CS240988B2 - Production method of a new3-sulphonylazacycloheptanon-2-es - Google Patents

Description

(54) A process for the preparation of new 3-sulfonylazacycloheptan-2-ones i

The present invention relates to a process for the production of novel 3-sulfonylazaoycloheptan-2-ones which are effective as a means of promoting the growth of animals and the recovery of animal feed.

It has been found that the novel 3-sulfonylazacycloheptan-2-ones of the general formula III in which

/ 111 /,

R1 is hydrogen, acetyl, propionyl, benzoyl or methylcarbamoyl,

R 1 is a phenyl group which is optionally substituted one or two times with halogen, trifluoromethyl, C 1 -C 3 alkyl or nitro, furthermore C 1 -C 12 alkyl or pyridyl, aid in animal growth and improve animal feed utilization .

It is known that two enantiomers exist for a molecule with one center of asymmetry and two diastereoisomers, and thus two pairs of enantiomers, for a molecule with two centers of asymmetry.

The 3-sulfonylaza-cycloheptan-2-ones of formula III have two centers of asymmetry and the scope of the invention 3e therefore also extends to all optical isomers and diastereomers.

According to the invention, the novel 3-sulfonylazacycloheptan-2-ones of formula (III) are prepared by reacting to the 3-haloazacycloheptan-2-ones of formula (IV) in which:

R 1 is as defined above and

X is halogen, the sulfinates of formula V act

₂ Θ Θ about ₂ S - Rj / V / in which

R 1 is as defined above and

M® is an alkali metal cation, optionally in the presence of inert solvents.

The 3-sulfonylazacycloheptan-2-ones according to the invention have a surprisingly strong nutritional effect which has not yet been found in the compounds of this compound group and, moreover, the compounds are neither mutagenic (Ames test) nor estrogenic and therefore enrich the state of the art.

For example, alpha-bromocaprolactam and sodium (4-chlorophenyl) sulfinates are used as starting materials, and the reaction scheme can be illustrated by the following reaction scheme:

In formula III, R1 is preferably acetyl, proplenyl, benzoyl or methylcarbamoyl.

The alkyl group R 1 represents a straight or branched alkyl group having 1 to 12 carbon atoms. Examples are methyl, ethyl, n- and isopropyl, η-, iso- and tert-butyl, pentyl, hexyl, dodecyl.

An optionally substituted phenyl group represented by R1 is a phenyl group containing optional substituents at the o-, m- or p-position. The optionally substituted phenyl group may contain 1 or 2 identical or different substituents such as a straight or branched alkyl group having from 1 to 3 carbon atoms, for example methyl, ethyl, n- and isopropyl, further trifluoromethyl, halo, preferably fluorine, chlorine or bromine, and nitro.

in formula IV, X is a halogen atom, preferably a chlorine atom, a bromine atom and a joa atom, in particular a chlorine atom and a bromine atom. R1 is as defined above.

The alpha-haloprolactams useful in the present invention are known or can be prepared by known methods (cf. for example, J. Amer. Chem. Soc. 80, 6238-6244 (1958).

In formula (V), R 1 is as defined above. M 2 is an alkali metal cation, preferably sodium or potassium cation.

The alkali metal sulfinates useful as starting materials according to the invention are known compounds / cf. Houben-Weyl, G. Thieme Verlag, Stuttgart, 1955, Vol. IX, pp. 289-342].

AND

Suitable diluents are all inert organic solvents. These preferably include alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane or tetrahydrofuran, dipolar aprotic solvents such as dimethylsulfoxide, dimethylformamide as well as N-methylpyrrolidone and water.

The process according to the invention can be carried out in the presence of exclusively one or more solvents or water and one or more solvents which are not miscible with water.

The reaction temperatures can be varied within a wide range. In general, temperatures between about 0 ° C and +250 ° C, preferably between + 50 ° C and + 190 ° C, are employed. The reaction can be carried out at atmospheric pressure but also at reduced or elevated pressure. Generally, the process is carried out at atmospheric pressure.

In carrying out the process according to the invention, the starting materials are used in equivalent amounts, but it may also be advantageous to use an alkali metal sulfinate of the general formula V in excess in order to increase the reaction rate.

Treatment of the reaction mixtures to isolate the compounds produced by the process of the invention is carried out according to a generally known method.

The new active compounds produced by the process according to the invention include the following compounds:

3- (butylsulfonyl) azacycloheptan-2-one

3- (phenylsulfonyl) azacycloheptan-2-one

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

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

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

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

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

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

3 - [(3-Trifluoromethylphenyl) sulfonyl] azacycloheptan-2-one 3 - [[4-methylphenyl / sulfonyl] azacycloheptan-2-one 1-acetyl-3- [[4-chlorophenyl] sulfonyl] azacycloheptan-2-one 1-propionyl -3- [[4-chlorophenyl / sulfonyl] azacycloheptan-2-one 1-methylcarbamoyl-3 - [[4-chlorophenyl / sulfonyl] azacycloheptan-2-one 1-acetyl-3- [(3,4-dichlorophenyl) sulfonyl] azacycloheptane] 2-one 1-propionyl-3 - [(3,4-dichlorophenyl) sulfonyl] azacycloheptan-2-one 3 - [[4-nitrophenyl / sulfonyl] azacycloheptan-2-one 3 - [(4-fluorophenyl) sulfonyl] azacycloheptan-2-one 3 - [(2-pyridyl) sulfonyl] azacycloheptan-2-one.

The azacycloheptan-2-ones of formula III produced by the process of the invention have the surprising ability to promote and accelerate the growth of animals, so that these compounds can be used in all areas of animal husbandry.

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

Animals which can be used with the compounds of the invention 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 III are used in the cultivation and rearing of ruminants such as calves, goats, sheep, as well as in the behavior of pigs and chickens.

The amount of the azacyclloheptan-2-ones of the formula (III) according to the invention which is applied to the animals to achieve 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 ingredients, as well as the corresponding duration of application, depends in particular on the species, age, sex, health and behavior of the animals and can be readily ascertained by the skilled person.

The compounds of the invention are administered to animals by conventional methods. The method of administration 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 (III) 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 in admixture with inedible non-toxic carriers, optionally in the form of premixes or feed concentrates.

The feed and / or the drinking water may contain the active compound combinations according to the invention, for example in a concentration by weight 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.

14-day chickens for fattening and S-weekly chickens for fattening, in which animals were administered 5 ppm to 500 ppm of compound of formula III together with feed, showed a marked weight gain in animals treated with α2 acycloheptan-2-ones of formula III compared to animals fed without the addition of azacycloheptan-2-ones of formula III.

The following examples illustrate the process according to the invention. However, they do not limit its scope in any way.

Example 1

192 g of alpha-bromocaprolactam and 164 g of benzenesulfinic acid sodium salt are heated to reflux in 600 ml of dimethylformamide for 10 hours. The precipitated salt is then filtered off and the mother liquor is concentrated in vacuo. The precipitated crystals are recrystallized from acetone.

Yield: 119 g / i. 47% of theory.

Melting point: 180-181 ° C.

In an analogous manner, the following compounds were prepared, Example Yield

boiling point (° C / Pa) or temp. melting point / ° C /

175

171

The following compounds were also prepared in an analogous manner to that described in Example 1:

example number

-Cl boiling point (° C / Pa) or melting point (° C)

171

Cl continuation table

174 to 176

188 to 189

162 to 163

227 to 229

194 to 196

141 to 142

154 to 155

The activity of the compounds produced by the method of the invention test:

demonstrate the results of the following

A: Test description

Cages of 3 to 5 days of age are used for the experiment. The duration of the experiments is 14 days.

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 direct controls is performed. At the start of the experiment, all animals in one test group have the same initial weight. Weight gain values are used as test evaluation criteria.

Claims (1)

SUBJECT 103.8% 107.7% 107.0% INVENTION U Process for the preparation of the novel 3-sulfonylazacycloheptan-2-ones of the general formula III (III), O ^H s ₂ - n ₂ in which R 1 represents a hydrogen atom, an acetyl group, a propionyl group, a benzoyl group or a methylcarbamoyl group, R ₂ represents phenyl which is optionally mono- or disubstituted by halogen, trifluoromethyl, alkyl having 1-3 carbon atoms or nitro, also represents an alkyl group having 1 to 12 carbon atoms or pyridylůvou group, characterized in that the 3-Halo-azacycloheptan-2-ones of formula IV N-Ri O (IV), wherein R ^ is as defined above and X is halogen, the sulfinates of formula V act Μ © Θ O ₂ -SR ₂ / v / in which R 1 is as defined above and M 2 is an alkali metal cation, optionally in the presence of an inert solvent.