WO2020143040A1 - 色氨酸衍生物及其应用 - Google Patents

色氨酸衍生物及其应用 Download PDF

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Publication number
WO2020143040A1
WO2020143040A1 PCT/CN2019/071413 CN2019071413W WO2020143040A1 WO 2020143040 A1 WO2020143040 A1 WO 2020143040A1 CN 2019071413 W CN2019071413 W CN 2019071413W WO 2020143040 A1 WO2020143040 A1 WO 2020143040A1
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Prior art keywords
tryptophan
feed
alkyl
acceptable salt
solvate
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PCT/CN2019/071413
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English (en)
French (fr)
Inventor
黄华成
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黄华成
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Priority to CN201980004549.9A priority Critical patent/CN111132962B/zh
Priority to PCT/CN2019/071413 priority patent/WO2020143040A1/zh
Publication of WO2020143040A1 publication Critical patent/WO2020143040A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K61/00—Culture of aquatic animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
    • A01K67/02—Breeding vertebrates
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
    • Y02A40/80—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in fisheries management
    • Y02A40/81—Aquaculture, e.g. of fish

Definitions

  • the invention relates to the field of animal feed additives, in particular to a tryptophan derivative and its application in animal feed additives.
  • Tryptophan is an essential amino acid for the maintenance and growth of animals. It is one of the basic constituents of the body's protein and has a variety of physiological functions. However, the animal cannot be synthesized and must be supplied from feed. In corn and soybean meal-type diets, Tryptophan is more likely to be lacking and requires additional addition. Tryptophan is a precursor of the neurotransmitter serotonin. Studies have shown that tryptophan has a certain regulatory effect on animal feed intake.
  • Tryptophan is ⁇ -indolyl alanine, it is used in feed additives or feed industry to add to premix or feed, stored at room temperature for a period of time very quickly degradation and deterioration, and color during feed pelleting The acid cannot tolerate the high-temperature granulation process above 40°C.
  • the purpose of the present invention is to find a heat-resistant tryptophan substitute with stable physicochemical properties when mixed in feed or premix to provide a stable and effective feed additive product or feed product for animal breeding. To improve the production performance of farmed animals.
  • tryptophan derivative or a salt acceptable in its feed, its stereoisomer, its tautomer, its solvate, and its prodrug molecule
  • the tryptophan derivative has the formula (I ) The structure shown:
  • R 1b and R 2b are independently C 3 -C 20 alkyl, C 3 -C 7 cycloalkyl, 1, 2, 3, 4 or 5 R 3 substituted C 1 -C 20 alkyl, or 1 , 2, 3, 4 or 5 R 3 substituted C 3 -C 7 cycloalkyl;
  • Y is H or alkyl
  • R 3 is OH, NH 2 , CN, SH or halogen
  • R 4 is -OH, -NH 2 , -NO 2 , -CN, -SH, halogen, -C 1 -C 5 alkoxy, -C 1 -C 5 alkyl, or -C 1 -substituted with halogen C 5 alkyl.
  • R 1b and R 2b are each independently C 3 -C 20 alkyl, or 1, 2, 3, 4 or 5 R 3 substituted C 1 -C 20 alkyl.
  • R 1b and R 2b are each independently C 3 -C 14 alkyl, or 1, 2, 3, 4 or 5 R 3 substituted C 3 -C 14 alkyl.
  • R 1b and R 2b are each independently a linear C 3 -C 14 alkyl group.
  • R 1a and R 2a are independently C 5 -C 12 aryl, -(C 1 -C 4 alkylene)-C 5 -C 12 aryl; wherein the C 5- The C 12 aryl group and -(C 1 -C 4 alkylene)-C 5 -C 12 aryl group may be independently optionally substituted with 1, 2, 3, 4 or 5 R 4 .
  • R 1a and R 2a are independently 1, 2, 3, 4, or 5 R 4 substituted phenyl groups, -(C 1 -C 4 alkylene)-phenyl, -(C 1 -C 4 alkylene)-phenyl can be independently optionally substituted with 1, 2, 3, 4 or 5 R 4 .
  • Y is H or -C 1 -C 20 alkyl.
  • Y is H or -C 1 -C 10 alkyl.
  • Y is H or -C 1 -C 4 alkyl.
  • Y is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.
  • the tryptophan derivative is selected from the following compounds:
  • the invention also provides a feed composition.
  • a feed composition comprising active ingredients capable of improving the production performance of farmed animals and acceptable raw materials and/or auxiliary materials in the feed; the active ingredients capable of improving the production performance of farmed animals are selected from the above-mentioned tryptophan derivatives Acceptable salts, their stereoisomers, their tautomers, their solvates, their prodrug molecules, and N-benzoyl-L-tryptophan and their acceptable feed At least one of the salts.
  • the acceptable excipients in the feed are selected from edible carriers, diluents, excipients, vehicles, or combinations thereof.
  • the feed composition further includes other animal feed additives.
  • the other animal feed additives are selected from nutritional feed additives and/or general feed additives and/or pharmaceutical feed additives.
  • the present invention also provides the above-mentioned tryptophan derivatives or their acceptable salts in feed, their stereoisomers, their tautomers, their solvates, their prodrug molecules, or the above-mentioned feed composition application.
  • the invention also provides a method for breeding animals. This method can effectively improve the production performance of farmed animals.
  • a method for breeding animals comprising the steps of: feeding the animals with feed containing active ingredients capable of improving the production performance of the farmed animals; the active ingredients capable of improving the production performance of the farmed animals are selected from the above-mentioned tryptophan derivatives Acceptable salts, their stereoisomers, their tautomers, their solvates, their prodrug molecules in their feeds, the above feed composition, and N-benzoyl-L-tryptophan And at least one of the acceptable salts in its feed.
  • the amount of the active ingredient that can improve the production performance of farmed animals in the feed is 0.1 ppm-10000 ppm.
  • the amount of the active ingredient that can improve the production performance of farmed animals in the feed is 100 ppm-500 ppm.
  • the animals include: poultry, livestock, aquaculture animals, and pets.
  • the tryptophan derivatives and their acceptable salts, their stereoisomers, their tautomers, their solvates, and their prodrug molecules provided by the present invention have the structure shown in formula (I)
  • the high thermal stability test of raw materials and the normal temperature stability test of feed both showed more stable physical and chemical properties than tryptophan. During the test period, the content of tryptophan derivatives did not exceed the acceptable change range of feed additives or feed .
  • the results of animal breeding experiments showed that the tryptophan derivatives and their acceptable salts, stereoisomers, tautomers, solvates, prodrug molecules and other compounds provided in the invention It can effectively improve the growth and feed performance of animals, and even has a better improvement effect than tryptophan. It can be used as an animal feed additive, or used to prepare animal feed additives or animal feed.
  • the compound involved in the present invention is a tryptophan derivative with the structure shown in formula (I),
  • R 1 and R 2 are substituents on the nitrogen atom (abbreviated as N);
  • Y is H or alkyl
  • R 1b and R 2b are independently substituted or unsubstituted C 3 -C 20 alkyl or C 3 -C 7 cycloalkyl; when R 1b and/or R 2b are substituted C 3 -C 20 alkyl Or substituted C 3 -C 7 cycloalkyl, the substituted C 3 -C 20 alkyl or C 3 -C 7 cycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 3 Substituted C 3 -C 20 alkyl or C 3 -C 7 cycloalkyl; R 3 is OH, NH 2 , CN, SH or X 1 , where X 1 is selected from F, Cl, Br or I;
  • R 1a and R 2a are independently substituted or unsubstituted -C 5 -C 12 aryl, -C 2 -C 12 heteroaryl, -(C 1 -C 4 alkylene)-C 5 -C 12 aryl Group, -(C 1 -C 4 alkylene)-C 2 -C 12 heteroaryl; when R 1a and/or R 2a is substituted -C 5 -C 12 aryl, substituted -C 2 -C 12 Heteroaryl, substituted -(C 1 -C 4 alkylene)-C 5 -C 12 aryl, or substituted -(C 1 -C 4 alkylene)-C 2 -C 12 heteroaryl , The substituted -C 5 -C 12 aryl, -C 2 -C 12 heteroaryl, -(C 1 -C 4 alkylene)-C 2 -C 12 aryl, -(C 1- C 4 alkylene)-C 2 -C
  • substituted means that one or more substitutable hydrogen atoms in a given structure are replaced by specific substituents.
  • a substituted group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents of a specific group, then the substituents may be substituted at the same positions or differently.
  • C a -C b alkyl means a linear or branched saturated alkyl group containing a to b carbon atoms, such as methyl, ethyl, propyl, isopropyl, ...
  • C 1 -C 5 alkyl means a linear or branched saturated alkyl group containing 1 to 5 carbon atoms
  • C 3 -C 7 cycloalkyl means 3 to 7 Cyclic alkyl groups containing only two elements of carbon and hydrogen, such as cyclopropyl, 2-methylcyclopropyl, cyclopentyl, etc.
  • C 1 -C 5 alkoxy means containing 1 to 5 A group of carbon atoms and an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, etc.
  • C 5 -C 12 aryl means that it contains 5 to 12 carbon atoms with aromatic Cyclic groups such as benzene ring, etc.
  • C 2 -C 12 heteroaryl means containing 2 to 12 carbon atoms and more than 1 heteroatom (including but not limited to oxygen atom (O), sulfur atom (S), nitrogen atom (N)) cyclic group having aromaticity, such as
  • R 1 in the tryptophan derivative is R 1a S( ⁇ O) 2 , R 1b S( ⁇ O) 2 or H
  • R 1 is H
  • R 2 is R 2a S( ⁇ O) 2 or R 2b S( ⁇ O) 2 .
  • R 1 is H
  • R 1a and R 2a in the tryptophan derivative are independently substituted or unsubstituted C 5 -C 12 aryl groups; when R 1a and/or R 2a are substituted C 5 -C 12 aryl group, the substituted C 5 -C 12 aryl is optionally substituted with 4 or 5 R 4 substituted C 5 -C 12 aryl group; R 4 is - OH, -NH 2 , -NO 2 , -CN, -SH, -X 2 , -C 1 -C 5 alkoxy, -C 1 -C 5 alkyl, or -C 1 -C substituted with X 2 5 alkyl, wherein X 2 is selected from F, Cl, Br or I.
  • R 1a and R 2a are independently substituted or unsubstituted phenyl; when R 1a and/or R 2a are substituted phenyl, the substituted phenyl is optionally substituted by 1 , 3, 4 or 5 R 4 substituted phenyl group; R 4 is -OH, -NH 2, -NO 2, -CN, -SH, -X 2, -C 1 -C 5 alkoxy , -C 1 -C 5 alkyl, or X 2 is a substituent of -C 1 -C 5 alkyl group, wherein X 2 is selected from F, Cl, Br or I.
  • R 1a and R 2a in the tryptophan derivative are independently substituted or unsubstituted -(C 1 -C 4 alkylene)-C 5 -C 12 aryl or- (C 1 -C 4 alkylene)-C 5 -C 12 aryl; when R 1a and/or R 2a are substituted -(C 1 -C 4 alkylene)-C 5 -C 12 aryl or When substituted -(C 1 -C 4 alkylene)-C 5 -C 12 aryl, the substituted -(C 1 -C 4 alkylene)-C 5 -C 12 aryl or -(C 1 -C 4 alkylene)-C 5 -C 12 aryl is optionally substituted with 1, 2, 3, 4 or 5 R 4 -(C 1 -C 4 alkylene)-C 5 -C 12 aryl or -(C 1 -C 4 alkylene)-C 5 -C 12 aryl; R 4
  • the R 1a and R 2a are independently substituted or unsubstituted -(C 1 -C 4 alkylene)-phenyl or -(C 1 -C 4 alkylene)-phenyl;
  • R 1a and/or R 2a are substituted -(C 1 -C 4 alkylene)-phenyl or substituted -(C 1 -C 4 alkylene)-phenyl
  • the substituted -( C 1 -C 4 alkylene)-phenyl or -(C 1 -C 4 alkylene)-phenyl is optionally substituted by 1, 2, 3, 4 or 5 R 4 -(C 1 -C 4 alkylene)-phenyl or -(C 1 -C 4 alkylene)-phenyl
  • R 4 is -OH, -NH 2 , -NO 2 , -CN, -SH, -X 2 , -C 1 -C 5 alkoxy, -C 1 -C 5 alkyl,
  • R 1a and R 2a in the acyl derivative of the amino acid are independently substituted or unsubstituted C 2 -C 12 heteroaryl; when R 1a and/or R 2a are substituted C In the case of 2 -C 12 heteroaryl, the substituted C 2 -C 12 heteroaryl is optionally C 5 -C 12 heteroaryl substituted with 1, 2, 3, 4 or 5 R 4 ; R 4 is -OH, -NH 2 , -NO 2 , -CN, -SH, -X 2 , -C 1 -C 5 alkoxy, -C 1 -C 5 alkyl, or-substituted by X 2- C 1 -C 5 alkyl, wherein X 2 is selected from F, Cl, Br or I.
  • R 1a and R 2a are independently substituted or unsubstituted C 5 heteroaryl; when R 1a and/or R 2a are substituted C 5 heteroaryl, the substituted C 5 Heteroaryl is optionally C 5 heteroaryl substituted with 1, 2, 3, 4 or 5 R 4 ;
  • R 4 is -OH, -NH 2 , -NO 2 , -CN, -SH,- X 2, -C 1 -C 5 alkoxy, -C 1 -C 5 alkyl, or
  • X 2 is a substituent of -C 1 -C 5 alkyl group, wherein X 2 is selected from F, Cl, Br or I.
  • the C 5 heteroaryl group is
  • R 1a and R 2a in the tryptophan derivative are independently substituted or unsubstituted -(C 1 -C 4 alkylene)-C 2 -C 12 heteroaryl;
  • R 1a and/or R 2a is a substituted -(C 1 -C 4 alkylene)-C 2 -C 12 heteroaryl
  • the substituted -(C 1 -C 4 alkylene)-C 2 -C 12 heteroaryl is optionally -(C 1 -C 4 alkylene)-C 2 -C 12 heteroaryl substituted by 1, 2, 3, 4 or 5 R 4 ;
  • R 1a and R 2a are independently substituted or unsubstituted -(C 1 -C 4 alkylene)-C 5 heteroaryl; when R 1a and/or R 2a are substituted- (C 1 -C 4 alkylene)-C 5 heteroaryl, the substituted -(C 1 -C 4 alkylene)-C 5 heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 R 4 substituted - (C 1 -C 4 alkylene) -C 5 heteroaryl; R 4 is -OH, -NH 2, -NO 2, -CN, -SH, -X 2 , -C 1 -C 5 alkoxy, -C 1 -C 5 alkyl, or X is a substituted 2 -C 1 -C 5 alkyl group, wherein X 2 is selected from F, Cl, Br or I.
  • the C 5 heteroaryl group is
  • R 1b and R 2b in the tryptophan derivative are independently substituted or unsubstituted C 3 -C 20 alkyl; when R 1b and/or R 2b are substituted C 3 -C 20 alkyl, the substituted C 3 -C 20 alkyl optionally substituted with 4 or 5 R 3 substituted C 3 -C 20 alkyl; R 3 is OH , NH 2 , CN, SH or X 1 , wherein X 1 is selected from F, Cl, Br or I;
  • each of R 1b and R 2b is independently preferably a linear C 3 -C 20 alkyl group, and more preferably a linear C 3 -C 14 alkyl group.
  • the linear alkyl group is n-propyl, n-butyl, n-pentyl, n-heptyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecane Base, n-dodecyl, n-tridecyl, n-tetradecyl.
  • each of R 1b and R 2b is independently preferably a branched C 3 -C 20 alkyl group.
  • the branched alkyl group is preferably isopropyl or tert-butyl.
  • R 1b and R 2b in the tryptophan derivative are independently substituted or unsubstituted C 3 -C 7 cycloalkyl; when R 1b and/or R 2b are substituted C when 3 -C 7 cycloalkyl, the substituted C 3 -C 7 cycloalkyl optionally substituted with 4 or 5 R 3 substituted C 3 -C 7 cycloalkyl; R 3 is OH, NH 2 , CN, SH or X 1 , wherein X 1 is selected from F, Cl, Br or I.
  • each of R 1b and R 2b is independently preferably C 3 -C 7 cycloalkyl.
  • the cycloalkyl group is cyclopropyl, cyclopentyl, or cyclohexyl.
  • Y is preferably H or -C 1 -C 20 alkyl; more preferably H or -C 1 -C 10 alkyl; more preferably H or -C 1 -C 4 alkyl.
  • Y is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.
  • the acyl derivatives of the amino acids of the present invention include: N-lauroyl-L-tryptophan, N-myristoyl-L-tryptophan, N-acetyl-L-color Leucine, N-benzoyl-L-tryptophan, N-butyryl-L-tryptophan, N-hexanoyl-L-tryptophan, N-octanoyl-L-tryptophan, N- Decanoyl-L-tryptophan, and the salts, stereoisomers, tautomers, solvates, and prodrug molecules that are acceptable in the feeds corresponding to the above compounds.
  • the preparation method of tryptophan derivatives shown in formula (I) according to the present invention uses tryptophan (abbreviated as Trp) as the starting material, and the chemical reactions mainly involved include acylation of amino groups, salt formation of carboxyl groups or Esterification of carboxyl groups.
  • Trp tryptophan
  • the synthetic route of the tryptophan derivative is as shown in formula (II):
  • R in formula (II) only represents a substituent group, if the raw material When the substance represented is not a single substance, then R should be understood as a collection of substituents (the same solution below); rt. means normal temperature, and base means that the reaction conditions are basic conditions.
  • the tryptophan derivative having the structure shown in formula (I) is prepared as an acceptable salt for feed, and the acceptable salt for feed is tryptophan prepared by the reaction process of formula (II)
  • the base derivative reacts with the metal base of the first main group or the second main group, or reacts with the metal ion halide under alkaline conditions to obtain the metal ion salt of the tryptophan derivative.
  • the acceptable salt for feed is the salt formed by the tryptophan derivative of the present invention and an organic base, inorganic base, organic acid or inorganic acid which is non-toxic to animals.
  • feed-acceptable means that the substance or composition must be chemically or toxicologically related to the constituent feed or edible farm animal.
  • the metal base includes but is not limited to sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like.
  • the metal ion halide is metal ion chloride, metal ion bromide or metal ion iodide.
  • the metal ion is a monovalent metal ion, a divalent metal ion or a trivalent metal ion.
  • the monovalent metal ions include but are not limited to sodium ion, potassium ion, lithium ion, ammonium ion;
  • the bivalent metal ions include but are not limited to calcium ion, magnesium ion, zinc ion, copper ion, sub-ion Iron ions, manganese ions;
  • the trivalent metal ions include but are not limited to iron ions, nickel ions, chromium ions, aluminum ions.
  • the metal ion is zinc ion.
  • the metal ions are copper ions.
  • the metal ion is sodium ion.
  • the metal ion is calcium ion.
  • the metal ions are iron ions.
  • tryptophan derivatives having the structure shown in formula (I) can also be prepared as their prodrug compounds.
  • the prodrug compound is a fatty ester, which is a carboxyl group of a fatty alcohol and tryptophan
  • HBTU O-benzotriazole-tetramethylurea hexafluorophosphate
  • Y in formula (II') is the fatty alkanyl portion of the fatty alcohol; R only represents a substituent group, if the raw material When the substance represented is not a single substance, then R should be understood as a collection of substituents (the same solution below); rt. means normal temperature, and base means that the reaction conditions are basic conditions.
  • the "prodrug compound” refers to a substance that is transformed into a substance that can bind to receptors or organs in the organism and exert its effect. Such conversion is affected by the prodrug compound in the gastrointestinal tract, blood, or tissue fluid of the organism. Effects of enzymes or pH in the body.
  • the prodrug compound of the tryptophan derivative according to the present invention can significantly improve the oil-water partition coefficient of the tryptophan derivative, increase the fat solubility, improve the absorption performance of the organism, and thus increase the bioavailability.
  • the fatty alcohol is a C 1 -C 20 fatty alcohol.
  • the fatty alcohol is a C 1 -C 20 linear fatty alcohol.
  • the fatty alcohol is methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol, n-nonanol and n-decyl alcohol.
  • the tryptophan derivative formed by aminoacylation of tryptophan is a chiral compound
  • the tryptophan derivative according to the present invention is selected from L-(-)- Tryptophan derivatives (structure like formula (III)), dextrorotatory D-(+)-amino acid derivatives (structure like formula (IV)) or racemic DL-( ⁇ ) amino acid derivatives.
  • the chiral stereoisomer of the tryptophan derivative can undergo a stereo conformation conversion under suitable conditions, such as the mutual change of the stereo conformation of the tryptophan derivative.
  • Formula (V) shows:
  • the reaction substrate can generate different geometric isomer products during the reaction.
  • stereoisomer refers to compounds having the same chemical structure but different arrangement of atoms or groups in space, including enantiomers, diastereomers, and conformational isomers , Geometric isomers, atropisomers, etc.
  • Enantiomer refers to two isomers of a compound that cannot overlap but form a mirror image relationship with each other.
  • Diastereomers refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other, and have different physical properties such as different melting points, boiling points, spectral properties, and reactivity. Diastereomer mixtures can be separated by high-resolution analytical operations such as electrophoresis or chromatography; "tautomers” refer to structural isomers with different energies that can be interconverted by low energy barriers.
  • the present invention provides that the preparation process of tryptophan derivatives also involves the separation, purification, or recrystallization process of the reaction product.
  • the reaction product can be obtained from the reaction system by the solvent removal method.
  • the crude product is dissolved and analyzed under an appropriate temperature, light and mechanical vibration in an alcohol solvent, an alcohol-water mixed solvent or other organic solvents that can be used for product recrystallization Crystal or precipitation or recrystallization and separation to obtain tryptophan derivatives with a certain crystalline state.
  • the tryptophan derivative having a certain crystalline state is a crystal of tryptophan derivative or a solvate of tryptophan derivative.
  • the solvate of the tryptophan derivative may be selected from the hydrate of the tryptophan derivative or the ethanolate of the tryptophan derivative.
  • Solvate refers to the process of contacting the compound of the present invention with a solvent molecule due to the combination of non-covalent intermolecular force and chemical equivalent or non-chemical equivalent of solvent molecules caused by external conditions and internal conditions. Eutectic association. Solvent-forming solvents include, but are not limited to, water, acetone, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, isopropyl alcohol, and other solvents. "Hydrate” means that the solvent molecule is an association or crystal formed by water, that is, a compound that combines stoichiometric or non-stoichiometric water by non-covalent intermolecular forces.
  • the preparation of the tryptophan derivative provided by the present invention can also be processed after salting out in order to obtain a solid substance with higher chemical purity and lower impurity content.
  • the salting-out method is the process of salt precipitation of amino acid derivatives with corresponding organic bases, inorganic bases, organic acids or inorganic acids using the principles of acid-base neutralization, acid-base coordination or acid-base chelation, Obtain feed acceptable salts; the inorganic acids include, but are not limited to, hydrochloride, hydrobromide, phosphate, sulfate, nitrate, or combinations thereof, and the organic base includes, but is not limited to, ammonia or triethyl amine.
  • the inorganic base includes but is not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide.
  • the tryptophan derivatives of the present invention form acid-base coordination salts and/or acid-base chelate salts with inorganic acids or organic acids during the salting-out precipitation process of post-treatment.
  • the organic acids include But not limited to acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate , Salicylate, glucuronate, galactitol, citrate, tartrate, aspartate, glutamate, benzoate, p-toluate, cinnamic acid Salt, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, or a combination thereof.
  • the tryptophan derivatives or their racemates, stereoisomers, tautomers, solvates, feed-acceptable salts or prodrug compounds provided by the present invention are provided at 60°C and in the form of feed
  • the stability of the compound was measured at room temperature.
  • the test period was 10 days to 45 days. During the test period, the content of the compound did not change significantly with time, overcoming the instability of tryptophan in the premix or feed .
  • the invention relates to the application of tryptophan derivatives.
  • tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or their prodrug compounds provided by the present invention are used in the preparation of animal feed additives.
  • the "animal” referred to in the present invention refers to a person or farming that 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, exercise and reproduction. animal.
  • Cosmetic animals include poultry, domestic animals, aquaculture animals, and other animals legally captured by 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” includes, for example, chickens, ducks, geese, quails, pigeons, and the like.
  • aquaculture animals includes, for example, fish, shrimp, turtles, turtles and the like.
  • the tryptophan derivatives provided by the present invention and their racemates, stereoisomers, tautomers, solvates, feed-acceptable salts or their prodrug compounds are prepared as animals at various growth stages
  • Non-nutritive additives to improve the production performance of animals the 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, cows, sheep, horses, rabbits, mink or donkeys
  • the poultry 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, turtle, bullfrog, eel or loach
  • the pets include but are not limited to dogs or cats of various subspecies.
  • the tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds provided by the present invention are Feed additives that improve the production performance of hogs have an improvement effect on the feed intake, average daily gain or feed conversion rate of hogs.
  • Feed additives can significantly improve the performance of broilers or laying hens.
  • it is prepared by using the tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed-acceptable salts or prodrug compounds provided by the present invention It is a feed additive to improve the production performance of fish.
  • the feed acceptable salt of the tryptophan derivative provided by the present invention used in the preparation of animal feed additives is a metal ion salt.
  • the feed-acceptable salt of the tryptophan derivative is a metal ion salt of the tryptophan derivative represented by the formula (I).
  • Y in the tryptophan derivative having the structure shown in formula (I) is H, and the metal ion salt is prepared by the feed additive obtained by exchanging the tryptophan derivative with the metal ion Or the salt required for feed preparation.
  • the metal ions are selected from monovalent metal ions, divalent metal ions or trivalent metal ions.
  • the monovalent metal ion is sodium ion (Na(I)), potassium ion (K(I)) or lithium ion (Li(I)).
  • the divalent metal ion is calcium ion Ca(II), magnesium ion Mg(II), copper ion Cu(II), zinc ion Zn(II), ferrous ion Fe(II), Manganese ion Mn(II), cobalt ion Co(II) or nickel ion Ni(II).
  • the metal ion salt of the tryptophan derivative used in the preparation of animal feed additives is zinc ion salts
  • the animal feed additive is an organic zinc agent for animals as a high-dose inorganic zinc replacement.
  • the metal ion salt of the tryptophan derivative used in the preparation of animal feed additives is a copper ion salt
  • the animal feed additive is organic copper for animals as a high-dose inorganic copper replacement for animals.
  • the metal ion salt of the tryptophan derivative used in the preparation of animal feed additives is an iron ion salt
  • the animal feed additive is an iron supplement for animals.
  • the trivalent metal ion is aluminum ion Al(III), chromium ion Cr(III) or iron ion Fe(III).
  • the feedable supplementary material is equivalent to the acceptable supplementary material in the feed, and is specifically a feedable carrier, diluent, excipient, solvent or a combination thereof.
  • the feed related to the present invention refers to products processed and manufactured by industry for animal consumption.
  • composition refers to a group of compounds comprising one or more compounds as active ingredients.
  • the “carrier” referred to in the present invention refers to a feedable 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 a lot of crude fibers, including but not limited to corn flour, corn cob flour, wheat bran, rice husk powder, defatted rice bran, whole bran, corn stalk powder, peanut shell powder, etc.
  • the inorganic carrier is a mineral substance, which is mainly divided into calcium salts and silicon oxides, which are used for the preparation of trace element premixes, including but not limited to calcium carbonate, silicate, vermiculite, zeolite, sea bubble Stone etc.
  • the "diluent” referred to in the present invention refers to materials that uniformly distribute additive raw materials in materials, dilute high-concentration additive raw materials into low-concentration premixes or premix materials, which can separate trace ingredients from each other and reduce active ingredients. The mutual reaction between them is to increase the stability of the active ingredients but does not affect 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, degermated corn flour, dextrose (glucose), sucrose, semolina flour with bran, fried soy flour, secondary flour, corn gluten meal, etc.; inorganic diluents include but not Limited to limestone, calcium dihydrogen phosphate, shell powder, kaolin (white clay), table salt and sodium sulfate.
  • the excipient is a wetting agent that induces the inherent viscosity of the substance itself, a binder that binds the substance, a disintegrant that breaks up the entire flake of the substance into many fine particles, and reduces particles Retention agent for inter-friction force or anti-adhesive agent to prevent material adhesion, including but not limited to magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, starch slurry, water, inorganic salts, dextrin, powdered sugar Wait.
  • solvent refers to a solvent required to dissolve or disperse solids, including but not limited to water, ethanol, glycerin and the like.
  • the feed composition further comprises additional (other) animal feed additives and/or animal feed ingredients.
  • the additional (other) animal feed additives are nutritional feed additives, general feed additives or pharmaceutical feed additives.
  • the nutritive feed additives refer to small or trace substances added to compound feeds to balance feed nutrients, improve feed utilization and directly exert nutritional effects on animals, such as amino acids, amino acid salts and their analogues, vitamins and quasi-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 refers to some non-nutritive substances added to the feed for improving feed utilization, ensuring feed quality and quality, beneficial to animal health or metabolism, including growth promoters, Insect repellent health care agent, flavoring and attractant, feed conditioner, feed modulator, feed storage agent and Chinese herbal medicine additive.
  • the non-nutritive additives are growth promoters, including but not limited to butyric acid, calcium butyrate, sodium butyrate, tannic acid, p-thymol, p-thyme phenolate, p-thyme phenolate, 2 -Hydroxybenzoic acid, ⁇ -acid, ⁇ -ester, ⁇ -acid, hexahydro ⁇ -acid, hexahydro ⁇ -ester, hexahydro ⁇ -acid, benzoic acid or calcium benzoate, zinc oxide, sulfuric acid Zinc, zinc chloride.
  • growth promoters including but not limited to butyric acid, calcium butyrate, sodium butyrate, tannic acid, p-thymol, p-thyme phenolate, p-thyme phenolate, 2 -Hydroxybenzoic acid, ⁇ -acid, ⁇ -ester, ⁇ -acid, hexahydro ⁇
  • the non-nutritive additive is calcium butyrate.
  • the non-nutritive additive is tannic acid.
  • the pharmaceutical feed additives include, but are not limited to, veterinary drug pre-mixtures that have the functions of preventing animal diseases, promoting animal growth, and can be used for a long time in the feed and incorporated into a carrier or diluent.
  • the pharmaceutical feed additive is a feed antibiotic
  • the feed antibiotic includes but is not limited to polymyxin, salinomycin, aviramycin, bacitracin, virginiamycin , Nosiheptide, flavomycin, enramycin, berimycin, olaquindox, oxytetracycline or chlortetracycline.
  • a composition comprising a tryptophan derivative and its racemate, stereoisomer, tautomer, solvate, feed-acceptable salt, or prodrug compound thereof, further comprises nutrition One or more of sex feed additives, general feed additives and pharmaceutical feed additives.
  • the animal feed ingredients are equivalent to the acceptable feed ingredients, specifically grains and their processed products, oilseeds and their processed products, leguminous crops and their processed products, tubers, roots and their roots Processed products, other seeds, fruit products and their processed products, forages, roughages and their 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 products Biological and its by-products, minerals, microbial fermentation products and by-products, other feed materials and other feed materials
  • the present invention relates to the use of the above feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof.
  • the feed composition comprising tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts, or prodrug compounds thereof Used in the preparation of animal feed additives.
  • Animal feed prepared by using the feed composition containing tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof
  • the additives are livestock feed additives, poultry feed additives, aquaculture animal feed additives or pet feed additives.
  • the feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparation Animal feed additives.
  • the livestock include, but are not limited to, pigs, cattle, sheep, horses, rabbits, mink, etc. at various growth stages.
  • the feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparation Poultry feed additives.
  • the poultry includes but is not limited to chickens, ducks, geese, pigeons, etc. at various growth stages.
  • the feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparation Feed additives for aquaculture animals.
  • the aquaculture animals include but are not limited to fish, shrimp, crab, turtle, eel, etc. at various growth stages.
  • the feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparation Pet feed additives.
  • the pets include but are not limited to artificially raised dogs or cats.
  • the composition comprising tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed-acceptable salts or prodrug compounds thereof
  • the prepared animal feed additive is a premix, a compound premix, a liquid or a granule.
  • the feed containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, or feed-acceptable salts or prodrug compounds thereof The composition is used in the preparation of animal feed.
  • Animal feed prepared by using the feed composition containing tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof
  • feed composition containing tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof
  • livestock feed poultry feed, aquaculture animal feed or pet feed.
  • the feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparation Livestock feed.
  • the livestock includes but is not limited to pigs, cattle, sheep, horses, rabbits, mink, etc. at various growth stages.
  • the feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparation Poultry feed.
  • the poultry includes but is not limited to chickens, ducks, geese, pigeons, etc. at various growth stages.
  • aquatic products are prepared by applying the feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof.
  • Feed for animal breeding The aquaculture animals include but are not limited to fish, shrimp, crab, turtle, eel, etc. at various growth stages.
  • the feed composition containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparation Pet feed.
  • the pets include but are not limited to dogs or cats raised artificially.
  • a feed composition comprising a tryptophan derivative and its racemate, stereoisomer, tautomer, solvate, feed acceptable salt, or prodrug compound thereof
  • the feed is a single feed, concentrated feed, compound feed, compound premix or concentrate supplement.
  • the compound feed is a full-price compound feed.
  • the farmer will include feeds containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds Additives and feeds given to animals for consumption can significantly improve animal production performance.
  • the feed additive is a premix, a compound premix, a granule, or a liquid
  • the animal feed is mixed with the animal feed.
  • the animals are domestic animals, poultry, aquaculture animals or pets.
  • the domestic animals include but are not limited to pigs, cattle, sheep, horses, rabbits, mink, etc. at various growth stages;
  • the domestic poultry include but are not limited to chickens, ducks, geese, pigeons, etc. at various growth stages;
  • the aquaculture animals include but are not limited to fish, shrimp, crab, turtle, eel, etc. at various growth stages;
  • the pets include but are not limited to dogs or cats raised artificially.
  • the farmer combines feed additives containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed-acceptable salts or prodrug compounds with Feeding the feed to the weaned pigs significantly improves the average daily weight gain rate and feed conversion rate of the weaned pigs.
  • the farmer combines feed additives containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed-acceptable salts or prodrug compounds with Feeding companion feed to broilers significantly reduces the feed-to-meat ratio of broilers and improves feed conversion.
  • the farmer combines feed additives containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed-acceptable salts or prodrug compounds with Feed the fish with food.
  • the farmer combines feed additives containing tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed-acceptable salts or prodrug compounds with Feed it to young dogs.
  • the farmer will include tryptophan derivatives and their racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds. Feeding the composition to animals can significantly improve the animal's production performance.
  • the feed composition is a feed additive premix, a feed additive compound premix, granules, or a liquid, and is given to animals for consumption with the feed.
  • the feed composition is a feed additive premix.
  • the feed composition is a feed additive compound premix.
  • the feed composition is a concentrated feed, a compound feed, a compound premix or a concentrate supplement, which is directly given to animals as animal feed.
  • the feed composition is a full-price compound feed.
  • the embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. If no specific conditions are indicated in the examples, the conventional conditions or the conditions recommended by the manufacturer shall be followed. The reagents or instruments used do not indicate the manufacturer, are all conventional products that can be obtained through commercial purchase.
  • the reaction solution was concentrated under reduced pressure with ethylene glycol dimethyl ether, concentrated hydrochloric acid to adjust the reaction pH3, an oily substance precipitated, ethyl acetate was extracted, the ethyl acetate was concentrated, and the remaining oily substance was beaten with 100 mL of n-heptane to obtain 50 g of the product as a yellow solid. , Yield 82.1%.
  • reaction solution was extracted with ethyl acetate (200 ml*3), and the ethyl acetate layers were combined.
  • the combined organic phase was washed with water (400 ml*3) and saturated brine, and concentrated under reduced pressure to obtain a thick solid.
  • the resulting solid was recrystallized from ethyl acetate-petroleum ether (8:1) to obtain 52 g of product as a yellow solid with a yield of 47%.
  • Test products L-tryptophan, N-acetyl-L-tryptophan, N-lauroyl-L-tryptophan, N-myristoyl-L-tryptophan, N-acetyl-L-color Calcium glutamate, N-benzoyl-L-tryptophan calcium, N-butyryl-L-tryptophan calcium salt, N-hexanoyl-L-tryptophan calcium, N-octanoyl-L-color Calcium amino acid, calcium N-decanoyl-L-tryptophan, ethyl ethyl N-butyryl-L-tryptophan.
  • Preparation of standard solution Weigh accurately 50mg of tryptophan derivative sample, add methanol to bring the volume to 50mL, and prepare standard stock solution. Take an appropriate amount of standard stock solution, dilute with methanol to a working solution with a concentration of 125ppm, 250ppm, 500ppm, 1000ppm, HPLC detection, make a standard curve.
  • HPLC detection conditions chromatographic column: C 18 column (250mm*4.6mm, 5 ⁇ m) column; mobile phase: methanol-0.02% phosphoric acid aqueous solution gradient elution; detection wavelength: 278nm; column temperature: 25°C; injection volume: 10 ⁇ L; Flow rate: 1ml/min.
  • Feed stability test at room temperature put feed samples containing tryptophan derivatives with a mass fraction of 2000 ppm in aluminum foil bags and seal them. At room temperature, take samples on the 5th, 10th, 20th and 45th days and add appropriate amounts of water respectively A 1000 ppm solution was prepared by ultrasonic dissolution, filtered through a 0.22 ⁇ m filter membrane, and then analyzed by HPLC. Each sample was sampled three times in parallel.
  • the content has dropped by nearly 10% by the fifth day of the test, which exceeds the acceptable range of the content change of feed additives, but surprisingly N-lauroyl-L -Tryptophan, N-myristoyl-L-tryptophan, N-benzoyl-L-tryptophan calcium, N-butyryl-L-tryptophan calcium salt, N-hexanoyl-L-
  • the content of tryptophan calcium, N-octanoyl-L-tryptophan calcium, N-decanoyl-L-tryptophan calcium and N-butyryl-L-tryptophan ethyl ester did not change significantly, not exceeding
  • the feed additive has a 5% acceptable variation range and remains relatively stable throughout the test period.
  • test period is 28 days, with each repeat as the unit, weighed at 93 days of age (without feeding for 12 hours, without stopping water) to calculate the average daily feed intake (ADFI, g/d* only) and average day of each test group Weight gain (ADG, g/d* only) and feed ratio (FCR). Calculated as follows:
  • Average daily feed intake (total ingredients-leftovers) / (number of test days ⁇ number of pigs per repeat);
  • Average daily weight gain (average body weight at the end of the test-average body weight at the beginning of the test)/days of the test;
  • Feed ratio average daily feed intake/average daily gain.
  • the tryptophan derivatives provided by the present invention can effectively improve the production performance of the test pigs.
  • the test pigs eat less food than the tryptophan group, the feed conversion rate is lower than that of the tryptophan group. It has a significant improvement, and the production performance has basically reached the level of tryptophan, of which the N-butyryl-L-tryptophan calcium group and the N-butyryl-L-tryptophan ethyl group are more effective than tryptophan. The group effect is better.
  • a single-factor random design was used in the experiment. 660 Beijing white layer hens of 147 days old and similar weight were selected and randomly divided into 11 treatment groups with 6 replicates in each group and 10 Beijing white layer hens in each replicate. Sterilize the house and utensils before the test. During the test period, cages were housed under the same feeding and management conditions in the same house. The basic diet is mainly corn-soybean meal, and no additional antioxidants and growth promoters are added during the entire feeding process. Each test group was a control group (group 1), a tryptophan control group (group 2), and groups 3-11. The control group was given only the basic diet.
  • Average egg weight (g) average daily total egg weight/number of eggs
  • Average daily egg weight (g) average daily total egg weight/number of chickens
  • Feed ratio average daily feed intake/average daily egg weight.
  • EPR (%) EW(g) ADFI(g/d) EDW(g/d) EPR team 1 - 75.4 61.1 124 46.1 2.692 2 teams L-tryptophan 78.0 62.8 129 49.0 2.626 3 groups N-acetyl-L-tryptophan 77.2 62.3 126 48.1 2.611 4 groups N-lauroyl-L-tryptophan 79.6 62.6 128 49.8 2.573 5 groups N-myristoyl-L-tryptophan 80.2 61.5 126 49.3 2.559 6 groups N-acetyl-L-tryptophan calcium 77.5 62.8 127 48.7 2.607 7 groups Calcium N-benzoyl-L-tryptophan 79.8 62.1 126 49.6 2.549 8 groups N-butyryl-L-tryptophan calcium salt 81.3 62.0 128 50.4 2.531 9 groups Calcium N-hexanoyl-L-tryptophan 79.4 62.4 126 49.5 2.5
  • a single-factor random design was used in the experiment, and 880 three-yellow feather broilers with a day-to-day weight average weight of 50g were selected and randomly divided into 11 treatment groups with 4 replicates in each group. Three yellow feather broilers. Sterilize the house and utensils before the test. During the test period, cages were housed under the same feeding and management conditions in the same house. The basic diet is mainly corn-soybean meal, and no additional antioxidants and growth promoters are added during the entire feeding process. Each test group was a control group (group 1), a tryptophan control group (group 2), and groups 3-11. The control group was given only the basic diet. In Experiments 2-11, 150 ppm of tryptophan or tryptophan derivatives were added to the basic diet respectively. See Table 4 for grouping.
  • the test period was 20 days.
  • the test chickens were free to drink water and feed, feeding twice a day. Take each repeat as the unit, weigh at 21 days of age (without feeding for 12h, without stopping water), count the test chicken consumption, and calculate the average daily feed intake of each group of test chickens (ADFI, g/d* only) 3.
  • the average daily weight gain (ADG, g/d* only) and feed-to-meat ratio (FCR), the calculation formula is as follows:
  • Feed ratio (FCR) average daily feed intake/average daily gain.
  • the test feed was prepared by itself, and different test groups added 400 ppm different tryptophan derivatives to the base material.
  • Each test group was a control group (group 1), a tryptophan control group (group 2), and groups 3-11.
  • the control group was given only the basic diet.
  • 150 ppm of tryptophan or tryptophan derivatives were added to the basic diet respectively. See Table 5 for grouping.
  • the experiment uses artificial limited feeding, and the feeding amount is adjusted once a week.
  • the feeding levels of the two groups (according to the initial body weight) are exactly the same.
  • the feeding is twice a day (7:30 and 15:00), and the total feeding amount is 510g/ Repeat the test group.
  • the trial will last for 8 weeks.
  • the water quality was monitored regularly.
  • the water temperature during the whole cultivation was 26.88 ⁇ 3.08°C, DO>5.0mg O L -1 , pH 7.8, ammonia nitrogen ⁇ 0.50mg N L -1 , nitrite nitrogen ⁇ 0.05mg N
  • Weight gain rate 100 ⁇ (average final weight-average initial weight)/average initial weight;
  • Feed coefficient (FCR) feeding amount / body weight gain.
  • the test group added with tryptophan or its derivatives is superior to the control group in terms of weight gain and feed conversion rate, and has a significant growth promoting effect, in which the acylated tryptophan Or the calcium salt of acylated tryptophan improves the production performance of test fish more significantly than tryptophan.

Abstract

一种色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，所述色氨酸衍生物具有式(I)所示结构。式(I)所示的色氨酸衍生物及其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子在原料高热稳定性试验中和在饲料的常温稳定试验中均体现了比色氨酸更稳定的物化性质，在试验期内色氨酸衍生物的含量变化未超过饲料添加剂或饲料可接受的变化范围，并且这些化合物能有效改善动物的生长和饲料报酬等生产性能，甚至具有比色氨酸更优异的改善效果，可作为动物饲料添加剂应用，或者用于制备动物饲料添加剂或者动物饲料。

Description

色氨酸衍生物及其应用 技术领域
本发明涉及动物饲料添加剂领域，具体涉及一种色氨酸衍生物及其在动物饲料添加剂中的应用。
背景技术：
色氨酸是动物维持和生长的必须氨基酸，是构成机体蛋白质的基本组成成分之一，具有多种生理功能，但动物体内不能合成，须从饲料中供给，在玉米豆粕型配合日粮中，色氨酸较易缺乏，需要额外添加。色氨酸是神经介质5-羟色胺的前体物。研究表明，色氨酸对动物的采食量有一定的调节作用。
色氨酸是β-吲哚基丙氨酸，将其应用在饲料添加剂或饲料工业中添加到预混剂或饲料中，常温下存放一段时间非常迅速的降解变质，并且在饲料制粒过程色氨酸无法耐受40℃以上的高热制粒过程。
发明内容
基于此，本发明的目的在于寻找一种耐热并在饲料或预混剂中混合时物化性质稳定的色氨酸替代物，以便为动物养殖提供一种稳定有效的饲料添加剂产品或者饲料产品，以提高养殖动物的生产性能。
具体技术方案如下：
一种色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，所述色氨酸衍生物具有式(I)所示结构：
Figure PCTCN2019071413-appb-000001
其中，R 1为R 1aC(＝O)，R 1bC(＝O)，R 1aS(＝O) 2，R 1bS(＝O) 2或H；
R 2为R 2aC(＝O)，R 2bC(＝O)，R 2aS(＝O) 2或R 2bS(＝O) 2；
R 1b和R 2b分别独立地为C 3-C 20烷基，C 3-C 7环烷基，1、2、3、4或5个R 3取代的C 1-C 20烷基，或者1、2、3、4或5个R 3取代的C 3-C 7环烷基；
Y为H或烷基；
R 3为OH，NH 2，CN，SH或卤素；
R 1a和R 2a分别独立地为C 5-C 12芳基，C 2-C 12杂芳基，-(C 1-C 4亚烷基)-C 5-C 12芳基或-(C 1-C 4亚烷基)-C 2-C 12杂芳基；其中所述C 5-C 12芳基，C 2-C 12杂芳基，-(C 1-C 4亚烷基)-C 5-C 12芳基和 -(C 1-C 4亚烷基)-C 2-C 12杂芳基可以独立任选地被1、2、3、4或5个R 4取代；并且当R 1为H，R 2为R 2aC(＝O)时，R 2a不为苯基；
R 4为-OH，-NH 2，-NO 2，-CN，-SH，卤素，-C 1-C 5烷氧基，-C 1-C 5烷基，或为卤素取代的-C 1-C 5烷基。
在其中一些实施例中，R 1为R 1bC(＝O)或H，并且R 2为R 2bC(＝O)；或者R 1为R 1aC(＝O)或H，并且R 2为R 2aC(＝O)。
在其中一些实施例中，R 1为H，R 2为R 2bC(＝O)或者R 2aC(＝O)。
在其中一些实施例中，R 1b和R 2b分别独立地为C 3-C 20烷基，或1、2、3、4或5个R 3取代的C 1-C 20烷基。
在其中一些实施例中，R 1b和R 2b分别独立地为C 3-C 14烷基，或1、2、3、4或5个R 3取代的C 3-C 14烷基。
在其中一些实施例中，R 1b和R 2b分别独立地为直链C 3-C 14烷基。
在其中一些实施例中，R 1a和R 2a分别独立地为C 5-C 12芳基，-(C 1-C 4亚烷基)-C 5-C 12芳基；其中所述C 5-C 12芳基和-(C 1-C 4亚烷基)-C 5-C 12芳基可以独立任选地被1、2、3、4或5个R 4取代。
在其中一些实施例中，R 1a和R 2a分别独立地为1、2、3、4或5个R 4取代的苯基，-(C 1-C 4亚烷基)-苯基，所述-(C 1-C 4亚烷基)-苯基可以独立任选地被1、2、3、4或5个R 4取代。
在其中一些实施例中，Y为H或-C 1-C 20烷基。
在其中一些实施例中，Y为H或-C 1-C 10烷基。
在其中一些实施例中，Y为H或-C 1-C 4烷基。
在其中一些实施例中，Y为H，甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基。
在其中一些实施例中，所述色氨酸衍生物选自如下化合物：
N-丁酰-L-色氨酸钙；
N-己酰-L-色氨酸钙；
N-辛酰-L-色氨酸钙；
N-癸酰-L-色氨酸钙；
N-月桂酰-L-色氨酸；
N-肉豆蔻酰-L-色氨酸；
N-丁酰-L-色氨酸乙酯。
本发明还提供了一种饲用组合物。
具体技术方案如下：
一种饲用组合物，包含能够提高养殖动物生产性能的活性成分和饲料中可接受的原料和/或辅料；所述能够提高养殖动物生产性能的活性成分选自：上述的色氨酸衍生物及其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，和N-苯甲酰-L-色氨酸及其饲料中可接受的盐中的至少一种。
在其中一些实施例中，所述饲料中可接受的辅料选自可饲用的载体、稀释剂、赋形剂、 溶媒或它们的组合。
在其中一些实施例中，所述的饲用组合物还包含其它动物饲料添加剂。
在其中一些实施例中，所述的其它动物饲料添加剂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。
本发明还提供了上述色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，或者上述饲用组合物的应用。
具体技术方案如下：
上述色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，上述饲用组合物，或者N-苯甲酰-L-色氨酸或其饲料中可接受的盐在制备动物饲料添加剂或者动物饲料中的应用。
本发明还提供了一种养殖动物的方法。该方法能有效提高养殖动物的生产性能。
具体技术方案如下：
一种养殖动物的方法，包括如下步骤：用含有能够提高养殖动物生产性能的活性成分的饲料饲养所述动物；所述能够提高养殖动物生产性能的活性成分选自：上述的色氨酸衍生物及其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，上述饲用组合物，和N-苯甲酰-L-色氨酸及其饲料中可接受的盐中的至少一种。
在其中一些实施例中，所述能够提高养殖动物生产性能的活性成分在所述饲料中的添加量为0.1ppm-10000ppm。
在其中一些实施例中，所述能够提高养殖动物生产性能的活性成分在所述饲料中的添加量为100ppm-500ppm。
在其中一些实施例中，所述动物包括：家禽、家畜、水产养殖动物和宠物。
本发明的色氨酸衍生物及其应用具有如下有益效果：
本发明提供的结构如式(I)所示的色氨酸衍生物及其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子在原料高热稳定性试验中和在饲料的常温稳定试验中均体现了比色氨酸更稳定的物化性质，在试验期内色氨酸衍生物的含量变化未超过饲料添加剂或饲料可接受的变化范围。
在动物养殖试验中结果表明，本发明提供的色氨酸衍生物及其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子等化合物能有效改善动物的生长和饲料报酬等生产性能，甚至具有比色氨酸更优异的改善效果，可作为动物饲料添加剂应用，或者用于制备动物饲料添加剂或者动物饲料。
具体实施方式
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。
化合物
本发明涉及的化合物是一种结构如式(I)所示的色氨酸衍生物，
Figure PCTCN2019071413-appb-000002
其中，R 1和R 2为氮原子(简写为N)上的取代基；
进一步地，R 1为R 1aC(＝O)，R 1bC(＝O)，R 1aS(＝O) 2，R 1bS(＝O) 2或H；R 2为R 2aC(＝O)，R 2bC(＝O)，R 2aS(＝O) 2或R 2bS(＝O) 2；Y为H或烷基；
其中，R 1b和R 2b分别独立为取代或非取代的C 3-C 20烷基或C 3-C 7环烷基；当R 1b和/或R 2b为取代的C 3-C 20烷基或取代的C 3-C 7环烷基时，所述取代的C 3-C 20烷基或C 3-C 7环烷基为任选的被1、2、3、4或5个R 3所取代的C 3-C 20烷基或C 3-C 7环烷基；R 3为OH，NH 2，CN，SH或X 1，其中X 1选自F、Cl、Br或I；
R 1a和R 2a分别独立为取代或非取代的-C 5-C 12芳基、-C 2-C 12杂芳基、-(C 1-C 4亚烷基)-C 5-C 12芳基、-(C 1-C 4亚烷基)-C 2-C 12杂芳基；当R 1a和/或R 2a为取代的-C 5-C 12芳基，取代的-C 2-C 12杂芳基，取代的-(C 1-C 4亚烷基)-C 5-C 12芳基，或取代的-(C 1-C 4亚烷基)-C 2-C 12杂芳基时，所述取代的-C 5-C 12芳基、-C 2-C 12杂芳基、-(C 1-C 4亚烷基)-C 2-C 12芳基、-(C 1-C 4亚烷基)-C 2-C 12杂芳基为任选地被1、2、3、4或5个R 4所取代的-C 5-C 12芳基、-C 2-C 12杂芳基、-(C 1-C 4亚烷基)-C 5-C 12芳基、-(C 1-C 4亚烷基)-C 2-C 12杂芳基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。
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 1-C 5烷基”是表示含有1个至5个碳原子的直链或支链的饱和烷基；“C 3-C 7环烷基”表示为包含3个-7个碳原子的只含碳氢两种元素的环状烷基，如环丙基、2-甲基环丙基、环戊基等；“C 1-C 5烷氧基”表示含有1个至5个碳原子和一个氧原子的基团，如甲氧基，乙氧基、丙氧基、异丙氧基等；“C 5-C 12芳基”表示含有5个至12个碳原子具有芳香性的环状基团，如苯环等；“C 2-C 12杂芳基”表示含有2个至12个碳原子和1个以上杂原子(包括但不限于氧原子(O)、硫原子(S)、氮原子(N))具有芳香性的环状基团，如吡咯烷基、吡啶烷基等；“C n-C m亚烷基”表示含有n个或m个亚甲基的烷基，如CH 2、(CH 2) 2等。
在一些实施方案中，所述的色氨酸衍生物中的R 1为R 1aS(＝O) 2、R 1bS(＝O) 2或H，R 2为R 2aS(＝O) 2或R 2bS(＝O) 2。
进一步地，所述的色氨酸衍生物中的R 1为H，R 2为R 2aS(＝O) 2或R 2bS(＝O) 2。
在一些实施方案中，所述的色氨酸衍生物中的R 1为R 1aC(＝O)、R 1bC(＝O)或H，R 2为R 2aC(＝O)或R 2bC(＝O)。
进一步地，所述的色氨酸衍生物中的R 1为H，R 2为R 2aC(＝O)或R 2bC(＝O)。
在一些实施方案中，所述的色氨酸衍生物中的R 1a和R 2a分别独立为取代或非取代的C 5-C 12芳基；当R 1a和/或R 2a为取代的C 5-C 12芳基时，所述取代的C 5-C 12芳基为任选地被1、2、3、4或5个R 4所取代的C 5-C 12芳基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。
可选地，所述的R 1a和R 2a分别独立为取代或非取代的苯基；当R 1a和/或R 2a为取代的苯基时，所述取代的苯基为任选地被1、2、3、4或5个R 4所取代的苯基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。在一些实施方案中，所述的色氨酸衍生物中的R 1a和R 2a分别独立为取代或非取代的-(C 1-C 4亚烷基)-C 5-C 12芳基或-(C 1-C 4亚烷基)-C 5-C 12芳基；当R 1a和/或R 2a为取代的-(C 1-C 4亚烷基)-C 5-C 12芳基或取代的-(C 1-C 4亚烷基)-C 5-C 12芳基时，所述取代的-(C 1-C 4亚烷基)-C 5-C 12芳基或-(C 1-C 4亚烷基)-C 5-C 12芳基为任选的被1、2、3、4或5个R 4所取代的-(C 1-C 4亚烷基)-C 5-C 12芳基或-(C 1-C 4亚烷基)-C 5-C 12芳基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。
可选的，所述的R 1a和R 2a分别独立为取代或非取代的-(C 1-C 4亚烷基)-苯基或-(C 1-C 4亚烷基)-苯基；当R 1a和/或R 2a为取代的-(C 1-C 4亚烷基)-苯基或取代的-(C 1-C 4亚烷基)-苯基时，所述取代的-(C 1-C 4亚烷基)-苯基或-(C 1-C 4亚烷基)-苯基为任选的被1、2、3、4或5个R 4所取代的-(C 1-C 4亚烷基)-苯基或-(C 1-C 4亚烷基)-苯基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。在一些实施方案中，所述的氨基酸的酰基衍生物中的R 1a和R 2a分别独立为取代或非取代的C 2-C 12杂芳基；当R 1a和/或R 2a为取代的C 2-C 12杂芳基时，所述取代的C 2-C 12杂芳基为任选的被1、2、3、4或5个R 4所取代的C 5-C 12杂芳基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。
可选地，所述的R 1a和R 2a分别独立为取代或非取代的C 5杂芳基；当R 1a和/或R 2a为取代的C 5杂芳基时，所述取代的C 5杂芳基为任选的被1、2、3、4或5个R 4所取代的C 5杂芳基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。
具体地，所述的C 5杂芳基为
Figure PCTCN2019071413-appb-000003
在一些实施方案中，所述的色氨酸衍生物中的R 1a和R 2a分别独立为取代或非取代的-(C 1-C 4亚烷基)-C 2-C 12杂芳基；当R 1a和/或R 2a为取代的-(C 1-C 4亚烷基)-C 2-C 12杂芳基时，所述取代的-(C 1-C 4亚烷基)-C 2-C 12杂芳基为任选的被1、2、3、4或5个R 4所取代的-(C 1-C 4亚 烷基)-C 2-C 12杂芳基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。
可选地，所述的R 1a和R 2a分别独立为取代或非取代的-(C 1-C 4亚烷基)-C 5杂芳基；当R 1a和/或R 2a为取代的-(C 1-C 4亚烷基)-C 5杂芳基时，所述取代的-(C 1-C 4亚烷基)-C 5杂芳基为任选的被1、2、3、4或5个R 4所取代的-(C 1-C 4亚烷基)-C 5杂芳基；R 4为-OH，-NH 2，-NO 2，-CN，-SH，-X 2，-C 1-C 5烷氧基，-C 1-C 5烷基，或为X 2取代的-C 1-C 5烷基，其中X 2选自F、Cl、Br或I。
具体地，所述的C 5杂芳基为
Figure PCTCN2019071413-appb-000004
在一些实施方案中，所述的色氨酸衍生物中的R 1b和R 2b分别独立为取代或非取代的C 3-C 20烷基；当R 1b和/或R 2b为取代的C 3-C 20烷基时，所述取代的C 3-C 20烷基为任选地被1、2、3、4或5个R 3所取代的C 3-C 20烷基；R 3为OH，NH 2，CN，SH或X 1，其中X 1选自F、Cl、Br或I；
可选地，所述的R 1b和R 2b分别独立优选为直链C 3-C 20烷基，更优选为直链C 3-C 14烷基。
在一些实施例中，所述的直链烷基为正丙基、正丁基、正戊基、正几基、正庚基、正辛基、正壬基、正癸基、正十一烷基、正十二烷基、正十三烷基、正十四烷基。
可选地，所述的R 1b和R 2b分别独立优选为支链C 3-C 20烷基。
在一些实施例中，所述的支链烷基优选为异丙基或叔丁基。
在一些技术方案中，所述的色氨酸衍生物中的R 1b和R 2b分别独立为取代或非取代的C 3-C 7环烷基；当R 1b和/或R 2b为取代的C 3-C 7环烷基时，所述取代的C 3-C 7环烷基为任选地被1、2、3、4或5个R 3所取代的C 3-C 7环烷基；R 3为OH，NH 2，CN，SH或X 1，其中X 1选自F、Cl、Br或I。
可选地，所述的R 1b和R 2b分别独立优选为C 3-C 7环烷基。
在一些实施例中，所述的环烷基为环丙基、环戊基或环已基。
在一些实施方案中，Y优选为H或-C 1-C 20烷基；更优选为H或-C 1-C 10烷基；更优选为H或-C 1-C 4烷基。
在一些具体的实施方式中，Y为H，甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基。
在一些具体的实施方式中，本发明所述的氨基酸的酰基衍生物包括：N-月桂酰-L-色氨酸、N-肉豆蔻酰-L-色氨酸、N-乙酰-L-色氨酸、N-苯甲酰-L-色氨酸、N-丁酰-L-色氨酸、N-己酰-L-色氨酸、N-辛酰-L-色氨酸、N-癸酰-L-色氨酸，以及上述化合物对应的饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子。
化合物的制备与纯化
本发明涉及的如式(Ⅰ)所示的色氨酸衍生物的制备方法以色氨酸(简称为Trp)为起始原料，主要涉及的化学反应主要包括氨基的酰基化、羧基成盐或羧基的酯化。
在一些实施方案中，所述色氨酸衍生物的合成路线如式(II)所示：
Figure PCTCN2019071413-appb-000005
要明确的是式(II)中的R仅表示取代基团，若原料
Figure PCTCN2019071413-appb-000006
所代表的物质不是单一物质时，则R应当理解为取代基的集合(以下同解)；rt.表示常温，base表示反应条件为碱性条件。
在一些实施方案中，结构如式(I)所示的色氨酸衍生物备制备成一种饲料可接受的盐，所述的饲料可接受的盐为式(II)反应过程制备的色氨酸基衍生物与第一主族或第二主族金属碱反应，或在碱性条件下与金属离子卤化物反应可得到色氨酸衍生物的金属离子盐。
饲料可接受的盐为本发明的色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。
可选地，所述的金属碱包括但不限于氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁等。
可选地，所述的金属离子卤化物为金属离子氯化物、金属离子溴化物或金属离子碘化物。
进一步地，所述的金属离子为一价金属离子、二价金属离子或三价金属离子。
具体地，所述的一价金属离子包括但不限于钠离子、钾离子、锂离子、铵离子；所述的二价金属离子包括但不限于钙离子、镁离子、锌离子、铜离子、亚铁离子、锰离子；所述的三价金属离子包括但不限于铁离子、镍离子、铬离子、铝离子。
在一些实施例中，所述的金属离子为锌离子。
在另一些实施例中，所述的金属离子为铜离子。
在另一些实施例中，所述的金属离子为钠离子。
在另一些实施例中，所述的金属离子为钙离子。
在另一些实施例中，所述的金属离子为铁离子。
在一些实施方案中，结构如式(I)所示的色氨酸衍生物还可以制备成其前药化合物，所述的前药化合物是一种脂肪酯，为脂肪醇与色氨酸的羧基在偶联剂HBTU(O-苯并三氮唑-四甲 基脲六氟磷酸盐)存在下发生酯化反应后的产物进而通过游离氨基的酰基化制备获得，反应历程如式(II’)所示。
Figure PCTCN2019071413-appb-000007
要明确的是式(II’)中的Y为脂肪醇的脂肪烷烃基部分；R仅表示取代基团，若原料
Figure PCTCN2019071413-appb-000008
所代表的物质不是单一物质时，则R应当理解为取代基的集合(以下同解)；rt.表示常温，base表示反应条件为碱性条件。
所述的“前药化合物”代表一个在生物体内转化为能与生物体内受体或器官结合并发挥功效的物质，这样的转化受该前药化合物在生物体内的胃肠道中、血液中或组织液中经酶或体内酸碱度的影响。本发明涉及的色氨酸衍生物的前药化合物可以显著的提高色氨酸衍生物的油水分配系数，增高脂溶性，改善生物体的吸收性能从而提高生物利用度。
可选地，所述的脂肪醇为C 1-C 20脂肪醇。
进一步的，所述的脂肪醇为C 1-C 20直链脂肪醇。
在一些实施例中，所述的脂肪醇为甲醇、乙醇、正丙醇、正丁醇、正戊醇、正己醇、正庚醇、正辛醇、正壬醇和正癸醇。
在一些实施方案中，所述的色氨酸的氨基酰基化生成的色氨酸衍生物是一种手性化合物，本发明所述的色氨酸衍生物选自左旋体L-(-)-色氨酸衍生物(结构如式(III))、右旋体D-(+)-氨基酸衍生物(结构如式(IV))或外消旋体DL-(±)氨基酸衍生物。
Figure PCTCN2019071413-appb-000009
在一些实施方案中，所述的色氨酸衍生物的手性立体异构体在合适的条件下可发生立体构型的转化，如色氨酸衍生物的立体构象互变，互变过程如式(V)所示：
Figure PCTCN2019071413-appb-000010
当涉及的反应物质与色氨酸等反应生成了相应的色氨酸衍生物具有刚性结构时，反应底物在反应过程中可生成不同的几何异构体产物。
上述的饲料可接受的盐、前药、立体异构体、互变异构体也包括在本发明的实施范围内。
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，包括对映异构体、非对映异构体、构象异构体、几何异构体、阻转异构体等。“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体，具有不同的熔点、沸点、光谱性质和反应性等物理性质。非对应异构体混合物可通过高分辨分析操作如电泳或色谱来分离；“互变异构体”是指具有不同能量的可通过低能垒互相转化的结构异构体。
在一些实施方案中，本发明提供色氨酸衍生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色氨酸衍生物。所述具有一定晶型状态的色氨酸衍生物是色氨酸衍生物结晶或色氨酸衍生物的溶剂合物。所述的色氨酸衍生物的溶剂合物可选自色氨酸衍生物的水合物或色氨酸衍生物的乙醇合物。
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。
本发明提供的色氨酸衍生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盐、氢溴酸盐、磷酸盐、硫酸盐、硝酸盐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。
在一些实施方案中，本发明的色氨酸衍生物在后处理的盐析沉淀过程中，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盐、马来酸盐、琥珀酸盐、扁桃酸盐、延胡索酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、丙酮酸盐、草酸盐、乙醇酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醇酸盐、柠檬酸盐、酒石酸盐、天冬氨酸盐、谷氨酸盐、苯甲酸盐、对甲基苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。
色氨酸衍生物的稳定性研究。
本发明提供的色氨酸衍生物或其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物在60℃条件下和以饲料形式在常温下测定化合物的稳定性，试验周期为10天至45天，在试验期内化合物的含量随着时间的变化没有发生显著变化，克服了色氨酸在预混剂或饲料中的不稳定性。
本发明涉及色氨酸衍生物的应用。
本发明提供的色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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。
应用本发明提供的色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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。
进一步地，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，应用本发明提供的色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用本发明提供的色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用本发明提供的色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物制备的是改善鱼的生产性能的饲料添加剂。
应用在制备动物饲料添加剂中的本发明提供的色氨酸衍生物的饲料可接受的盐是一种金属离子盐。
可选地，所述的色氨酸衍生物的饲料可接受的盐是结构如式(Ⅰ)所示的色氨酸衍生物的金属离子盐。
进一步地，所述的结构如式(I)所示的色氨酸衍生物中的Y为H，所述的金属离子盐是所述色氨酸衍生物与金属离子交换所得的符合饲料添加剂制备或饲料制备要求的盐。
具体地，所述的金属离子选自一价金属离子、二价金属离子或三价金属离子。
在一些实施例中，所述的一价金属离子为钠离子(Na(I))、钾离子(K(I))或锂离子(Li(I))。
在一些实施例中，所述的二价金属离子为钙离子Ca(II)、镁离子Mg(II)、铜离子Cu(II)、锌离子Zn(II)、亚铁离子Fe(II)、锰离子Mn(II)、钴离子Co(II)或镍离子Ni(II)。
在一实施例中，应用在制备动物饲料添加剂中的色氨酸衍生物的金属离子盐是锌离子盐，所述的动物饲料添加剂是动物用有机锌剂作为高剂量无机锌替换物。
在一实施例中，应用在制备动物饲料添加剂中的色氨酸衍生物的金属离子盐是铜离子盐，所述的动物饲料添加剂是动物用有机铜作为动物用高剂量无机铜替换物。
在一实施例中，应用在制备动物饲料添加剂中的色氨酸衍生物的金属离子盐是铁离子盐，所述的动物饲料添加剂是动物用铁元素补充剂。
在一些实施例中，所述的三价金属离子为铝离子Al(III)、铬离子Cr(III)或铁离子Fe(III)。
本发明涉及的饲用组合物。
一种包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物的至少一种和可饲用辅料的饲用组合物。可饲用辅料等同于饲料中可接受的辅料，具体为可饲用的载体、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。
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。
所述的赋形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(其它的)动物饲料添加剂和/或动物饲料原料。
所述附加(其它)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，包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物的组合物，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等同于饲料中可接受的原料，具体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色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物的饲用组合物的应用。
在一些实施例中，所述包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物的饲用组合物应用于制备动物饲料添加剂中。
应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料 可接受的盐或其前药化合物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，应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，以所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物或、饲料可接受的盐或其前药化合物的饲用组合物应用于制备动物饲料中。
应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，应用所述的包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，养殖户将包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，养殖户将包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，养殖户将包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，养殖户将包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物的饲料添加剂与饲料伴服给与鱼食用。
在一实施例中，养殖户将包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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，养殖户将包含色氨酸衍生物及其消旋体、立体异构体、互变异构体、溶剂合物、饲料可接受的盐或其前药化合物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。下面将结合实施例对本发明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发明，而不应视为限制本发明的范围。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。
A化合物的制备
实施例A1 N-乙酰-L-色氨酸的制备
Figure PCTCN2019071413-appb-000011
将30g(147mmol，1.0eq)L-色氨酸溶解于含有11.75g(294mmol,2eq)氢氧化钠(NaOH)的350mL水溶液中，搅拌30min，将45g(441mmol，3eq)乙酸酐缓慢滴入，室温搅拌过夜，有固体产生，过滤，45℃真空干燥，得到26g产物，为土黄色固体，产率为71.8％。 1HNMR(500MHz,DMSO-d 6)δ:12.53(s,1H),10.80(s,1H),8.09(d,1H),7.51(d,1H),7.32(d,1H),7.13(d,1H),7.06(t,1H),6.98(t,1H),4.44-4.48(m,1H),3.13(q,1H),2.96(q,1H),1.80(s,1H).
实施例A2 N-乙酰-L-色氨酸钙的制备
Figure PCTCN2019071413-appb-000012
将20g(81.0mmol，1.0eq)N-乙酰-L-色氨酸投入到40mL水中，搅拌下将含有3.25g(81.0mmol，1.0eq)氢氧化钠的20mL水溶液缓慢加入，室温搅拌20min，将4.51g(40.6mmol，1.0eq)无水氯化钙(CaCl 2)溶于10mL水的溶液滴入，反应液澄清，室温搅拌反应5h，浓缩反应液，得到黄色固体。
实施例A3 N-丁酰-L-色氨酸钙的制备
Figure PCTCN2019071413-appb-000013
将60g(294.0mmol，1.0eq)L-色氨酸投入到含有13g(325.0mmol，1.1eq)氢氧化钠的200mL水溶液中，室温搅拌10min，将38.3g丁酸酐缓慢滴入，用6M氢氧化钠控制反应pH7左右，室温搅拌反应6h，将38g(346.0mmol，1.2eq)无水氯化钙溶于200mL水溶液滴入，有油状物产生，继续搅拌过夜，油状物转化为固体，过滤，得到50g产物，为黄色固体，产率60％。 1HNMR(500MHz,DMSO-d 6)δ:7.49-7.53(m,2H),7.26(d,1H),7.14(s,1H),7.00(t,1H),6.88(t,1H),4.47(d,1H),3.30(q,1H),3.04(q,1H),1.97-2.03(m,2H),1.40-1.45(m,2H),1.08(t,3H).
实施例A4 N-苯甲酰-L-色氨酸钙的制备
Figure PCTCN2019071413-appb-000014
将6.5g(162.5mmol，1.1eq)氢氧化钠溶于120mL水中，将120mL四氢呋喃加入，将反应液冷却至0℃，将30g(147.0mmol，1.0eq)L-色氨酸加入，搅拌反应10min，将19mL苯甲酰氯缓慢滴入，反应期间用4M氢氧化钠溶液控制反应pH8左右，保温反应3.0h，升温至室温反应2.0h，浓缩反应液减压蒸出四氢呋喃，将9g(81.9mmol，0.5eq)无水氯化钙溶解于200mL水的溶液滴入，有固体产生，继续搅拌反应3.0h，过滤，滤饼干燥，得到43g产物，为土黄色固体，产率90％。 1HNMR(500MHz,DMSO-d 6)δ:10.79(s,1H),8.28(d,1H),7.79(t,2H),7.54(d,1H),7.46(d,1H),7.35-7.40(m,2H),7.27(d,1H),7.21(d,1H),6.99(t,1H),6.84(t,1H),4.72(s,1H),3.47(d,1H),3.28(q,1H).
实施例A5 N-己酰-L-色氨酸钙的制备
Figure PCTCN2019071413-appb-000015
将40g(195.8mmol，1.0eq)L-色氨酸溶解于200mL水和200mL乙二醇二甲醚的混合溶液中，将17.3g(432.5mmol，1.1eq)氢氧化钠加入，搅拌溶解，将反应液降温至0℃，将32.7mL己酰氯缓慢滴入，反应期间用4M氢氧化钠控制反应pH7-8之间，控制内温小于5℃，滴毕保温反应2.0h，升温至室温反应，减压浓缩反应液中乙二醇二甲醚，将12g(108.1mmol，0.5eq)氯化钙溶解在100mL水的溶液滴入，有油状物产生，继续搅拌仍为粘稠状油状物，分液，油状物加乙醇溶解，浓缩乙醇，得到60g产物，为黄色固体，产率95％。 1HNMR(500MHz,DMSO-d 6)δ:10.80(s,1H),7.57(d,1H),7.52(d,1H),7.28(t,1H),7.14(s,1H),7.00-7.12(m,1H),6.91(q,1H),4.45(m,1H),3.33(d,1H),3.03-3.29(m,1H),2.01(t,2H),1.39(q,2H),1.24(q,2H),1.01-1.16(m,2H),0.77(t,3H).
实施例A6 N-辛酰-L-色氨酸钙的制备
Figure PCTCN2019071413-appb-000016
将45g(195.8mmol，1.0eq)L-色氨酸溶解于200mL水和200mL乙二醇二甲醚的混合溶液中，将17.3g(432.5mmol，2.2eq)氢氧化钠加入，搅拌溶解，将反应液降温至0℃，将45.1mL 辛酰氯缓慢滴入，反应期间用4M氢氧化钠控制反应pH7-8之间，控制内温小于5℃，滴毕保温反应2.0h，升温至室温反应，减压浓缩反应液中乙二醇二甲醚，将15g(135.2mmol，0.7eq)氯化钙溶解在150mL水的溶液滴入，有油状物产生，继续搅拌仍为粘稠状油状物，分液，油状物加乙醇溶解，浓缩乙醇，得到70g产物，为黄色固体，产率90％。LC-MS(ESI,neg.ion)m/z:329.1[M-Ca] -。
实施例A7 N-癸酰-L-色氨酸钙的制备
Figure PCTCN2019071413-appb-000017
将45g(195.8mmol，1.0eq)L-色氨酸溶解于200mL水和200mL乙二醇二甲醚的混合溶液中，将11g氢氧化钠加入，搅拌溶解，将反应液降温至0℃，将52.6mL癸酰氯缓慢滴入，反应期间用4M氢氧化钠控制反应pH7-8之间，控制内温小于5℃，滴毕保温反应2.0h，升温至室温反应，减压浓缩反应液中乙二醇二甲醚，将15g(135.2mmol，0.7eq)氯化钙溶解在150mL水的溶液滴入，有油状物产生，继续搅拌仍为粘稠状油状物，分液，油状物加乙醇溶解，浓缩乙醇，得到55g产物，为黄色固体，产率66％。LC-MS(ESI,pos.ion)m/z:357.2[M-Ca] -。
实施例A8 N-月桂酰-L-色氨酸的制备
Figure PCTCN2019071413-appb-000018
将30g(146.9mmol，1.0eq)L-色氨酸溶解于100mL水和100mL乙二醇二甲醚的混合溶液中，将7g(175.0mmol，1.2eq)氢氧化钠加入，搅拌溶解，将反应液降温至0℃，将41mL月桂酰氯缓慢滴入，反应期间用4M氢氧化钠控制反应pH7-8之间，控制内温小于5℃，滴毕保温反应2.0h，升温至室温反应，减压浓缩反应液中乙二醇二甲醚，浓盐酸调反应pH至3，有油状物析出，乙酸乙酯萃取，浓缩乙酸乙酯，剩余油状物100mL正庚烷打浆，得到48g产物，为黄色固体，产率84.5％。LC-MS(ESI,neg.ion)m/z:385.5[M-H] -。
实施例A9 N-肉豆蔻酰-L-色氨酸合成
Figure PCTCN2019071413-appb-000019
将30g(146.9mmol，1.0eq)L-色氨酸溶解于100mL水和100mL乙二醇二甲醚的混合溶 液中，将8g(200.0mmol，1.4eq)氢氧化钠加入，搅拌溶解，将反应液降温至0℃，将47.3mL十四酰氯缓慢滴入，反应期间用4M氢氧化钠控制反应pH7-8之间，控制内温小于5℃，滴毕保温反应2.0h，升温至室温反应，减压浓缩反应液中乙二醇二甲醚，浓盐酸调反应pH3，有油状物析出，乙酸乙酯萃取，浓缩乙酸乙酯，剩余油状物100mL正庚烷打浆,得到50g产物，为黄色固体，产率82.1％。LC-MS(ESI,neg.ion)m/z:413.5[M-H] -。
实施例A10 N-丁酰-L-色氨酸乙酯的制备
Figure PCTCN2019071413-appb-000020
向1000mL单口瓶中加入320mL(5.48mol,40eq.)无水乙醇，向其中加入60g(294.0mmol，1.0eq)L-色氨酸和11.2g(29.4mmol，0.1eq)HBTU，室温反应6h，再加入含有13g(325.0mmol，1.1eq)氢氧化钠的200mL水溶液，室温搅拌10min，将38.3g丁酸酐缓慢滴入，用6M氢氧化钠控制反应pH7左右，室温搅拌反应6h，有油状物产生，继续搅拌过夜。反应液加入乙酸乙酯萃取(200ml*3)，合并乙酸乙酯层，合并的有机相经水(400ml*3)和饱和食盐水洗涤后减压浓缩得粘稠固体。所得固体经乙酸乙酯-石油醚(8:1)重结晶得到52g产物，为黄色固体，产率47％。
B化合物的稳定性研究
考察色氨酸衍生物的原料在60℃稳定性试验条件下和色氨酸衍生物质量分数为2000ppm的饲料在常温条件下其主要成分含量随时间的变化情况。
实验仪器：药物稳定性培养箱、Waters高效液相色谱仪(HPLC)等。
供试品：L-色氨酸、N-乙酰-L-色氨酸、N-月桂酰-L-色氨酸、N-肉豆蔻酰-L-色氨酸、N-乙酰-L-色氨酸钙、N-苯甲酰-L-色氨酸钙、N-丁酰-L-色氨酸钙盐、N-己酰-L-色氨酸钙、N-辛酰-L-色氨酸钙、N-癸酰-L-色氨酸钙、N-丁酰-L-色氨酸乙酯。
实验试剂：甲醇(色谱级)、磷酸(分析纯)。
实验步骤：
标准溶液的制备：分别准确称取50mg色氨酸衍生物样品，加入甲醇定容至50mL，制成标曲储备液。取适量标曲储备液，用甲醇分别稀释至浓度为125ppm、250ppm、500ppm、1000ppm的工作液，HPLC检测，做标准曲线。
HPLC检测条件：色谱柱：C 18柱(250mm*4.6mm，5μm)柱；流动相：甲醇-0.02％磷酸水溶液梯度洗脱；检测波长：278nm；柱温：25℃；进样量：10μL；流速：1ml/min。
试验方法：
60℃下稳定性试验：供试品原料样品及预混剂放置于培养皿中，摊成≤5mm的薄层，放置于60℃下，于第5天、10天取样分别加入适量水超声溶解配成1000ppm溶液，经0.22μm滤膜过滤后进行HPLC分析，每种样品平行取样三次。
常温下饲料稳定性试验：将含色氨酸衍生物质量分数为2000ppm的饲料样品放置于铝箔袋中封口，常温环境下，于第5天、10天、20天、45天时取样分别加入适量水超声溶解配成1000ppm溶液，经0.22μm滤膜过滤后进行HPLC分析，每种样品平行取样三次。
结果如表1所示。
表1色氨酸衍生物的稳定性研究结果
Figure PCTCN2019071413-appb-000021
由表1结果可知，在60℃的高热稳定性试验中，N-乙酰-L-色氨酸、N-乙酰-L-色氨酸钙、N-苯甲酰-L-色氨酸钙、N-月桂酰-L-色氨酸、N-肉豆蔻酰-L-色氨酸、N-丁酰-L-色氨酸钙盐、N-己酰-L-色氨酸钙、N-辛酰-L-色氨酸钙、N-癸酰-L-色氨酸钙和N-丁酰-L-色氨酸乙酯含量很稳定，保持在97％以上，L-色氨酸在试验进行到第5天时含量已经发生明显的下降，到第10天时含量下降到94.49％，由此可见，N-酰基化-L-色氨酸及其相关盐的原料的热稳定性比L-色氨酸较优。
在常温下饲料稳定性试验中，L-色氨酸的降解迅速，45天的试验期内成分含量下降了 38.19％；N-乙酰-L-色氨酸和N-乙酰-L-色氨酸钙较L-色氨酸稳定些许，然而试验进行到第五天时含量已经下降了接近10％，超过了饲料添加剂中成分含量变化的可接受范围，但是令人意外的是N-月桂酰-L-色氨酸、N-肉豆蔻酰-L-色氨酸、N-苯甲酰-L-色氨酸钙、N-丁酰-L-色氨酸钙盐、N-己酰-L-色氨酸钙、N-辛酰-L-色氨酸钙、N-癸酰-L-色氨酸钙和N-丁酰-L-色氨酸乙酯的含量变化却不显著，未超过饲料添加剂5％的可接受变化范围，并在整个试验期内保持比较稳定的状态。
C养殖试验
实施例C1色氨酸衍生物对肉猪生产性能的影响
体重相近的65日龄“杜长大”三元杂交瘦肉型小猪180头，随机分成12个处理组，每组3个重复，每个重复5头。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。各试验组分别为空白对照组(1组)、色氨酸对照组(2组)、试验3组～12组。其中，对照组仅给与基础日粮，试验2～11组分别给与在基础日粮的基础上添加200ppm色氨酸或不同色氨酸衍生物的日粮，具体如表2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28天，以每个重复为单位，于93日龄(停料12h、不停水)称重，计算各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：
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2所示。
表2色氨酸衍生物对小猪的生产性能影响结果
试验组 供试品 ADFI(g/d*只) ADG(g/d*只) FCR
1组 - 1680 590 2.846
2组 L-色氨酸 2150 771 2.789
3组 N-乙酰-L-色氨酸 2052 775 2.647
4组 N-月桂酰-L-色氨酸 2021 772 2.618
5组 N-肉豆蔻酰-L-色氨酸 1999 769 2.600
6组 N-乙酰-L-色氨酸钙 2008 760 2.641
7组 N-苯甲酰-L-色氨酸钙 1983 763 2.598
8组 N-丁酰-L-色氨酸钙盐 2095 809 2.590
9组 N-己酰-L-色氨酸钙 1913 733 2.609
10组 N-辛酰-L-色氨酸钙 1946 745 2.612
11组 N-癸酰-L-色氨酸钙 1937 743 2.606
12组 N-丁酰-L-色氨酸乙酯 2048 792 2.586
从表2结果可知，本实验从采食量、增重和饲料转化率三方面考核色氨酸衍生物对试验猪的生产性能的影响。具体的：对于采食量方面，所涉及的色氨酸衍生物和色氨酸均显著的 提升试验猪的采食量，色氨酸衍生物对试验猪的采食量的提升效果虽有显著提升但是提升效果不如色氨酸组；在试验猪的平均日增重方面，各试验组与对照组相比均有显著的提升，提升了24.24％～37.12％，并且色氨酸衍生物组的试验猪平均日增重与色氨酸组的效果基本达到相当水平；对于料肉比，各色氨酸衍生物试验组均有显著的下降，下降率约为8.99％～6.99％。
由此可见，本发明所提供的色氨酸衍生物能够有效改善试验猪的生产性能，与色氨酸相比虽然试验猪进食量比色氨酸组少但是饲料转化率却比色氨酸组具有显著的提高，生产性能上基本达到了色氨酸的水平，其中N-丁酰-L-色氨酸钙组和N-丁酰-L-色氨酸乙酯组的效果比色氨酸组效果更优。
实施例C2色氨酸衍生物对蛋鸡生产性能的影响
试验采用单因子随机设计，选择147日龄、体重相近的京白蛋鸡660只，随机分为11个处理组，每组6个重复，每个重复10只京白蛋鸡。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)、色氨酸对照组(2组)、试验3～11组。其中对照组仅给与基础日粮，试验2～11在基础日粮中分别添加200ppm的色氨酸或色氨酸衍生物，分组见表3。预饲期10天，试验期158天，试验鸡自由饮水和采食，日喂料2次。试验以每个重复为单位，每天记录总产蛋数、产蛋量、采食量，计算试验全期蛋鸡的产蛋率(EPR)、平均日采食量(ADFI，g/d)、平均蛋重(EW,g)、平均日产蛋重(EDW，g)和料蛋比(FER)。计算公式如下：
产蛋率(％)＝平均日总蛋数/鸡数×100；
平均蛋重(g)＝平均日总蛋重/蛋数
平均日产蛋重(g)＝平均日总蛋重/鸡数；
料蛋比＝平均日采食量/平均日产蛋重。
试验结果如表3所示。
表3色氨酸衍生物在蛋鸡料中的应用效果研究
  供试品 EPR(％) EW(g) ADFI(g/d) EDW(g/d) EPR
1组 - 75.4 61.1 124 46.1 2.692
2组 L-色氨酸 78.0 62.8 129 49.0 2.626
3组 N-乙酰-L-色氨酸 77.2 62.3 126 48.1 2.611
4组 N-月桂酰-L-色氨酸 79.6 62.6 128 49.8 2.573
5组 N-肉豆蔻酰-L-色氨酸 80.2 61.5 126 49.3 2.559
6组 N-乙酰-L-色氨酸钙 77.5 62.8 127 48.7 2.607
7组 N-苯甲酰-L-色氨酸钙 79.8 62.1 126 49.6 2.549
8组 N-丁酰-L-色氨酸钙盐 81.3 62.0 128 50.4 2.531
9组 N-己酰-L-色氨酸钙 79.4 62.4 126 49.5 2.552
10组 N-辛酰-L-色氨酸钙 79.9 61.7 126 49.3 2.564
11组 N-癸酰-L-色氨酸钙 80.5 61.8 127 49.7 2.558
由表3所示结果可知，色氨酸衍生物对试验蛋鸡的生产性能的影响效果非常显著。具体 的，与对照组结果相比较可知，各试验组的产蛋率、平均蛋重和平均日产蛋重均有明显的提高。与色氨酸对照组相比，除了N-乙酰-L-色氨酸和N-乙酰-L-色氨酸钙组外其他各组的产蛋率、、平均日产蛋重和料蛋比均有了明显的改善，尤其是料蛋比的下降率达到了4.4％-6％。
实施例C3色氨酸衍生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880只，随机分为11个处理组，每组4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(1组)、色氨酸对照组(2组)、试验3～11组。其中对照组仅给与基础日粮，试验2～11在基础日粮中分别添加150ppm的色氨酸或色氨酸衍生物，分组见表4。
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)，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4所示。
表4色氨酸衍生物在肉鸡料中的应用效果研究
  供试品 ADFI(g/d*只) ADG(g/d*只) FCR
1组 - 35.38 15.12 2.34
2组 L-色氨酸 37.86 17.03 2.22
3组 N-乙酰-L-色氨酸 37.15 17.07 2.18
4组 N-月桂酰-L-色氨酸 36.98 17.44 2.12
5组 N-肉豆蔻酰-L-色氨酸 37.11 17.59 2.11
6组 N-乙酰-L-色氨酸钙 37.20 17.14 2.17
7组 N-苯甲酰-L-色氨酸钙 37.08 17.66 2.10
8组 N-丁酰-L-色氨酸钙盐 37.50 17.81 2.11
9组 N-己酰-L-色氨酸钙 37.28 17.34 2.15
10组 N-辛酰-L-色氨酸钙 37.33 17.53 2.13
11组 N-癸酰-L-色氨酸钙 37.46 17.59 2.13
由表4结果可知，色氨酸衍生物试验组无论是在试验鸡的平均日采食量上还是在平均日增重和料肉比上均体现出了比对照组更优的效果。并且色氨酸衍生物对试验鸡生产性能的影响与色氨酸相比平均日增重和料肉比的改善效果更好，尤其是在料肉比方面色氨酸衍生物的改善效果具有明显的优势。
实施例C4色氨酸衍生物在鱼料中的应用
本实验在广州英赛特试验场水产场进行，所用试验鱼为草鱼。健康活泼、规格一致的草鱼种在大网箱中饲养4周后才用于正式养殖试验，实验体系为浮性小网箱。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1d的草鱼440尾随机分成11组，每组设4个重复，每个重复放10尾鱼，整体称重后随机 放入44个网箱中，分别饲喂不同的试验饲料。试验用饲料自行配制，不同试验组按在基础料中分别加入400ppm不同的色氨酸衍生物。各试验组分别为对照组(1组)、色氨酸对照组(2组)、试验3～11组。其中对照组仅给与基础日粮，试验2～11在基础日粮中分别添加150ppm的色氨酸或色氨酸衍生物，分组见表5。试验采用人工限食投喂，投食量每周调整一次，两组投喂水平(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510g/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,％)和饲料系数(FCR)。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)＝喂食量/鱼体增重。
不同的色氨酸衍生物对鱼的促生长试验结果见表5。
表5色氨酸衍生物在草鱼料中的应用试验分组及结果
  供试品 平均初重(g) 平均末重(g) 增重率(％) (FCR)
1组 - 364 635 74.53 1.88
2组 L-色氨酸 354 639 80.48 1.79
3组 N-乙酰-L-色氨酸 359 695 93.46 1.52
4组 N-月桂酰-L-色氨酸 365 707 93.78 1.49
5组 N-肉豆蔻酰-L-色氨酸 361 713 97.43 1.45
6组 N-乙酰-L-色氨酸钙 358 696 94.34 1.51
7组 N-苯甲酰-L-色氨酸钙 351 723 106.06 1.37
8组 N-丁酰-L-色氨酸钙盐 350 725 107.14 1.36
9组 N-己酰-L-色氨酸钙 355 714 101.17 1.42
10组 N-辛酰-L-色氨酸钙 360 730 102.66 1.38
11组 N-癸酰-L-色氨酸钙 362 737 103.59 1.36
由如上表5所示的试验结果可知，添加有色氨酸或其衍生物的试验组在增重和饲料转化率方面均优于对照组，具有明显的促生长效应，其中酰基化的色氨酸或酰基化色氨酸的钙盐对试验鱼的生产性能的改善效果比色氨酸更为显著。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (19)

  1. 一种色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，所述色氨酸衍生物具有式(I)所示结构：
    Figure PCTCN2019071413-appb-100001
    其中，R 1为R 1aC(＝O)，R 1bC(＝O)，R 1aS(＝O) 2，R 1bS(＝O) 2或H；
    R 2为R 2aC(＝O)，R 2bC(＝O)，R 2aS(＝O) 2或R 2bS(＝O) 2；
    R 1b和R 2b分别独立地为C 3-C 20烷基，C 3-C 7环烷基，1、2、3、4或5个R 3取代的C 1-C 20烷基，或者1、2、3、4或5个R 3取代的C 3-C 7环烷基；
    Y为H或烷基；
    R 3为OH，NH 2，CN，SH或卤素；
    R 1a和R 2a分别独立地为C 5-C 12芳基，C 2-C 12杂芳基，-(C 1-C 4亚烷基)-C 5-C 12芳基或-(C 1-C 4亚烷基)-C 2-C 12杂芳基；其中所述C 5-C 12芳基，C 2-C 12杂芳基，-(C 1-C 4亚烷基)-C 5-C 12芳基和-(C 1-C 4亚烷基)-C 2-C 12杂芳基可以独立任选地被1、2、3、4或5个R 4取代；并且当R 1为H，R 2为R 2aC(＝O)时，R 2a不为苯基；
    R 4为-OH，-NH 2，-NO 2，-CN，-SH，卤素，-C 1-C 5烷氧基，-C 1-C 5烷基，或为卤素取代的-C 1-C 5烷基。
  2. 根据权利要求1所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，R 1为R 1bC(＝O)或H，并且R 2为R 2bC(＝O)；或者R 1为R 1aC(＝O)或H，并且R 2为R 2aC(＝O)。
  3. 根据权利要求2所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，R 1为H，R 2为R 2bC(＝O)或者R 2aC(＝O)。
  4. 根据权利要求1-3任一项所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，R 1b和R 2b分别独立地为C 3-C 20烷基，或1、2、3、4或5个R 3取代的C 1-C 20烷基。
  5. 根据权利要求4所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，R 1b和R 2b分别独立地为C 3-C 14烷基，或1、2、3、4或5个R 3取代的C 3-C 14烷基。
  6. 根据权利要求5所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，R 1b和R 2b分别独立地为直链C 3-C 14烷基。
  7. 根据权利要求1-3任一项所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，R 1a和R 2a分别独立地为C 5-C 12芳基，-(C 1-C 4亚烷基)-C 5-C 12芳基；其中所述C 5-C 12芳基和-(C 1-C 4亚烷基)-C 5-C 12芳基可以独立任选地被1、2、3、4或5个R 4取代。
  8. 根据权利要求7所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，R 1a和R 2a分别独立地为1、2、3、4或5个R 4取代的苯基，-(C 1-C 4亚烷基)-苯基，所述-(C 1-C 4亚烷基)-苯基可以独立任选地被1、2、3、4或5个R 4取代。
  9. 根据权利要求1-3任一项所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，Y为H或-C 1-C 20烷基。
  10. 根据权利要求9所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，Y为H或-C 1-C 10烷基。
  11. 根据权利要求10所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，Y为H或-C 1-C 4烷基。
  12. 根据权利要求11所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，Y为H，甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基。
  13. 根据权利要求1所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，其特征在于，所述色氨酸衍生物选自如下化合物：
    N-丁酰-L-色氨酸钙；
    N-己酰-L-色氨酸钙；
    N-辛酰-L-色氨酸钙；
    N-癸酰-L-色氨酸钙；
    N-月桂酰-L-色氨酸；
    N-肉豆蔻酰-L-色氨酸；
    N-丁酰-L-色氨酸乙酯。
  14. 一种饲用组合物，其特征在于，其包含能够提高养殖动物生产性能的活性成分和饲料中可接受的原料和/或辅料；所述能够提高养殖动物生产性能的活性成分选自：权利要求1-13任一项所述的色氨酸衍生物及其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，和N-苯甲酰-L-色氨酸及其饲料中可接受的盐中的至少一种。
  15. 根据权利要求14所述的饲用组合物，其特征在于，还包含其它动物饲料添加剂，所 述的其它动物饲料添加剂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。
  16. 权利要求1-13任一项所述的色氨酸衍生物或者其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，或者权利要求14-15任一项所述的饲用组合物，或者N-苯甲酰-L-色氨酸或其饲料中可接受的盐在制备动物饲料添加剂或者动物饲料中的应用。
  17. 一种养殖动物的方法，其特征在于，包括如下步骤：用含有能够提高养殖动物生产性能的活性成分的饲料饲养所述动物；所述能够提高养殖动物生产性能的活性成分选自：权利要求1-13任一项所述的色氨酸衍生物及其饲料中可接受的盐、其立体异构体、其互变异构体、其溶剂合物、其前药分子，权利要求14-15任一项所述的饲用组合物，和N-苯甲酰-L-色氨酸及其饲料中可接受的盐中的至少一种。
  18. 根据权利要求17所述的养殖动物的方法，其特征在于，所述能够提高养殖动物生产性能的活性成分在所述饲料中的添加量为0.1ppm-10000ppm。
  19. 根据权利要求17或18所述的养殖动物的方法，其特征在于，所述动物包括：家禽、家畜、水产养殖动物和宠物。
PCT/CN2019/071413 2019-01-11 2019-01-11 色氨酸衍生物及其应用 WO2020143040A1 (zh)

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