘氨酰谷氨酰胺以谷氨酸为起始原料经羧酸的酯化、氨基的氯代乙酰化、氨解及乙酰化等四步反应制备而得。
在一些实施方案中，所述的谷氨酸是一种手性化合物，本发明所述的谷氨酸选自左旋体L-(-)-谷氨酸(结构如式(Ⅱ))、右旋体D-(+)-谷氨酸(结构如式(Ⅲ))或外消旋体DL-(±)谷氨酸，在相关反应条件下得到具有手性中心的N-乙酰甘氨酰谷氨酰胺的立体异构体或外消旋体。
Figure PCTCN2019087524-appb-000002
在一些实施方案中，所述的谷氨酸的手性立体异构体和N-乙酰甘氨酰谷氨酰胺的立体异构体在合适的条件下可发生立体构型的转化，如谷氨酸或N-乙酰甘氨酰谷氨酰胺及其制备反应中间体的立体构象互变。
当涉及谷氨酸经历了羧酸的酯化、氨基的氯代乙酰化、氨解及乙酰化等四步反应生成了相应的N-乙酰甘氨酰谷氨酰胺具有刚性结构时，反应底物在反应过程中可生成不同的几何异构体产物。
上述的立体异构体、几何异构体、互变异构体也包括在本发明的实施范围内。
在一些实施方案中，本发明提供N-乙酰甘氨酰谷氨酰胺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N-乙酰甘氨酰谷氨酰胺。所述具有一定晶型状态的N-乙酰甘氨酰谷氨酰胺是N-乙酰甘氨酰谷氨酰胺结晶或N-乙酰甘氨酰谷氨酰胺的溶剂合物。所述的N-乙 酰甘氨酰谷氨酰胺的溶剂合物可选自N-乙酰甘氨酰谷氨酰胺的水合物或N-乙酰甘氨酰谷氨酰胺乙醇合物。
本发明提供的N-乙酰甘氨酰谷氨酰胺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N-乙酰甘氨酰谷氨酰胺与相应的有机碱、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。
在一些实施方案中，N-乙酰甘氨酰-L-谷氨酰胺原料在影响因素考察试验条件下置于适宜容器中，摊成不超过5mm厚的薄层，在相应时间点取样检测有关指标，N-乙酰甘氨酰-L-谷氨酰胺未发生显著变化。
在一实施例中，所述的影响因素考察条件为高温稳定性考察条件，N-乙酰甘氨酰-L-谷氨酰胺未发生显著变化。
在另一实施例中，所述的影响因素考察条件为高湿稳定性考察条件，在考察期内第5天的各项检测指标显示N-乙酰甘氨酰-L-谷氨酰胺与对照含量相比下降了约5％，在其余考察周期的各项检测指标与第5天的检测指标相比无显著变化。
在另一实施例中，所述的影响因素考察条件为光照稳定性考察条件，N-乙酰-甘氨酰-L-谷氨酰胺未发生显著的变化。
在一些实施方案中，N-乙酰甘氨酰-L-谷氨酰胺的预混剂在影响因素考察试验条件下置于适宜容器中，摊成不超过5mm厚的薄层，在相应时间点取样检测有关指标，N-乙酰甘氨酰-L-谷氨酰胺未发生显著变化。
在一实施例中，所述的影响因素考察条件为高温稳定性考察条件，N-乙酰甘氨酰-L-谷氨酰胺在预混剂中未发生显著变化。
在另一实施例中，所述的影响因素考察条件为高湿稳定性考察条件，N-乙酰甘氨酰-L-谷氨酰胺在预混剂中未发生显著变化。
在另一实施例中，所述的影响因素考察条件为光照稳定性考察条件，N-乙酰甘氨酰-L-谷氨酰胺在预混剂中未发生显著变化。
本发明涉及N-乙酰甘氨酰谷氨酰胺的应用。
本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、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。
在一些实施方案中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是谷氨酰胺替代物，作为各个 生长阶段的动物的谷氨酰胺的体外来源。
应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、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谷氨酰胺的体外来源的谷氨酰胺替代物，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N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为断奶猪所需的谷氨酰胺的体外来源的谷氨酰胺替代物。
在另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为中猪营养所需的谷氨酰胺的体外来源的谷氨酰胺替代物。
在另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为仔鸡所需的谷氨酰胺的体外来源的谷氨酰胺替代物。
在又另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为鱼所需谷氨酰胺的体外来源替代物。
在一些实施方案中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是甘氨酰谷氨酰胺替代物，作为各个生长阶段的动物的谷氨酰胺的体外来源。
应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、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谷氨酰胺的体外来源的甘氨酰谷氨酰胺替代物，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N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几 何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为断奶猪所需的谷氨酰胺的体外来源的甘氨酰谷氨酰胺替代物。
在另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为中猪营养所需的谷氨酰胺的体外来源的甘氨酰谷氨酰胺替代物。
在另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为仔鸡所需的谷氨酰胺的体外来源的甘氨酰谷氨酰胺替代物。
在又另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为鱼所需谷氨酰胺的体外来源的甘氨酰谷氨酰胺替代物。
在一些实施方案中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是甘氨酰谷氨酰胺替代物，作为各个生长阶段的动物生产性能改善所需的氨基酸二肽物质的体外来源。
应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、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生产性能改善所需的氨基酸二肽物质的体外来源的甘氨酰谷氨酰胺替代物，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N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为断奶猪生产性能改善所需的氨基酸二肽物质的体外来源的甘氨酰谷氨酰胺替代物。
在另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为中猪生产性能改善所需的氨基酸二肽物质的体外来源的甘氨酰谷氨酰胺替代物。
在另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为仔鸡生产性能改善所需的氨基酸二肽物质的体外来源的甘氨酰谷氨酰胺替代物。
在又另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为鱼生产性能改善所需的氨基酸二肽物质的体外来源替代物。
在一些实施方案中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、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生产性能改善所需的氨基酸二肽物质的体外来源。
应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、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生产性能改善所需的氨基酸三肽物质的体外来源，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N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为断奶猪生产性能改善所需的氨基酸三肽物质的体外来源。
在另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为中猪生产性能改善所需的氨基酸三肽物质的体外来源。
在另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为仔鸡生产性能改善所需的氨基酸三肽物质的体外来源。
在又另一实施例中，应用本发明提供的N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为鱼生产性能改善所需的氨基酸三肽物质的体外来源替代物。
本发明涉及的饲用组合物。
一种包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的至少一种和可饲用辅料的饲用组合物，所述的可饲用辅料为可饲用的载体、稀释剂、赋形剂、溶媒或它们的组合。
本发明涉及的“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、花生壳粉等。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、海泡石等。
本发明涉及的“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)、食盐和硫酸钠。
所述的辅剂为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或防止物料黏着的抗黏剂，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、糖粉等。
本发明涉及的“溶媒”是指溶解或分散固体所需的溶剂，包括但不限于水、乙醇、甘油等。
在一些实施方案中，所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，为氨基酸、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、饲料贮藏剂和中草药添加剂。
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、β-酸、β-酸酯、β-酸盐、六氢β-酸、六氢β-酸酯、六氢β-酸盐、苯甲酸或苯甲酸钙、氧化锌、硫酸锌、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。
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。
更进一步具体地，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。
在一些实施例中，包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的组合物，还包含营养性饲料添加剂、一般饲料添加剂和药物饲料添加剂中的一种或多种。
在一些实施例中，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。
本发明涉及上述包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物的应用。
在一些实施例中，所述包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物应用于制备动物饲料添加剂中。
应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备的动物饲料添加剂为家畜饲料添加剂、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，应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，以所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的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。
在一些实施例中，所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物应用于制备动物饲料中。
应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，应用所述的包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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。
在一些饲喂实施例中，养殖户将包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的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。
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N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐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，养殖户将包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的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，养殖户将包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲料添加剂与饲料伴服给与鱼食用。
在一实施例中，养殖户将包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的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，养殖户将包含N-乙酰甘氨酰谷氨酰胺及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的的饲用组合物给与动物食用，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。
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。
在一实施例中，所述的饲用组合物是全价配合饲料。
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式加以说明。本发明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发明的范围内。另外，本发明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。
具体实施方式：
为了使本发明的目的、技术方案及优点更加清楚明白，以下通过实施例对本发明的化合物、组合物及应用进行进一步的详细说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明。
本发明涉及的名词简写如表1所示。
表1 化合物制备过程涉及的名词及其简写词
序号 名词 简写
1 浓硫酸 Conc.H 2SO 4
2 室温 r.t.
3 氨水 NH 3H 2O
4 乙醇 EtOH
5 乙酸 CH 3COOH
6 升 L
7 毫升 mL
8 克 g
9 摄氏度 ℃
10 小时 h
11 薄层色谱 TLC
12 当量 eq
13 摩尔 mol
14 高效液相色谱 HPLC
15 硝酸钾 KNO 3
16 湿度 RH
17 微升 μL
18 分钟 min
19 体积 V
A化合物的制备
实施例A1 N-乙酰甘氨酰-L-谷氨酰胺的制备
N-乙酰甘氨酰-L-谷氨酰胺的合成方案如下：
Figure PCTCN2019087524-appb-000003
步骤1：L-谷氨酸单乙酯(化合物2)的制备
向3L三口瓶中加入200g(1.07mol,1eq)L-谷氨酸钠一水化合物和1.87L(32.03mol,30eq)无水乙醇，搅拌，冷却至0-5℃；随后缓慢滴加浓硫酸105mL(1.97mol,1.8eq)，使体系温度控制在0-5℃，浓硫酸滴加完毕后，升温至室温搅拌。TLC监控反应至反应终点。反应体系冷却至0-5℃，向体系缓慢滴加三乙醇胺使体系温度控制在0-5℃，调节酸碱度至pH 8后保温搅拌2h。反应液抽滤，滤饼经200mL水打浆4h后抽滤，滤饼于45℃鼓风干燥至恒重，得L-谷氨酸单乙酯为白色固体，产量93.18g，收率49.76％。
MS(ESI,pos.ion)m/z:176[M+H] +；
1H-NMR(D 2O,400MHz):δ(ppm)1.16(t,3H),2.07(m,2H),2.47(m,2H),3.68(t,1H),4.08(q,2H)。
步骤2：氯乙酰-L-谷氨酸单乙酯胺盐(化合物4)的制备
称取Na 2CO 3 90.47g(853.57mol,1.5eq)于2L三口瓶中，加入650mL水和500mL乙酸乙酯，搅拌溶解，冷却至0-5℃，随后加入100.00g(570.84mmol,1eq)L-谷氨酸单乙酯，搅拌冷却至0-5℃，再向体系缓慢滴加150mL氯乙酰氯[71.03g(628.92mmol,1.1eq)]的乙酸乙酯溶液，使体系温度控制在0-5℃，滴加完毕后，在0℃反应。TLC监控反应至反应终点。用浓盐酸调节pH至2，分离有机相。水相用乙酸乙酯(500mL*2)萃取，合并乙酸乙酯层，乙酸乙酯层经饱和食盐水洗涤、无水硫酸钠干燥、减压浓缩得黄色透明油状液体。将黄色油状液体溶于750mL无水乙醇中，滴加150mL 28％氨水，随着氨水加入，逐渐析出固体，氨水滴加完毕搅拌反应2h后抽滤，滤饼于45℃鼓风干燥至恒重，得氯乙酰-L-谷氨酸单乙酯胺 盐为白色固体，产量为92.93g，收率60.62％。
MS(ESI,pos.ion)m/z:250[M+NH 4] +；
1H-NMR(D 2O,500MHz):δ(ppm)1.16(t,3H),1.83(m,1H),2.06(m,1H),2.29(t,2H),4.00(m,4H),4.09(q,1H)。
步骤3：甘氨酰-L-谷氨酰胺(化合物5)的制备
于500mL单口瓶中加入氯乙酰-L-谷氨酸单乙酯氨盐20.02g(74.51mmol,1eq)，随后加入28％氨水255mL(1.85mol,25eq)，室温搅拌。TLC反应至终点。反应液旋蒸除去溶剂后加入30mL水溶解，升温至55℃，滴加120mL无水甲醇，滴加完毕后在55℃下恒温反应1h后移至室温搅拌反应3h。反应液抽滤，滤饼于45℃鼓风干燥至恒重，得甘氨酰-L-谷氨酰胺为白色固体，产量为12.57g，收率83.08％。
MS(ESI,pos.ion)m/z:202[M+H] +；
1H-NMR(D 2O,400MHz):δ(ppm)1.96(m,1H),2.14(m,1H),2.33(m,2H),3.84(s,2H),4.22(m,1H)。
步骤4：N-乙酰甘氨酰-L-谷氨酰胺(化合物6)的制备
称取甘氨酰-L-谷氨酰胺20.01g(98.47mmol,1eq)于250mL单口瓶中，加入60mL冰乙酸和12.24g(119.89mmol,1.2eq)乙酸酐，室温搅拌。TLC监控反应至终点。抽滤反应液，滤饼于45℃下鼓风干燥至恒重，得N-乙酰甘氨酰-L-谷氨酰胺为白色固体，产量为20.48g，收率84.77％。
MS(ESI,pos.ion)m/z:244[M-H] +；
1H-NMR(DMSO-d6,,500MHz):δ(ppm)1.75(m,1H),1.84(s,3H),1.94(m,1H),2.11(m,2H),3.70(m,2H),4.15(m,1H),6.80(s,1H),7.30(s,1H),8.09(t,1H),8.18(d,1H),12.61(s,1H)。
实施例A2 N-丁酰甘氨酰-L-谷氨酰胺的制备
Figure PCTCN2019087524-appb-000004
称取40.00g(196.85mmol,1eq)甘氨酰-L-谷氨酰胺于500mL单口瓶中，加入120mL冰乙酸和37.53g(237.25mmol,1.2eq)丁酸酐，室温搅拌。TLC检测至反应终点。反应液旋转蒸 发干燥后溶于120mL水中，所得水溶液旋转蒸发干燥，重复4次，得到无色透明油状液体，置于冰箱冷冻析晶。所得固体用300mL乙酸乙酯搅拌过夜，抽滤，滤饼于45℃鼓风干燥至恒重，得N-丁酰甘氨酰-L-谷氨酰胺为白色固体，产量为43.95g，收率81.78％。
MS(ESI,pos.ion)m/z:272[M+H] +；
1H-NMR(DMSO-d6,500MHz):δ(ppm)0.86(t,3H),1.51(m,2H),1.76(m,1H),1.95(m,1H),2.11(m,4H),3.71(m,2H),4.17(m,1H),6.73(s,1H),7.24(s,1H),7.96(t,1H),8.06(d,1H),12.55(s,1H)。
B化合物的稳定性研究
实施例B1 N-酰基甘氨酰-L-谷氨酰胺的稳定性研究
B1.1供试品：
N-丁酰甘氨酰-L-谷氨酰胺(Butyryl-Gly-Gln)、N-乙酰甘氨酰-L-谷氨酰胺(Ac-Gly-Gln)、甘氨酰谷氨酰胺(Gly-Gln)。
B1.2实验仪器：
药物稳定性培养箱、高效液相色谱仪等。
B1.3实验步骤：
标准工作液的制备：准确称取0.0500g供试品，加入去离子水定容至25mL，制成工作储备液。取适量工作储备液，用水分别稀释至浓度为250ppm、500ppm、1000ppm、2000ppm的工作液，待测。检验样品浓度与HPLC峰面积响应值是否成线性相关。
供试品溶液的制备：
将一定量的待测供试品原料分别放置于60℃药物稳定性培养箱和放置有KNO 3饱和溶液(25℃，RH90％)的药物稳定性培养箱中，于第5天和第10天取样0.0500g(精确到0.0001)，加入去离子水定容至25mL，制成工作液进行HPLC(高效液相色谱)检测，每种样品平行取样三次(以0天时主成分含量为100％计算)。
将甘谷二肽及乙酰甘谷二肽的1％水溶液放置于常温环境下，于第5天时取样进行HPLC检测，每种样品平行取样三次(以0天时主成分含量为100％计算)。
高效液相色谱检测条件：
色谱柱：C18柱(250mm*4.6mm，5μm)柱；
流动相：乙腈-0.02％磷酸水溶液(V/V＝30/70)；
检测波长：215nm；
柱温：25℃；
进样量：10μL；
流速：1mL/min。
B1.4实验结果：
试验数据采用SPSS18软件进行统计分析，先对数据作单因素方差分析(ANOVA)，若处理间差异显著，再用Duncan's法进行多重比较，显著性水平为0.05。试验结果以“平均值±标准误”表示，如表2所示。
B1.5结果：
在60℃高温条件下，N-乙酰甘氨酰-L-谷氨酰胺在10天的试验期中含量比第0天时下降了约1％，含量下降幅度不显著；N-丁酰甘氨酰-L-谷氨酰胺在高温稳定性试验进行到第5天时化合物受热分解严重，含量下降至约7.25％。
在25℃下的RH95％条件下，N-乙酰甘氨酰-L-谷氨酰胺在10天的试验期中含量比第0天时下降了约4.7％，与第0天的含量相比下降幅度显著；N-丁酰甘氨酰-L-谷氨酰胺在高温稳定性研究进行到第5天时化合物受潮水解严重，含量下降至8.22％左右。
在常温的稳定性试验条件下，在第5天试验期内甘氨酰谷氨酰胺及N-乙酰甘氨酰-L-谷氨酰胺的1％水溶液的主成分含量分别下降至94.01％、99.13％，可见甘氨酰谷氨酰胺在水溶液环境下比N-乙酰甘氨酰-L-谷氨酰胺表现出相对更差的稳定性。
表2 酰基化谷氨酰胺衍生物在高温及高湿稳定性研究中的含量变化结果
Figure PCTCN2019087524-appb-000005
实施例B2 N-乙酰甘氨酰-L-谷氨酰胺的稳定性研究
B2.1供试品：
N-乙酰甘氨酰-L-谷氨酰胺(Ac-Gly-Gln)的原料、30％预混剂及1％饲料。
B2.2实验仪器：
药物稳定性培养箱、高效液相色谱仪等。
B1.3实验步骤：
B1.3.1标准工作液的制备
准确称取0.05g(精确到0.0001)供试品，加入去离子水定容至25mL，制成工作储备液。取适量工作储备液，用水分别稀释至浓度为250ppm、500ppm、1000ppm、2000ppm的工作液，待测。检验样品浓度与HPLC峰面积响应值是否成线性相关。
B1.3.2待测样制备
30％预混剂待测样制备：准确称取6g(精确到0.0001)乙酰甘谷二肽样品(Ac-Gly-Gln)，玉米芯粉20g，置于搅拌机中混合均匀。
1％饲料供试品待测样的制备：准确称取1.5g(精确到0.0001)乙酰甘谷二肽样品，肉鸡空白饲料150g，置于搅拌机中混合均匀。
B1.3.3供试品溶液的制备
按表3设置的试验组要求将一定量的待测试样分别放置于60℃药物高温稳定性培养箱、40℃药物加速条件稳定性培养箱、25℃药物恒温稳定性培养箱、25℃95％RH药物高湿稳定性培养箱、4500Lx光药物光稳定性培养箱中，于不同时间取样进行HPLC检测，每组样品平行取样三次。
原料供试品溶液的制备：准确称取放置于不同条件下的乙酰甘谷二肽原料(Ac-Gly-Gln)0.05g(精确到0.0001)，加入去离子水定容至25mL，制成工作液，待测。
30％预混剂供试品溶液的制备：准确称取放置于不同条件下的乙酰甘谷二肽30％预混剂0.15g(精确到0.0001)，加入去离子水定容至25mL，制成工作液，待测。
1％饲料供试品溶液的制备：准确称取放置常温的乙酰甘谷二肽1％饲料5g(精确到0.0001)，加入甲醇定容至25mL，制成工作液，待测。
B1.3.4高效液相色谱检测条件：
色谱柱：C18柱(250mm*4.6mm，5μm)柱；
流动相：乙腈-0.02％磷酸水溶液(V/V＝30/70)；
检测波长：215nm；
柱温：25℃；
进样量：10μL；
流速：1mL/min。
B1.4实验结果：
试验数据采用SPSS18软件进行统计分析，先对数据作单因素方差分析(ANOVA)，若处理间差异显著，再用Duncan's法进行多重比较，显著性水平为0.05。试验结果以“平均值±标准误”表示，如表3所示。
B1.5结果：
N-乙酰甘氨酰-L-谷氨酰胺原料在60℃高温稳定性试验、光稳定性试验、40℃加速长期稳定性试验、25℃恒温稳定性等试验试验条件下含量变化不显著，但是25℃95％RH高湿稳定性试验条件下化合物在试验第5天出现了显著的降解并含量下降到95％并与试验第10天的含量相比变化不显著，表明N-乙酰甘氨酰-L-谷氨酰胺化合物在高温、高湿、光照条件下表现出稳定的物化性质并具有存放储备稳定性。
N-乙酰甘氨酰-L-谷氨酰胺的30％预混剂在60℃高温稳定性试验、25℃95％RH高湿稳定性试验、光稳定性试验、40℃加速长期稳定性试验、25℃恒温稳定性等试验的试验周期范围内，N-乙酰甘氨酰-L-谷氨酰胺在高湿条件下第5天出现了较为显著的降解使得含量下降到约97％，而在光照条件下第10天也出现较为显著的降解使得含量下降到98％。N-乙酰甘氨酰-L-谷氨酰胺在30％预混剂中在稳定性考察因素试验下表现出显著的稳定性。
N-乙酰甘氨酰-L-谷氨酰胺的1％饲料按照饲料储存稳定性要求进行为期一个月的25℃恒温稳定性考察，当稳定性试验进行到1个月时1％饲料中的N-乙酰甘氨酰-L-谷氨酰胺含量与起始含量相比下降到96.94％，未超过饲料加工或饲料添加剂加工所允许的0～5％变化范围。
表3 N-乙酰甘氨酰-L-谷氨酰胺系列产品在稳定性研究中的含量变化结果
Figure PCTCN2019087524-appb-000006
Figure PCTCN2019087524-appb-000007
C N-乙酰甘氨酰-L-谷氨酰胺在动物养殖试验中的应用
实施例C1 N-乙酰甘氨酰-L-谷氨酰胺对断奶猪生产性能的影响研究
从70窝28±2日龄“杜长大”三元杂交断奶猪中选择临床检查健康的体重相近的600头为试验猪，随机分成10组，每组3个重复，每个重复公母各半共20头。仔猪从7日龄开始诱食，28日龄断奶猪舍为水泥地板，钢筋围栏，通风良好，温度适宜。试验前对猪圈及器具进行消毒。试验期，试验猪在同一猪圈同一饲养管理条件下分栏圈养，自由采食和饮水；猪舍每天清扫一次，每三天冲洗地面一次，保持清洁的卫生条件；日喂料3次。各试验组分为对照组和试验组。Ⅰ组为对照组，仔猪饲喂基础日粮；试验组Ⅱ组仔猪饲喂的日粮为基础日粮基础上分别添加5000ppm的谷氨酰胺(Gln)；Ⅲ和Ⅳ组仔猪饲喂的日粮为基础日粮基础上分别添加2500ppm和5000ppm的甘氨酰-L-谷氨酰胺(Glycyl-Gln)；Ⅴ～Ⅹ组仔猪饲喂的日粮为基础日粮基础上分别添加1000ppm、1500ppm、2000ppm、3000ppm、4000ppm和5000ppm的N-乙酰甘氨酰-L-谷氨酰胺(Ac-Glycyl-Gln)。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。试验期为14天。
在试验开始后的0和14天的上午7:00～9:00对试验猪称重。试验期，每天观察仔猪采食和健康状况并称量剩余的日粮，记录饲料消耗量、各组腹泻头数，计算平均日采食量(ADFI，g/d*只)、平均日增重(ADG，g/d*只)、料肉比(FCR)和腹泻率(DR)。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；
腹泻率＝每日腹泻头数之和/(试验天数×每重复猪数)。
试验数据采用SPSS18软件进行统计分析，先对数据作单因素方差分析(ANOVA)，若处理间差异显著，再用Duncan's法进行多重比较，显著性水平为0.05。试验结果以“平均值±标准误”表示，试验结果如表4所示。
从断奶猪的饲养试验结果可知，谷氨酰胺应用在断奶猪的早期饲养中可以有效地控制腹泻率的发生、增加猪的采食量并提高饲料的转化率；甘氨酰-L-谷氨酰胺的用量在2500ppm时可以达到5000ppm的谷氨酰胺对断奶猪的生产性能的改善和缓解腹泻的功效，但是当用量达到高剂量5000ppm时试验猪的采食量明显的下降；N-乙酰甘氨酰-L-谷氨酰胺添加在断奶猪的基础日粮中可增加断奶猪的采食量的同时提高饲料的转化率并有效地控制断奶猪的腹泻率，呈现一定的剂量梯度效应，并且当用量在1500ppm时与5000ppm谷氨酰胺和2500ppm的甘氨酰-L-谷氨酰胺具有相似的控制生产性能功效。
表4 谷氨酰胺衍生物对断奶仔猪的生产性能影响研究
Figure PCTCN2019087524-appb-000008
实验例C2 N-乙酰甘氨酰-L-谷氨酰胺在鸡料中的应用研究
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1200只，随机分为6个处理组，每组6个重复，公母各半，每个重复20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、试验Ⅰ～Ⅵ组。其中对照组仅给与基础日粮，试验Ⅰ在基础日粮中添加4000ppm的谷氨酰胺(Gln)，试验Ⅱ组在基础日粮中添加2000ppm的甘氨酰-L-谷氨酰胺(Glycyl-Gln)，其他试验组在基础日粮中添加N-乙酰甘氨酰-L-谷氨酰胺(Ac-Glycyl-Gln)，分组见表5。试验期共20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21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)。
参数统计：试验时，停料不停水12h后称重，计算各组试验组的平均日采食量(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。
试验数据采用SPSS18软件进行统计分析，先对数据作单因素方差分析(ANOVA)，若处理间差异显著，再用Duncan's法进行多重比较，显著性水平为0.05。试验结果以“平均值±标准误”表示，试验结果如表5所示。
从结果可知，N-乙酰甘氨酰-L-谷氨酰胺具有与谷氨酰胺和甘氨酰-L-谷氨酰胺相似的改善肉鸡生产性能的功效。
表5 N-乙酰甘氨酰-L-谷氨酰胺在肉鸡料中的应用效果研究
Figure PCTCN2019087524-appb-000009
实验例C3 N-乙酰甘氨酰-L-谷氨酰胺在鱼料中的应用研究
1)试验材料
试验用鱼：所用试验鱼为当年的健康活泼、规格一致的草鱼种在大网箱中(4×2×1.5m 3)饲养4周后才用于正式养殖试验，实验体系为浮性小网箱(规格1.1×1.1×1.1m 3)，每个小网箱均 置有一个充气头，每天24h充气。小网箱与暂养网箱均置于试验场一个3500m 2的池塘中，池塘水深约1.5m，池塘水为充分曝气底下水。试验时，将饥饿1天的草鱼560尾随机分成7组，每组设4个重复，每个重复放20尾鱼，以每个重复为单位称重后放入36个网箱中，分别饲喂苯甲酸锌含量不同的试验饲料。
试验饲料：试验用饲料按表6配方自行配制，不同试验组按表7分别添加不同含量的N-乙酰甘氨酰-L-谷氨酰胺。所用饲料原料经超微粉碎后通过江苏牧羊膨化机组制成粒径3mm浮性膨化饲料，出模温度130℃，通过喷油设备外喷3％豆油，阴凉处密封保存备用。
表6 试验用草鱼饲料配方及化学成分(％wt.)
原料组成 含量(％) 原料组成 含量(％)
鱼粉 9.0 豆油 3.0
肠衣粉 3.0 磷脂菜粕 9.0
豆粕 12.0 谷朊粉 4.0
菜粕 12.0 血球粉 2.0
味精蛋白 3.0 Vc-磷酸酯 0.1
次粉 12.6 磷酸二氢钙 1.8
面粉 17.0 氯化胆碱 0.2
膨润土 0.70 多维 0.1
米糠 10.0 微矿预混剂 0.5
表7 N-乙酰甘氨酰-L-谷氨酰胺的促生长试验分组
组别 供试品 剂量(ppm)
对照组 - -
Ⅰ组 N-乙酰甘氨酰-L-谷氨酰胺 100
Ⅱ组 N-乙酰甘氨酰-L-谷氨酰胺 200
Ⅲ组 N-乙酰甘氨酰-L-谷氨酰胺 400
Ⅳ组 N-乙酰甘氨酰-L-谷氨酰胺 800
Ⅴ组 N-乙酰甘氨酰-L-谷氨酰胺 1500
Ⅵ组 N-乙酰甘氨酰-L-谷氨酰胺 3000
(2)试验方法
试验管理：试验采用人工限食投喂，投食量每周调整一次，每组投喂水平(按初始体重)完全一致，每天投喂两次(7:30及15:00)，总投喂食量为580g/重复试验组。试验为期8周。试验期间定时对水质进行监控，养殖全程水温26.88±3.08℃、DO>5.0mg O L -1、pH 7.8、氨氮<0.50mg N L -1、亚硝酸盐氮<0.05mg N L -1。
参数统计：试验时，停喂1d后对各网箱鱼进行整体称重，计算其增重率(WG,％)、饲料系数(FCR)和存活率(SR,％)。计算公式如下：
增重率(WG，％)＝100×(平均末重－平均初重)/平均初重；
饲料系数(FCR)＝摄食量/鱼体增重；
存活率(SR，％)＝100×试验结束时鱼数量/试验开始时鱼数量。
(3)试验结果
从表8所示的试验结果可知N-乙酰甘氨酰-L-谷氨酰胺应用在草鱼饲料中可显著的降低草鱼的料肉比提高饲料的转化率，虽然可提高草鱼的平均增重率但是不显著；且N-乙酰甘氨酰-L-谷氨酰胺对草鱼的生产性能的影响与对照组相比具有显著的改善效果然而在给与不同含量N-乙酰甘氨酰-L-谷氨酰胺饲料的试验组间差异不显著。
表8 N-乙酰甘氨酰-L-谷氨酰胺在水产料中的应用试验结果
Figure PCTCN2019087524-appb-000010
以上所述实施例仅表达了本发明的几种实施方式，还有其他方式用来实施本发明。相应地，本发明的实施例是将作为例证进行说明，但并不能因此而理解为对本发明的专利范围的限制，还可能是在本发明范围内以及同一发明构思内所作的修改或在权利要求中所添加的等同内容。

Claims (10)

  1. N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐在制备动物饲料添加剂中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述的动物饲料添加剂是饲用谷氨酰胺替代物。
  3. 根据权利要求1所述的应用，其特征在于，所述的动物饲料添加剂是饲用甘氨酰谷氨酰胺替代物。
  4. 根据权利要求1所述的应用，其特征在于，所述的N-乙酰甘氨酰谷氨酰胺为N-乙酰甘氨酰-L-谷氨酰胺。
  5. 根据权利要求1-4任一项所述的应用，其特征在于，所述的动物为各个生长阶段的家畜、家禽、水产养殖动物或宠物。
  6. 一种包含N-乙酰甘氨酰谷氨酰胺或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐和可饲用辅料的饲用组合物。
  7. 根据权利要求6所述的组合物，其特征在于，所述的组合物还包含动物饲料原料。
  8. 根据权利要求6或7所述的组合物，其特征在于，所述的组合物还包含附加的动物饲料添加剂。
  9. 根据权利要求8所述的组合物，其特征在于，所述的附加的动物饲料添加剂为营养性动物饲料添加剂、非营养性饲料添加剂或药物饲料添加剂。
  10. 根据权利要求6所述的组合物，其特征在于，所述的N-乙酰甘氨酰谷氨酰胺为N-乙酰甘氨酰-L-谷氨酰胺。
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