IL43614A - 3-substituted-amino-benzo-1,2,4-triazine-1,4-di-n-oxides their production and pharmaceutical compositions containig them - Google Patents

Abstract

1423585 Benzo-1,2,4-triazine-1,4-di-N-oxides BAYER AG 15 Nov 1973 [15 Nov 1972 9 Dec 1972 27 April 1973] 53070/73 Heading C2C Novel benzo-1,2,4-triazine-1,4-di-N-oxides of the general formula wherein each of X<SP>1</SP> and X<SP>2</SP> is a hydrogen or halogen atom or an optionally substituted alkyl or alkoxy group and A is -R, -COR<SP>1</SP>, -COCH 2 COCH 3 or -CONHR<SP>2</SP>, in which R is an optionally substituted alkyl, alkenyl or aralkyl group, R<SP>1</SP> is a hydrogen atom or an optionally substituted alkyl or aryl group and R<SP>2</SP> is an optionally substituted alkyl, cycloalkyl or aryl group, are prepared (a) when A is -R, by alkylating, alkenylating or aralkylating the corresponding compound in which A is a hydrogen atom with RY, wherein Y is a labile radical which is split off during the reaction; (b) when A is -COR<SP>1</SP> or -COCH 2 COCH 3 , by acylating the corresponding compound in which A is a hydrogen atom with ketene, diketene or R<SP>1</SP>COY; and (c) when A is -CONHR<SP>2</SP>, by reacting the corresponding compound in which A is a hydrogen atom with R<SP>2</SP>NCO. The 3 - amino - benzo - 1,2,4 - triazine - 1,4- di-N-oxide starting materials used in (a), (b) and (c) above are prepared by reacting a benzofuroxan of the general formula with disodium cyanamide. Pharmaceutical compositions having antimicrobial and growth-promoting activity comprise, as active ingredient, a benzo-1,2,4-triazine-1,4-di-N-oxide of the first general formula above, together with an appropriate carrier. [GB1423585A]

Description

43614/2 ϊηικ D' ^aDn ηιηρη *n»s?3m τ*ηχ»;» ,D'T»cpiK 3-S bstituted-amino-benzo-t ,2,4-triazine-1 ,4-di»K-oxides, their pred- ction and pharmaceutical coiapositionB containing them BAYER AKTIEMGESELLSCHAFT C: 41592 The present invention relates to new derivatives 3-amino-benzo-l , 2 , 4-triazine-l , 4-di-N-oxide , their production and their anti-microbial use, especially as anti-bacterial drugs and feedstuff additives.

This invention provides compounds which are 1,2, triazine-1, 4-di-N-oxides of the general formula:- in which 1 2 X and X are hydrogen and A is alkyl,-COCH2COCH3 of COR' wherein R' is alkyl, cycloalkyl, lower haloalkyl, phenyl or mono- or di-nitrophenyl .

This invention also provides a process for the production of a compound as defined above in which a compound of the ✓ general formula: [in which. X and X are as defined above] is either:-a) alkylated with a compound of the general formula R - Y III [in which R is alkyl and T is a labile. radical which..is split off during the alk lation reaction] optionally in the presence of an acid-binding agent; or b) acylated with ketene, diketene or a compound of the general formula:.

R" - co - z iv ·· [in which R" is as defined above; and Z is a labile radical which is split off during the acylation reaction] optionally in the presence of an acid-binding agent.

Throughout this specification the two variations (a) and (b) in the process of the invention will be referred__to as Process Variants (a), and. (b) respectively.

Surprisingly, the new 3-amino-benzo-l , 2 , 4-t.riazine-1, 4-di N-oxides of the general formula I (hereinafter refe to as "the compounds of the invention") display a very good antimicrobial activity and very good activity in promoting and accelerating the growth of animals. The compounds according to the invention thus represent an enrichment of the art.

If for example 3-amino-benzo-l,2,4-triazine-l,4-di-N-oxide and dimethyl sulphate are used as starting compounds, the course of the reaction can be represented by the following equation (l) (Process Variant (a)): (1) If for example 3-amino-benzo-l,2,4—triazine-1,4-di-N-oxide and acetic anhydride, benzoyl chloride and di-ketene are used as starting compounds, the course of the reaction can be represented. by the following equations (2) (4) (Process Variant (b)): (2) Le A 14 659-RTF - 4 - As the alkylating agent of the general formula III ^ (Process Variant (a) ) there may in principle be used any alkylating agent which carries the radical R.

Compounds preferably employed include those in which the ' labile radical of the alkylating agent Y, which is split off in the alkylation reaction, represents a halogen atom (including fluorine, chlorine, bromine and iodine, especially chlorine, bromine and iodine) that is to say alkyl halides, ' £or example methyl iodide. Other preferred compounds of general formula III are those in which Y represents the -0-SO--OR3 group (in which R3 preferably represents analkyl radical (as defined in the case of R) ) , especially dialkyl sulphates (for example dimethyl sulphate and diethyl sulphate) .

Further preferred compounds III are those in which Y represents 4 4 an-O-SC^-R radical, in which R is an optionally substituted aryl radical, preferably phenyl or 4-methylphenyl, that is to say arylsulphonic acid esters (for example phenyl- sulphonic acid methyl ester and 4-methyl-phenylsulphonic acid methyl ester) .

As acylating agents of the general formula IV there may in principle he used any acylating agent that carries the radical R'-CO-. Preferably, compounds are employed in which the labile radical Z , which is split off in the acylation reaction, is a halogen atom (such as fluorine, chlorine and bromine , especially fluorine and chloride), that is to say acid halides, for example acetyl chloride.

Other preferred compounds IV are those in which Z represents the -0-CO-R group, where in I can have the same meaning as R' , that is to say carboxylic acid anhydrides, for example acetic anhydride.

The compounds of the general formula II which can he used according to "the invention are known or can be They can also be produced according to a proposal of our own as disclosed in Israel Patent Specification No.414 by reacting benzofuroxanes of the general formula : [in whic X and X are as defined above] with a two-fold molar amount of disodium cyanamide in aqueous methanol at about 20 to about 60°C, filtering off the compound of the general formula II which has precipitated in the crude form, dissolving the precipitate in water and acidifying the aqueous solution with acetic acid. Hereupon, the compounds of the general formula II separate out as crystals,, An example of a starting compound of general formula II is the following: 3-amino-benzo-l 2 , 4-triazine-l , 4-di-N-oxide The compounds of the general formula III which can be used as starting compounds according to the invention are known or are obtainable according to generally customary methods. As examples there may be mentioned: methyl iodide, ethyl bromide, i-propyl chloride, n-propyl iodide, dimethyl sulphate, diethyl sulphate and di-n-propyl sulphate.

The starting compounds of the general formula IV are known or can be obtained by generally known methods. The following may be mentioned as examples: acetyl chloride, propionyl bromide, propionyl chloride, butyric acid chloride, valeric acid chloride, hexanoic acid chloride, eyelohexanoic acid chloride acetic anhydride and n-propionic anhydride. 43614/2 Possible diluents for use in all Process Variants are all inert organic solvents. Preferred solvents include ethers (for example diethyl ether, dioxane and tetrahydro-furan), lower alkyl ketones (for example acetone and methyl ethyl ketone), lower dialkylformamides (for example dimethyl-formamide), aliphatic or aromatic hydrocarbons optionally carrying one or more halogen, lower alkyl or nitro radicals as substituents (for example methylene chloride, chloroform, carbon tetrachloride, nitromethane , hexane, heptane, benzene, toluene, the xylenes, chlorobenzene, dichlorobenzene and nitrobenzene), lower alkylnitriles (for example acetonitrile) and hetero-aromatic compounds (for example pyridine). It ie also possible to use mixtures of these solvents with one another and, in cases in which the starting compounds employed are inert towards water, it is also possible additionally to use water. In many cases, a reactant present in excess (for example a carboxylic acid anhydride) can also be employed as the solvent.

In principle any acid-binding agent can be employed in Process Variants (a) and (b). Preferred acid-binding agents- include, alkali metal hydroxides_ and alkaline earth metal hydroxides, alkaline earth metal oxides, alkali metal carbonates and bicarbonates and alkaline earth metal carbonates and bicarbonates and tertiary aliphatic and aromatic amines, as well as heterocyclic bases. Sodium hydroxide, potassium hydroxide and calcium hydroxide, calcium oxidey- sodium-earbonate-~and—otassium—GarbonateT—sodium-bicarbonate and potassium bicarbonate, triethylamine , diaza-bicyclo-nonene. and- diaza-bicy.clo_-undecene_ may^ be mentioned as examples.

The reaction temperatures in all Process Variants can be varied over a substantial range. In general, the reaction is carried out at between Oaad 150°C, preferably between 20 and 100°C. However, it is also possible to work belo -or_ above^these temperatures.

The reaction can be carried out under normal pressure but also under super-atmospheric pressure. In general, normal^pressuxe^iB -used. - In carrying out the process according to the invention, it 3s desirable to employ in eac -case about 1 to about 5, preferably 1 to 2, mole of the reactan s of the general i formulae III or JV per 1 mol of the compound' of the general formula II, and, in cases In which an acid is liberated, additionally to employ 1 to 10, preferably 1 to 2j mols of acid-binder.- It is possible to deviate from the Le A 14 659-RTF - 9 -\ 43614/2 molar ratios mentioned, within wide ranges, without significantly impairing the result of the reaction.

In carrying out the process according to the invention, the compound of the general formula II is usually dissolved or suspended in a diluent and the second reactant, of the general formulae III or iv, jis added, in portions if appropriate, and together with the acid-binding agent, if used. The reactants can be added to the reaction vessel in any order. In most cases the end products of the general formula I. separate- o.ut_:in_a cry^alline form after a short time, if necessary after evaporation of the diluent. They can be isolated and purified according to customary methods, for example by recrystallisation.

Individually, the following may be mentioned as new active compounds according to the" invention: 3-(N-methylamino)-benzo-l,2,4-triazine-l,4-di-N-oxide ; 3-(N-ethylamino)-benzo-l,2,4-triazine-l,4-di-N-oxide 3-(N-n-propylamino)-benzo-l,2,4-triazine-l,4-di-N-oxide; 3-(N-i-propylamino)-benzo-l,2,4-triazine-l,4-di-N-oxide ; 3-(N-acetylamino )-benzo-l, 2 ,4-triazine-l,4-i-di^N-oxide ; 3-(N-n-propion lamino)-T-benzo- ,¾4^-triazine.rl, 4-di-N-oxide 3-(N-i-propionylamino)-benzo-1,2,4-triazine-l,4-di-N-oxide ; 3^(N-benzoylamino_)-benzoyl,2jj4^ riazi e-l,4-di-N-oxide; and 3-(N-stearylamino)-benzo-l,2,4-triazine-l,4-di-N-oxide 43614/2 The compounds of the invention display powerful anti-microbial effects. Their activity extends "both to Gram-positive and to Gram-negative bacteria, and in particular to the following families of bacteria, genera of bacteria and varieties of bacteria Enterobacteriaceae , for example Escherichia, (especially Escherichia coli); Klebsiella (especially Klebsiella penumoniae) and Enterobacter; Proteus (especially Proteus vulgaris, Proteus mirabilis, Proteus morganil and Protean-rettgjeri) and Salmonella (especially Salmonella typhimurium and Salmonella enteritidis-) — Pseudomonadaceae . for example Pseudomonas aeruginosa and Aeromonas. -for example Aeromonas liquefaciens; Clostridia, for example Clostridium botulinum and Clostridium tetani; Micrococcaceae . for example Staphylococcus aureus and Staphylococcus epidermidis ; Streptococcaceae. for example Strepto6occu3 pyogenes and Streptococcus faecalis (Enterococcua) ; Mycoplasmatacaea. or- example^Mycoplasma,.pneumoniae and Mycoplasma arthritidis and Mycobacteriacaae . for example Mycobacterium tuberculosis and Mycobacterium leprae.

The excellent and "broad anti-bacterial activity of the active compounds of the invention permits their use both in human medicine and in veterinary medicine, and they can be employed both to prevent and to treat systemic or local bacterial infections.

The compounds" of"the-invention can also be used as feedstuff additives for promoting growth and improving feedstuff utilisation in animal raising, especially in raising fatstock such as, for example, cattle, pigs and poultry.

As stated above, therefore, the invention also relates to the use in veterinary medicine of the compounds of the invention.

The present invention provides a pharmaceutical composition containing as active ingredient a compound of the ~ invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.

The invention further provides a pharmaceutical com-position containing as active ingredient a compound of the invention in the form of a sterile or isotonic aqueous solution.

The . invention also provides a medicament in dosage unit form comprising a compound of the invention either alone or in admi ture with a diluent.

The inventio also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention either alone or in admixture with the diluent.

"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically discrete coherent portions suitable for medical administration each containing a daily dose or a multiple (up to four times) or sub-multiple (down to a fortieth) of a daily dose of the compound of the invention. Whether the medicament contains a daily dose or, for example, a half, a third, or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.

• The pharmaceutical compositions according to the invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powders .

The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcdaol, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g.

Le A 14 659-RTP - tf$ - talc, calcium and magnesium stearate and solid polyethylene glycols. ' The tablets, dragees, capsules and pills formed from the pharmaceutical c ompositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.

The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned diluents.

The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters [e.g. C-^-alcohol with C-^-fatty acid]) or mixtures of these diluents..

The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, 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.

The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellents, e.g. chlorofluorohydrocarbons.

Le Ά 14 659-RTF - j - - The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers ; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimeth lformamide , oils [for example ground nut oil], glycerol, tetrahydrofur-furyl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.

For parenteral administration, the solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof).

All the pharmaceutical c ompositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).

The pharmaceutical compositions according to the invention preferably contain about 0.1 to 99.5» more preferably from about 0.5 to 9 $ of the active ingredient by weight of the total composition.

In addition to a compound of the invention, the Le A 14 659-RTP - 3& - pharmaceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.

Any diluent in the medicaments of the present invention may "be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.

Such medicaments may include solvents of molecular weight ~- less than 200 as sole diluent.

The discrete coherent portions constituting the medicament according to the invention (whether in dosage unit form or not) may be, for example, any of the following: tablets, (including lozenges and granules), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective" envelope"which renders the portions of the medicament physically discrete and coherent.

The preferred daily dose for administration of the medicaments of the invention is 250 mg. and 15 g. , preferably 1.25 g. to 7.5 g. of active ingredient.

The production of the above^mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active -ingredient(s). with_the_ diluen (s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).

This invention further provides a method of combating (including prevention, relief and cure of) the above-mentioned diseases in 'non-human animals, which comprises administering to the animals a compound Le A 14 659-RTF - 16 _ j of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.

It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally or intravenously), rectally or locally, preferably parenterally, especially intravenously. Preferred pharmaceutical compositions and medicaments are therefore those adapted for parenteral administration, such as injectable solutions and ampoules of injectable solutions respectively. Administration in the method of the invention is preferably parenteral.

In general it has proved advantageous to administer amounts of from 5 to 150, preferably 25 to 75 mg/kg of body weight per day to achieve effective results. Nevertheless, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subject to the treatment, the type of formulation in which the active ingredient is administered and the mode in which the administration is carried out, and the point in the progress of the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the above-mentioned minimum dosage rate, whilst other cases the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered it can be advisable to divide these into several individual adm nistrations over the course of the day.

When used for promoting growth in animals the compounds according to the invention can be administered mixed with the fodder or with the drinking water. They can be made up Le A 14 659-fiTF - as medicated feedstuff concentrates comprising a compound according to the invention and an ingestible diluent or carrier, and mixed with the fodder proper immediately before it is distributed to the animals in an amount appropriate to give the desired final concentration.

The invention thus provides medicated fodder comprising an animal feedstuff and a compound according to the invention.

This medicated fodder can also contain other nutritionally, prophylactically or curatively desirable additives, such as vitamins and mineral salts.

The strong anti-microbial activity of the compounds of the invention is demonstrated by the following in vitro and in vivo experiments. 1) In vitro experiments (Table l) The minimum inhibitory concentration (MIC) was determined in the plate test on a complete nutrient base of the following composition: 10 g of proteose-peptone, 10 g of veal infusion, 2 g of dextrose, 3 g of sodium chloride, 2 g of disodium phosphate, 1 g of sodium acetate, 0.01 g of adenine sulphate, 0.01 g of guanine hydrochloride, 0.01 g of uracil, 0.01 g of xantin, 12 g of agar-agar and 1 litre of water.

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

The mycoplasmae were tested in the series dilution test (PPIO-medium) at 37°C, with observations after 18, 24 and 48 hours. 2) The compounds of Examples 1, 4 and 6 furthermore showed a minimum inhibitory concentration of 32 γ/ml of nutrient medium against Mycobacterium tuberculosis in the series dilution test, Jenssen egg medium,37°C. lie A 14 659-RTF - ^T- A261 C165 1017 8085 63 B 133 2 <0,5 <0f5 1 <0,5 <0,5<0,5 4 8 <0, 7 4 4 4 1 1 8 128 128 1 3 4 4 1 1 4 128 128 1 4 8 8 8 8 4 128 128 128' 8 6 128 128 128 128 8 128 128 128 12 1 8 8 8-16 128 8 128 8 128 8 2) In vivo experiments (Table 2) The ED,-,- was determined as the dose in mg/kg of body weight at which 50 of the white mice used as test animals survived 24 hours after intraperitoneal infection. The active compounds were administered subcutaneously 15 minutes before infection.

Table 2 Pathogens Compound from Klebsiella Escherichia Example No: coll 8085 0165 1 2 25 9 25 - The production of the compounds according to the invention, is illustrated by the following Examples.

Example 1: 17.8 g (0.1 mol) of 3-amino-benzo-l,2,4-triazine-l,4-di-N-oxide and 15.1 g (0.12 mol) of dimethyl sulphate are suspended or dissolved, respectively, in 60 ml of dimethyl-formamide. A solution of 5.6 g (0.1 mol) of potassium hydroxide in 5 ml of water is added dropwise thereto. An exothermic reaction takes place and the 3-amino-¾enzo-l,2,4-triazine-l,4-di-N-oxide dissolves to give a blue colour. After some time, the colour changes to brown and orange-coloured crystals separate out from the solution. 15 g (78$ of theory) of 3-(N-methylamino)-benzo-l,2,4-triazine-l,4-di-N-oxide are Le A 14 6 9-RTF - *T - obtained in the form of orange-coloured crystals which after recrystallisation from dimethylformamide/acetonitrile melt at 210°C, with decomposition.

Example 2; 17.8 g (0.1 mol) of 3-aniino-benzo-l,2,4-triazine-l,4-di-N-oxide are suspended in 100 ml of acetone and 10.2 g (0.1 mol) of acetic anhydride are added dropwise. After 4 hours the product is filtered off and 21 g (96 of theory) of 3-(N-acetylamino)-benzo-l,2,4-triazine-l,4-di-N-oxide are obtained in the form of yellow crystals which melt, with decomposition, at 200°C after recrystallisation from aceto-nitrile.

Example 3: 3-Amino-benzo-l,2,4-triazine-l,4-di-IT-oxide and propionic anhydride yield, by a process as described in Example 2, 3-(N-propipnylamino)-benzo-l,2,4-triazine-l,4-di-N-oxide of decomposition point 168°C.

Example 4: 3-amino-benzo-l, 2,4-triazine-l,4-di-N-oxide and di-ie A 14 659-RCT - 2 - ketene yield, by the process described in Example 2, 3-( -acetoacetylamino )-benzo-1, 2 ,4-triazine-l,4-di-N-oxide of decomposition point 169°C.

Example : 17.8 g (0.1 mol) of 3-amino-benzo-l, 2,4-triazine-l,4-di-N-oxide are dissolved in a mixture of 80 ml of water and 4 g (0.1 mol) of sodium hydroxide. 10.5 g (0.1 mol) of benzoyl chloride are added dropwise to the blue solution. A weakly exothermic reaction commences and a brown precipitate separates out. This is filtered off and 25 g (89 of theory) of 3-(N-benzoylamino)-benzo-1, 2,4-triazine-l,4-di-N-oxide are obtained as yellow-brown crystals which after recrystallisation from dimethylformamide/acetonitrile melt, with decomposition, at 178°C.

Example 6 : 3-Amino-benzo-l,2 ,4-triazine-l,4-di-N-oxide and stearic acid chloride yield, by the process described in Example 5» 3-N-stearylamino-benzo-l, 2,4-triazine-l,4-di-N-oxide of decomposition point 148°C. 43614/2 Example 7 ; 35.6 g (0.2 mol) of 3-amino-benzo-l , 2 , 4-triazine-l , 4-di- N-oxide are dissolved in 1.5 1 ocf pyridine and added dropwise 87.4 g (0.4 mol) of dedecanoicjacid chloride. After 1 hour the thick slurry formed is poured into 2 1 of water and after filtering 52 g (72 %) of 3- (dodecanoyl-amino) -benzo- 1, 2, 4-triazine-l, 4-di-N-oxide of m.p. 135°C are obtained.

Analysis: Cir.H_D N.O_ 1 19 28 4 3 C H Calculated: 63.4 7.8 15.6 Found : 63.3 7.6 15.6 17.8 g ((0.1 mol) of 3-amino-benzo-l, 2, 4-triazine-l, 4-di-N-oxide are suspended in 120 ml of pyridine and reacted with 29.2 g (0.2 mol) of cyclohexanoic acid chloride. After 8 hours the solution is filtered and 15 g (53 %) of 3-(cyclo-hexanoylamino_-benzo-l,2, 4-triazine-l, 4-di-N-oxide of m.p. 182 °C are obtained.

Analysis: C14H16N4°3 (288) Calculated of 3-(li-chloroacetylamino)-benzo-l,2,4-triazine-di-N-oxid o are obtained, melting, with decomposition, at 137 C after recrystallisation from dimethylformamide .

Example JLO: 0 0 3-Amino-benzo-l,2, 4-triazine-di-N-oxide and 4-nitro- benzoyl chloride yield, by the process described in Example 9f 3-(N-4 »-nitrobenzoylamino)-benzo-l,2,4-triazine-di-N-oxide of decomposition point- 202°C.

Example 11: 3-Amino-benzo-l,2,4-triazine-di-N-0xide and 3,5-di-nitro- benzoyl chloride yield, by the process described in Example 9, 3-(N-3' ,5 ,-dinitrobenzoylamino)-benzo-l,2,4-triazlne-di-N- oxide of decomposition point 205°C Example A: I 13.6 g (0.1 mol) of benzofuroxane are suspended In Ia mixture of 40 ml of methanol and 40 ml of HgO at room temperature (about 20°C) and 17.2 (0.2 mol) of disodium cyanamide are added in portions. Meanwhile, the temperature rises to about 50 to 60°C and the solution assumes a blue-_ violet colour. The mixture is stirred for a further 40 minutes at about 60°C and the precipitate which has separated out is then' freed of ~the~mother liquor"b ~~fiPtration.

The precipitate is dissolved in water, the solution is filtered and the -filtrate is acidified with acetic acid. Hereupon 12.5 g of 3-amino-l,2,4-benzo-triazine-l,4-di-N-oxide (71 of theory) separate out in the form of red-golden crystals which melt, with decomposition, at 220°C.

The remaining starting compounds used in the process according to the invention, of the general formula II, are obtainable analogously. 43614/: 3

Claims (6)

1. CLAIMS 1. Compounds which are 1, 2, 4-triazine-l, 4-di-N-oxides of the general formula:- 0 in which and X . are hydrogen, and A is alkyl, -COCH2COCH3 or COR ' wherein R ' is alkyl, cycloalkyl, lower haloalkyl, phenyl or mono- or dinitrophenyl .

2. Compounds according to Claim 1, in which A is a radical R, which is a methyl, or a -CO.R1 radical in which R' is a methyl, ethyl, stearyl or phenyl radical. 2 ^ 3-(ii-methylamino )-benzo-1, 2 ,4-triazine-l, 4-di-N-oxide . 4 3-(N-acetylamino ) -benzo-1, 2 , 4-triazine-l, 4-di-N-oxide . ^ 3-(N-propionylamino)~benzo-l, 2, 4-triazine-l,4-di- ϊί-oxide . ' , " . * . ' 3-(N-acetoacetylamino)-benzo-l, ,4-triazine-l,4-di- N-oxide. 3-('N-stearylamino )-benzo-l, 2 , 4-triazine-l,4—di-N- oxide. . . g ^ 3-(N-chlorpacet lami.no)-benzo-1, 2 ,4—triazine-1,4-di-N-oxide . 9.. Compounds according to claim 1 that, are hereinbefore expressly mentioned other. than those according to claims. 3-8 and those described in Examples 10 and 11. !O.; The compounds according to claim 1 that are hereinbefore expressly mentioned in Examples 10 and 11. 11_. -A- process for the production of a compound according to any of claims 1 to - Q in Tfhich a comppund of the general formula:— "· r- 1 2 ' in which x and X are as defined in claim lj is either:-a) alkylated with a compound of the general formula R - Y |in which R is alkyl; and Y is a labile radical which is split off during the alkylation reaction] ; or b) acylated with ketene, diketene or a compound of the general formula: - R ' - CO - Z [in which R' is as defined in claims 1 or 2 ; and Z is a labile radical which is split off during the acylation reaction] 12. A process according to claim 11 (a) or (b) in which the alkylation or acylation respectively is carried out in^ the presence of an acid-binding agent. 1

3. A process according to claim 11 or 12 in which the reaction is carried out at 20 - 100°C. 14 A process according to claim 11 (a) in which Y is a 3 3 chlorine, fluorine, bromine, -O.SC^.OR [in which R is an optionally substituted alkyl ,alkenyl , or aralkyl radical] , 4 4 or -O.SC^.R [ in which R is an optionally substituted aryl radical] radical. 15. A process according to claim 11 (b) in which Z is a 5 5 fluorine, chlorine, or -0-CO.R radical [in which R is hydrogen, optionally substituted alkyl, or optionally sub 43614/2 16> A process for the production of a compound according to claim 1 substantially as hereinbefore described in any of Examples 1 to 8. 17. A process for the production of a compound according to Claim 1 substantially as hereinbefore described in Example 9, 10 or 11. 18. Compounds according to Claim 1 whenever produced by a process according to any of Claims 11 to 16. 19. Compounds according to Claim 1 whenever produced by a process according to Claim 17. 20. A pharmaceutical composition containing as an active ingredient a compound according to any of Claims 1 to 7 and 9 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of molecular weight less than 200 except in the presence of a surface-active agent. 21. A pharmaceutical composition containing as an active ingredient a compound according to any of Claims 1 to 7 and 9 in the form of a sterile or iotonic aqueous solution. 22. A composition according to Claim 20 or 21 containing from 0.5 to 95 % of active ingredient, by weight. 23. A composition according to Claim 20, 21 or 22 in which the active" ingredient is"a compound according to Claim "8, 10 or 19. 2

4. A composition -according—to-Glaim—20 or 21, substantially as hereinbefore described. 2

5. A medicament in dosage unit form comprising a compound according to any of Claims 1 to 7 , 9 and 18 either alone or in admixture with a diluent. 2

6. A medicament in the form of tablets, pills, dragees, capsules, ampoules or suppositories comprising a compound according to any of Claims 1 to 7, 9 and 18, either alone 43614/2 the active ingredient is a compound according to Claim 8, 10 or 19. 28. A medicament according to Claim 25 or 26 substantially as hereinbefore described. 29. A method of combating bacterial infections in non-human animals , and or promoting the growth of non-human animals, comprising administering to the animals an active compound according to any of Claims 1 to 7, 9 and 18 either alone or in admixture w-ith a diluent or in the form of a medicament according to Claim 25 or 26. 30. A method according to Claim 29 in which the active compound is administered parenterally. 31. A method according to Claim 29 or 30 in which the active compound is administered in an amount of 25-27mg/kg body weight per day. 32. A method according to Claim 29 or 30 for prompting the growth of non-human animals in which the active ingredient is administered mixed with the animal's drinking water or fodder. 33. A method according to any of Claims 29-32 in which the active compound is a compound according to Claims 8, 10 or 19. 34. A method according to Claim 29 substantially as hereinbefore described. 35. Medicated fodder comprising an animal feedstuff and a compound according to any of Claims 1 to 7, 9 and 18. 36. Medicated fodder comprising an animal feedstuff and