JPH0123A - animal growth promoter - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Industrial applications The present invention relates to an animal growth promoter.

BACKGROUND OF THE INVENTION Currently, various antibiotics such as aureomycin and monensin are frequently used for the purpose of promoting the growth of livestock (broilers, pigs, cows, etc.) and improving feed efficiency.

The growth promoting effect of these antibiotics is based on the antibacterial action of antibiotics, which kills or reduces the activity of various bacteria present in the digestive organs (stomach, intestines, etc.), such as intestinal bacteria, thereby reducing the This is achieved by preventing it from being metabolized by bacteria before being absorbed into the animal body.

For example, some carbohydrates in feed that are orally ingested are metabolized by intestinal bacteria and converted into acetic acid, propionic acid, butyric acid, etc. via pyruvate, but acetic acid or butyric acid is produced. In some cases, some of the energy is lost as methane, carbon dioxide, or hydrogen, and the antibacterial action of antibiotics reduces the activity of bacteria in the digestive tract and prevents energy loss, thereby increasing feed efficiency. improvements have been achieved.

Issues that Japan is trying to solve: When eggs and meat from these livestock are eaten, they contain residual antibiotics, but the fact that these antibiotics have antibacterial activity means that unnecessary antibacterial substances are ingested with food. This poses public health problems such as the development of antibiotic resistance.

The present inventors have discovered that certain erythromycin derivatives have a strong motilin-like gastrointestinal contraction motility promoting effect despite having no or greatly attenuated antibacterial activity. I am discovering that. This time, we further discovered that these erythromycin derivatives have the effect of promoting growth and improving feed efficiency in animals, and conceived the idea that they could be a means to solve the above problems, and as a result of intensive research, we completed the present invention.

That is, the present invention provides an animal growth promoter containing an erythromycin derivative in which the dimethylamino group at the 3' position is converted to a primary to tertiary amino group or a quaternary ammonio group other than the dimethylamino group. It is.

The above-mentioned erythromycin derivatives used in the present invention include 1, for example, the general formula [wherein R1 is hydrogen or acyl which may have a substituent, R2 is hydrogen, acyl which may have a substituent or a substituent] R3 is hydrogen or methyl, R4 is hydrogen or a hydroxyl group, RI' Ra is a formula -N< (wherein Rb is hydrogen, lower alkyl or RC or cycloalkyl, RC represents hydrogen, lower alkyl, cycloalkyl, lower alkenyl, or lower alkynyl, each of which may have a substituent, or R
b and Rc together with the nitrogen atom form a cyclic alkylamino. However, when Rb is methyl, Ro represents hydrogen, lower alkyl having 2 or more carbon atoms which may have a substituent, cycloalkyl, lower alkenyl, or lower alkynyl. )
or Rd formula -N8←R'-'X'' (in the formula, R', R''' and Ro are the same F or are different and lower alkyl, cycloalkyl, lower alkenyl or lower each represents alkynyl, or Rd forms a cyclic alkylamino together with Ro and a nitrogen atom, and xo represents an anion), and Ahan\□.

acyl which may have a substituent or alkyl which may have a substituent; Ra represents hydrogen, lower carboxylic acid acyl or alkyl which may have an alkylthio as a substituent, respectively; acyl which may have a substituent or a cyclic alkyl together with a carbon atom, or where one is hydrogen, alkyl or aryl and the other is dialkylamino) respectively. , ), H11'' and RIN are both hydrogen or both form a chemical bond, respectively.

or alkyl which may be of the formula, ), or ). Erythromycin having the basic skeleton represented by compound (I) is also called an anhydroerythromycin derivative.

Compound (I) is characterized in that the 3' position is a converted non-natural primary to tertiary amino group or a quaternary ammonio group, whereas the natural erythromycin is a dimethylamino group. It is something.

In the above formula, the acyl represented by R1 may be an acyl carboxylate, an acyl sulfonate, an acyl phosphite or an acyl phosphate.

In the above formula, the acyl represented by R2, R5 or R7 may be an acyl carboxylate or an acyl sulfonate.

The acyl carboxylate refers to an acyl group derived from a carboxylic acid, and the carboxylic acid may be a monocarboxylic acid or a polycarboxylic acid, and may be a saturated carboxylic acid or an unsaturated carboxylic acid.

The monocarboxylic acid acyl includes a saturated or unsaturated aliphatic acyl group having 1 to 20 carbon atoms (eg, formyl, acetyl, propionyl, butyryl).

Isobutyryl, valeryl, isovaleryl, hexanoyl, pivaloyl, lauroyl, myristoyl.

Valmitoyl, stearoyl, acryloyl, propioloyl, methacryloyl, etc.) and arylcarboxylic acid acyl (eg, benzenecarboxylic acid, naphthalenecarboxylic acid, etc.).

Examples of the polycarboxylic acyl include a saturated or unsaturated aliphatic acyl group having 2 to 6 carbon atoms that may form an ester (for example, oxazole).

Carboxyacetyl, 3-carboxypropionyl.

Examples include acyl dicarboxylate such as cis-3-carboxyacryloyl, trans-3-carboxyacryloyl, cis-3-methyl-3-carboxyacryloyl.

The acyl sulfonate refers to an acyl group derived from sulfonic acid.
represents alkyl, aryl or aralkyl. ). The alkyl preferably has 1 to 6 carbon atoms, and may be linear or branched.

Specific examples of the alkyl include methyl and ethyl.

Propyl, isopropyl, butyl, isobutyl.

Examples include 5ec-butyl, tart-butyl, n-pentyl, n-hexyl, and the like. Examples of the aryl include phenyl, naphthyl, and the like. The aryl may have a substituent, such as lower alkyl (e.g. methyl), lower alkoxy (
e.g. methoxy), halogen (e.g. fluorine, chlorine, bromine)
, nitro, carboxy, etc. Examples of the aralkyl include 2-phenethyl.

The acyl phosphite refers to an acyl group derived from phosphorous acid, for example, the general formula R15OP (=O))I-(
In the formula, R15 is hydrogen, alkyl, aryl
Or indicates aralkyl. ). The alkyl is preferably one having, for example, 1 to 6 carbon atoms, and may be linear or branched. Specific examples of the alkyl include methyl, ethyl, propyl, isopropyl, and butyl.

Isobutyl, 5ee-butyl, tert-butyl,
Examples include n-pentyl and n-hexyl. Examples of the aryl include phenyl, tolyl, naphthyl, and the like. Examples of the aralkyl include arylalkyl, and the aryl is preferably the above-mentioned aryl, and the alkyl preferably has 1 to 3 carbon atoms, such as methyl and ethyl.

Examples include propyl.

The acyl phosphate refers to an acyl group derived from phosphoric acid, for example, the general formula (R''O), P(=0)-(in the formula,
R1' has the same meaning as R1. ).

Examples of the substituent on the optionally substituted acyl represented by RL, R1, RL and R7 include halogen, alkoxy and alkylthio.

Examples of the halogen include chlorine, bromine, fluorine and iodine.

The alkoxy has 1 to 4 carbon atoms.

Examples include methoxy, ethoxy, propoxy and butoxy.

The alkylthio includes those having 1 to 4 carbon atoms, such as methylthio, ethylthio, and propylthio.

Isopropylthio, butylthio, isobutylthio.

Examples include 5ec-butylthio and tart-butylthio.

In the above formula, the lower acyl carboxylate represented by R6 is a monocarboxylic acyl or a polycarboxylic acyl having 1 to 6 carbon atoms, such as formyl.

Examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, oxaloacarboxyacetyl, 3-carboxypropionyl, and the like.

In the above formula, the alkyl optionally having a substituent represented by R2, Rg or R7 is,
It preferably has 1 to 3 carbon atoms, and may be linear or branched. Specific examples of the alkyl include methyl, ethyl, propyl, isopropyl and the like. The substituent is preferably alkoxy having 1 to 3 carbon atoms or alkoxyalkoxy having 2 to 6 carbon atoms,
Examples of the alkoxy include methoxy, ethoxy, propoxy; examples of the alkoxyalkoxy include methoxyethoxy, methoxypropoxy, methoxybutoxy, methoxypentyloxy, ethoxyethoxy, ethoxypropoxy, ethoxybutoxy, propoxypropoxy, etc. .

In the above formula, the alkyl represented by R6 which may have alkylthio as a substituent includes methyl. Examples of the alkylthio as the substituent include a group represented by the general formula R17S- (wherein R1'r represents lower alkyl). The lower alkyl preferably has 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, propyl, and the like.

In the above formula, the alkyl represented by R8 includes those having 1 to 6 carbon atoms, preferably those having 1 to 3 carbon atoms, and specific examples of the alkyl include methyl, ethyl, propyl, etc. can be mentioned. Examples of the aryl represented by Re include phenyl, tolyl, naphthyl, and the like.

In the above formula, the alkyl represented by R9 and RLO may be linear or branched and include those having 1 to 6 carbon atoms, and specific examples include methyl, ethyl, propyl. , isopropyl, butyl, isobutyl, 5ee-butyl.

Examples include tert-butyl, n-pentyl, n-hexyl and the like. Among them, those having 1 to 3 carbon atoms are preferred, and examples of the alkyl include methyl, ethyl, and propyl, which may be linear or branched.

Examples include isopropyl.

In the above formula, the carbon chains represented by R9 and RLO that form a cyclic alkyl together with the acetal-bonded carbon atoms include those having 4 to 5 carbon atoms, such as tetramethylene and pentamethylene.

In the above formula, the aryl (a
(ryl) includes, for example, phenyl, tolyl, naphthyl, and the like.

In the above formula, the dialkylamino represented by Rg or Run includes the general formula -NR2'' (in the formula, R18 represents lower alkyl). Examples of the lower alkyl include those having 1 to 3 carbon atoms; For example, methyl, ethyl,
Examples include propyl.

Regarding Ra, in the above formula, the lower alkyl represented by RLO or R4 preferably has 1 to 6 carbon atoms, such as methyl and ethyl.

Propyl, isopropyl, butyl, isobutyl.

Examples include 5ec-butyl, pentyl, inpentyl, hexyl, and the like.

The lower alkyl in the lower alkyl which may have a substituent represented by Re or R' has a carbon number of 1
-6 are preferred, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.

In the above formula, the cycloalkyl represented by RLO, R" or R' or the cycloalkyl which may have a substituent includes those having 3 to 7 carbon atoms, such as cycloalkyl propyl,
Cyclobutyl, cyclopentyl.

Examples include cyclohexyl, cycloheptyl, etc.
Among them, those having 4 to 6 carbon atoms, ie, cyclobutyl, cyclopentyl, cyclohexyl, etc., are preferable.

The lower alkenyl optionally having a substituent represented by R'' or R' is preferably one having 2 to 6 carbon atoms, such as vinyl, allyl, 2-butenyl, methylallyl, Examples include 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl and the like.

The lower alkynyl in the optionally substituted lower alkynyl represented by Re or R1 preferably has 2 to 6 carbon atoms, and examples include ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl.

l-pentyn-3-yl, 3-pentyn-1-yl, 4
-pentyn-2-yl, 3-hexyn-1-yl and the like.

Alkyl which may have the above-mentioned substituents.

Substituents on cycloalkyl, alkenyl and alkynyl include, for example, hydroxy.

C1-5 Schiff 07) L/ “lr /L’t C@
-z. ary-/l/, C,-, flukoxy, C, alkoxy-C,a-alkyl.

C1-5 cycloalkyloxy, C,-, aryloxy, C7-1□aralkyloxy, C1-
4 alkylthio, C,scycloalkylthio, C,
-,. Arylthio, C,1□aralkylthio, amino, monoC□-4alkylamino, diC1-4alkylamino.

C2-, cycloalkylamino, C,1°arylamino, C1-, □aralkylamino, azide, nitro.

Halogen, cyano, carboxy, C,4 alkoxycarbonyl, C,1°aryloxycarbonyl.

C,, cycloalkyloxycarbonyl, C,-.

aralkyloxycarbonyl (these carbonyls are
co may be acetalized. ) C□-, alkanoyl, formyloxykylsulfinyl, C,,.

Arylsulfinyl.

C10a. Rukylsulfonyl, C, -1. arylsulfonyl, C. -, Alkanoyloxy, sulfo, carbamoyl, carbamoyl which may have a substituent,
Carbamoyloxy, carbamoyloxy which may have a substituent, formylamino.

C. -, alkanoylamino, C,. Arylcarbonylamino, C□-, alkoxycarbonylamino,
C, 1□aralkyloxycarbonylamino.

Oxo, epoxy, thioxo, sulfonamide.

Heterocyclic group, heterocyclic thio, heterocyclic carbonylamino.

heterocyclicoxy, heterocyclic amino, C,4 alkoxycarbonyloxy, C,4 alkylsulfonyloxy, C,
1. Examples include arylsulfonyloxy, sulfamino, sulfamoylamino, ureido, and silyloxy.

The cycloalkyl, aryl, C1-4 alkyl and heterocyclic groups which are optionally substituted on the above alkyl, alkenyl, alkynyl or cycloalkyl may further have a substituent.

Such substituents include, for example, hydroxy.

C1-4 alkyl (which may have a substituent; in this case, the substituent is the same as the substituent for alkyl described above. The following 01- and alkyl-containing groups also have similar substituents. ).

C1-4 alkoxy, C□-, alkylthio, amino.

C1-4 alkylamino, diC1-, alkylamino.

C. arylamino, azide, nitro, halogen,
Oxo, cyano, carboxyt C,, alkoxycarbonyl, C,. Aryloxycarbonyl, C,, alkanoyl, C,-, alkanoyloxy, sulfo, carbamoyl,! ! ! Examples thereof include carbamoyl, carbamoyloxy, C1-4 furucatsuylamino, C-ni, alkoxycarbonylamino, and sulfonylamino, each having a substituent.

When each of the above groups has a substituent, the number of substituents is preferably 1 to 3.

These substituents will be explained in detail below.

Examples of 01-4 alkyl as a substituent are:

Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and the like.

Examples of C,G cycloalkyl include cyclopropyl, cyclobutyl, and cyclopentyl.

Examples include cyclohexyl.

C. −□. Examples of aryl include phenyl,
Examples include naphthyl.

Examples of alkoxy include methoxy,
Ethoxy, propoxy, inpropoxy.

Examples include butoxy, tart-butoxy, and the like.

Examples of C11 cycloalkyloxy include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

C5-z. Examples of aryloxy include phenoxy, naphthyloxy, and the like.

Examples of C7-1, aralkyloxy include benzyloxy, 2-phenethyloxy, 1-phenethyloxy, and the like.

Examples of C, alkylthio include methylthio, ethylthio, propylthio, butylthio, and the like.

Examples of C11 cycloalkylthio include cyclopropylthio and cyclopentylthio.

Examples include cyclohexylthio.

Examples of C$-1°arylthio include phenylthio and naphthylthio.

Examples of C7-1□aralkylthio include benzylthio, 2-phenethylthio, 1-phenethylthio, etc.6 Examples of monoC1-4 alkylamino include methylamino, ethylamino, propylamino, isopropyl amine, butylamino, inbutylamino, te
Examples include rt-butylamino.

Examples of diC-alkylamino include dimethylamino, diethylamino, dipropylamino, dibutylamino, N-methyl-N-ditylamino, N-methyl-N-propylamino, and N-methyl-N-butylamino. Examples include.

Examples of C3-6 cycloalkylamino include cyclopropylamino, cyclobutylamino, cyclopentylamino, and cyclohexylamino.

Examples of C1-1°arylamino include anilino.

Examples of C7-, aralkylamino include benzylamino, 2-phenethylamino, and 1-phenethylamino.

Examples of halogens include fluorine and chlorine.

Examples include bromine and iodine.

Examples of C1-4 alkoxycarbonyl include methoxycarbonyl and ethoxycarbonyl.

Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,
Examples include imbutoxycarbonyl.

C5-□. As an example of aryloxycarbonyl.

Examples include phenoxycarbonyl.

Examples of C1-6 cycloalkyloxycarbonyl include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, and the like.

Examples of C,1,aralkyloxycarbonyl include benzyloxycarbonyl, 1-phenethyloxycarbonyl, 2-phenethyloxycarbonyl, and the like.

Examples of C1- and alkanoyl include formyl, acetyl, propionyl, butyryl, pivaloyl, and the like.

Examples of C-, S-alkanoyloxy include formyloxy, acetoxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy,
Examples include dodecanoyloxy, tridecanoyloxy, tetrazokayloxy, pentadecanoyloxy and the like.

Examples of carbamoyl having a substituent include N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, and N.

Examples include N-dinitylcarbamoyl, N-phenylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl, and N-benzylcarbamoyl.

Examples of carbamoyloxy having substituents include:
For example, N-methylcarbamoyloxy.

N, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-benzylcarbamoyloxy, N
, N-dibenzylcarbamoyloxy, N-phenylcarbamoyloxy, and the like.

Examples of C-alkanoylamino groups include formylamino, acetylamino, propionylamino, butyrylamino, and the like.

Examples of the C6-1゜arylcarbonylamino group are:
Examples include benzoylamino.

Examples of C-nee, alkoxycarbonylamino groups are:
Examples include methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino, and the like.

Examples of the C7-1□aralkyloxycarbonylamino group include benzyloxycarbonylamino, 4
-methoxybenzyloxycarbonylamino, 4-nitrobenzyloxycarbonylamino.

Examples include 4-chlorobenzyloxycarbonylamino.

Examples of sulfonylamino groups include methanesulfonylamino and ethanesulfonylamino.

butanesulfonylamino, pencenesulfonylamino,
Examples include toluenesulfonylamino, naphthalenesulfonylamino, trifluoromethanesulfonylamino, 2-chloroethanesulfonylamino, 2,2°2-trifluoromethanesulfonylamino, and the like.

The heterocyclic group includes 1 to 1 nitrogen atom, oxygen atom, and sulfur atom.
Examples include cyclic groups containing 5 groups, such as pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxasilyl, inoxasilyl, inthiazolyl.

Thiazolyl, piperidinyl, pyridyl, pyridazinyl,
Pyrazinyl, piperazinyl, pyrimidinyl.

Pyranyl, tetrahydropyranyl, tetrahydrofuryl, indolyl, quinolyl, 1,3.4-oxadiazolyl, cheno[2,3-d]pyridyl, 1,2.3-
Thiadiazolyl, 1,3,4-thiadiazolyl, 1
,2.3-triazolyl, 1,2.4-,triazolyl, 1,3.4-triazolyl, tetrazolyl, 1,
3-dioxolanyl, tetracylo[1,5-bl pyridazinyl, benzothiazolyl, benzoxacylyl, benzimidazolyl.

Examples include benzothienyl and morpholinyl.

Examples of heterocyclic thio, heterocyclic oxy, heterocyclic amino and heterocyclic carbonylamino include groups in which the above-mentioned heterocycles are bonded to a sulfur atom, an oxygen atom, a nitrogen atom or a carbonylamino group, respectively.

Examples of C□-4 alkylsulfonyloxy include methanesulfonyloxy, ethanesulfonyloxy, butanesulfonyloxy, and the like.

Examples of Cs-1n arylsulfonyloxy include benzenesulfonyloxy and toluenesulfonyloxy.

Examples of silyloxy include trimethylsilyloxy, t-butyldimethylsilyloxy, t-butyldiphenylsilyloxy, and the like.

Examples of C□- and alkylsulfinyl include methylsulfinyl and ethylsulfinyl.

Examples include propylsulfinyl and butylsulfinyl.

CG-L. Examples of arylsulfinyl include phenylsulfinyl, naphthylsulfinyl, and the like.

Examples of C1-4 alkylsulfonyl include methanesulfonyl, nitanesulfonyl, butanesulfonyl, and the like.

Examples of C6-1°arylsulfonyl include benzenesulfonyl and toluenesulfonyl.

Examples of C1-4 alkoxycarbonyloxy include methoxycarbonyloxy, nidoxycarbonyloxy, tert-butoxycarbonyloxy, and the like.

More specific examples of each of the above groups include chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, chloroethyl, and bromoethyl.

Iodoethyl, chloropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy-2-phenylethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-chlorocyclobutylmethyl, benzyl .

4-chlorobenzyl, 4-nitrobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 4-methylbenzyl, 2-ethoxyethyl, 2-(2,2,2-trifluoro ethoxy)
ethyl.

Methoxymethyl, 2,2-dimethoxyethyl, 2,2-
Jetoxyethyl, cyclopropylmethoxymethyl.

Cyclobutylmethoxymethyl, 2-cyclopropylmethoxyethyl, 2-cyclobutylmethoxyethyl.

2-benzyloxyethyl, 3-benzyloxypropyl, 2-phenoxyethyl, 2-(2-phenetoxy)ethyl, 3-phenylpropyl, methylthiomethyl.

2-methylthioethyl, 2-phenylthioethyl, 2-
Benzylthioethyl, 2-butylthioethyl, cyclohexylthiomethyl, 2-(4-pyridylthio)ethyl, aminomethyl, 2-aminoethyl, 2-methylaminoethyl, 2-tert-butylaminoethyl, 2-dimethylaminoethyl , 3-dimethylaminopropyl.

2-cyclohexylaminoethyl, 2-benzylaminoethyl, 2-azidoethyl, nitromethyl, 2-nitroethyl, cyanomethyl, 2-cyanoethyl, 4-cyanobutyl, carboxymethyl, 2-carboxyethyl, ethoxycarbonylmethyl, phenoxycarbonylmethyl, Cyclopentyloxycarbonylmethyl, acetylmethyl, benzoylmethyl.

4-chlorobenzoylmethyl, 3-(4-bromobenzoyl)propyl, 3-methoxybenzoylmethyl, 2
-Formyloxyethyl, 2-methylsulfinylethyl, 2-phenylsulfinylethyl, 2-methylsulfonylnityl, 3-phenylsulfonylpropyl, 2-
Acetoxyethyl, 4-acetoxybutyl.

pivaloyloxymethyl, 3-sulfopropyl, carbamoylmethyl, 3-carbamoylpropyl, pyrrolidinocarbonylmethyl, 2-(N-ethyl-benzylamino)ethyl, 2-(2-oxopyrrolidino)ethyl,
2-formylaminoethyl, 3-formylaminopropyl, 3-trifluoroacetamidopropyl.

2-Benzamidoethyl, 3-tart-butoxyluponylaminobrovir, benzyloxycarbonylaminopropyl, 2,3-epoxypropyl, 2-thioacetamidoethyl, 3-sulfaminopropyl, 2-(1
, 3-dioxolan-2-yl)ethyl, 2-. 3-
．． 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, furfuryl, 3
-(2-furyl)allyl, 3-(2-furyl)propyl, 2-(2-pyranyloxy)ethyl, 2-(3
-indolyl)ethyl, 3-(1-indolyl)propyl, 3-(2-benzimidazolyl)propyl, 2
-morpholinoethyl, (3-isoxazolyl)methyl,
2-(2-pyridylthio)ethyl, 2-(2-benzthiazolyl)ethyl, 2-(2-pyrimidinylthio)ethyl, 2-(2-aminoethylthio)ethyl, 2-isonicotinoylaminoethyl, 2-te Noylaminoethyl, 2-furoylaminoethyl, 2-(tart-butoxycarbonyloxy)ethyl, 3-(tert-butoxycarbonyloxy)propyl, 2-methylsulfonyloxyethyl e 2-(p-toluenesulfonyloxy)ethyl , 2-(tert-butyldimethylsilyloxy)ethyl, sulfaminomethyl, 2-sulfaminoethyl, ureidomethyl, 2-ureidoethyl, sulfamoylaminomethyl, 2-sulfamoylaminoethyl, (2-methoxyethoxy ) Methyl, etc.

Regarding Ra- above, more preferable substituents in lower alkyl, cycloalkyl, lower alkenyl, and lower alkynyl which may have the substituent include, for example, halogen (eg, chlorine, bromine).

iodine, fluorine), lower alkoxy having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy), lower alkylthio having 1 to 4 carbon atoms (e.g. methylthio, nitylthio, propylthio, butylthio),
Aryl (e.g., fninyl, tolyl, naphthyl, etc.), hydroxyl group, alkoxycarbonyloxy (e.g., tert-butoxycarbonyloxy), aralkyloxycarbonyloxy (e.g., benzyloxycarbonyloxy), amino, substituted amino (e.g., dimethylamino, diethylamino), heterocyclic group (cyclic amino) (e.g., morpholino, piperidino, pyrrolidino, 2-oxopyrrolidino), acyloxy having 1 to 3 carbon atoms (e.g., formyloxy, acetoxy, trifluoroacetoxy), 1 carbon number ~3 acylamino (eg, acetamide, trifluoroacetamide), carboxy.

Examples include lower ((,,,)) alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl), carbamoyl, substituted carbamoyl (e.g., N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl), sulfo, and the like.

In the above formula, the carbon chains represented by Rb and RC or R4 and Re forming a cyclic alkylamino together with the nitrogen atom at the 3' position include those having 3 to 6 carbon atoms, such as trimethylene and tetramethylene.

Examples include pentamethylene and hexamethylene.

In the above formula, the anion represented by Xe is:

For example, halogen ions (e.g., iodide ions, bromide ions, chloride ions, etc.), sulfate ions, phosphate ions,
Nitrate ion, methanesulfate ion, P-tolyl sulfate ion, benzenesulfate ion, hydroxide ion, organic carboxylate ion (e.g. oxalate ion, maleite ion, fumarate ion, succinate ion, citrate) ion, lactate ion, trifluoroacetate ion, lactobionate ion, acetate ion, propionate ion, ethylsuccinate ion), and the like.

In the present invention, in compound CI), R1 is hydrogen or aliphatic (alkyl)carboxylic acid acyl having 1 to 5 carbon atoms, and RZ is hydrogen, aliphatic carboxylic acyl having 1 to 5 carbon atoms, or 1 carbon atom ~5 acyl alkylsulfonate or alkylthiomethyl having 1 to 5 carbon atoms, R
3 is methyl, R4 is hydrogen, 2 is 1-5 acyl furkylsulfonate, Rs is alkyl having 1 to 3 carbon atoms, or R1 and R"'e cyclic alkyl can be formed.

For Rf, unsubstituted or substituted carbon number 1
~5 alkyl, or alkenyl or alkynyl having 2 to 6 carbon atoms is preferred.

In addition, when Rb and Rc are different from each other and are hydrogen or alkyl having 1 to 3 carbon atoms and form a secondary or tertiary amino group as Ra, R"+R" are both hydrogen, or ni is hydrogen or aliphatic. Particularly preferred are compounds in which R2 is hydrogen and Rg and RG are both hydrogen or at least one is an aliphatic carboxylic acyl having 1 to 5 carbon atoms, and when Ra is 41F & ammonium salt. , R', R" are both hydrogen, r+'
, RG is preferably an acyl aliphatic carboxylate having 1 to 5 carbon atoms.

In the present invention, in compound CI), R4 is preferably a quaternary ammonium salt, and in particular R'' and Rc1 form a 5- to 7-membered cyclic alkylamino (e.g., pyrrolidino, piperidino, hexamethyleneimino, etc.) or Rd and Re are both alkyl having 1 to 5 carbon atoms, and R
It is preferred that f is alkyl having 1 to 5 carbon atoms or alkenyl or alkynyl having 2 to 6 carbon atoms, and when these have substituents, especially hydroxy and carboxy.

C□-, alkoxycarbonyl, halogen, cyano, etc. are preferred. Further, as X in the quaternary ammonium salt, chlorine, bromine, and iodine are preferable.

Regarding the production method and physicochemical properties of each compound included in the above compound (1), please refer to EP-A-02136.
The method is described in detail in Japanese Patent No. 17, but briefly, the method is described below.

Alternatively, they can be produced by appropriately combining them.

The compound in which R'' is -NHCH3 or -NH2 is 1
For example, it can be obtained by reacting a corresponding compound in which R4 is N(CH3)z with iodine under alkaline conditions according to the method of JP-A No. 47-9129.

A compound having a b-class amino group can be produced by subjecting a compound in which R4 is -NHCH or -NH to an N-alkylation, N-alkenylation or N-alkynylation reaction. In this reaction, Ha is -NHCH,
or -NH, for example, R. K. Clark Jr. and M. Freifelder,
Antibiotics and Chemotherapy, E, 4
83 (1957) [Antibiotics an
dchernotherapYt, 483 (19
57)), the reaction may be carried out by reacting the corresponding ketone or aldehyde under reducing conditions (e.g., under catalytic reduction using palladium on carbon as a catalyst).
It can also be carried out by reacting a compound in which <R' is -NHCH or -NH2 with a corresponding alkyl, alkenyl or alkynyl halide, for example, in the presence of a base (e.g. diisopropylethylamine). . The latter alkylation, alkenylation or alkynylation reaction is carried out using about 1 to about 100 molar equivalents, preferably about 2 to about 25 molar equivalents, per mol of the starting compound in a halogenated hydrocarbon solvent such as dichloromethane. Using the reaction reagent, from about 0°C to about 100°C,
Preferably, it can be carried out at a temperature of room temperature (about 15 to about 25°C) to about 80°C. Reaction time is about 2 to about 48 hours.

b It is also possible to produce a tertiary amine compound in which Ra is -N. Reagents used in the reaction include, for example, the corresponding alkyl, alkenyl or alkynyl halides, and the halogen is preferably iodine, but in the case of reactive alkenyl or alkynyl halides, chlorine, bromine (e.g. Allyl bromide, propargyl chloride) are also preferably used. The solvent and reaction temperature are the same as above, but the reaction time can be reduced to about 100 ml [References: P. Klass et al., Experientia
ientia), 27, 362 (1971);
Kroleicki and Nie Zamoyski, The Journal of Antibiotics.
al of (R3) can be obtained by subjecting it to reduction (see JP-A-49-1588).

Among the compounds used in the invention, R1, R''.

Compounds in which R', R' are acyl (including sulfonyl) or alkyl, and compounds in which RM, R@ form a boronate, carbonate, sulfinate or ketal, respectively, may be protected, A raw material compound in which RL, R2, R8 to R' are hydrogen atoms is subjected to a reaction known per se to form an acylating agent [
Examples: carboxylic anhydrides (e.g. acid anhydride V)], alkylating agents [e.g. alkyl iodides (e.g. iodomethane), dimethyl sulfoxide and acetic anhydride], boronate agents (e.g.
phenylboric acid), carbonating agents (e.g. ethylene carbonate), sulfinylating agents (e.g. ethylene sulfite), ketalizing agents (e.g. 2-methoxypropene)
After reacting with, it can be produced by subjecting it to a deprotection reaction if necessary.

The reaction with the acylating agent is preferably carried out in a solvent in the presence of a base; preferred solvents include dichloromethane and pyridine, and examples of the base include pyridine and diisopropylethylamine. The reaction temperature is from about 0° C. to about 80° C. for reactions with carboxylic acid-derived acylating agents and from about 0° C. to about 50° C. for reactions with sulfonic acid-derived acylating agents. The duration is about 10 minutes to about 2 weeks and about 10 minutes to about 2 days, respectively.

The reaction with the alkylating agent is also preferably carried out in a solvent, and chloroform, dimethyl sulfoxide, etc. are preferably used as the solvent. The reaction temperature is about 0"C to about 80
℃, and the reaction time is about 15 minutes to about 1 week.

If necessary, a base is added to accelerate the reaction and stabilize the raw materials and/or products. Examples of preferred bases include pyridine and diisopropylethylamine.

In the boronate reaction, the amount of the boronate agent used is preferably about 1 to 3 times the mole of the raw material, and the reaction temperature is 80°C to about 130°C in a solvent such as benzene or toluene.
It is preferable to carry out the reaction at a temperature of about 1 to about 5 hours.

In the carbonation reaction, the carbonation agent is preferably used in a molar amount of about 2 to about 10 times, and the reaction temperature is 25°C to about 130°C, and the reaction time is about 30 minutes to about 1 day. is preferred, and when ethylene carbonate is used as the carbonating agent, it is preferable to add a base such as potassium carbonate.

In the sulfinylation reaction, it is preferable to use about 2 to 3 times the molar amount of the sulfinylation agent, for example, in a solvent such as methanol or ethanol, at a reaction temperature of 20°C to about 30°C, and a reaction time of about 2 to 3 days. It is better to do it at In this reaction, addition of a base such as potassium carbonate often gives good results.

In the ketalization reaction, for example, chloroform is preferred as a solvent, but the other ketal agent itself may also be used as a solvent.The amount of the ketalization agent used is about 2 to about 100 times the mole, preferably about 2 to about It is about 4 times the molar amount. The reaction is accelerated by adding, for example, pyridinium chloride as a catalyst. The reaction temperature is 0° C. to about 80° C., preferably about 15° C. to about 25° C., and the reaction time is about several hours to about 72 hours, preferably about 12 hours to about 24 hours.

In each of the above reactions, the order of reactivity of the 2', 4', 11 and 12-position hydroxyl groups in the optionally protected raw material compound is 2'>4'≧11>12, and the acylating agent or By selecting the amount of alkylating agent, reaction temperature, and reaction time, it is possible to acylate or alkylate hydroxyl groups to 4 to 4 hydroxyl groups. In addition, the Q-acetyl group at the 2' position, the 4
The ○-formyl group at the ′-position and the ○-silyl group at the 4′-position and the 11-position are used as protective groups that can be removed by treatment with methanol at temperatures ranging from about room temperature to about 80°C. Or by using in combination,
The compounds of interest can be manufactured.

The animal growth promoter containing the erythromycin derivative of the present invention exhibits excellent growth promoting effects and feed efficiency improving effects in livestock such as cows, pigs, sheep, and chickens.

Furthermore, the growth promoter of the present invention has low toxicity and has no or significantly reduced antibacterial activity, so it can be safely administered to animals.

Usually, for example, one or more of the above compounds (I) are added to a solid or liquid carrier at a final concentration of 0.00001.
~0.1% (w/w), especially 0.0001-0.0
They are mixed and fed at a concentration of 5% (1 to 500 ppm).

Solid carriers include, for example, forage such as hay, grass, silage, cereals (corn, barley, etc.).

Concentrated feed such as wheat, barley, oats, etc.), oil meal (soybean meal, safflower meal, etc.), bran (rice bran, bran, etc.),
Plus lactose, sucrose, glucose, and yeast.

Examples of the carrier include fish meal, talc, acid clay, and clay. Examples of the liquid carrier include water, physiological saline, and a physiologically harmless organic solvent.

Other appropriate adjuvants, such as emulsifiers, dispersants, suspending agents, wetting agents, thickeners, gelling agents, and solubilizers, may be added in appropriate amounts, as well as preservatives, fungicides, growth promoters (
Vitamins, amino acid 5 synthetic estrous hormone, etc.), antibiotics for disease treatment, enzyme preparations, and lactic acid bacteria preparations may be added.

When mixing the above compounds, compound (1) may be mixed as is, or it may be diluted with an auxiliary agent such as lactose and mixed, or a premix containing compound (I) (usually about 10% by weight) It can also be mixed as

When administering the erythromycin derivative of the present invention by adding it to feed, the appropriate dosage is selected depending on the type of animal, the type of anvil and feed, etc., but usually 0.0
001-1 g/kg, preferably about 0.001-0.
It is about 5g/kg.

By changing the dimethylamino group at the 3' position of Muzato's natural erythromycin to a primary or tertiary amino group other than dimethylamino, or a quaternary ammonio group, we have achieved antibacterial activity while maintaining the effect of improving animal feed efficiency. This can be said to be an excellent animal growth promoter.

Experimental Example 1 shows the minimum inhibitory concentration (M I C: l! Icg/
m Q ) is as shown below, and it can be seen that the antibacterial activity of the product of the present invention is significantly weakened compared to the control.

The abbreviations of the test bacteria are as follows.

5A(I): Staphylococcus aureus ATCC
6538P (S, aureus ATCC6538P)
SA (2): Staphylococcus aureus FDA
209P (S, aureus FDA 209P)B
S: Bacillus subtilis (B, 5ubtilis)
BC: Bacillus cereus IFO3001 (B, ear
eus IFO3001) EC22 Schierichia coli N
IHJ (E, coli NIHJ) KP: Talebsiella pneumoniae ATCC10031 (K, pneu
moniae ATCC10031) Experimental Example 2 Using 160 day-old broiler breed (Hubbard) males, 8,9-anhydroerythromycin, 6,9-hemiketal propargyl chloride (compound No. , 51) to 0°1.0.10.
0 and 100.0 ppm in Ry ration (Ry
The mice were given feed supplemented with 100% feed (e-ration) and allowed to take it freely for 14 consecutive days. The chicks were arranged and housed in groups using the Latin method in an electric battery brooder (internal temperature: 32°C). Table 6 shows the results of examining the survival rate and weight gain rate at 7 days of age and 144 days of age.

Table 6 Clostridium perfringens in excrement (
C1ostridiu+n perfringens)
Approximately 50 to 50 fresh excreta per group at 7 days of age.
1 g of the 80 g collected was subjected to 10-fold serial dilution method.
Spread on a CW agar medium containing 5% egg yolk, and
Table 7 shows the results of counting the number of bacteria after anaerobic culture at ℃ for 20 hours (BBL gas back method).

Table 7 Experimental Example 3 The administered compounds were ethyl-true 8,9-anhydroerythromycin 8, 6,9-hemiketal (compound No. 1).
Table 8 shows the results of examining the survival rate and weight gain rate of day-old broiler-only (Hubbard) males using the same method as in Experimental Example 2.

Table 8 Table 9 shows the results of examining the number of Clostridium perfringens in the above excrement using the method of Experimental Example 2.

Table 9 Example 1 8.9-Anhydroerythromycin A 6,9-hemiketal propargyl chloride was ground to a particle size of 149 μm or less, and 1 part by weight was added to 9 parts by weight of rice bran and mixed with stirring to prepare an erythromycin derivative l. .

% containing formulation (premix) is obtained.

Example 2 The 10% preparation obtained in Example 1 was added to and mixed with feed for early broilers (see Table 10) to a concentration of 0.2% by weight to obtain feed for broilers containing 200 ppm of an erythromycin derivative.

Table 1o (Feed for early broilers) Ingredients Weight % Corn, yellow 55.55 Soybean flour 24.00 Fish meal (white fish meal) 10.00 Dried alfalfa 3.00 Animal fat
3.00 Calcium diphosphate
2.50 Calcium carbonate 1
．． 00 salt 0.25
DL-Methionine 0.20 Vitamin Premix 0.40 Mineral Premix 0.10 Total
100.00 Example 3 The 10% formulation obtained in Example 1 was added to artificial milk feed F
Add and mix 0.2% by weight to S-B-3 (see Table 11), and add 200 ppm of erythromycin derivative.
Obtain containing pig feed.

Corn and yellow world) 19.60 Barley 19.00 Wheat
15.00 Soybean flour
4.00 fusuma
6.80 rice bran oil cake
4.00 Fishmeal (white fishmeal)
3.00 Skimmed milk powder 10
．． 65 Defatted soybean preparation 5.00
Whey 5. OO refined sugars glucose) 5.00 animal fats and oils
1.50 Calcium phosphate (trilime phosphate, phosphorus 18% or more) 0.70 Artificial sweetener 0.15 Salt
0.40 vitamin and mineral premix 0.20 total
100.00 Example 4 Ethyl-True 8,9-Anhydroerythromycin A
6,9-hemiketal is added and mixed to Calfmanna (manufactured by Kyodo Feed Co., Ltd.), a feed for rearing calves at a concentration of 500 ppme, to obtain a feed for calves containing an erythromycin derivative.

The animal growth promoter containing the erythromycin derivative of the present invention exhibits no antibacterial activity or has significantly reduced antibacterial activity, and has an excellent feed efficiency improvement effect in livestock. have

Claims (1)

[Claims] An animal growth promoter comprising an erythromycin derivative in which the dimethylamino group at the 3' position is converted to a primary to tertiary amino group other than a dimethylamino group or a quaternary ammonio group.