DE2656783A1 - Quinoxaline di-(N)-oxide derivs. - useful as antimicrobial, esp. antibacterial agents - Google Patents

Abstract

Quinoxaline di-N-oxides of formula (I) are new: (where R1 and R2 are H, halogen, alkyl or alkoxy; R3 is an opt. substd., opt. unsatd. aliphatic or alicyclic gp.). (I) are antimicrobial agents, e.g. active against a wide range of Gram-positive and -negative bacteria. They can be used in human and veterinary medicine (systemically or topically) and as animal feed additives. In an example, (I; R1=R2=H, R3=Me) is prepd. from 2-methyl-3-carbamoylquinoxaline di-N-oxide, paraformaldehyde and 1,3,5-trimethyl-hexahydro-s-triazine.

Description

Process for the production of new quinoxaline di-N-oxides

as well as their use as medicaments The present invention relates to a new chemically peculiar process for making new antibacterial effective quinoxaline di-N-oxides and their use as drugs, in particular as antibacterial agents and feed additives.

It has already become known that 2-methyl-3-carbamoylquinoxaline di-N-oxides CJ.K. have antibacterial properties. Landquist and J.A. Silke, J. Chem. Soc. 1956. 20522.

However, these substances are toxic and very soluble in terms of their solubility unsatisfactory.

It has been found that the new quinoxaline di-N-oxides of the formula (I) in which R1 and R2 can be identical or different and represent hydrogen, halogen, alkyl or alkoxy and R3 represents an optionally substituted and optionally unsaturated aliphatic or cycloaliphatic radical is obtained when 2-methyl-3-carbamoylquinoxaline-di -N-oxides of the formula (II) in which R¹ and R2 have the meaning given above with formaldehyde or formaldehyde-releasing agents and primary amines of the formula (III) H2N-R3 or with hexahydrotriazines of the formula (IV) in which Rs has the meaning given above, reacts in the presence of inert solvents at temperatures between OD and 100.degree.

The new quinoxaline di-N-oxides of the formula (I) have strong antibacterial properties Properties on.

It is to be described as extremely surprising that 9 ~ according to the reaction according to the invention quinoxaline di-N-oxides of the formula (I) arise. In view of the state of the art, one had to do so in the case of implementation Formaldehyde and primary amines expect that from formaldehyde and primary amines Hexahydrotriazines are formed tThe Chemistry of Heterocyclic Compounds, s-Triazines 1959, Interscience Publishers INC., New York, pp. 473-5067.

In the case of reaction with formaldehyde and hexahydrotriazines had to on the other hand, it is expected that the carbamoyl compounds of the formula (II) the corresponding hydroxymethyl compounds would form tAngew. Chem. 69, p 463 (1957) 7.

If 2-methyl-3-carbamoyl-quinoxaline-di-N-oxide, formaldehyde and methylamine are used as starting materials, the course of the reaction can be represented by the following equation: If 2-methyl-3-carbamoyl-quinoxaline-di-N-oxide and 1,3,5-triethyl-hexahydro-s-triazine are used as starting materials, the course of the reaction can be represented by the following equation: In the formula (I), R¹ and R² are hydrogen, halogen such as. B. fluorine, chlorine and bromine, especially fluorine and chlorine, alkyl radicals with 1-4 carbon atoms or alkoxy radicals with 1-4 carbon atoms, one of the radicals R1 and R2 always being hydrogen. R3 stands for an optionally substituted, optionally unsaturated aliphatic hydrocarbon radical with 1-12, preferably 1-4 carbon atoms or a cycloaliphatic hydrocarbon radical with up to 6, preferably 5-6 carbon atoms. The substituents of the hydrocarbon radical are the hydroxyl groups, the alkoxy group with 1 - 4 carbon atoms, the carboxyl group, the carboalkoxy group with 1 - 4 carbon atoms, the dialkylamino group with 1 - 4 carbon atoms, the cyano group, the nitro group, halogens such as. B. fluorine, chlorine or bromine or an aryl radical, preferably the phenyl radical in question. The 2-methyl-3-carbamoyl-quinoxaline di-N-oxides which can be used according to the invention are known L7.K. Landquist and JA Silk, J. Chem.

Soc. 1956, 20527.

Examples are: 2-methyl-3-carbamoyl- -quinoxaline-di-N-oxide "5 or 6-methyl-" "-äthyl-" "-propyl-" "-fluor-" " -chlor- "" -bromo- "" -methoxy- "" -ethoxy- "" -propoxy- "lt -butoxy- lt Die Primary amines which can be used according to the invention are already known. Let us take as an example called: methylamine, ethylamine, n- and i-propylamine, the isomeric gutylamine, hexylamine, Dodecylamine, allylamine, cyclopentylamine, cyclohexylamine, ethanolamine, 3-methoxypropylamine, 3-dimethylaminopropylamine, 8-aminopropiononitrile, methyl 2-asinoacetate and benzylamine.

The hexahydro-s-triazines which can be used according to the invention instead of primary amines are also known. They are made by reacting primary amines and formaldehyde obtained [The Chemistry of Heterocyclic Compounds, see Triazines 1959, Interscience Publishers INC, New York, pp. 473-506].

Formaldehyde can be in solid form as paraformaldehyde or trioxane or can be used in the form of an aqueous solution.

Polar organic solvents can be used as diluents. These include preferably nitriles such as acetonitrile, propionic acid nitrile, adipic acid dinitrile, Benzonitrile, formamides such as formamide, N-methyl-formamide, N, N-dimethyl-formamide and Dimethyl sulfoxide.

The reaction temperatures can vary over a wide range wird0 In general, one works between 0 and about 10ODC, preferably between 2O0C and 7 C.

When carrying out the process according to the invention, one sets up 1 mole of 2-methyl-3-carbamoyl-quinoxaline-di-N-oxide at least 3 moles of formaldehyde and 2 moles of primary amine or, when working with hexahydro-s-triazines, at least 1 mole Formaldehyde and 2/3 moles of hexahydro-s-triazine. But there can also be an excess of formaldehyde and primary amine or hexahydros-triazine can be used.

The reaction is carried out in such a way that the mixture of quinoxaline di-N-oxide, Formaldehyde and primary amine resp.

Hexahydro-s-triazine in a diluent at temperatures between 2S and 700C implemented. The end of the reaction can be recognized by the fact that the In contrast to the initial products, end products dissolve clearly in aqueous acids. The reaction products are usually deposited in solid crystalline form and can In some cases the end products are dissolved in the diluent and can be obtained by evaporating the reaction solution.

The active ingredients of formula (I) have strong chemotherapeutic, in particular antimicrobial effects. Their effectiveness extends to for example gram-positive and gram-negative bacteria, with the following bacteria families as examples, Bacterial genera and types of bacteria may be mentioned: Enterobacteriaceae, z. B. Escherichia, especially Escherichia coli; Klebsiella, especially Klebsiella pneumoniae, Enterobacter; Proteus, in particular Proteus vulgaris, Proteus mirabilis, Proteus morganii, Proteus rettgeri and Salmonella, in particular Salmonella typhimurium, Salmonella enteritidis; from the family of the Pseudomonadaceae, e.g. B. Pseudomonas aeruginosa, Aeromonas, e.g. B. Aeromonas liquefaciens; Clostridia, e.g. B. Clostridium botulinum, Clostridium tetani; from the family of the Micrococcaceae, e.g. B. Staphylococcus aureus, Staphylococcus epidermidis; from the family of the Streptococcaceae, e.g. B. Streptococcus pyogenes, Streptococcus faecalis (Enterococcus); from the family of Mycoplasmataceae, e.g. B. Mycoplasma pneumoniae.

The excellent and broad antibacterial effectiveness of the active ingredients enables their use in both human and veterinary medicine, being both for the prevention and for the treatment of systemic or local bacterial infections can be used.

The compounds can also be used as feed additives to promote of growth and to improve feed evaluation in animal husbandry, in particular in keeping of beef cattle, such as B. cattle, pigs and Poultry, etc. can be used.

The active ingredients are then preferably applied via the Feed and / or drinking water. The active ingredients can also be used in feed concentrates as well as in preparations containing vitamins and / or mineral salts.

Mixing with the feed or in the feed concentrates and the other feed preparations are made in the form of a premix if necessary the usual methods.

The present invention includes pharmaceutical preparations, which in addition to non-toxic, inert pharmaceutically suitable carriers one or contain several compounds of the formula (I) or those of one or more compounds of formula (I) exist, as well as a process for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, z. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can be, for. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or Contain 1/4 of a single dose. A single dose preferably contains the amount Active ingredient that is administered in one application and that usually corresponds to a whole, corresponds to half a day or a third or a quarter of a daily dose.

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

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, suppositories, solutions, suspensions and emulsions, Called pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, coated tablets, capsules, pills and granules can be the or the active ingredient (s) contain in addition to the usual carriers, such as a) fillers and extenders, z. B. starches, lactose, cane sugar, glucose, mannitol and silica, b) binders, z. B. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, c) humectants, e.g.

Glycerine, d) disintegrants, e.g. B. agar agar, calcium carbonate and sodium bicarbonate, e) solution retarders, e.g. B. paraffin, and f) absorption accelerators, e.g. B. quaternary Ammonium compounds, g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, h) Adsorbents, e.g. B. kaolin and bentonite, and i) lubricants, e.g. B. Talc, Calcium and magnesium stearate and solid polyethylene glycols or mixtures of the below a) to i) listed substances.

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and casings, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably in a certain part of the intestinal tract possibly be delayed, with such. B. Polymer substances and waxes can be used.

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

In addition to the active ingredient (s), suppositories can contain the usual water-soluble ones or contain water-insoluble carriers, e.g. B. polyethylene glycols, fats, z. B. cocoa fat, and higher esters (e.g. C14 alcohol with C16 fatty acid) or mixtures these substances.

Ointments, pastes, creams and gels can be used in addition to the active ingredient or ingredients contain the usual carriers, e.g. B.

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 carriers, e.g. B. 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. B. chlorofluorocarbons contain.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the customary carriers, such as solvents, solubilizers and Emulsifiers, e.g. B. water, ethyl alcohol, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, Corn oil, olive oil, castor oil and sesame oil, glycium, glycerin formal, tetrahydrofurfuryl alcohol, Contain polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can include the usual carriers, such as liquid diluents, e.g. B.

Water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated Isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, Aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances contain.

The formulation forms mentioned can also contain colorants and preservatives as well as odor and taste improving additives, z. B. peppermint oil and eucalyptus oil, and sweeteners, e.g. B. saccharin.

The therapeutically active compounds are intended to be in those listed above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95 percent by weight of the total mixture to be available.

The pharmaceutical preparations listed above can except Compounds of the formula (I) also contain other pharmaceutically active ingredients.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, for. B. by mixing the or the active ingredients with the carrier or carriers.

The present invention also includes the use of the compounds of formula (I) and of pharmaceutical preparations containing one or more compounds of formula (I) contained in human and veterinary medicine for prevention, improvement and / or cure the diseases listed above.

The active ingredients or the pharmaceutical preparations can be used locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.

The new active ingredients should be used in both human and veterinary medicine used to treat bacterial diseases. It turned out to be proven advantageous to use the active ingredient (s) in amounts of about 5 to about 150, preferably 25 to 75 mg / kg body weight per 24 hours, optionally in the form give multiple doses to achieve the desired results. It however, it may be necessary to deviate from the stated dosages depending on the type and body weight of the object to be treated, the kind and the Severity of the disease, the type of preparation and the application of the drug and the period or interval within to which the administration takes place. So in some cases it may be sufficient get by with less than the above amount of active ingredient, while in others Cases the amount of active ingredient listed above must be exceeded. The definition the required optimal dosage and type of application of the active ingredients can easily be done by any skilled person on the basis of their specialist knowledge.

The new active ingredients have strong antibacterial effectiveness, which is demonstrated by the following in vitro experiments.

In vitro experiments (Table 1) The determination of the minimum inhibitory concentration (MIC) takes place in the plate test on a complete culture medium with the following composition: 10 g proteose peptone, 10 g veal infusion, 2 g dextrose, 3 g table salt, 2 g disodium phosphate, 1 g sodium acetate, 0.01 g adenine sulfate, 0.01 g guanine hydrochloride, 0.01 g uracil, 0.01 g xanthine, 12 g agar and 1 liter of water.

The incubation temperature was 37 ° C. and the incubation time was 24 hours.

Table 1 MIC values in mcg / ml Active ingredient Escherichia coli. Proteus vulgaris Klebsiella Neumann A 261 1017 8085 O ## NCO-N # N-CH2CH2CH2OCH3 10 10 8 8 N N CH3 CH2Ch2CH2OCH3 # O O CH3 - ## N-CO-N # N-CH3 20 20 8 20 N CH3 N # # O CH3 example 1 21.9 g (0.1 mol) of 2-methyl-3-carbamoyl-quinoxaline-di-N-oxide together with 4.5 g (0.15 mol) of paraformaldehyde and 12.9 g (0.1 mol) 1,3,5-trimethyl-hexahydro-s-triazine in 200 ml of acetonitrile and stirred for 3 hours at 700C.

The resulting clear solution is evaporated in vacuo and the remaining residue was stirred up in methanol. This gives 27 g (85%) Quinoxaline di-N-oxide as yellow crystals, which after dissolving from ethanol at 240 ° C melt with decomposition.

Analysis C15H18N3O6 (317) Calc .: G 56.7 H 5.99 N 22.0 Gei.-: C 56.3 II 5.69 N 21.7 Example 2 21.9 g (0.1 mol) of 2-methyl-3-carbamoyl-quinoxaline-di-N-oxide are added together with 4.5 g (0.15 mol) of paraiormaldehyde and 17 g of 1,3,5-triethyl hexahydro-s-triaine in 200 ml of acetonitrile for 4 hours at 700C. The resulting clear solution is evaporated in a water jet vacuum and the residue is stirred in methanol. 28 g (81%) of ghinoxaline di-N-oxide derivative are obtained as pale yellow crystals which, after being poured from methanol, melt at 188-189 ° C.

Analysis C17H25N2O5 (345) Calc .: C 59.1 H 6.6 N 20.0 Found: C 58.6 H 6.5 N -19.9 Example 3 21.9 g (0.1 mol) of 2-methyl-3-carbamoyl-quinoxaline-di-N-oxide, together with 12 g (0.4 mol) of paraformaldehyde and 30 g (0.3 mol) of cyclohexylamine in 200 ml of acetonitrile was stirred at 70 ° C. for 30 minutes. After cooling and filtering with suction, 42 g (93%) of quinoxaline di-N-oxide derivative are obtained as yellow crystals which melt at 116 ° -1170 ° C. after being redissolved from methanol.

Analysis C25H35N5O3 (453) Calc .: C 66.2 H 7.7 N 15.4 wt .: C 66.4 H. 7.9 N 15.3 Example 4 The same reaction as in Example 3 is carried out at room temperature (20-260C), the reaction is complete after 12 hours.

Example 5 21.9 g (0.1 mol) of 2-methyl-3-carbamoyl-quinoxaline-di-N-oxide, 45 g (0.45 mol) of 30% aqueous formaldehyde solution and 17.7 g (0.3 mol) n-Propylamine are stirred in 200 ml of acetonitrile for 2 hours at 70.degree. It is then cooled and filtered off with suction and 27 g (72 d,) of quinoxaline di-N-oxide derivative are obtained as yellow crystals which melt at 192 ° -1940 ° C. after being redissolved from methanol.

Example 6 21.9 g (0.1 mol) 2-methyl-3-carbamoyl-quinoxaline-di-N-oxide, 13.5 g (0.15 mol) trioxane and 25.2 g (0.3 mol) 70% Aqueous isopropylamine solution is stirred in 200 ml of acetonitrile at 70 ° C. for 2 hours. The resulting clear solution is evaporated in a water jet vacuum and the residue is brought up in methanol. 24 g (64%) of quinoxaline di-N-oxide derivative are obtained as yellow crystals which melt at 146 ° -148 ° C. after being redissolved from methanol.

The following were produced in the same way:

Claims (4)

Claims 1. Process for the preparation of quinoxaline di-N-oxides of the formula (I) In which R1 and R2 can be the same or different and stand for hydrogen, halogen, alkyl or alkoxy and R3 stands for an optionally substituted and optionally unsaturated aliphatic or cycloaliphatic radical, characterized in that 2-methyl-3-carbamoylquinoxaline-di- N-oxides of the formula (II) in which R1 and R2 have the meaning given above with formaldehyde or formaldehyde-releasing agents and primary amines of the formula (III) H2N-R³ (III) or with hexahydrotriazines of the formula (IV) in which R3 has the meaning given above, reacts in the presence of inert solvents at temperatures between 00 and 1000C. 2. Quinoxaline di-N-oxides according to the formula (1) in claim 1. 3. Medicines, characterized by a content of at least one Quinoxaline di-N-oxide according to the formula [I) in claim 1. 4. Process for the preparation of (antibacterial) agents, thereby characterized in that quinoxaline di-N-oxides according to the formula (I) in claim 1 mixed with inert, non-toxic, pharmaceutically suitable carriers.