CS240989B2 - Fodder for animals - Google Patents

Abstract

The present invention relates to animal feed containing new as an active ingredient sulfinyl or sulfonylazacycloheptane-2-yne. Said feed is used to stimulate animal growth and improved feed utilization.

Description

The present invention relates to an animal feed containing the novel sulfinyl or sulfonylazacycloheptan-2-ones as an active ingredient. Said feed is used to stimulate animal growth and improve feed utilization.

It has been found that the novel sulfinyl- and sulfonylazacycloheptan-2-ones of formula (I)

where ^ 2 n is 1 or 2,

R ₂ represents hydrogen, alkyl having 1 to 4 carbon atoms which is optionally substituted by cyano, furthermore represents acetyl, propionyl, benzoyl or methylkarbamoylovouiskupinu,

R ₂ represents an alkyl group having 1 to 12 carbon atoms optionally substituted by hydroxy, carboxy or phenyl, furthermore represents phenyl which is optionally mono- or disubstituted by halogen, optionally halogen-substituted alkyl group having 1 to 4 carbon atoms, amino, , nitro or C 1 -C 4 alkoxycarbonyl, furthermore C 2 -C 4 alkenyl, or pyridyl or benzthiazolyl, wherein the sulfinyl or sulfonyl group may be in the alpha or beta position and including gamma-alkylsulfinylcarbolactam having 1 to 4 carbon atoms in the alkyl moiety, promote animal growth and improve animal feed utilization.

The subject of the present invention is an animal feed, characterized in that, in addition to the nutritional and / or auxiliary ingredients, at least one sulfinyl or sulfonylazacycloheptan-2-one contains the above-mentioned and defined general formula I as active ingredient.

It is known that for a molecule with one center of asymmetry there are two enantiomers and for a molecule with two centers of asymmetry there are two diastereomers and thus two pairs of enantiomers.

The sulfinyl or sulfonylazacycloheptan-2-ones of the formula I according to the invention have two centers of asymmetry or one center of asymmetry, and therefore the scope of the invention also extends to all optical isomers and diastereomers.

Particularly preferred are the sulfinyl- and sulfonylazacycloheptan-2-ones of formula (Ia)

wherein R 2 to R @ ₂ have the abovementioned meanings and sulfinyl or sulfonyl group is in the .alpha.- or .beta.-position.

The sulfinyl and sulfonylazacycloheptan-2-ones of the formula I are novel compounds.

Surprisingly, the sulfinyl and sulfonylazacycloheptan-2-ones of the formula I exhibit a strong nutritional effect which has not yet been observed with the compounds of this class of substances and, moreover, they are neither mutagenic (Ames test) nor estrogenic and thus enrich the technique.

In formula (I), optionally cyano-substituted alkyl groups R 1 are straight or branched alkyl groups of up to 4 carbon atoms. Examples which may be mentioned are cyano-substituted methyl, ethyl, n- and isopropyl, η-, iso and this. butyl group.

R _x is further preferably an acetyl group, a propionyl group, a benzoyl group or a methylcarbamoyl group.

An optionally substituted alkyl group R ₂ is a straight or branched alkyl group having 1 to 12 carbon atoms.

Examples are optionally substituted methyl, ethyl, n- and isopropyl, η-, iso- and tert-butyl, pentyl, hexyl, dodecyl. Suitable substituents are hydroxy, carboxy and phenyl.

As the alkenyl group represented by R ₂ there may be straight or branched alkenyl group having up to 4 carbon atoms. Examples include ethenyl, 1-propenyl, 2-propenyl and 3-butenyl.

and

An optionally substituted phenyl group represented by R1 is a phenyl group containing optional substituents at the o-, m- or p-position.

An optionally substituted phenyl group may contain one or two identical or different substituents, such as a straight or branched alkyl group having 1 to 4 carbon atoms, which is itself optionally optionally substituted by halogen, for example methyl, ethyl, n- and isopropyl, η- , iso- and target. butyl and trifluoromethyl, trichloromethyl, C 1 -C 4 alkoxycarbonyl, for example methoxycarbonyl and ethoxycarbonyl, halogen, preferably fluoro, chloro, bromo, amino and nitro.

The following are examples of novel active substances:

3- (butylsulfinyl) azacycloheptan-2-one

4- (butylsulfinyl) azacycloheptan-2-one

5- (butylsulfinyl) azacycloheptan-2-one

3- [(2-hydroxyethyl) sulfinyl] azacycloheptan-2-one

3- [(carboxymethyl) sulfinyl] azacycloheptan-2-one

4- [(carboxymethyl) sulfinyl] azacycloheptan-2-one

3- (dodecylsulfinyl) azacycloheptan-2-one

3- (benzylsulfinyl) azacycloheptan-2-one.

4- (benzylsulfinyl) azacycloheptan-2-one

3- (allylsulfinyl) azacycloheptan-2-one

4- (allylsulfinyl) azacycloheptan-2-one

3- (phenylsulfinyl) azacycloheptan-2-one

4- (phenylsulfinyl) azacycloheptan-2-one

3- [(4-chlorophenyl) sulfinyl] azacycloheptan-2-one

4- [(4-chlorophenyl) sulfinyl] azacycloheptan-2-one

3- [(3-chlorophenyl) sulfinyl] azacycloheptan-2-one

4- [(3-chlorophenyl) sulfinyl] azacycloheptan-2-one

3- [(2-chlorophenyl) sulfinyl] azacycloheptan-2-one

4- [[2-chlorophenylsulfinyl] azacyclophen-2-one

3- [(3,4-dichlorophenyl) sulfinyl] azacycloheptan-2-one

4- [(3,4-dichlorophenyl) sulfinyl] azacycloheptan-2-one

3- [(2,4-dichlorophenyl) sulfinyl] azacycloheptan-2-one

4- (2,4-dichlorophenyl) sulfinyl] azacycloheptan-2-one

3- [(3,5-dichlorophenyl) sulfinyl] azacycloheptan-2-one

4- [(3,5-dichlorophenyl) sulfinyl] azacycloheptan-2-one

3- [(3-fluoro-4-chlorophenyl) sulfinyl] azacycloheptan-2-one

4- [[3-fluoro-4-chlorophenyl / sulfinyl] azacycloheptan-2-one

3- [(3-Trifluoromethylphenyl) sulfinyljazacycloheptan-2-one

4- [(3-Trifluoromethylphenyl) sulfinyl] azacycloheptan-2-one

3- [(4-methylphenyl) sulfinyl] azacycloheptan-2-one

4- [(4-methylphenyl) sulfinyl] azacycloheptan-2-one

3- [(4-nitrophenyl) sulfinyl] azacycloheptan-2-one

4- [(4-nitrophenyl) sulfinyl] azaoycloheptan-2-one

3- [(4-bromophenyl) sulfinyl] azacycloheptan-2-one

4- [(4-bromophenyl) sulfinyl] azacycloheptan-2-one

3- [[4-Aminophenyl] sulfinyl-cyclohexyl-2-one

4- [(4-aminophenyl) sulfinyl] azacycloheptan-2-one 1-methyl-3-allylsulfinylazacycloheptan-2-one 1-acetyl-3-allylsulfinylazacycloheptan-2-one 1-methylcarbamoyl-3-allylsulfinylazacycloheptan-2-one 1- ethyl 3 - [(4-chlorophenyl) sulfinyl] azacycloheptari-2-one 1-acetyl-3 - [[4-chlorophenyl] sulfinyl] azacycloheptan-2-one 1-acetyl-4- [(4-chlorophenyl)] sulfinyl] azacycloheptan-2-one

1-Propionyl-3- [(4-chlorophenyl) sulfinyl] azacycloheptan-2-one

1-Propionyl-4- [(4-chlorophenyl) sulfinyl] azacycloheptan-2-one 1-methylcarbamoyl-3 - [[4-chlorophenyl] sulfinyl] azacycloheptan-2-one 1-methylcarbamoyl-4 - [(4-chlorophenyl)] sulfinyl] azacycloheptan-2-one 3- (butylsulfonyl) azacycloheptan-2-one

3- (allylsulfonyl) azacycloheptan-2-one

3- (benzylsulfonyl) azacycloheptan-2-one

3- (phenylsulfonyl) azacycloheptan-2-one

4- (phenylsulfonyl) azacycloheptan-2-one

3- [(4-chlorophenyl) sulfonyl] azacycloheptan-2-one

4- [(4-chlorophenyl) sulfonyl] azacycloheptan-2-one

3- [(3-chlorophenyl) sulfonyl] azacycloheptan-2-one

4- [(3-chlorophenyl) sulfonyl] azacycloheptan-2-one

3- [(2-chlorophenyl) sulfonyl] azaoycloheptan-2-one

4- [(2-chlorophenyl) sulfonyl] azacycloheptan-2-one

3- [(2,4-dichlorophenyl) sulfonyl] azacycloheptan-2-one

4- [(2,4-dichlorophenyl) sulfonyl] azacycloheptan-2-one

3- [(3,4-dichlorophenyl) sulfonyl] azacycloheptan-2-one

4- [(3,4-dichlorophenyl) sulfonyl] azacycloheptan-2-one

3- [(3,5-dichlorophenyl) sulfonyl] azacycloheptan-2-one

4- [(3,5-dichlorophenyl) sulfonyl] azaoycloheptan-2-one

3- [β-trifluoromethylphenylsulfonyl] azacycloheptan-2-one

4- [(3-trifluoromethylphenyl) sulfonyl] azacycloheptan-2-one

3- [(4-methylphenyl) sulfonyl] azacycloheptan-2-one

4- [(4-methylphenyl) sulfonyl] azacycloheptan-2-one

3- [(4-nitrophenyl) sulfonyl] azacycloheptan-2-one

4- [(4-nitrophenyl) sulfonyl] azacycloheptan-2-one

3- [(4-aminophenyl) sulfonyl] azacycloheptan-2-one

4- [(4-aminophenyl) sulfonyl] azacycloheptan-2-one

3- [(4-fluorophthyl) sulfonyl] azacyclopentan-2-one

4- [(4-Fluorophenyl) sulfonyl] azacycloheptan-2-one 1-acetyl-3 - [[4-chlorophenyl] sulfonyljazacycloheptan-2-one]

1-Acetyl-4- [(4-chlorophenyl) sulfonyl] azacycloheptan-2-one

2-Propionyl-3- [(4-chlorophenyl) sulfonyl] azacycloheptan-2-one 1-Propionyl-4 - [[4-chlorophenyl] sulfonyl] azacycloheptan-2-one 1-methylcarbamoyl-3- [(4-chlorophenyl)] sulfonyl] azacycloheptan-2-one 1-methylcarbamoyl-4- [(4-chlorophenyl) sulfonyl] azacycloheptan-2-one 1-ethyl-3- [(3,4-dichlorophenyl) sulfonyl] azacycloheptan-2-one 1-ethyl -4 - [(3,4-dichlorophenyl) sulfonyl] azacycloheptan-2-one 1-acetyl-3 - [[3,4-dlchlorophenyl] sulfonyl] azacycloheptan-2-one 1-acetyl-4 - [/ 3,4 Dichlorophenyl / sulfonyl] azacycloheptan-2-one 1-nropionyl-3 - [(3,4-dichlorophenyl) sulfonyl] azacycloheptan-2-one 1-Propionyl-4 - [(3,4-dichlorophenyl) sulfonyljazacycloheptan-2-one

3- [(2-benzothlazolyl) sulfinyl] azacycloheptan-2-one

4- [(2-benzothiazolyl) sulfinyl] azacycloheptan-2-one

3- [(2-benzothlazolyl) sulfonyl] azacycloheptan-2-one

4- [(2-benzothiazolyl) sulfonyl] azacycloheptan-2-one

3- [(2-pyridyl) sulfinyl] azacycloheptan-2-one

4- [(2-pyridyl) sulfinyl] azacycloheptan-2-one

3- [(2-pyridyl) sulfinyl] azacycloheptan-2-one

4- [(2-pyridyl) sulfonyl] azacycloheptan-2-one.

Specific examples of sulfinyl and sulfonyl-azacycloheptan-2-ones which are used as active ingredients in the compositions of this invention are listed in Table 1 below:

melting point / ° C / boiling point / ° C / Pa /

Table example number formula

H

185-189

119

166-168

S-CH 2 is 2

-COOH

H

144-145

130-131

158-162

- 100

115/70

156-158

162-164 table melting point boiling point continued example number formula

187-189

135/90

143-148

176-177

178-180

180-182

155-156

153-155

175-179

173 - 176 ° c / '° C / Pa / no ₂ continued table boiling point / C / Pa / melting point / ° C / example number no.

101 - 105 (decomposition)

NH

0 «X

^CH 2 ^CH 3

158-159 o ^H s - (o) —Cl

H S - (O) -Cl

126-139

H, S- (O) - ^Cl

HIM

HS— (O, & ^N '

NH-CH,

H JS - (CH ₂ ) ₃ - CH ₃ O

O, x

NH-CH,

^HC 12 ^H 25 'X,

NHCHj

HS -CH, -CH-CH ₂ o

- χ

X ^^ nhchj < ^{w w}

189-192

147-148

120

114

132 - 136 example number boiling point / ° C / Pa / formula melting point / θθ /

Cl continuation table example number

175

H

O> —CH ₃ continued table

Example number Boiling point / ° C / Pa / Melting point / ° C /

171

Surprisingly, the azacyclloheptan-2-ones of the formula I according to the invention have the ability to promote and accelerate the growth of animals, so that these compounds can be used in all areas of animal cultivation and breeding.

The activity of the compounds according to the invention is essentially independent of the species and sex of the animals. The azacycloheptan-2-ones of the formula I according to the invention have proved to be particularly valuable in the cultivation and breeding of young and fed animals.

Animals which the compound may be used to stimulate and accelerate growth include, for example, the following utility and ornamental animals:

warm-blooded animals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, furry animals such as mink and chinchilla, poultry such as hens, geese, ducks, turkeys, broilers, pigeons, parrots and canaries and cold-blooded animals such as fish such as carp, and reptiles such as snakes.

Preferably, the azacycloheptan-2-ones of formula X are used in the cultivation and breeding of ruminants such as calves, goats, sheep, as well as in the behavior of pigs and chickens.

The amount of the azacycloheptan-2-ones of the formula I according to the invention which is applied to the animals to obtain the desired effect can be varied within wide limits. This amount is preferably about 0.5 to 500, in particular 1 to 100 mg / kg of body weight per day.

The application period can vary from a few hours or days to several years. The appropriate amount of active substances as well as the corresponding duration of application depend in particular on the species, age, sex, health and behavior of the animals and can be readily ascertained by one skilled in the art.

The compounds of the invention are administered to animals by conventional methods. The method of application depends in particular on the species, behavior and health of the animals. Thus, administration can be performed once or several times a day at regular or irregular intervals orally or parenterally. In most cases, oral administration is expedient, particularly preferably at the same time as the intake of food and / or beverages.

The compounds produced according to the invention can be administered as pure substances or in the form of compositions, i.e. in admixture with non-toxic inert carriers. Such carriers are solid, semi-solid or liquid diluents, fillers and auxiliaries of any kind.

The azacyclloheptan-2-ones of the formula I according to the invention are also applied, if appropriate, in the form of compositions, together with pharmaceutically active substances, mineral salts, trace elements, vitamins, proteins, fats, colorants and / or flavorings in a suitable form.

Oral administration together with feed and / or drinking water may be recommended, with all or part of the feed and / or drinking water being added to the active ingredients as appropriate.

The compounds according to the invention are added to the feed and / or to the drinking water according to the usual methods by simple mixing in the form of pure substances, preferably in finely dispersed form or in the form of compositions mixed with inedible non-toxic carriers.

The feed and / or drinking water may contain the active compound combinations according to the invention, for example in a weight concentration of from about 5 to 500 ppm, in particular from 5 to 100 ppm. The optimum level of concentration of the active ingredients in the feed and / or drinking water depends in particular on the amount of feed and / or drinking water taken up by the animal and can be readily determined by one skilled in the art.

The nature of the feed and its composition is of immaterial importance. All commonly used or special feed compositions that contain preferably the usual balance necessary for balanced nutrition from energy and building materials including vitamins and minerals may be used. The feed may consist, for example, of plant substances such as hay, beet, grain, grain by-products, animal substances such as meat, fat, bone meal, fish products, and vitamins such as vitamin A, D-complex and B-complex, from proteins, amino acids such as DL-methionine and inorganic substances such as lime and table salt.

The feed concentrates contain the azacycloheptan-2-ones of the formula I according to the invention in addition to ingestible substances such as rye flour, soy flour or lime, optionally together with other nutrients and nutrients, as well as proteins, mineral salts and vitamins. They can be prepared by conventional mixing methods.

In premixtures and feed concentrates, the active compounds may optionally also be protected by suitable means covering their surface, for example with non-toxic waxes or gelatin, from air, light and / or moisture

An example of a chicken feed composition containing the azacycloheptan-2-one of formula I according to the invention:

200 g of wheat, 340 g of corn, 361 g of soya meal, 60 g of beef tallow, 15 g of dicalcium phosphate, 10 g of calcium carbonate, 4 g of iodized common salt, 7,5 g of a mixture of vitamins and minerals and 2,5 g of premix provides 1 kg of feed after careful mixing.

The mixture of vitamins and minerals consists of: 6 000 IU of vitamin A, 1 000 IU of vitamin D ₃ , 10 mg of vitamin E, 1 mg of vitamin K ₃ , 3 mg of riboflavin, 2 mg of pyridoxium, 20 mg of vitamin χ _χ2 , 5 mg of calcium pumantothenate 30 mg nicotinic acid, 200 mg choline chloride, 200 mg of MnSO ^ X H ₂ 0, 140 mg of ZnSO _fourth H ₂ O, 100 mg FeSO 3. 7 H ₂ O and 20 mg CuSO ₄ . 5 H ₂ 0.

The premix of the active ingredients contains the azacycloheptan-2-ones of the formula I according to the invention in the required amount, for example 100 mg and in addition 1 g of DL-methionine and enough soybean meal to produce 2.5 g of the premix.

Example / composition of a feed for the production of pigs containing a combination of active substances according to the invention:

630 g of feed grain meal / consisting of 200 g of maize, 150 g of barley meal,

150 g oat meal and 130 g wheat meal /, 80 g fish meal, 60 g soy meal, g tapioca meal, 38 g beer yeast, 50 g pigs / vitamins / composition for example the same as in chicken feed preparation /, 30 g of flaxseed meal, 30 g of fodder corn, 10 g of soybean oil, 10 g of sugar cane molasses and 2 g of premix containing active ingredients / composition for example the same as in the case of chicken feed / provides for careful mixing 1 kg of feed.

Said feed mixtures are preferably intended for the cultivation of chickens or pigs or for feeding on feed, but may also be used in the same or similar composition for growing or feeding on the feed of other animals.

The following examples illustrate the efficacy of the compounds of the invention, but are not intended to limit the scope of the invention in any way.

Example

A. Test description:

Cages of 3 to 5 days of age are used for the experiment. The duration of the experiment is 14 days or 6 weeks in total.

The animals receive the feed to which the compounds according to the invention have been admixed at a dose of 10 and 25 ppm, respectively. At the same time a negative control (feed without admixture) is performed. At the start of the experiment, all animals in one test group had the same initial weight.

Weight gain, feed consumption and feed evaluation are used as test evaluation criteria.

The results of the experiment are summarized in the following tables.

B. Animal characteristics and feed

Sorted hybrid per animal, male specimens 24 animals / experiment / 4x6 / 50-65 g

Feed: uniform feed for chickens KA 57 / Hoveler / without antibiotics and coccidiostats as follows:

Value components:

% crude protein% crude fiber% ash% calcium 0.7% phosphorus

Ingredients:

% feed grain scrap / 40% corn, 12% wheat /

17.5% soya meal

5.2% feed corn sebum 5.2% wheat bran

3.1% fish meal 3.1% tapioca meal

3.1% green alfalfa meal

2.1% wheat germ (pulverized)

1.7% bone meal

1,6% Whey powder 1,4% calcium carbonate 1,0% dicalcium phosphate 1,0% molasses

Test results:

14-day experiment with chickens feeding active substance dose (mg / kg feed)

weight gain / control = 100% /

103.5%

102.0%

102.8%

102,5%

103.2%

102,7 i

103.3%

103.3%

102.8%

102.7%

continued table active substance dose

weight gain / control · 100% /

103.3%

103.1% 103.4%

103.8%

107.7% 107.0%

O

Cl

101.3% 111.9% 110.8%

H S — CH, —COOH O

105.4 «105.9% .6-week experiment with chickens / broilers /:

dose ppm number animal weight consumption feed increase /% / / »/ feed evaluation /% / control positive control penicillin _ H

- 37 100 ALIGN! 100 ALIGN! 100 ALIGN! 20 May 39 104.8 102.5 97.8 10 38 103.4 102.4 99.0 25 37 103.3 98.6 95.4

Claims (2)

SUBJECT OF THE INVENTION 1. Feed for animals, characterized in that in addition to the nutritional or / and auxiliary ingredients comprises as active ingredient at least one sulfinyl or sulfonylazacykloheptan-2-one of the formula I / 1 / I * wherein R ₂ n is 1 or 2 , R 1 is hydrogen, C 1 -C 4 alkyl optionally substituted with cyano, furthermore acetyl, proplonyl, benzoyl or methylcarbamoyl, R ₂ represents an alkyl group having 1 to 12 carbon atoms optionally substituted by hydroxy, carboxy or phenyl, furthermore represents phenyl which is optionally mono- or disubstituted by halogen, optionally halogenerii substituted alkyl group having 1 to 4 carbon atoms, amino, C 1 -C 4 nitro or C 1 -C 4 alkoxycarbonyl, furthermore C 2 -C 4 alkenyl, or pyridyl or benzthlazolyl, wherein the sulfinyl or sulfonyl group may be in alpha or in beta-position and including gamma-alkylsulfinylcaprolactam having 1 to 4 carbon atoms in the alkyl radical. Feed according to claim 1, characterized in that it contains, in addition to the nutritional and / or auxiliary components, at least one sulfinyl or sulfonylazacycloheptan-2-one of the formula Ia as active ingredient. Wherein R ₂ is as defined above and the sulfinyl or sulfonyl group is in the alpha or beta position.