DE2934355A1 - Antibacterial alpha-amino-lactam urethane and thio:urethane derivs. - prepd. e.g. by reaction of an alpha-amino-lactam with a carbonic or thiocarbonic acid ester halide - Google Patents

Abstract

New alpha-acylamino- and alpha-thioacylamino lactam derivs. are cpds.of formula (I) (where A is an opt. branched 2-10C bivalent radical, opt. substd. by aryl, aralkyl, cycloalkyl or halogen, which may form part of a carbocyclic system and/or interrupted by O, opt.substd. N or S; X and Y are O or S; R1 and R2 are H or opt.substd. alkyl, allyl, propargyl, cycloalkyl, aralkyl or aryl; R3 is alkyl or opt. substd. allyl, propargyl, cycloalkyl, aryl or heterocyclyl when X and Y are both O, or is opt. substd. alkyl, allyl, propargyl, cycloalkyl, aralkyl, aryl or heterocyclyl, or a salt-forming cation when at least one of X and Y is S). (I) have antimicrobial activity, and may be used in medicine, as growth promoting and feed utilization improving agents in animals, and as preservatives. (I) show strong antibacterial activity against both gram-positive and gram-negative organisms. When administered orally and subcutaneously to mice, the excreted urine has strong antibacterial activity.

Description

(L-acyl (thioacyl) amino-lactams, method for their

Manufacture as well as their use as pharmaceuticals, feed additives and preservatives The present invention relates to new g-acylamino or. g -thioacylamino-lactams, process for their preparation and their use as Medicines, in particular as antimicrobial agents, as promotional agents the growth and improvement of feed conversion in animals and as a preservative.

From Chem. And Ind. 1960, No. 41, pages 1268-1269, the benzyloxycarbonylornithine lactam is of the formula became known without any statements about its biological properties.

It has also become known that simple urethanes as well the derivatives of thiocarbamic acids and of Dithiocarbamic acids LChem are antimicrobially effective. Reviews 65, 567 (1965); E.E. Reid, Organic Chemistry of Bivalent Sulfur, Vol IV (1962), Chemical Publishing Co., Inc. (New York); The Chemistry of cyanates and their thio derivates (1977) John Wiley (New Kork) 7. These known compounds, however, lack urinary activity.

It has been found that the new CC acylamino or

-Thioacylamino-lactams of the formula (I) in which A stands for a divalent, straight-chain or branched carbon chain, optionally substituted by aryl, aralkyl, cycloalkyl and halogen, with 2-10, preferably 2-4 carbon atoms, which is optionally part of a carbocyclic system and / or optionally substituted by oxygen Nitrogen or sulfur may be interrupted, X is oxygen or sulfur, Y is oxygen or sulfur, R1 is H, optionally substituted alkyl, optionally substituted allyl or propargyl, optionally substituted cycloalkyl, aralkyl or optionally substituted aryl, and R2 is H , optionally substituted alkyl, optionally substituted allyl or propargyl, optionally substituted cycloalkyl, optionally substituted aralkyl or optionally substituted aryl, R3 in the case where X = Y = oxygen, represents alkyl, optionally substituted allyl or propargyl, optionally substit uated cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, and R3 in the event that X and Y are oxygen or sulfur but not X = Y = oxygen, optionally substituted alkyl, optionally substituted allyl or propargyl, optionally substituted cycloalkyl, optionally substituted Aralkyl, optionally substituted aryl, optionally substituted heterocyclyl or a salt-forming cation, have a strong and broad antimicrobial activity and improve the growth and feed conversion in animals.

OC-acyl (thioacyl) amino-lactams of the general formula are particularly effective in which A is - (CH2) 2-, - (CH2) 3- or - (CH2) 4-, X and Y f is oxygen or sulfur and R3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl or a salt-forming cation stands.

It has also been found that the new oc-acylamine or 4-thioacylamino-lactams of the general formula (I) are obtained if a) carbonic acid ester chlorides, thiocarbonic acid ester chlorides or dithiocarbonic acid ester chlorides of the formula (II) in which X, Y stand for oxygen or sulfur and R3a stands for the neutral radicals given above under R3, with crC -amino-lactams of the formula (III) in which A, R1, R2 have the meaning given above, reacts in the presence of acid binders and optionally inert solvents, or b) α-amino lactams of the formula (III) in which A, R1 and R2 have the meaning given above, with carbonates or thiocarbonates of the formula (IV) in which R3a stands for the neutral radicals given above under R3 and X and Y are oxygen or sulfur, optionally reacts in the presence of inert solvents, or c) carbon disulfide or carbon oxysulfide with <(- amino lactams of the formula (III)) in which A, R1, R2 have the meaning given above, reacts in the presence of acid binders and optionally inert solvents, or d) the salts obtained according to c) with halides of the formula (V) R5-Hal (V) in which R5 is optionally substituted alkyl, optionally substituted allyl or propargyl, optionally substituted cycloalkyl, optionally substituted aralkyl, activating substituted aryl or activated heterocyclyl, and Hal is halogen, or reacts with di-lower alkyl sulfates or lower alkyl tosylates, optionally in the presence of inert solvents.

The dC-acylamino- or ε-thioacylamino-lactams according to the invention show strong and broad antimicrobial effectiveness. In contrast to already known simple urethanes and derivatives of thiocarbamic acid or

The substances according to the invention show dithiocarbamic acid after peroral Give an antibacterial urinary activity in mice. These properties make it possible their use as chemotherapeutic agents in medicine and as substances for the preservation of inorganic and organic materials, especially of organic materials of all kinds, e.g. polyols, lubricants, paints, varnishes, Fibers, leather, paper and wood, food and water.

Because of their antibacterial properties and their ability to To improve the growth and feed conversion in animals, provide the invention new compounds represent an enrichment of pharmacy and technology.

Method a If, for example, carbonic acid-phenyl ester chloride and it-amino-piperidone are used as starting materials, the course of the reaction can be represented by the following equation: In the general formula (II), the optionally substituted alkyl R3a is straight-chain or branched alkyl having 1 to 18, preferably 1 to 12, carbon atoms. Optionally substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl, hexyl and dodecyl may be mentioned as examples.

R3a is optionally substituted allyl or propargyl preferably groups with 3 to 6, in particular 3 to 4 carbon atoms.

Examples are allyl, propargyl, 1-propen-1-yl and 1-propyn-1-yl called.

Optionally substituted cycloalkyl R3a is mono-, bi- or tri-cyclic and preferably contains 3 to 10, in particular 3 to 7, carbon atoms. Be exemplary optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cyclohexenyl, Cycloheptyl, Bicycl-z2.2.17-heptyl and Adamantyl called.

Optionally substituted aralkyl R3a is Aralkyl substituted in the aryl part and / or alkyl part with preferably 6 or 10, in particular 6 carbon atoms in the aryl part and preferably 1 to 4, in particular 1 or 2 carbon atoms in the alkyl part, the alkyl part being straight-chain or branched can be. Optionally substituted benzyl and phenylethyl are exemplary called.

Optionally substituted aryl R3a is aryl with preferably 6 to 10 carbon atoms in the aryl part.

Optionally substituted phenyl or naphthyl are exemplary called. Substituents in the phenyl ring are in the o, m or p position.

Optionally substituted heterocyclyl R3a are heteroparaffinic, heteroaromatic or heteroolefinic 5- to 7-membered, preferably 5- or 6-membered rings with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms.

The heteroatoms are oxygen, sulfur or nitrogen. As examples are optionally substituted thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxdiazolyl, thiadiazolyl, triazolyl, Oxtriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydrofuranyl, Dioxanyl, pyrrolidinyl, piperidinyl and morpholinyl, called.

Optionally substituted alkyl, allyl, propargyl, cycloalkyl, Aralkyl, aryl and heterocyclyl radicals can contain one or more, preferably 1 Carry up to 3, in particular 1 or 2, identical or different radicals R4, where R4 for straight-chain or branched alkyl with preferably 1 to 6, in particular 1 to 4 carbon atoms, e.g.

Methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, as well as for aryl, e.g. phenyl, lower alkyl-oxy, preferably wise CH30-, C2H50-, as well as for aryl-oxy, e.g. phenoxy, furthermore for lower alkyl-thio, e.g. CH3S-, C2H5S-, for HCO-NH-, for di-lower alkylamino, e.g. dimethylamino, diethylamino, for lower alkyl-O-CO-, e.g.

CH30-CO- and C2H50-CO-, for halogen, preferably fluorine, chlorine, bromine and stands for -NO2.

The carbonic acid ester chlorides, thiocarbonic acid ester chlorides which can be used according to the invention or dithiocarbonic acid ester chlorides of the formula (II) are already known or can be prepared by known processes iouben-Weyl, Vol. VIII. 101, Vol. IX, 807, 810, 815, 817, 819; and C. Feri, Reactions of Organic Synthesis, G. Thieme Verlag (1978), pp. 625-6327.

In the general formula (III), as substituents of a bivalent, straight-chain or branched carbon atoms A with 2 to 10, preferably 2 to 4 carbon atoms, called: aryl radicals with 6 to 12 carbon atoms, such as phenyl, naphthyl, biphenyl, preferably phenyl; Aralkyl radicals with 7 to 12 carbon atoms, such as benzyl, phenethyl, are preferred Benzyl; Cycloalkyl radicals with 4 to 7 carbon atoms, such as cyclopentyl, cyclohexyl, cycloheptyl, preferably cyclopentyl and cyclohexyl.

Preferred halogens are chlorine and bromine. R1 is H, optionally substituted alkyl radicals with up to 6 carbon atoms, preferably up to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl; optionally substituted Cycloalkyl with up to 7 carbon atoms, preferably up to 6 carbon atoms, such as cyclopentyl, Cyclohexyl, optionally substituted allyl or propargyl with preferably 3 to 6, in particular 3 to 4 carbon atoms, e.g. allyl, propargyl, 1-propen-1-yl and 1-propyn-1-yl, optionally substituted aralkyl with preferably 6 carbon atoms in the aryl part and preferably 1 to 4, in particular 1 to 2 carbon atoms in the alkyl part, e.g. optionally substituted benzyl and phenylethyl, and optionally substituted Aryl with preferably 6 carbon atoms in the aryl part, e.g. optionally substituted Phenyl.

R2 stands for H, optionally substituted alkyl radicals with up to 6 carbon atoms, preferably up to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, Hexyl; optionally substituted cycloalkyl with up to 7 carbon atoms, preferred up to 6 carbon atoms, such as cyclopentyl, cyclohexyl, optionally substituted allyl or propargyl with preferably 3 to 6, especially 3 to 4 carbon atoms, e.g. allyl, Propargyl, 1-propen-1-yl and 1-propyn-1-yl, optionally substituted aralkyl with preferably 6 carbon atoms in the aryl part and preferably 1 to 4, in particular 1 or 2 carbon atoms in the alkyl part, e.g. optionally substituted Benzyl and phenylethyl, optionally substituted aryl with preferably 6 carbon atoms in the aryl part, e.g. optionally substituted phenyl. Preference is given to R1 and R2 for hydrogen.

The & -amino-lactams which can be used according to the invention are of the general Formula (III) are already known or can be prepared by known processes are Synthesis 1978, 614- / 16; Helv. Chim. Acta 41, 181 (1958); Zh. org. Chem. 9: 496-503 (1973); Chem. And Ind. 41: 1268-1269 (1960); J. org. Chem. 26, 3347-3350 (1961); T. Kaneko et. al. (Editors), Synthetic Production and Utilization of Amino Acids, John Wiley, New York (1974) 7.

Further suitable lactams can be found in Houben-Weyl, Vol. 11/2, pp. 529-585 (1958) and with R.G. Glushkov, The Chemistry of Lactim Ethers, Advan. Heterocycl. Chem. 12, 185 (1970).

All inert organic solvents can be used as diluents in question. These preferably include hydrocarbons, such as benzene and toluene, chlorinated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2,2-trichloroethane and chlorobenzene, as well as ethers such as diethyl ether, Dioxane or tetrahydrofuran. The inventive Procedure can be carried out in the presence of only one or more organic Solvents or water and one or more water-immiscible solvents.

All customary acid-binding agents can be used as acid-binding agents will. These include inorganic and organic bases. As examples of inorganic Bases are sodium, potassium and calcium hydroxide, alkali carbonates and alkali hydrogen carbonates called. Examples of organic bases are tertiary amines, preferably lower alkylamines, e.g. triethylamine, and / or cyclic bases, e.g. pyridine.

The reaction temperatures can vary over a wide range will. In general, the temperature is between about −200 ° C. and about + 500 ° C., preferably between 0 and + 200C.

The reaction can take place at normal pressure, but also at reduced pressure increased pressure. In general, normal pressure is used.

When carrying out the process according to the invention, the proportions can the reactants of the formulas (II) and (III) can be varied within wide limits, without adversely affecting the result. The starting materials can e.g. are reacted with one another in equimolecular amounts. However, it can expedient be, one of the two reactants in excess to be used to purify or purify the desired compounds facilitate and increase the yield.

For example, you can the reactants of the formula (II) with a Use an excess of 0.1 to 0.3 molar equivalents; this avoids any saponification losses balanced, and also the reactants of the general formula (III) better used.

Preferably, 1 mole of the substance of the formula (11) is used for 1 mole Substance of the formula (III) and 1 mol of base.

The work-up of the reaction batches to isolate the inventive Connections are made in a generally known manner.

Process b) If, for example, diphenyl carbonate and aminopiperidone are used as starting materials, the course of the reaction can be represented by the following equation: All compounds mentioned under a) come into consideration as o (-amino-lactams which can be used according to the invention; in the general formula (IV), X, Y and R3a have the meaning given under a).

The solvents mentioned under a) are used as diluents in question.

The reaction temperatures can be varied within a relatively wide range will. In general, the temperature is between about 50 ° C. and about 2500 ° C., preferably between 100 and 200 "C.

The reaction can take place under normal pressure, but also under reduced pressure be performed. In general, normal pressure or pressure is used between about 0.1 mbar and normal pressure, preferably at 5 to 100 mbar.

When carrying out the process according to the invention, one sets up 1 mol of dt-amino-lactam of the formula (III) 1 to 2, preferably 1 mol of carbonate or Thiocarbonate of formula (IV).

The reaction batches are worked up in a generally known manner Way.

Process c) If, for example, carbon disulfide and oG-amino-piperidone are used as starting materials, the course of the reaction can be represented by the following equation: All compounds mentioned under a) come into consideration as K -amino-lactams which can be used according to the invention.

As diluents there are additionally those mentioned under a) organic solvents or alcohols, preferably methanol, ethanol or isopropanol in question, as well as water. All customary inorganic and organic acids can be used as acid binders Acid binding agents (bases) can be used.

Examples of inorganic bases are: alkali and alkaline earth hydroxides, Alkali and alkaline earth carbonates and alkali hydrogen carbonates such as sodium and potassium hydrogen carbonate; Aluminum hydroxide, zinc hydroxide and ammonium hydroxide. As organic amines can primary, secondary and tertiary aliphatic amines and heterocyclic amines are used will.

Examples include: di- and tri-lower alkylamines, e.g. diethylamine, Triethylamine, tri-B-hydroxyethylamine, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, N-Benzyl-B-phenyl-ethylamine, N-methyl- and N-ethylmorpholine, 1-ephenamine, Dehydroabietylamine, N, N'-bis-dehydroabietylethylenediam, N-lower alkylpiperidine. So-called basic amino acids such as lysine or arginine can also be beneficial Bases are used, as well as the OC-amino-lactams themselves. The reaction temperatures can be varied in a larger range. Generally one works between about -20 to 1000C, preferably between 0 and 20CC.

The reaction can be carried out under normal pressure, but also under increased pressure will. In general, pressures between normal pressure and about 10 are used bar, preferably between normal pressure and 5 bar. When performing the invention The method is based on 1 mol of Oc-amino-lactam (III) 1 to 2, preferably 1 mol Carbon disulfide or 1 to 10, preferably 1 to 3 moles of carbon oxysulfide. The reaction batches are always worked up in a generally known manner and way.

Process d) If the inventive sodium salt of dithiocarbamic acid 1 and ethyl bromide are used as starting materials, the course of the reaction can be represented by the following formula scheme: All salts according to the invention which can be obtained according to c) can be used in the reaction, preferably alkali, di- or tri-lower alkylammonium and (1-aza-cycloalkan-2-on-3-yl) ammonium salts.

In formula (V), R5 represents optionally substituted alkyl radicals having 1 to 6 carbon atoms, for example optionally substituted methyl, ethyl, i- and n-propyl, i- and n-butyl, pentyl and hexyl, optionally substituted allyl or propargyl with preferably 3 to 6, in particular 3 to 4 carbon atoms, for example allyl, propargyl, 1-propen-1-yl and 1-propyn-1-yl, optionally substituted cycloalkyl with preferably 3 to 7 carbon atoms, for example cyclopentyl, Cyclohexyl and cycloheptyl; optionally substituted aralkyl with preferably 6 carbon atoms in the aryl part and 1 to 4, in particular 1 or 2 carbon atoms in the alkyl part, for example optionally substituted benzyl and phenylethyl. A substituted aryl R5 is preferably aryl substituted in the o- and / or p-position by -I- and -M-substituents, for example as activated heterocyclyl, for example, may be mentioned In formula (V), halogen represents fluorine, chlorine, bromine or iodine.

The halides of the formula (V) which can be used according to the invention are already known.

Examples are: CH3J, C2H5Br, (CH3) 2CH-Cl, n-C4H9Cl, n-C5H11J, n-C6Hr3Br, CH = CH-CH2-Br, HC = -C-CH2-Br, cyclopentyl and cyclohexyl chloride, and Dimethyl and diethyl sulfate may be mentioned as di-lower alkyl sulfates, and p-toluenesulfonic acid methyl ester as lower alkyl tosylate.

The inert organic solvents described under a) can be used as diluents Solvent in question.

The process according to the invention can be carried out in the presence of only one or more organic solvents or water and one or more water-immiscible solvents.

The reaction temperatures can be varied within a relatively wide range will. In general, between about -5 and about + 50 ° C. is used, preferably between 0 and 200C.

The reaction can take place at normal pressure, but also at heights Printing can be carried out. in general, one works with prints between about 5 bar and normal pressure, preferably normal pressure.

When carrying out the process according to the invention, one sets up 1 mol of the salts according to the invention described under c) 1 to 1.3, preferably 1 mole of halide of formula (V).

The working up of the reaction batches is generally carried out in general known way.

The following are examples of new active ingredients: The compounds according to the invention surprisingly have strong antibacterial effects on both gram-positive and gram-negative bacteria and thus represent an enrichment in human and veterinary medicine.

In vitro antibacterial activity Description of the experiment: The minimum Inhibitory concentrations against bacteria were determined in the agar dilution test. In addition were different preparation concentrations together with the test strain in liquid DST agar medium suspended and poured into Petri dishes (diameter 5 cm).

The number of germs per plate was 5 × 10 3 germs. As an MHK, the Specifies the preparation concentration at which within 24 hours no or maximum 1-3 colonies had grown.

For example, the compounds of the invention showed against Streptococcus pyogenes W., Staphylococcus aureus 133, E. coli. Neumann, Klebsiella 8085 and Proteus vulgaris 1017 favorable MIC values.

The compounds according to the invention can due to their microbistatic and microbicidal action can be used as antimicrobial agents. You let familiarize themselves with liquid, pasty or solid preparations th, e.g. in suspensions, emulsions and solutions in organic solvents. Such antimicrobial preparations can be used in a wide variety of fields found, especially in medicine but also as cleaning agents, disinfectants and preservatives.

In antimicrobially active preparations according to the invention to be used compounds in amounts of 0.1 to 10 wt .-%, preferably 0.5 to 5% by weight, based on the total product, were used.

In addition, the compounds can be used for the preservation of technical Products that are susceptible to attack by bacteria or other microbial destruction such as starch, paste, glue, emulsion paints, cutting and drilling oils, especially from organic materials of all kinds, e.g. polymers, Lubricants, fibers, leather, paper and wood, from food to cosmetics, such as Creams and ointments, as well as water, are used.

For this purpose, an addition of 0.1 is generally required up to 2 percent by weight, based on the material to be preserved, is sufficient.

The active ingredients according to the invention are good for prophylaxis and chemotherapy suitable for local and systemic infections in human and veterinary medicine, caused by bacteria and bacteria-like microorganisms.

In contrast to already known simple urethanes and derivatives the thiocarbamic acid or dithiocarbamic acid is found in the inventive Substances after oral and subcutaneous administration to mice have a strong antibacterial Activity in excreted urine, which are the parent compounds and / or to structurally closely related metabolism products of the active ingredients according to the invention can act.

As diseases that are prevented by the active ingredients according to the invention, can be improved and / or cured, for example: Diseases the respiratory tract and the pharynx; Otitis; Pharyngitis, pyelonephritis; Cystitis; as well as local infections e.g. of the skin and locally accessible mucous membranes.

For example, local and / or systemic diseases can be treated and / or prevented by the following pathogens or by mixtures the following pathogens: Micrococcaceae, such as staphylococci, e.g. Staphylococcus aureus. Staph. Epidermidis; Lactobacteriaceae, such as streptococci, e.g. Streptococcus pyogenes - or B-haemolytic streptococci, not ( g -) hemolyzing streptococci, St. viridans, St. faecalis (enterococci); Corynebacteriaceae, such as Corynebacteria, e.g. Cornebacterium diphtheriae, C.pyogenes, C.Acnes, Enterobacteriaceae, such as Escherichiae bacteria of the Coli group: Escherichia bacteria, e.g. Escherichia coli, Klebsiella bacteria, e.g. K. pneumoniae, Proteae bacteria of the Proteus group: Proteus, e.g., Proteus vulgaris, Pr. Mirabilis; Providencia and Salmonella bacteria or mycoplasmas, e.g. Mycoplasma gallisepticum.

The above list of pathogens is only exemplary and by no means to be understood as limited.

In addition to the good antibacterial effectiveness, those according to the invention have Compounds also have properties that enable them to be used as feed additives.

The application leads to an accelerated growth, an accelerated one Weight gain and better feed conversion. The new active ingredients can mixed in the usual way with any feed and / or drinking water and so administered to the animals. Of course, you can also use feed concentrates, Preparations containing vitamins and / or minerals are added. Here they are preferably used in amounts of about 1 to 200 ppm, in particular 10 to 50 ppm, the feed, the feed supplements rides and drinking water added. Depending on the species, age of the animals and the general conditions of the Animal husbandry, it can be useful to vary the concentrations of the active ingredients. Particularly good results in promoting growth and feed conversion are achieved when rearing young animals such as calves, piglets as well Poultry, such as chicks.

The active ingredient (s) can optionally be combined with one or more of the above-mentioned carriers are also in microencapsulated form.

Ointments, pastes, creams and gels can be used in addition to the active ingredient or ingredients contain the usual carriers, e.g. animal and vegetable fats, waxes, Paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, Silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can be the usual ones in addition to the active ingredient or ingredients Contain carrier substances, e.g. lactose, talc, silica, aluminum hydroxide, Calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used the usual propellants e.g. contain chlorofluorocarbons.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the common carriers such as solvents, Solubilizer and Emulsifiers, e.g. water, ethyl acetate, benzyl alcohol, propylene glycol, 1,3-butylene glycol, Dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, Castor oil and sesame oil, glycerine, glycerine formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

In addition to the active ingredient or ingredients, suspensions can contain the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, aluminum methahydroxide, agar-agar or mixtures of these substances.

For the production of medical, especially veterinary Usable formulations can use the compounds according to the invention as such or in combination with inert, non-toxic, semi-solid or liquid carriers come into use. The compounds should preferably be in one concentration from 0.1 to 99.5% by weight, preferably from about 0.5 to 90% by weight, of the total mixture can be used.

The new compounds are used in the customary manner, with combinations with other active ingredients can also be used.

The present invention includes pharmaceutical preparations, which in addition to non-toxic, inert pharmaceutically suitable carrier substances or contain more than one active ingredient according to the invention or one or more There are active ingredients according to the invention and processes for the production of these preparations.

Among non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Solutions and suspensions are preferred pharmaceutical preparations and called emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, e.g. by mixing the Active ingredients with the carrier (s).

The present invention also includes the use of the invention Active ingredients and pharmaceutical preparations that contain one or more of the invention Contains active ingredients in human and veterinary medicine for prevention and improvement and / or cure the diseases listed above.

For use in the technical area or on the Hygiene sector the active compounds according to the invention can be used in unmodified form or with one Carrier, e.g. dispersed on a finely divided solid, or used as dust will. Such mixtures can also be used in water with the aid of a wetting agent can be dispersed and the resulting emulsions can be used as a spray will. In other working methods, the products can be used as active ingredients in solvent solutions, Oil-in-water or water-in-oil emulsions can be used. The mixes can can be formulated as concentrates and then with additional liquid or solid Auxiliaries are diluted to make the finishing mixture.

Examples Example 1 25.6 g (0.2 mol) of O (-aminocaprolactam are introduced into 200 ml of methylene chloride, a solution of 8 g (0.2 mol) of sodium hydroxide in 100 ml of water is added and 37.7 g of ( 0.2 mol) of phenyl dithiocarbonate is added dropwise After stirring for four hours at room temperature, the organic phase is separated off, dried with sodium sulfate and the methylene chloride is stripped off. The crystalline residue is recrystallized from acetone.

Yield: 46.5 g (= 83 8 of theory) of N- (hexahydro-2H-azepin-2-on-3-yl) -dithiocarbamidsAure-Phenylester mp: 149-1520C The same procedure was used to prepare: Example Formula Yield Fp (OC) No. i%) LH 2> O H8 90 144-145 / qCb q 56 38-39 where S 3 56 38-39 Example formula yield m.p. (° C) No. Cf NH sc, Mr. 5 Qx .0 92 170-172 i8 6 l 90 134-135 NS ° C.Rs 7 CI 83 157-163 \ 4H # + o 03 8 r 79 128-130 \ NH NHH cooc; i 9 3 57 158-160 \ <NHlo e 10> H 78 128-130 11 '8 78 153-156 c ° S Nile J05SC43 Example formula Yield Fp (OC) No. 12 9 - 8 72 126-128 ? 0 p oCrHr d0 76 9 CN0t \ NHOI8 4 CX 0 62 160 f6 4 62 160 16 50 67 157 160 +0 0 5 67 157 160 90 93 9 o0 0 S tlz Ytb 7 CH3 96 i27 130 ? ° O \ H + 0t Example 18 21.4 g (0.1 mol) of diphenyl carbonate and 12.8 g (0.1 mol) of α-amino-caprolactam are heated to 100 ° C. for 2 hours.

Phenol and unreacted diphenyl carbonate are distilled in vacuo from, the residue is taken up in acetone, the insolubles are filtered off and the Acetone phase.

Yield: 14 g (= 56% of theory) of N- (hexahydro-2H-azepin-2-on-3-yl) -carbamic acid phenyl ester mp: 170-172 ° C. Example 19 38.4 g (0.3 mol) α-aminocaprolactam are placed in 500 ml of toluene, then 22.8 g (0.3 mol) of carbon disulfide are allowed to slowly flow in while cooling with ice. The mixture is then stirred for 10 minutes and filtered off with suction.

Yield: 36 g (= 77% of theory) of N- (hexahydro-2H-azepin-2-on-3-yl) -dithiocarbamic acid, (hexahydro-2H-azepin-2-on-3-yl) ammonium salt Melting point: 104-1060C (decomp.) The following were represented in the same way: Example formula Yield Fp (OC) No. (%) 20 nt t 63 123-127 A <eO s? NZ H 21 47 Q NUI Example 22 11.4 g (0.1 mol) of o'-aminopiperidone and 7.6 g (0.1 mol) of carbon disulfide are added to 4 g (0.1 mol) of sodium hydroxide in 100 ml of water. After stirring for 4 hours at room temperature, the water is distilled off azeotropically with benzene. The crystalline residue, yield: 21.2 g (practically quantitative), has melting point:> 1550C (decomp.) The following were prepared in the same way: Example formula Yield Fp (OC) No. (%) 23 9 100 - EIH $ 8 Well N Well H 24 9 100> 1600C (dec.) NH> t iZ n "t Example 25 33.2 g (0.1 mol) of N- (hexahydro-2H-azepin-2-on-3-yl) -dithiocarbamic acid, (hexahydro-2H-azepin-2-on-3-yl) -ammonium salt are placed in 100 ml of water and 10.9 g (0.1 mol) of ethyl bromide in 100 ml of methylene chloride are added. After 4 hours at room temperature, the phases are separated and the organic phase is evaporated. The residue is recrystallized from acetone.

Yield: 17 g (= 73% of theory) N- (hexahydro-2H-azepin-2-on-3-yl) -dithiocarbamic acid ethyl ester. Example formula Yield Fp (0C) Entry Formula Yield Mp (s) r9t H 26 9 0 67 126-127 HASCL # S

Claims (5)

Claims C i? Acyl (thioacyl) amino-lactams of the general formula in which A is a divalent, straight-chain or branched carbon chain, optionally substituted by aryl, aralkyl, cycloalkyl and halogen, with 2-10, preferably 2-4 carbon atoms, which is optionally part of a carbocyclic system and / or optionally substituted by oxygen Nitrogen or sulfur may be interrupted, X is oxygen or sulfur, Y is oxygen or sulfur, R1 is H, optionally substituted alkyl, optionally substituted allyl or propargyl, optionally substituted cycloalkyl, aralkyl or optionally substituted aryl, and R2 is H , optionally substituted alkyl, optionally substituted allyl or propargyl, optionally substituted cycloalkyl, optionally substituted aralkyl or optionally substituted aryl, R3 in the case where X = Y = oxygen is alkyl, optionally substituted allyl or propargyl, optionally substituted s is cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, and R3 in the event that X and Y are oxygen or sulfur but not X = Y = oxygen, optionally substituted alkyl, optionally substituted allyl or propargyl, optionally substituted cycloalkyl, optionally substituted Aralkyl, optionally substituted aryl, optionally substituted heterocyclyl or a salt-forming cation. 2. oG-acyl (thioacyl) amino-lactams according to claim 1 of the general formula in which A for - (CH2) 2-, - (CH2) 3- or - (CH2) 4-, X for oxygen or sulfur, Y for oxygen or sulfur and R3 for optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl or is a salt-forming cation. 3. A process for the preparation of g-acyl (thioacyl) amino-lactams of the general formula (I) in claim 1, characterized in that either a) carbonic acid ester chlorides, thiocarbonic acid ester chlorides or dithiocarbonic acid ester chlorides of the formula ( II) in which X, Y stand for oxygen or sulfur and R3a stands for the neutral radicals given above under R3, with SC-amino-lactams of the formula (III) in which A, R1, R2 have the meaning given above, reacts in the presence of acid binders and optionally inert solvents, or b) z -amino-lactams of the formula (III) in which A, R1 and R2 have the meaning given above, with carbonates or thiocarbonates of the formula (IV) in which R3a stands for the neutral radicals given above under R3 and X and Y mean oxygen or sulfur, optionally reacts in the presence of inert solvents, or c) carbon disulfide or carbon oxysulphide with o5-amino-lactams of the formula (III) in which A, R1, R2 have the meaning given above, reacts in the presence of acid binders and optionally inert solvents, or d) the salts obtained according to c) with halides of the formula (V) R5-Hal (V) in which R5 is optionally substituted alkyl, optionally substituted allyl or propargyl, optionally substituted cycloalkyl, optionally substituted aralkyl, activating substituted aryl or activated heterocyclyl, and Hal is halogen, or reacts with di-lower alkyl sulfates or lower alkyl tosylates, optionally in the presence of inert solvents. 4. Medicines, characterized by a content of at least one α-acyl (thioacyl) aminolactam of the general formula (I) in claim 1. 5. Animal feed additive, characterized by a content of at least a dc-acyl (thioacyl) aminolactam of the general formula (I) in claim 1.