CN111132962B - Tryptophan derivative and application thereof - Google Patents

Tryptophan derivative and application thereof Download PDF

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CN111132962B
CN111132962B CN201980004549.9A CN201980004549A CN111132962B CN 111132962 B CN111132962 B CN 111132962B CN 201980004549 A CN201980004549 A CN 201980004549A CN 111132962 B CN111132962 B CN 111132962B
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tryptophan
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CN111132962A (en
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黄华成
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Peng Xianfeng
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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; AVICULTURE; APICULTURE; PISCICULTURE; 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; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified 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

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  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

A tryptophan derivative or a salt acceptable in feed, a stereoisomer, a tautomer, a solvate and a prodrug molecule thereof, wherein the tryptophan derivative has a structure shown in a formula (I). The tryptophan derivatives shown in the formula (I) and acceptable salts, stereoisomers, tautomers, solvates and prodrug molecules in the feed show physical and chemical properties more stable than tryptophan in a high-thermal stability test of raw materials and a normal-temperature stability test of the feed, the content change of the tryptophan derivatives in the test period does not exceed the acceptable change range of a feed additive or feed, and the compounds can effectively improve the growth of animals, the production performance of feed rewards and the like, even have an excellent improving effect compared with tryptophan, and can be applied as an animal feed additive or used for preparing an animal feed additive or an animal feed.

Description

Tryptophan derivative and application thereof
Technical Field
The invention relates to the field of animal feed additives, in particular to a tryptophan derivative and application thereof in animal feed additives.
The background technology is as follows:
tryptophan is an essential amino acid for animal maintenance and growth, is one of basic components forming organism proteins, has multiple physiological functions, but cannot be synthesized in an animal body, and needs to be supplied from a feed, so that tryptophan is easily lacking in corn and bean pulp type mixed ration and needs to be added additionally. Tryptophan is a precursor of the neuromediator 5-hydroxytryptamine. The research shows that tryptophan has a certain regulation effect on the feed intake of animals.
Tryptophan is beta-indolylalanine, and is applied to feed additives or feed industry and added into premix or feed, so that the tryptophan can be degraded and deteriorated rapidly after being stored for a period of time at normal temperature, and the tryptophan can not withstand the high-temperature granulating process above 40 ℃ in the granulating process of the feed.
Disclosure of Invention
Based on this, the object of the present invention is to find a tryptophan alternative which is heat resistant and which is stable in its physicochemical properties when mixed in a feed or premix, in order to provide a stable and effective feed additive product or feed product for animal farming in order to improve the productivity of the farmed animals.
The specific technical scheme is as follows:
a tryptophan derivative or a feed acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a solvate thereof, or a prodrug molecule thereof, the tryptophan derivative having a structure represented by formula (I):
wherein R is 1 Is R 1a C(＝O)，R 1b C(＝O)，R 1a S(＝O) 2 ，R 1b S(＝O) 2 Or H;
R 2 is R 2a C(＝O)，R 2b C(＝O)，R 2a S(＝O) 2 Or R is 2b S(＝O) 2 ；
R 1b And R is 2b Each independently is C 3 -C 20 Alkyl, C 3 -C 7 Cycloalkyl, 1, 2, 3, 4 or 5R 3 Substituted C 1 -C 20 Alkyl, or 1, 2, 3, 4 or 5R 3 Substituted C 3 -C 7 Cycloalkyl;
y is H or alkyl;
R 3 is OH, NH 2 CN, SH or halogen;
R 1a and R is 2a Each independently is C 5 -C 12 Aryl, C 2 -C 12 Heteroaryl, - (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl or- (C) 1 -C 4 Alkylene) -C 2 -C 12 Heteroaryl; wherein said C 5 -C 12 Aryl, C 2 -C 12 Heteroaryl, - (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl and- (C) 1 -C 4 Alkylene) -C 2 -C 12 Heteroaryl groups may independently optionally be substituted with 1, 2, 3, 4 or 5R 4 Substitution; and when R is 1 Is H, R 2 Is R 2a At C (=O), R 2a Is not phenyl;
R 4 is-OH, -NH 2 ，-NO 2 -CN, -SH, halogen, -C 1 -C 5 Alkoxy, -C 1 -C 5 Alkyl, or halogen-substituted-C 1 -C 5 An alkyl group.
In some of these embodiments, R 1 Is R 1b C (=o) or H, and R 2 Is R 2b C (=o); or R is 1 Is R 1a C (=o) or H, and R 2 Is R 2a C(＝O)。
In some of these embodiments, R 1 Is H, R 2 Is R 2b C (=o) or R 2a C(＝O)。
In some of these embodiments, R 1b And R is 2b Each independently is C 3 -C 20 Alkyl, or 1, 2, 3, 4 or 5R 3 Substituted C 1 -C 20 An alkyl group.
In some of these embodiments, R 1b And R is 2b Each independently is C 3 -C 14 Alkyl, or 1, 2, 3, 4 or 5R 3 Substituted C 3 -C 14 An alkyl group.
In some of these embodiments, R 1b And R is 2b Each independently is a straight chain C 3 -C 14 An alkyl group.
In some of these embodiments, R 1a And R is 2a Each independently is C 5 -C 12 Aryl, - (C) 1 -C 4 Alkylene) -C 5 -C 12 An aryl group; wherein said C 5 -C 12 Aryl and- (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl groups may independently optionally be substituted with 1, 2,3. 4 or 5R 4 And (3) substitution.
In some of these embodiments, R 1a And R is 2a Each independently is 1, 2, 3, 4 or 5R 4 Substituted phenyl, - (C) 1 -C 4 Alkylene) -phenyl, said- (C) 1 -C 4 Alkylene) -phenyl groups may independently optionally be substituted with 1, 2, 3, 4 or 5R 4 And (3) substitution.
In some of these embodiments, Y is H or-C 1 -C 20 An alkyl group.
In some of these embodiments, Y is H or-C 1 -C 10 An alkyl group.
In some of these embodiments, Y is H or-C 1 -C 4 An alkyl group.
In some of these embodiments, Y is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.
In some of these embodiments, the tryptophan derivative is selected from the following:
calcium N-butyryl-L-tryptophan;
calcium N-hexanoyl-L-tryptophan;
calcium N-octanoyl-L-tryptophan;
calcium N-decanoyl-L-tryptophan;
N-lauroyl-L-tryptophan;
N-myristoyl-L-tryptophan;
N-butyryl-L-tryptophan ethyl ester.
The invention also provides a feeding composition.
The specific technical scheme is as follows:
a feed composition comprising an active ingredient capable of enhancing the productivity of a farmed animal and a feed acceptable raw material and/or adjuvant; the active ingredients capable of improving the productivity of the cultured animals are selected from the group consisting of: at least one of the above tryptophan derivatives and feed acceptable salts thereof, stereoisomers thereof, tautomers thereof, solvates thereof, prodrug molecules thereof, and N-benzoyl-L-tryptophan and feed acceptable salts thereof.
In some embodiments, the acceptable adjuvant in the feed is selected from a feed-ready carrier, diluent, excipient, vehicle, or combination thereof.
In some embodiments, the feeding composition further comprises other animal feed additives.
In some embodiments, the other animal feed additive is selected from a nutritional feed additive and/or a general feed additive and/or a pharmaceutical feed additive.
The invention also provides application of the tryptophan derivative or acceptable salt in feed, stereoisomer, tautomer, solvate and prodrug molecule thereof or the feed composition.
The specific technical scheme is as follows:
the use of a tryptophan derivative or a salt acceptable in the feed, a stereoisomer, a tautomer, a solvate, and a prodrug molecule thereof, a feed composition, or N-benzoyl-L-tryptophan or a salt acceptable in the feed, for preparing an animal feed additive or an animal feed.
The invention also provides a method for breeding animals. The method can effectively improve the production performance of the cultured animals.
The specific technical scheme is as follows:
A method of raising an animal comprising the steps of: feeding said animal with a feed containing an active ingredient capable of enhancing the productivity of the farmed animal; the active ingredients capable of improving the productivity of the cultured animals are selected from the group consisting of: at least one of the above tryptophan derivatives and the acceptable salts thereof in the feed, the stereoisomers thereof, the tautomers thereof, the solvates thereof, the prodrug molecules thereof, the above feeding composition, and the N-benzoyl-L-tryptophan and the acceptable salts thereof in the feed.
In some of these embodiments, the active ingredient capable of improving the productivity of the farmed animal is added to the feed in an amount of 0.1ppm to 10000ppm.
In some of these embodiments, the active ingredient capable of improving the productivity of the farmed animal is added to the feed in an amount of 100ppm to 500ppm.
In some of these embodiments, the animal comprises: poultry, livestock, aquaculture animals and pets.
The tryptophan derivative and the application thereof have the following beneficial effects:
the tryptophan derivative with the structure shown in the formula (I) and acceptable salts, stereoisomers, tautomers, solvates and prodrug molecules in the feed show more stable physicochemical properties than tryptophan in both a high-thermal stability test of the raw materials and a normal-temperature stability test of the feed, and the content change of the tryptophan derivative in the test period does not exceed the acceptable change range of a feed additive or feed.
The results of animal breeding experiments show that the tryptophan derivatives and the compounds such as acceptable salts, stereoisomers, tautomers, solvates, prodrug molecules and the like in the feed can effectively improve the growth of animals and the production performance such as feed rewards, even have an excellent improvement effect compared with tryptophan, and can be applied as an animal feed additive or used for preparing an animal feed additive or an animal feed.
Detailed Description
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. In addition, certain features of the invention are apparent from and are described separately in connection with separate embodiments, but may be provided in combination or in any suitable subcombination in a single embodiment.
Compounds of formula (I)
The invention relates to a tryptophan derivative with a structure shown as a formula (I),
wherein R is 1 And R is 2 Is a substituent on a nitrogen atom (abbreviated as N);
Further, R 1 Is R 1a C(＝O)，R 1b C(＝O)，R 1a S(＝O) 2 ，R 1b S(＝O) 2 Or H; r is R 2 Is R 2a C(＝O)，R 2b C(＝O)，R 2a S(＝O) 2 Or R is 2b S(＝O) 2 The method comprises the steps of carrying out a first treatment on the surface of the Y is H or alkyl;
wherein R is 1b And R is 2b Each independently being substituted or unsubstituted C 3 -C 20 Alkyl or C 3 -C 7 Cycloalkyl; when R is 1b And/or R 2b Is substituted C 3 -C 20 Alkyl or substituted C 3 -C 7 In the case of cycloalkyl, the substituted C 3 -C 20 Alkyl or C 3 -C 7 Cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5R 3 Substituted C 3 -C 20 Alkyl or C 3 -C 7 Cycloalkyl; r is R 3 Is OH, NH 2 CN, SH or X 1 Wherein X is 1 Selected from F, cl, br or I;
R 1a and R is 2a Each independently being substituted or unsubstituted-C 5 -C 12 Aryl, -C 2 -C 12 Heteroaryl, - (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl, - (C) 1 -C 4 Alkylene) -C 2 -C 12 Heteroaryl; when R is 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, 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 12 Heteroaryl is optionally substituted with 1, 2,3. 4 or 5R 4 substituted-C 5 -C 12 Aryl, -C 2 -C 12 Heteroaryl, - (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl, - (C) 1 -C 4 Alkylene) -C 2 -C 12 Heteroaryl; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I.
In general, "substituted" means that one or more of the substitutable hydrogen atoms in a given structure are replaced with a particular substituent, a substituent may be substituted at each substitutable position of the group, and when more than one position in a given formula may be substituted with one or more substituents of a particular group, then the substituents may be the same or different at each position.
In the present invention, "C a -C b Alkyl "means a straight-chain or branched saturated alkyl group containing a to b carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, … …, e.g." C 1 -C 5 Alkyl "is a straight or branched saturated alkyl group containing 1 to 5 carbon atoms; "C 3 -C 7 Cycloalkyl "means a cyclic alkyl group containing only two elements of carbon and hydrogen, such as cyclopropyl, 2-methylcyclopropyl, cyclopentyl, etc., containing 3 to 7 carbon atoms; "C 1 -C 5 Alkoxy "means a group containing 1 to 5 carbon atoms and one oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, and the like; "C 5 -C 12 Aryl "represents a cyclic group having 5 to 12 carbon atoms with aromaticity, such as a benzene ring, etc.; "C 2 -C 12 Heteroaryl "means a cyclic group having 2 to 12 carbon atoms and 1 or more heteroatoms including, but not limited to, oxygen (O), sulfur (S), nitrogen (N), such as pyrrolidinyl, and the like, with aromaticity; "C n -C m Alkylene "means an alkyl group containing n or m methylene groupsFor example CH 2 、(CH 2 ) 2 Etc.
In some embodiments, R in the tryptophan derivatives 1 Is R 1a S(＝O) 2 、R 1b S(＝O) 2 Or H, R 2 Is R 2a S(＝O) 2 Or R is 2b S(＝O) 2 。
Further, R in the tryptophan derivative 1 Is H, R 2 Is R 2a S(＝O) 2 Or R is 2b S(＝O) 2 。
In some embodiments, R in the tryptophan derivatives 1 Is R 1a C(＝O)、R 1b C (=O) or H, R 2 Is R 2a C (=O) or R 2b C(＝O)。
Further, R in the tryptophan derivative 1 Is H, R 2 Is R 2a C (=O) or R 2b C(＝O)。
In some embodiments, R in the tryptophan derivatives 1a And R is 2a Each independently being substituted or unsubstituted C 5 -C 12 An aryl group; when R is 1a And/or R 2a Is substituted C 5 -C 12 Aryl, substituted C 5 -C 12 Aryl is optionally substituted with 1, 2, 3, 4 or 5R 4 Substituted C 5 -C 12 An aryl group; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I.
Optionally, said R 1a And R is 2a Each independently a substituted or unsubstituted phenyl group; when R is 1a And/or R 2a When substituted phenyl, the substituted phenyl is optionally substituted with 1, 2, 3, 4 or 5R 4 Substituted phenyl; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I. In some embodiments, R in the tryptophan derivatives 1a And R is 2a Each independently being substituted or unsubstituted- (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl or- (C) 1 -C 4 Alkylene) -C 5 -C 12 An aryl group; when R is 1a And/or R 2a Is substituted- (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl or substituted- (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl groups, 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 5R 4 Substituted- (C) 1 -C 4 Alkylene) -C 5 -C 12 Aryl or- (C) 1 -C 4 Alkylene) -C 5 -C 12 An aryl group; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I.
Optionally, said R 1a And R is 2a Each independently being substituted or unsubstituted- (C) 1 -C 4 Alkylene) -phenyl or- (C 1 -C 4 Alkylene) -phenyl; when R is 1a And/or R 2a Is 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 with 1, 2, 3, 4 or 5R 4 Substituted- (C) 1 -C 4 Alkylene) -phenyl or- (C 1 -C 4 Alkylene) -phenyl; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I. In some embodiments, R in the acyl derivative of the amino acid 1a And R is 2a Each independently being substituted or unsubstituted C 2 -C 12 Heteroaryl; when R is 1a And/or R 2a Is substituted C 2 -C 12 Heteroaryl, the substituted C 2 -C 12 Heteroaryl is optionally substituted with 1, 2, 3, 4 or 5R 4 Substituted C 5 -C 12 Heteroaryl; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I.
Optionally, said R 1a And R is 2a Each independently being substituted or unsubstituted C 5 Heteroaryl; when R is 1a And/or R 2a Is substituted C 5 Heteroaryl, the substituted C 5 Heteroaryl is optionally substituted with 1, 2, 3, 4 or 5R 4 Substituted C 5 Heteroaryl; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I.
Specifically, the C 5 Heteroaryl is
In some embodiments, R in the tryptophan derivatives 1a And R is 2a Each independently being substituted or unsubstituted- (C) 1 -C 4 Alkylene) -C 2 -C 12 Heteroaryl; when R is 1a And/or R 2a Is substituted- (C) 1 -C 4 Alkylene) -C 2 -C 12 Heteroaryl, substituted- (C) 1 -C 4 Alkylene) -C 2 -C 12 Heteroaryl is optionally substituted with 1, 2, 3, 4 or 5R 4 Substituted- (C) 1 -C 4 Alkylene) -C 2 -C 12 Heteroaryl; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I.
Optionally, said R 1a And R is 2a Each independently being substituted or unsubstituted- (C) 1 -C 4 Alkylene) -C 5 Heteroaryl; when R is 1a And/or R 2a Is substituted- (C) 1 -C 4 Alkylene) -C 5 Heteroaryl, substituted- (C) 1 -C 4 Alkylene) -C 5 Heteroaryl is optionally substituted with 1, 2, 3, 4 or 5R 4 Substituted- (C) 1 -C 4 Alkylene) -C 5 Heteroaryl; r is 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 substituted-C 1 -C 5 Alkyl, wherein X 2 Selected from F, cl, br or I.
Specifically, the C 5 Heteroaryl is
In some embodiments, R in the tryptophan derivatives 1b And R is 2b Each independently being substituted or unsubstituted C 3 -C 20 An alkyl group; when R is 1b And/or R 2b Is substituted C 3 -C 20 In the case of alkyl, the substituted C 3 -C 20 Alkyl is optionally substituted with 1, 2, 3, 4 or 5R 3 Substituted C 3 -C 20 An alkyl group; r is R 3 Is OH, NH 2 CN, SH or X 1 Wherein X is 1 Selected from F,Cl, br or I;
optionally, said R 1b And R is 2b Each independently is preferably a straight chain C 3 -C 20 Alkyl, more preferably straight chain C 3 -C 14 An alkyl group.
In some embodiments, the straight chain alkyl is n-propyl, n-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl.
Optionally, said R 1b And R is 2b Are each independently preferably branched C 3 -C 20 An alkyl group.
In some embodiments, the branched alkyl group is preferably isopropyl or tert-butyl.
In some embodiments, R in the tryptophan derivatives 1b And R is 2b Each independently being substituted or unsubstituted C 3 -C 7 Cycloalkyl; when R is 1b And/or R 2b Is substituted C 3 -C 7 In the case of cycloalkyl, the substituted C 3 -C 7 Cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5R 3 Substituted C 3 -C 7 Cycloalkyl; r is R 3 Is OH, NH 2 CN, SH or X 1 Wherein X is 1 Selected from F, cl, br or I.
Optionally, said R 1b And R is 2b Are respectively and independently preferably C 3 -C 7 Cycloalkyl groups.
In some embodiments, the cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl.
In some embodiments, Y is preferably H or-C 1 -C 20 An alkyl group; more preferably H or-C 1 -C 10 An alkyl group; more preferably H or-C 1 -C 4 An alkyl group.
In some embodiments, Y is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.
In some embodiments, the acyl derivatives of amino acids described herein include: N-lauroyl-L-tryptophan, N-myristoyl-L-tryptophan, N-acetyl-L-tryptophan, N-benzoyl-L-tryptophan, N-butyryl-L-tryptophan, N-hexanoyl-L-tryptophan, N-octanoyl-L-tryptophan, N-decanoyl-L-tryptophan, and the corresponding feed acceptable salts, stereoisomers, tautomers, solvates and prodrug molecules thereof.
Preparation and purification of the Compounds
The invention relates to a preparation method of tryptophan derivatives shown in a formula (I), which takes tryptophan (Trp for short) as a starting material, and mainly relates to chemical reactions mainly comprising acylation of amino groups, salification of carboxyl groups or esterification of carboxyl groups.
In some embodiments, the tryptophan derivative is synthesized according to the formula (II):
it is to be noted that R in the formula (II) represents only a substituent, if the starting materials areWhere the substance represented is not a single substance, then R should be understood as the collection of substituents (hereinafter the same solution); rt. the room temperature and base the reaction conditions are alkaline.
In some embodiments, tryptophan derivatives having the structure shown in formula (I) are prepared into a feed acceptable salt, wherein the feed acceptable salt is a metal ion salt obtained by reacting tryptophan-based derivatives prepared in the reaction process of formula (II) with metal bases of the first main group or the second main group or metal ion halides under alkaline conditions.
The feed acceptable salt is a salt formed by the tryptophan derivative and an organic base, an inorganic base, an organic acid or an inorganic acid which is nontoxic to animals. By "feed acceptable" it is meant that the substance or composition must be suitable for chemical or toxicological use, in connection with the feed or the farmed animal being consumed.
Optionally, the metal base includes, but is not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and the like.
Optionally, the metal ion halide is a metal ion chloride, a metal ion bromide or a metal ion iodide.
Further, the metal ion is a monovalent metal ion, a divalent metal ion or a trivalent metal ion.
Specifically, the monovalent metal ions include, but are not limited to, sodium ions, potassium ions, lithium ions, ammonium ions; the divalent metal ions include, but are not limited to, calcium ion, magnesium ion, zinc ion, copper ion, ferrous ion, manganese ion; the trivalent metal ions include, but are not limited to, iron ions, nickel ions, chromium ions, and aluminum ions.
In some embodiments, the metal ion is zinc ion.
In other embodiments, the metal ion is copper ion.
In other embodiments, the metal ion is sodium.
In other embodiments, the metal ion is a calcium ion.
In other embodiments, the metal ion is an iron ion.
In some embodiments, tryptophan derivatives with the structure shown in formula (I) can be further prepared into a prodrug compound, wherein the prodrug compound is a fatty ester, and is a product obtained by esterification of fatty alcohol and carboxyl of tryptophan in the presence of a coupling agent HBTU (O-benzotriazole-tetramethylurea hexafluorophosphate), and further prepared by acylation of free amino groups, and the reaction process is shown in formula (II').
It is to be noted that Y in formula (II') is an aliphatic alkane moiety of an aliphatic alcohol; r represents a substituent only, if the starting materials areWhere the substance represented is not a single substance, then R should be understood as the collection of substituents (hereinafter the same solution); rt. the room temperature and base the reaction conditions are alkaline.
The term "prodrug compound" means a substance which is converted in vivo into a substance which binds to and exerts its effect on receptors or organs in the living body, and such conversion is affected by the pH of the prodrug compound in the gastrointestinal tract, blood or interstitial fluid in the living body via enzymes or in vivo. The prodrug compound of the tryptophan derivative can obviously improve the oil-water partition coefficient of the tryptophan derivative, increase the fat solubility and improve the absorption performance of organisms so as to improve the bioavailability.
Optionally, the fatty alcohol is C 1 -C 20 Fatty alcohols.
Further, the fatty alcohol is C 1 -C 20 Linear fatty alcohols.
In some embodiments, the fatty alcohol is methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol, n-nonanol, or n-decanol.
In some embodiments, the tryptophan derivative generated by aminoacylation of tryptophan is a chiral compound, and the tryptophan derivative is selected from a L- (-) -tryptophan derivative (structure shown as formula (III)), a D- (+) -amino acid derivative (structure shown as formula (IV)) or a DL- (+ -) amino acid derivative of a racemate.
In some embodiments, the chiral stereoisomer of the tryptophan derivative may undergo a transformation of a stereochemistry under suitable conditions, such as a tautomerism of the stereochemistry of the tryptophan derivative, which is depicted in formula (V):
when the reaction substance and tryptophan react to generate the corresponding tryptophan derivative with a rigid structure, the reaction substrate can generate different geometrical isomer products in the reaction process.
The aforementioned feed acceptable salts, prodrugs, stereoisomers, tautomers are also included within the scope of the invention.
"stereoisomers" as referred to herein refers to compounds having the same chemical structure but different arrangements of atoms or groups in space, and includes enantiomers, diastereomers, conformational isomers, geometric isomers, atropisomers and the like. "enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other. "diastereoisomers" refers to stereoisomers which have two or more chiralities and whose molecules are not mirror images of each other, and which have different physical properties such as melting point, boiling point, spectral properties and reactivity. The non-enantiomeric mixture can be separated by high-resolution analytical procedures such as electrophoresis or chromatography; "tautomer" refers to structural isomers having different energies that can be converted to each other by a low energy barrier.
In some embodiments, the present invention provides processes for the preparation of tryptophan derivatives that also involve isolation, purification, or recrystallization of the reaction product. The reaction product can be obtained into crude product from the reaction system by a desolventizing method. In order to obtain solid matters with higher chemical purity and lower impurity content, the crude products are dissolved, crystallized or precipitated or recrystallized and separated in alcohol solvent, alcohol-water mixed solvent or other organic solvents which can be used for product recrystallization under the conditions of proper temperature, illumination, mechanical vibration and the like to obtain tryptophan derivatives with certain crystal form states. The tryptophan derivative with a certain crystal form state is tryptophan derivative crystal or tryptophan derivative solvate. The solvate of the tryptophan derivative may be selected from a hydrate of the tryptophan derivative or an ethanolate of the tryptophan derivative.
The term "solvate" as used herein refers to a eutectic association formed by the combination of chemical or non-chemical equivalent solvent molecules by non-covalent intermolecular forces caused by external and internal conditions during the contact of the compounds of the present invention with the solvent molecules. Solvents that form solvates include, but are not limited to, water, acetone, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, isopropanol, and the like. "hydrate" refers to a compound in which the solvent molecule is an association or crystal of water, i.e., a chemical or non-chemical equivalent of water bound by non-covalent intermolecular forces.
The tryptophan derivative provided by the invention can be prepared to obtain solid matters with higher chemical purity and lower impurity content by a salting-out method. The salting-out method is a process of salifying and precipitating amino acid derivatives and corresponding organic bases, inorganic bases, organic acids or inorganic acids by utilizing the principles of an acid-base neutralization method, an acid-base coordination method or an acid-base chelating method, so as to obtain acceptable salts of feed; the inorganic acid includes but is not limited to hydrochloride, hydrobromide, phosphate, sulfate, nitrate or combinations thereof and the organic base includes but is not limited to ammonia or triethylamine. The inorganic base includes, but is not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide.
In some embodiments, tryptophan derivatives of the invention form acid-base complex salts and/or acid-base chelate salts with inorganic acids or organic acids including, but not limited to, acetates, maleates, succinates, mandelates, fumarates, malonates, malates, 2-hydroxypropionates, pyruvates, oxalates, glycolates, salicylates, glucuronates, galactonolates, citrates, tartrates, aspartate, glutamate, benzoates, p-methylbenzates, cinnamates, p-toluenesulfonates, benzenesulfonates, methanesulfonates, ethanesulfonates, trifluoromethanesulfonates, or combinations thereof during post-treatment salting-out precipitation.
Stability studies of tryptophan derivatives.
The tryptophan derivative or racemate, stereoisomer, tautomer, solvate, feed acceptable salt or prodrug compound thereof provided by the invention has the advantages that the stability of the compound is measured at the temperature of 60 ℃ and at the normal temperature in a feed form, the test period is 10 days to 45 days, the content of the compound is not changed obviously along with the change of time in the test period, and the instability of tryptophan in the premix or feed is overcome.
The invention relates to application of tryptophan derivatives.
The tryptophan derivative provided by the invention and racemate, stereoisomer, tautomer, solvate, feed acceptable salt or prodrug compound thereof are applied to preparation of animal feed additives.
The term "animal" as used herein refers to a human or a cultured animal that cannot synthesize an inorganic substance into an organic substance, but can use the organic substance as a foodstuff to perform such activities as ingestion, digestion, absorption, respiration, circulation, excretion, sensation, movement, and reproduction. "farmed animals" include poultry, livestock, aquaculture animals and other animals that are legally captured by artificial feeding include pets, such as cats and dogs. The term "livestock" is, for example, pigs, cattle, horses, goats, sheep, deer and any of a number of useful rodents. The term "poultry" is intended to include, for example, chickens, ducks, geese, quails, pigeons, and the like. The term "aquaculture animal" includes, for example, fish, shrimp, tortoise, soft-shelled turtle, etc.
The tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof provided by the invention are used for preparing non-nutritional additives for improving animal production performance of animals in each growth stage, wherein the animals can be selected from livestock, poultry, aquaculture animals or pets in each growth stage.
Further, the livestock includes, but is not limited to, pigs, cattle, sheep, horses, rabbits, minks, or donkeys, the poultry includes, but is not limited to, chickens, turkeys, ducks, geese, quails, or pigeons, the aquaculture animals include, but are not limited to, fish, shrimp, tortoise, crab, turtle, bullfrog, eel, or loach, and the pets include, but are not limited to, dogs or cats of each subspecies.
In one embodiment, the tryptophan derivative, the racemate, the stereoisomer, the tautomer, the solvate, the feed acceptable salt or the prodrug compound thereof provided by the invention is used for preparing the feed additive for improving the production performance of the pork pigs, and has an improvement effect on the feed intake, average daily gain or feed conversion rate of the pork pigs.
In another embodiment, the feed additive prepared by the tryptophan derivative, the racemate, the stereoisomer, the tautomer, the solvate, the feed acceptable salt or the prodrug compound thereof can obviously improve the productivity of broiler chickens or laying hens.
In another embodiment, the tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof provided by the invention are used for preparing the feed additive for improving the production performance of fish.
The feed acceptable salt of the tryptophan derivative provided by the invention, which is applied to the preparation of animal feed additives, is a metal ion salt.
Optionally, the feed acceptable salt of the tryptophan derivative is a metal ion salt of the tryptophan derivative shown in the structural formula (I).
Further, Y in the tryptophan derivative with the structure shown in the formula (I) is H, and the metal ion salt is salt which is obtained by exchanging the tryptophan derivative with metal ions and meets the requirements of feed additive preparation or feed preparation.
Specifically, the metal ion is selected from monovalent metal ion, divalent metal ion or trivalent metal ion.
In some embodiments, the monovalent metal ion is sodium ion (Na (I)), potassium ion (K (I)), or lithium ion (Li (I)).
In some embodiments, the divalent metal ion is calcium ion Ca (II), magnesium ion Mg (II), copper ion Cu (II), zinc ion Zn (II), iron ion Fe (II), manganese ion Mn (II), cobalt ion Co (II), or nickel ion Ni (II).
In one embodiment, the metal ion salt of a tryptophan derivative used in the preparation of the animal feed additive is a zinc ion salt, and the animal feed additive is an organic zinc agent for animals as a high-dose inorganic zinc substitute.
In one embodiment, the metal ion salt of a tryptophan derivative used in the preparation of the animal feed additive is a copper ion salt, and the animal feed additive is an animal use organic copper as a high dose inorganic copper substitute for animals.
In one embodiment, the metal ion salt of a tryptophan derivative used in the preparation of the animal feed additive is an iron ion salt, and the animal feed additive is an animal elemental iron supplement.
In some embodiments, the trivalent metal ion is aluminum ion Al (III), chromium ion Cr (III), or iron ion Fe (III).
The present invention relates to a feed composition.
A feeding composition comprising at least one of a tryptophan derivative, and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof, and a feeding adjuvant. The auxiliary materials for feeding are equivalent to the auxiliary materials acceptable in the feed, and are specifically carriers, diluents, excipients, solvents or combinations thereof for feeding.
The invention relates to a feed which is a product for animals to eat and is prepared through industrial processing.
The "composition" according to the present invention means a compound set containing one or more kinds of compound constituent active ingredients.
The term "comprising" as used herein is an open-ended expression, including what is meant by the present invention, but not excluding other aspects.
The carrier refers to a feedable substance which can bear active ingredients, improve the dispersibility of the active ingredients and has good chemical stability and adsorptivity, and is an organic carrier and an inorganic carrier. The organic carrier is a material containing a large amount of crude fibers, including but not limited to corn flour, corncob powder, wheat bran, rice hull powder, defatted rice bran, corn stalk powder, peanut hull powder and the like. The inorganic carrier is mineral, is mainly divided into calcium salts and silicon oxides, and is used for preparing trace element premix, including but not limited to calcium carbonate, silicate, vermiculite, zeolite, sepiolite and the like.
The diluent refers to a substance which is obtained by uniformly distributing additive raw materials in materials, diluting the additive raw materials with high concentration into a premix or a premix with low concentration, separating trace components from each other, reducing interaction between active components, increasing stability of the active components without affecting physical and chemical properties of related substances, and is an organic diluent or an inorganic diluent. Organic diluents include, but are not limited to, corn flour, degerminated corn flour, dextrose (glucose), sucrose, wheat middlings with bran, fried soybean flour, secondary flour, corn gluten meal, and the like; inorganic diluents include, but are not limited to, limestone, monocalcium phosphate, shell powder, kaolin (kaolin), salt and sodium sulfate.
The excipient is a wetting agent which induces the inherent viscosity of the substance, a binding agent which binds the substance, a disintegrating agent which breaks the whole sheet of the substance into a plurality of fine particles, a retention aid which reduces the friction force between the particles or an anti-sticking agent which prevents the adhesion of the substance, including but not limited to magnesium stearate, talcum powder, vegetable oil, magnesium lauryl sulfate, starch slurry, water, inorganic salts, dextrin, sugar powder and the like.
The "solvent" referred to herein refers to a solvent required to dissolve or disperse the solid, including but not limited to water, ethanol, glycerol, and the like.
In some embodiments, the feeding composition further comprises additional (other) animal feed additives and/or animal feed materials.
The additional (other) animal feed additive is a nutritional feed additive, a general feed additive or a pharmaceutical feed additive.
The nutritional feed additive is a small amount or trace amount of substances which are added into compound feed, balance feed nutrients, improve feed utilization rate and directly exert nutritional effects on animals, and is amino acid, amino acid salt and analogues thereof, vitamins, retinoids, mineral elements and complex (chelate) thereof, microbial enzyme preparations or non-protein nitrogen.
The general feed additive is also called non-nutritional additive, and refers to some non-nutritional substances which are added into feed to improve the feed utilization rate, ensure the quality and quality of the feed and are beneficial to animal health or metabolism, including growth promoters, insect repellent health care agents, flavoring and phagostimulants, feed conditioning agents, feed storage agents and Chinese herbal medicine additives.
Further specifically, the non-nutritive additive is a growth promoter including, but not limited to, butyric acid, calcium butyrate, sodium butyrate, tannic acid, p-thymol ester, p-thymol salt, 2-hydroxybenzoic acid, beta-acid ester, beta-acid salt, hexahydro beta-acid ester, hexahydro beta-acid salt, benzoic acid or calcium benzoate, zinc oxide, zinc sulfate, zinc chloride.
In one embodiment, the non-nutritional additive is calcium butyrate.
In another embodiment, the non-nutritive additive is tannic acid.
In particular, the pharmaceutical feed additives include, but are not limited to, veterinary premix materials which have the effect of preventing animal diseases, promoting animal growth, and which can be added to feed for long periods of time for incorporation into carriers or diluents.
Still more particularly, the pharmaceutical feed additive is a feeding antibiotic including, but not limited to, polymyxin, salinomycin, avilamycin, bacitracin, virginiamycin, nosiheptide, flavomycin, enramycin, norrilmycin, olaquindox, terramycin, or aureomycin.
In some embodiments, the composition comprising a tryptophan derivative, as well as racemates, stereoisomers, tautomers, solvates, feed acceptable salts, or prodrug compounds thereof, further comprises one or more of a nutritional feed additive, a general feed additive, and a pharmaceutical feed additive.
In some embodiments, the animal feed material is equivalent to feed acceptable materials, particularly grains and processed products thereof, oil seeds and processed products thereof, legume seeds and processed products thereof, tubers and processed products thereof, other seeds, fruit products and processed products thereof, forage grass, roughage and processed products thereof, other plants, algae and processed products thereof, dairy products and byproducts thereof, land animal products and byproducts thereof, fish, other aquatic organisms and byproducts thereof, minerals, microbial fermentation products and byproducts thereof, other feed materials and the like.
Use of a feed composition.
The present invention relates to the use of the above-described feeding composition comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof.
In some embodiments, the feeding composition comprising a tryptophan derivative, as well as racemates, stereoisomers, tautomers, solvates, feed acceptable salts, or prodrug compounds thereof, is used in the preparation of an animal feed additive.
The animal feed additive prepared by the feed composition containing tryptophan derivatives, racemates, stereoisomers, tautomers, solvates and feed acceptable salts or prodrug compounds thereof is a livestock feed additive, a poultry feed additive, an aquaculture animal feed additive or a pet feed additive.
Specifically, the feed composition containing tryptophan derivatives, racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof are used for preparing livestock feed additives, and the livestock comprises but is not limited to pigs, cows, sheep, horses, rabbits, martens and the like in each growth stage.
Specifically, the feed composition containing tryptophan derivatives, racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof are used for preparing the feed additive for poultry, wherein the poultry comprises but is not limited to chickens, ducks, geese, pigeons and the like in each growth stage.
In particular, the feed composition comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof are used for preparing aquaculture animal feed additives, wherein the aquaculture animals comprise but are not limited to fish, shrimp, crab, soft-shelled turtle, eel and the like in each growth stage.
Specifically, the feeding composition containing tryptophan derivatives, racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof are used for preparing pet feed additives, and the pets comprise, but are not limited to, artificially fed dogs or cats.
In some embodiments, the animal feed additive prepared from the composition comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is a premix, a complex premix, an aqueous solution or a granule.
In some embodiments, the feeding composition comprising a tryptophan derivative, as well as racemates, stereoisomers, tautomers, solvates, or a feed acceptable salt or prodrug compound thereof, is used in the preparation of an animal feed.
The animal feed prepared by the feed composition containing tryptophan derivative and racemate, stereoisomer, tautomer, solvate, feed acceptable salt or prodrug compound thereof is livestock feed, poultry feed, aquaculture animal feed or pet feed.
Specifically, the feed composition containing tryptophan derivatives, racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparing livestock feed, wherein the livestock comprises but is not limited to pigs, cows, sheep, horses, rabbits, martens and the like in each growth stage.
Specifically, the feed composition containing tryptophan derivatives, racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparing poultry feed, wherein the poultry comprises but is not limited to chickens, ducks, geese, pigeons and the like in each growth stage.
In particular, the feed composition comprising tryptophan derivatives, racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparing aquaculture animal feeds, wherein the aquaculture animals comprise but are not limited to fish, shrimp, crab, soft-shelled turtle, eel and the like in each growth stage.
Specifically, the feeding composition containing tryptophan derivatives, racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof is used for preparing pet feed, wherein the pets comprise but are not limited to artificially fed dogs or cats.
In some embodiments, the feed prepared from the feed composition comprising a tryptophan derivative, as well as racemates, stereoisomers, tautomers, solvates, feed acceptable salts, or prodrug compounds thereof, is a single feed, a concentrated feed, a compound premix, or a concentrate supplement.
Specifically, the compound feed is a complete compound feed.
A method for improving the productivity of farmed animals.
In some feeding embodiments, a farmer administers a feed additive comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof with the feed to the animals, which can significantly improve the productivity of the animals.
In some embodiments, the feed additive is a premix, a composite premix, a granule or a water agent, and is eaten by animals after being mixed with animal feed.
The animal is livestock, poultry, aquaculture animal or pet.
Specifically, the livestock include, but are not limited to, pigs, cows, sheep, horses, rabbits, minks, etc. at each growth stage; the poultry include, but are not limited to, chickens, ducks, geese, pigeons, etc. at various stages of growth; the aquaculture animals include, but are not limited to, fish, shrimp, crab, soft-shelled turtle, eel, etc. at each growth stage; such pets include, but are not limited to, artificially fed dogs or cats.
In one embodiment, a farmer administers a feed additive comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof with feed to weaned pigs, and significantly improves the average daily gain rate and feed conversion rate of the weaned pigs.
In one embodiment, the farmer administers the feed additive comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof with the feed to the broiler chickens, thereby remarkably reducing the feed conversion rate of the broiler chickens.
In one embodiment, the farmer administers a feed additive comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof with the feed for the fish.
In one embodiment, the farmer administers a feed additive comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof with the feed for puppies.
In other feeding embodiments, feeding compositions comprising tryptophan derivatives and racemates, stereoisomers, tautomers, solvates, feed acceptable salts or prodrug compounds thereof are administered to animals by farmers, which can significantly improve the productivity of the animals.
Optionally, the feed composition is a feed additive premix, a feed additive composite premix, a granule or a water agent, and is taken with feed for animals.
In one embodiment, the feeding composition is a feed additive premix.
In one embodiment, the feed composition is a feed additive composite premix.
Optionally, the feed composition is a concentrated feed, a compound premix or a concentrate supplement, and is directly taken as animal feed for animals.
In one embodiment, the feeding composition is a complete formula. Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Preparation of A Compounds
EXAMPLE A preparation of 1N-acetyl-L-tryptophan
30g (147 mmol,1.0 eq) of L-tryptophan were dissolved in 350mL of aqueous solution containing 11.75g (254 mmol,2 eq) of sodium hydroxide (NaOH), stirred for 30min, 45g (441 mmol,3 eq) of acetic anhydride were slowly added dropwise, stirred at room temperature overnight, solids were produced, filtered off and dried under vacuum at 45℃to give 26g of product as a earthy yellow solid in 71.8% yield. 1 HNMR(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).
EXAMPLE A preparation of calcium 2N-acetyl-L-tryptophan
20g (81.0 mmol,1.0 eq) of N-acetyl-L-tryptophan are introduced into 40mL of water, a 20mL aqueous solution containing 3.25g (81.0 mmol,1.0 eq) of sodium hydroxide is slowly added with stirring, and stirring is carried out at room temperature for 20min, 4.51g (40.6 mmoles) l,1.0 eq) anhydrous calcium chloride (CaCl) 2 ) The solution dissolved in 10mL of water was dropped, the reaction solution was clarified, stirred at room temperature for 5 hours, and the reaction solution was concentrated to obtain a yellow solid.
EXAMPLE A preparation of calcium N-butyryl-L-tryptophan
60g (294.0 mmol,1.0 eq) of L-tryptophan was added to 200mL of an aqueous solution containing 13g (325.0 mmol,1.1 eq) of sodium hydroxide, stirred at room temperature for 10min, 38.3g of butyric anhydride was slowly dropped, the reaction pH was controlled to about 7 with 6M sodium hydroxide, stirred at room temperature for 6h, 38g (346.0 mmol,1.2 eq) of anhydrous calcium chloride was dissolved in 200mL of aqueous solution and dropped, an oily substance was generated, stirring was continued overnight, the oily substance was converted to a solid, and filtration was carried out to obtain 50g of the product as a yellow solid, yield 60%. 1 HNMR(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).
EXAMPLE A preparation of calcium 4N-benzoyl-L-tryptophan
6.5g (162.5 mmol,1.1 eq) of sodium hydroxide is dissolved in 120mL of water, 120mL of tetrahydrofuran is added, the reaction solution is cooled to 0 ℃, 30g (147.0 mmol,1.0 eq) of L-tryptophan is added, stirring reaction is carried out for 10min, 19mL of benzoyl chloride is slowly dripped into the reaction solution, the reaction pH is controlled to be about 8 by using 4M sodium hydroxide solution during the reaction, the reaction is kept for 3.0h, the temperature is raised to room temperature for 2.0h, tetrahydrofuran is distilled off under reduced pressure from the concentrated reaction solution, 9g (81.9 mmol,0.5 eq) of anhydrous calcium chloride is dripped into 200mL of water, solids are generated, stirring reaction is continued for 3.0h, filtering and the filter cake is dried, 43g of a product is obtained as a earthy yellow solid, and the yield is 90%. 1 HNMR(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).
EXAMPLE A preparation of 5N-hexanoyl-L-tryptophan calcium
40g (195.8 mmol,1.0 eq) L-tryptophan was dissolved in a mixture of 200mL water and 200mL ethylene glycol dimethyl ether, 17.3g (432.5 mmol,1.1 eq) sodium hydroxide was added and dissolved with stirring, the reaction solution was cooled to 0 ℃, 32.7mL hexanoyl chloride was slowly added dropwise, during the reaction, the reaction pH was controlled between 7 and 8 with 4M sodium hydroxide, the internal temperature was controlled to be less than 5 ℃, the reaction was continued for 2.0h, the reaction was warmed to room temperature, the ethylene glycol dimethyl ether in the reaction solution was concentrated under reduced pressure, 12g (108.1 mmol,0.5 eq) calcium chloride was dissolved in a solution of 100mL water, an oily substance was produced, stirring was continued, the oily substance was still a viscous oily substance, ethanol was added for dissolution, ethanol was concentrated, 60g of the product was a yellow solid, and the yield was 95%. 1 HNMR(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).
EXAMPLE A preparation of 6N-octanoyl-L-tryptophan calcium
45g (195.8 mmol,1.0 eq) L-tryptophan is dissolved in a mixed solution of 200mL water and 200mL ethylene glycol dimethyl ether, 17.3g (432.5 mmol,2.2 eq) sodium hydroxide is added, stirred and dissolved, the reaction solution is cooled to 0 ℃, 45.1mL octanoyl chloride is slowly dripped, 4M sodium hydroxide is used for controlling the reaction pH between 7 and 8 during the reaction, the internal temperature is controlled to be less than 5 ℃, the reaction is carried out after the reaction is carried out for 2.0h, the temperature is increased to room temperature, the ethylene glycol dimethyl ether in the reaction solution is concentrated under reduced pressure, 15g (135.2 mmol,0.7 eq) calcium chloride is dissolved in 150mL water solution, oily matters are generated, and stirring is continued As a viscous oil, the oil was separated, dissolved in ethanol and the ethanol was concentrated to give 70g of the product as a yellow solid in 90% yield. LC-MS (ESI, neg. Ion) m/z 329.1[ M-Ca] - 。
EXAMPLE A preparation of calcium 7N-decanoyl-L-tryptophan
45g (195.8 mmol,1.0 eq) L-tryptophan is dissolved in a mixed solution of 200mL water and 200mL ethylene glycol dimethyl ether, 11g sodium hydroxide is added, stirring is carried out, the reaction solution is cooled to 0 ℃, 52.6mL decanoyl chloride is slowly dripped, 4M sodium hydroxide is used for controlling the reaction pH between 7 and 8 during the reaction, the internal temperature is controlled to be less than 5 ℃, the reaction is carried out for 2.0h after the dripping is carried out, the temperature is raised to room temperature for reaction, the ethylene glycol dimethyl ether in the reaction solution is concentrated under reduced pressure, 15g (135.2 mmol,0.7 eq) calcium chloride is dissolved in 150mL water, an oily matter is produced, stirring is continued, the oily matter is still a viscous oily matter, the oily matter is separated, ethanol is added for dissolution, and the ethanol is concentrated to obtain 55g of product as yellow solid, and the yield is 66%. LC-MS (ESI, pos.ion) m/z 357.2[ M-Ca ]] - 。
EXAMPLE A preparation of 8N-lauroyl-L-tryptophan
30g (146.9 mmol,1.0 eq) of L-tryptophan is dissolved in a mixed solution of 100mL of water and 100mL of ethylene glycol dimethyl ether, 7g (175.0 mmol,1.2 eq) of sodium hydroxide is added, stirring is carried out for dissolution, the reaction solution is cooled to 0 ℃, 41mL of lauroyl chloride is slowly dripped into the reaction solution, the reaction pH is controlled between 7 and 8 by using 4M sodium hydroxide during the reaction, the internal temperature is controlled to be less than 5 ℃, the reaction is carried out after the reaction is carried out at the constant temperature for 2.0h, the temperature is raised to room temperature, the ethylene glycol dimethyl ether in the reaction solution is concentrated under reduced pressure, the reaction pH is adjusted to 3 by concentrated hydrochloric acid, oily matters are separated out, ethyl acetate is extracted, ethyl acetate is concentrated, and the residual oily matters are pulped by 100mL of n-heptane, so that 48g of products are obtained as yellow solid, and the yield is 84.5%. LC-MS (ESI, neg. Ion) m/z 385.5[ M ] H] - 。
EXAMPLE A9N-myristoyl-L-tryptophan Synthesis
30g (146.9 mmol,1.0 eq) of L-tryptophan is dissolved in a mixed solution of 100mL of water and 100mL of ethylene glycol dimethyl ether, 8g (200.0 mmol,1.4 eq) of sodium hydroxide is added, stirring is carried out for dissolution, the reaction solution is cooled to 0 ℃, 47.3mL of tetradecanoyl chloride is slowly dripped into the reaction solution, the reaction pH is controlled between 7 and 8 by using 4M sodium hydroxide during the reaction, the internal temperature is controlled to be less than 5 ℃, the reaction is carried out after the reaction is carried out for 2.0h at the constant temperature, the reaction is carried out at room temperature, the ethylene glycol dimethyl ether in the reaction solution is concentrated under reduced pressure, the reaction pH is regulated to 3 by concentrated hydrochloric acid, oily matters are separated out, ethyl acetate is extracted, ethyl acetate is concentrated, and the residual oily matters are pulped by 100mL of n-heptane, so that 50g of products are obtained as yellow solid, and the yield is 82.1%. LC-MS (ESI, neg. Ion) m/z 413.5[ M-H ]] - 。
Example A preparation of 10N-butyryl-L-tryptophan ethyl ester
To a 1000mL single flask, 320mL (5.48 mol,40 eq.) of absolute ethanol was added, 60g (294.0 mmol,1.0 eq.) of L-tryptophan and 11.2g (29.4 mmol,0.1 eq.) of HBTU were added thereto, the reaction was carried out at room temperature for 6 hours, a further 200mL of aqueous solution containing 13g (325.0 mmol,1.1 eq.) of sodium hydroxide was added, stirring was carried out at room temperature for 10 minutes, 38.3g of butyric anhydride was slowly dropped, the reaction pH was controlled to about 7 with 6M sodium hydroxide, stirring was carried out at room temperature for 6 hours, and stirring was continued overnight. Ethyl acetate extraction (200 ml x 3) was added to the reaction solution, the ethyl acetate layers were combined, and the combined organic phases were washed with water (400 ml x 3) and saturated brine and concentrated under reduced pressure to give a viscous solid. The resulting solid was recrystallized from ethyl acetate-petroleum ether (8:1) to give 52g of the product as a yellow solid in 47% yield.
Stability study of Compounds B
The change of the main component content of the raw material of the tryptophan derivative with time under the condition of 60 ℃ stability test and the condition of normal temperature of the feed with the tryptophan derivative mass fraction of 2000ppm is examined.
Experimental instrument: drug stability incubator, waters High Performance Liquid Chromatograph (HPLC), etc.
Test article: l-tryptophan, N-acetyl-L-tryptophan, N-lauroyl-L-tryptophan, N-myristoyl-L-tryptophan, N-acetyl-L-tryptophan calcium, N-benzoyl-L-tryptophan calcium, N-butyryl-L-tryptophan calcium, N-caproyl-L-tryptophan calcium, N-capryloyl-L-tryptophan calcium, N-decanoyl-L-tryptophan calcium, N-butyryl-L-tryptophan ethyl ester.
Experimental reagent: methanol (chromatographic grade), phosphoric acid (analytically pure).
The experimental steps are as follows:
preparation of standard solution: respectively accurately weighing 50mg tryptophan derivative samples, adding methanol to constant volume to 50mL, and preparing standard yeast stock solution. And (3) taking a proper amount of standard curve stock solution, respectively diluting the standard curve stock solution with methanol to working solutions with the concentration of 125ppm, 250ppm, 500ppm and 1000ppm, and performing HPLC detection to obtain a standard curve.
HPLC detection conditions: chromatographic column: c (C) 18 Column (250 mm 4.6mm,5 μm) column; mobile phase: gradient elution is carried out by methanol-0.02% phosphoric acid aqueous solution; detection wavelength: 278nm; column temperature: 25 ℃; sample injection amount: 10. Mu.L; flow rate: 1ml/min.
The test method comprises the following steps:
stability test at 60 ℃): placing the raw material sample and premix of the test sample in a culture dish, spreading into a thin layer less than or equal to 5mm, placing at 60 ℃, sampling on the 5 th day and the 10 th day, respectively adding a proper amount of water for ultrasonic dissolution to prepare 1000ppm solution, filtering by a 0.22 mu m filter membrane, and performing HPLC analysis, wherein each sample is sampled three times in parallel.
Feed stability test at normal temperature: the feed sample containing 2000ppm of tryptophan derivative is placed in an aluminum foil bag for sealing, and at normal temperature, the feed sample is sampled at 5 days, 10 days, 20 days and 45 days, and a proper amount of water is respectively added for ultrasonic dissolution to prepare 1000ppm solution, and after filtration through a 0.22 mu m filter membrane, HPLC analysis is carried out, and each sample is sampled three times in parallel.
The results are shown in Table 1.
TABLE 1 stability study results of tryptophan derivatives
As is clear from the results in Table 1, in the high heat stability test at 60 ℃, the contents of N-acetyl-L-tryptophan, N-acetyl-L-tryptophan calcium, N-benzoyl-L-tryptophan calcium, N-lauroyl-L-tryptophan, N-myristoyl-L-tryptophan, N-butyryl-L-tryptophan calcium, N-caproyl-L-tryptophan calcium, N-caprylyl-L-tryptophan calcium, N-decanoyl-L-tryptophan calcium and N-butyryl-L-tryptophan ethyl ester were stable and remained at 97% or more, and the contents of L-tryptophan had been significantly reduced by the time of the test to day 5 and reduced to 94.49% by the time of day 10, thus it was found that the heat stability of the raw materials of N-acylated-L-tryptophan and its related salts was superior to L-tryptophan.
In the feed stability test at normal temperature, the degradation of L-tryptophan is rapid, and the component content is reduced by 38.19% in the test period of 45 days; the contents of N-acetyl-L-tryptophan and N-acetyl-L-tryptophan calcium were somewhat more stable than L-tryptophan, however, the contents had been reduced by nearly 10% by the time the test was conducted by the fifth day, exceeding the acceptable range of variation in the contents of the ingredients in the feed additive, but surprisingly, the contents of N-lauroyl-L-tryptophan, N-myristoyl-L-tryptophan, N-benzoyl-L-tryptophan calcium, N-butyryl-L-tryptophan calcium, N-hexanoyl-L-tryptophan calcium, N-octanoyl-L-tryptophan calcium, N-decanoyl-L-tryptophan calcium and N-butyryl-L-tryptophan ethyl ester were not significantly varied, did not exceed the acceptable range of variation of 5% of the feed additive, and remained relatively stable throughout the test period.
C cultivation test
Example C1 Effect of tryptophan derivatives on production performance of pork pigs
Approximately 65 day-old "Du Changda" three-way hybrid lean piglets 180 are randomly divided into 12 treatment groups of 3 replicates each and 5 replicates each. The pigsty and the appliances were sterilized prior to the test. The test period is carried out in columns under the same feeding management condition of the same pigsty. During the test period, the test pigs eat and drink water freely, and feed for 2 times a day. The test groups are blank control group (1 group), tryptophan control group (2 group) and test 3-12 groups respectively. Of these, the control group was given only the basic diet, and the test 2 to 11 groups were given diets to which 200ppm tryptophan or different tryptophan derivatives were added based on the basic diet, as shown in Table 2.
No other antioxidant components and no growth promoters are added in each test group in the whole feeding process. The test period was 28 days, weighing at 93 days of age (12 h stopped without stopping water) in each repetition, and calculating average daily feed intake (ADFI, g/d) and average daily gain (ADG, g/d) and feed to meat ratio (FCR) for each test group. The calculation formula is as follows:
average daily feed intake= (total ingredients-amount of residuals)/(days tested x number of pigs per repeat);
average daily gain= (average body weight at the end of test-average body weight at the beginning of test)/test day;
feed to meat ratio = average daily feed intake/average daily gain.
The test results are shown in Table 2.
TABLE 2 Effect of tryptophan derivatives on the productivity of piglets
From the results in Table 2, the effect of tryptophan derivatives on the productivity of the test pigs was examined from three aspects of feed intake, weight gain and feed conversion rate. Specific: regarding the feed intake, the tryptophan derivatives and tryptophan are both remarkable in improving the feed intake of the test pigs, and the tryptophan derivatives have remarkable improving effects on the feed intake of the test pigs but are inferior to those of tryptophan groups; in the aspect of average daily gain of the test pigs, compared with a control group, each test group is obviously improved by 24.24-37.12%, and the average daily gain of the test pigs of the tryptophan derivative group is basically equivalent to the effect of the tryptophan group; for the feed conversion ratio, each tryptophan derivative test group has a significant decrease of about 8.99% -6.99%.
Therefore, the tryptophan derivative provided by the invention can effectively improve the production performance of test pigs, compared with tryptophan, the feed conversion rate of the test pigs is obviously improved compared with that of the tryptophan, the production performance basically reaches the level of tryptophan, and the effects of the N-butyryl-L-tryptophan calcium group and the N-butyryl-L-tryptophan ethyl ester group are better than those of the tryptophan group.
Example C2 Effect of tryptophan derivatives on the performance of laying hens
The test adopts a single-factor random design, 660 Beijing white laying hens with 147 days of age and similar weight are selected and randomly divided into 11 treatment groups, 6 repeats are carried out on each group, and 10 Beijing white laying hens are carried out on each repeat. The chicken house and the appliances were sterilized before the test. And (5) carrying out cage culture under the same feeding management condition in the same henhouse in the test period. The basic ration is mainly composed of corn-soybean meal, and other antioxidant components and growth promoters are not added in the whole feeding process. The test groups are a control group (1 group), a tryptophan control group (2 group) and test 3-11 groups. Wherein the control group only gives basic ration, and experiments 2 to 11 respectively add 200ppm tryptophan or tryptophan derivatives into the basic ration, and the groups are shown in Table 3. The pre-feeding period is 10 days, the test period is 158 days, and the test chickens drink and eat freely, and feed is 2 times a day. The total egg production, egg production and feed intake were recorded daily for each repeat unit of the test, and the Egg Production Rate (EPR), average daily feed intake (ADFI, g/d), average egg weight (EW, g), average daily egg weight (EDW, g) and feed to egg ratio (FER) were calculated for the whole period of the test.
The calculation formula is as follows:
egg yield (%) = average total number of eggs per chicken x 100;
average egg weight (g) =average total daily egg weight/egg number
Average daily egg weight (g) =average daily total egg weight/chicken number;
feed to egg ratio = average daily feed intake/average daily egg weight.
The test results are shown in Table 3.
TABLE 3 research on application effect of tryptophan derivatives in laying hen feed
Test article EPR(％) EW(g) ADFI(g/d) EDW(g/d) EPR
Group 1 - 75.4 61.1 124 46.1 2.692
Group 2 L-tryptophan 78.0 62.8 129 49.0 2.626
Group 3 N-acetyl-L-tryptophan 77.2 62.3 126 48.1 2.611
Group 4 N-lauroyl-L-tryptophan 79.6 62.6 128 49.8 2.573
Group 5 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 N-benzoyl-L-tryptophan calcium 79.8 62.1 126 49.6 2.549
8 groups of N-butyryl-L-tryptophan calcium salt 81.3 62.0 128 50.4 2.531
9 groups N-hexanoyl-L-tryptophan calcium 79.4 62.4 126 49.5 2.552
10 groups N-octanoyl-L-tryptophan calcium 79.9 61.7 126 49.3 2.564
11 groups of N-decanoyl-L-tryptophan calcium 80.5 61.8 127 49.7 2.558
As shown in Table 3, the effect of tryptophan derivatives on the productivity of the test layer was very remarkable. Specifically, as compared with the results of the control group, the egg laying rate, average egg weight and average daily egg weight of each test group were significantly improved. Compared with tryptophan control group, the egg laying rate, average daily egg weight and feed egg ratio of each group except N-acetyl-L-tryptophan and N-acetyl-L-tryptophan calcium group are obviously improved, and especially the reduction rate of feed egg ratio reaches 4.4% -6%.
Example C3 Effect of Tryptophan derivatives on the production Performance of broilers
The test adopts a single factor random design, and 880 three yellow feather broilers with the average weight of 50g, which are 1 day old and close in weight, are selected and randomly divided into 11 treatment groups, wherein each group is divided into 4 repetitions, each male and female half, and each repetition is divided into 20 three yellow feather broilers. The chicken house and the appliances were sterilized before the test. And (5) carrying out cage culture under the same feeding management condition in the same henhouse in the test period. The basic ration is mainly composed of corn-soybean meal, and other antioxidant components and growth promoters are not added in the whole feeding process. The test groups are a control group (1 group), a tryptophan control group (2 group) and test 3-11 groups. Wherein the control group only gives basic ration, and experiments 2 to 11 respectively add 150ppm tryptophan or tryptophan derivatives to the basic ration, and the groups are shown in Table 4.
The test period is 20 days, and the test chickens drink and eat freely, and feed for 2 times a day. In each repetition unit, weighing at 21 days old (stopping feed for 12 hours without stopping water), counting the feed consumption of the test chickens, and calculating the average daily feed intake (ADFI, g/d) of each group of test chickens, the average daily gain (ADG, g/d) and the feed/meat ratio (FCR), wherein the calculation formula is as follows:
feed to meat ratio (FCR) =average daily feed intake/average daily gain.
The test results are shown in Table 4.
Table 4 application effect study of tryptophan derivatives in broiler feed
As is clear from the results in Table 4, the tryptophan derivative test group exhibited an effect superior to that of the control group, both in terms of average daily feed intake of the test chickens and in terms of average daily gain and feed conversion ratio. And the effect of the tryptophan derivative on the production performance of the test chicken is better than the average daily gain and the improvement effect of the feed conversion ratio of the tryptophan, and particularly the improvement effect of the tryptophan derivative on the feed conversion ratio has obvious advantages.
Example C4 application of Tryptophan derivative in fish feed
The experiment is carried out in the aquatic farm of Guangzhou Yingxi test places, and the test fish is grass carp. Healthy and lively grass carp seeds with consistent specification are bred in a large net cage for 4 weeks and then used for formal breeding experiments, and the experimental system is a buoyancy small net cage. The small net cage and the temporary culture net cage are both arranged at 3500m of the test field 2 The pond water depth is about 1.5m, and the pond water is the fully aerated sewage. During the test, the 440 tail grass carp hungry 1d is randomly divided into 11 groups, 4 repeats are arranged in each group, 10 fish are placed in each repeat, and the whole grass carp hungry 1d is randomly placed in 44 net cages after being weighed, and different test feeds are respectively fed. The test feeds were self-formulated and 400ppm of different tryptophan derivatives were added to the base stock for each test group. The test groups are a control group (1 group), a tryptophan control group (2 group) and test 3-11 groups. Wherein the control group only gives basic ration, and experiments 2 to 11 respectively add 150ppm tryptophan or tryptophan derivatives to the basic ration, and the groups are shown in Table 5. The experiment adopts manual feeding limiting feeding, the feeding amount is adjusted once a week, and two groups of feeding levels (according to the initial stage Initial weight) was completely consistent, and fed twice daily (7:30 and 15:00) for a total feed of 510 g/repeat trial. The test was 8 weeks. The water quality is monitored at regular time during the test period, the water temperature is 26.88+/-3.08 ℃ and DO is carried out in the whole cultivation process>5.0mg O L -1 pH 7.8, ammonia nitrogen<0.50mg N L -1 Nitrite nitrogen<0.05mg N L -1 。
Parameter statistics: in the test, after stopping feeding for 1d, the whole weight of each cage fish is weighed, and the weight gain rate (WG,%) and the Feed Coefficient (FCR) are calculated. The calculation formula is as follows:
weight gain rate (WG,%) =100× (average last weight-average initial weight)/average initial weight;
feed Coefficient (FCR) =feed amount/weight gain of fish.
The results of the growth-promoting test of various tryptophan derivatives on fish are shown in Table 5.
TABLE 5 application of tryptophan derivatives in grass carp feed test groups and results
From the test results shown in table 5 above, it is evident that the test group added with tryptophan or a derivative thereof is superior to the control group in weight gain and feed conversion rate, and has a remarkable growth promoting effect, wherein the effect of the acylated tryptophan or the calcium salt of the acylated tryptophan on improving the productivity of the test fish is more remarkable than that of the tryptophan.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (9)

1. A tryptophan derivative or a salt acceptable in feed thereof, a stereoisomer thereof, or a tautomer thereof, wherein the tryptophan derivative has a structure represented by formula (I):
(I)
wherein R is 1 Is H;
R 2 is R 2a C(=O)，R 2b C(=O)；
R 2b Selected from the group consisting of n-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, and n-tetradecyl;
y is H or-C 1 -C 20 An alkyl group;
R 2a is phenyl or- (C) 1 -C 4 Alkylene) -phenyl; wherein said phenyl or- (C) 1 -C 4 Alkylene) phenyl groups may independently optionally be substituted with 1, 2, 3, 4 or 5R 4 Substitution; and when R is 1 Is H, R 2 Is R 2a At C (=O), R 2a Is not phenyl;
R 4 is-OH, -NH 2 ，-NO 2 -CN, -SH, halogen, -C 1 -C 5 Alkoxy, -C 1 -C 5 Alkyl, or halogen-substituted-C 1 -C 5 An alkyl group.
2. Tryptophan derivatives or a feed acceptable salt thereof, a stereoisomer thereof, a tautomer thereof according to claim 1, wherein Y is H, methyl, ethyl, propyl or butyl.
3. Tryptophan derivatives or a feed acceptable salt thereof, a stereoisomer thereof, a tautomer thereof according to claim 1, wherein the tryptophan derivatives or the feed acceptable salt thereof, the stereoisomer thereof, the tautomer thereof is selected from the group consisting of:
calcium N-butyryl-L-tryptophan;
calcium N-hexanoyl-L-tryptophan;
calcium N-octanoyl-L-tryptophan;
calcium N-decanoyl-L-tryptophan;
N-butyryl-L-tryptophan ethyl ester.
4. A feed composition comprising an active ingredient capable of enhancing the productivity of a farmed animal and a feed acceptable raw material and/or adjuvant; the active ingredients capable of improving the productivity of the cultured animals are selected from the group consisting of: a tryptophan derivative according to any one of claims 1 to 3 and at least one of its feed acceptable salts, its stereoisomers, its tautomers, and N-benzoyl-L-tryptophan and its feed acceptable salts.
5. The feeding composition according to claim 4, further comprising other animal feed additives selected from the group consisting of nutritional feed additives and/or general feed additives and/or pharmaceutical feed additives.
6. Use of a tryptophan derivative or a salt acceptable in the feed thereof, a stereoisomer thereof, a tautomer thereof or a feed composition thereof for the preparation of an animal feed additive or an animal feed;
the tryptophan derivative has a structure shown in a formula (I):
(I)
wherein R is 1 Is H;
R 2 is R 2a C(=O)，R 2b C(=O)；
R 2b Selected from the group consisting of n-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, and n-tetradecyl;
y is H or-C 1 -C 20 An alkyl group;
R 2a is phenyl or- (C) 1 -C 4 Alkylene) -phenyl; wherein said phenyl or- (C) 1 -C 4 Alkylene) phenyl groups may independently optionally be substituted with 1, 2, 3, 4 or 5R 4 Substitution; and when R is 1 Is H, R 2 Is R 2a At C (=O), R 2a Is not phenyl;
R 4 is-OH, -NH 2 ，-NO 2 -CN, -SH, halogen, -C 1 -C 5 Alkoxy, -C 1 -C 5 Alkyl, or halogen-substituted-C 1 -C 5 An alkyl group.
7. A method of raising an animal comprising the steps of: feeding said animal with a feed containing an active ingredient capable of enhancing the productivity of the farmed animal; the active ingredients capable of improving the productivity of the cultured animals are selected from the group consisting of: a tryptophan derivative according to any one of claims 1 to 3, and its feed acceptable salts, stereoisomers, tautomers thereof, and a feeding composition according to any one of claims 4 to 5.
8. The method for raising animals according to claim 7, wherein the amount of the active ingredient capable of improving the productivity of the animals to be raised is 0.1 ppm to 10000 ppm in the feed.
9. The method of raising an animal according to claim 7 or 8, wherein the animal comprises: poultry, livestock, aquaculture animals and pets.
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