IL43613A - 1,4-dioxo-benzo-1,2,4 triazin-3-yl-ureas their production and pharmaceutical and veterinary compositions containing them - Google Patents

Abstract

1438180 1,2,4 - Benzotriazine - 1,4 - dioxides BAYER AG 15 Nov 1973 [15 Nov 1972] 53069/73 Heading C2C 1,2,4 - Benzotriazine - 1,4 - dioxides of the Formula I wherein X<SP>1</SP> and X<SP>2</SP> are H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl or halogen; R<SP>1</SP> and R<SP>2</SP> are H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted cycloalkyl, or R<SP>1</SP> and R<SP>2</SP> together with the nitrogen atom to which they are attached form a heterocyclic ring, the compound being novel, provided that neither R<SP>1</SP> nor R<SP>2</SP> is H when the other is optionally substituted alkyl or optionally substituted cycloalkyl, except when one or both of X<SP>1</SP> and X<SP>2</SP> is optionally substituted alkenyl, are prepared by reacting compound of the formula with 2 - oxo - [1,2,4]oxadiazolo[2,3 - c][1,2,4]- benzotriazine-5-oxides of the Formula II 2 - Oxo - [1,2,4]oxodiazolo[2,3-c][1,2,4]benzotriazine-5-oxide is prepared by reacting phosgene with 3-amino-1,2,4-benzotriazine-1,4-dioxide, obtained by treating benzofuroxan with disodium cyanamide. Pharmaceutical compositions, suitable for oral, parenteral, topical or rectal administration, contain the above 1,2,4-benzotriazine-1,4-dioxides in admixture with solid or liquid diluents or carriers. [GB1438180A]

Description

43613/2 7 US'" ,B-a- -«- *-3-7 '»τκ'τβ-4,2,1-ιΤΛη-ιορ,ίΝ»ι-4,1 1 ,4-Moxo-benzo-1 ,2,4-triazin-3-yl-ureae, their production and pharmaceutical and veterinary compositions containing them BAYER A TIKNGESi≤LLSCHi¾FT C: 41591 The present invention relates to certain new 1,4-dioxo-benzo-l, 2 , 4-triazin-3-yl-ureas , to an unobvious process for their production, and to their use as antimicrobial drugs, especially as anti-bacterial agents and feedstuff additives.

This invention provides new compounds which are [l,4-dioxo-benzo-l,2,4-triazin-l-yl]-ureas of the following general formula:— in which X 1 and X2 are hydrogen atoms ; R^" is hydrogen or lower alkyl; 2 R is hydrogen, lower alkyl optionally substituted with hydroxyj and cycloloweralkyl; or R1 and R2, together with the amide nitrogen atom between them, form a saturated heterocyclic ring , optionally interrupted by" an oxygen hetero- atom..

This invention also provides a process for the production of the new compounds, in which a compound of the general formula is reacted with an amino compound of the general formula:- R1 (i ) \ 2 R [in which general formulae II and III, X1, X2, R1 and R2 are as defined above, at temperatures between 0 and 150°C.

It is distinctly surprising that the new compounds of the general formula (I) are produced by the reaction of the invention since it was not foreseeable from the prior art whether and, if so, in what way, the compounds of the general formula (II) would react with the compounds of the general formula (III). In the process according to the invention it is not the usually rather reactive *?N-0-ring linkage in the compound of general formula (II) which is opened but, surprisingly, the -0-C0- ring linkage.

In the use of the process of the invention, the new compounds of the invention can be obtained in a smooth reaction, in excellent yield and high purity. The process according to the invention thus represents an enrichment of the art.

The new compounds display strong anti-microbial properties and can improve the growth and feedstuff utilisation in animals.

If 2-oxo[l,2,4-oxa-diazolo(2,3-3,4)benzo-l,2,4-triazine]-5-N-oxide (see general formula II, with X1 and X2 representing hydrogen) and dimethylamine are used as starting Le A 14 681-RTF - 3 - substances, the course of the reaction can be represented by© the following equation: - R and R together with the amide nitrogen atom between them can form a saturated heterocyclic ring. As well 1 2 as the amide nitrogen atom bei ween R and R , the heterocyclic ring can also contain 1 oxygen atom; The heterocyclic ring generally contains 5 to 7, preferably 5 or 6 , ring members. The 6-membered heterocyclic ring preferably contains a hetero-atom or hetero-group in the para -position to the amide nitrogen atom. As examples, of the heterocyclic rings there may be mentioned pyrrolidine, piper-idine, and morpholine.

The compounds of the general formula (II) used as starting materials in the process according to the invention are not previously known but cari be obtained according to a proposal of our own as disclosed in Israel Patent Specification No. 41426, by the reaction of compounds of the general formula: [in which X and X are as defined above] with approximately the stoichiometric amount of phosgene at between 20 and 180°C, for example between 80 and 90°C, in the presence of an aliphatic or aromatic hydrocarbon as the diluent, for example toluene; the reaction product precipitates. The reaction takes place according to the following equation: [in which X and X are as defined above].

The compounds of the general formula (IV) which can be used to produce the starting compounds of the general formula II for the process according to the invention are known or can be produced by known processes (compare J.C.

Mason and G. Tennant, J. Chem. Soc. London, B 1970» 711).

They can also be produced according to a proposal our own as disclosed in Israel Patent Specification No. 414 by reacting a benzofuroxane of the general formula :- [in which and X are as defined above], with a preferably two-fold molar amount of disodium cyan- amide in aqueous methanol at about 20 to 60°C, filtering off the compound of the general formula (IV), which precipitates in a crude form, dissolving the precipitate in water, and acidifying the aqueous solution with acetic acid. The compound of the general formula (IV) separatee out as crystals.

The amino-compounds of the general formula (III) which sire~used~as-starting~compounds i the' process according to the invention are already known. As examples of these compounds there ma be mentioned: ammonia, methylamine, ethyl- amine, n- and iso-propylamine , n-, iso- and tert ♦-butylamine , dodecylamine , cyclohexylamine, ethaholamine , di e hylar^he, diethylamine, diethanolamine , pyrrolidine, piperidine and morpholine.

Possible diluents for the process of the invention are all inert organic solvents and water. Preferred diluents are polar organic solvents [for example, alcohols, especially alkanols having up to 6 carbon atoms, such as methanol, ethanol, n- and i-propanol and n-, i- and t-butanol], nitriles [preferably alk lnitriles having up to 6 carbon atoms, such as acetonitrile] , dimethylformamide , ethers [for example dioxane and tetrahydrofuran] , hetero-aromatic compounds [for example pyridine], and nitrobenzene, and mixtures of these solvents with one another. In some cases no additional diluent is necessary, the amine of the general formula (III) itself serving as diluent.

The reaction is carried out at temperatures between 0 and 150°C, preferably between 20 and 80°C.

The reaction can be carried out under normal pressure but also at elevated pressure. In general, normal pressure is used.

In carrying out the process according to the invention, at least 1 mol, preferably 1 to 20, especially 2 to 5 moIs of the amino compound of the general ormula (III) are employed per 1 mol of 2-oxo-[l,2,4-oxa-diazolo(2,3-3, 4)benzo-l,2,4-triazine]-5-N-oxide of the general formula (II).

If an excess of amine is used, the l,4-dioxo-benzo-l,2,4-triazin-3-yl-urea compounds of the invention precipitate in the form of their ammonium salts. The free compounds of the general formula (I) can then be obtained in the usual manner by treating the salts with a suitable organic or inorganic acid (preferably of PKs = 5) . Examples of suitable acids are aliphatic carboxylic acids having up to 6 carbon atoms (such as formic acid, acetic acid, trifluoroacetic acid and propionic acid), aliphatic and aromatic sulphonic acids (such as methanesulphonic acid, ethanesulphonic acid, benzene-sulphonic acid an toluene sulphonic acid) , hydrohalic acids (such as hydrofluoric acid, hydrochloric acid and hydro-bromic acid), sulphuric acid, and phosphoric acids. The free compounds of the general formula (I) can be isolated, and purified if necessary, according to customary methods.

The compounds according to the invention display strong chemotherapeutic, and in particular anti-microbial, effects. Their activity extends, for example, over a broad spectrum of pathogens, including both G-ram-positive and Gram-negative bacteria; the following families, genera and types of bacteria may be mentioned as examples: Enterobacteriaceae♦ for example Escherichia, especially Escherichia coli ; Klebsiella [especially Klebsiella pneumoniae 1 and Enterobacter: Proteus [especially Proteus vulgaris . Proteus mirabilis. Proteus morganii and Proteus rettgeri], and Salmonella [especially Salmonella typhimurium and Salmonella enteritidisl ; Pseudomonadaceaeι [ Pseudomonas aeruginosa and Aeromonas [for example Aeromonas liquefacienal ; Clostridia [for example Clostridium otulin m and Clostridium tetanil : Micrococcaceae* for example Staphylococcus aureus and Staphylococcus epidermidis Streptococcaceae« for example Streptococcus pyogenes and Streptococcus faecalis (Enterococcus ) 1 ; ycoplasmataceae » example Mycoplasma pneumoniae and Mycoplasma arthritidis and also Mycobacteriaceae [for example Mycobacterium tuberculosis and Mycobacterium leprae 1.

The excellent and broad anti-bacterial activity of the Le A 14 681÷RTF - - 43613/2 compounds of the invention permits them to be used both in human medicine and in veterinary medicine, and they can be employed both for the prevention and for the treatment of systemic or local bacterial infections.

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

In the latter case, the active compounds according to the invention are preferably administered through the feedstuff and/or drinking water. The active compounds can, however, also be used in fodder concentrates and in preparations containing also vitamins and/or mineral salts.

For administration to animals the new active compounds of the inventions can if desired be supplied in the form of a fodder premix containing the active compound and an ingestible diluent or carrier. The premix is then added to the fodder immediately before the latter is distributed to the animals.

As stated above, the invention relates to the use in veterinary medrc ne—of—t e—compounis—of—the—i-nvention-ί— 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 jbhan 200 (preferably-less than 350) except in the presence of a surface active agent.

The invention further provides a pharmaceutical composition containing an 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 admixture with a diluent.

The invention 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 thia 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 powde: The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills in&ide the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, Le A 14681-RTF - - 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 alcohol, glycerol monostearate ; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols.

The tablets, dragees, capsules and pills formed from the pharmaceutical compositions 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 propellants, e.g. chlorofluorohydrocarbons.

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, dimethylformamide, oils [for example ground nut oil], glycerol, tetrahydro-furfuryl 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, polyoxsrethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium metahyd oxide, bentonite, agar-agar and tragacanth Le A 14 681-RTF -^T- or mixtures thereof.

All the pharmaceutical compositions 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 . of the active ingredient by weight of the total composition.

In addition to a compound of the invention, the 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 250 mg - 13. g, preferably 1.2 g - 6.75g of active ingredient.

The production of the above-mentioned pharmaceutical Le A 14 681-RT? - 25 - compositions and medicaments is carried out "by any method ^ known in the art, for example, by mixing the active ingredi-ent(s) with the diluent(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) microbial infections in non-human animals, or of enhancing the growth rate of animals, which comprises administering to the animals a compound 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 locally. Preferred pharmaceutical compositions are therefore those adapted for local administration, such as ointments and lotions. Administration in the method of the invention for combating microbial infections_is preferably local. However in_the. method—of- the ._.- invention for enhancing the growth rate of animals the active compoiind—is-pr-eferably—a^i^ ster^d-^-ed^it -^fche-f-od4e.?— or drinking water. For this purpose, the invention provides medicated fodder for domestic animals comprising an animal feedstuff and a compound of the invention.

In-genera-l-it-has-proved- adva tageous~both~in"human— medicine and in veterinary medicine to administer the active compound or compounds in amounts of 5 to 150, preferably 25 to 75, mg/kg of body weight every 24 hours, optionally in the form of several individual administrations, in order to achieve the desired results. However, it can be necessary to deviate from the dosages mentioned and in particular to do so as a function of the nature and "body weight of the subject to be treated, the nature and the severity of the illness, the nature of the preparation and of the administration of the medicine, and the time or interval over which the administration takes place. Thus it can suffice in some cases to manage with less than the abovementioned amount of active compound whilst in other cases the abovementioned amount of active compound must be exceeded. For local use, preparations which contain, for example, 0.01 to 10, preferably 0.1$ of active compound can be used. The particular required optimum dosage and the type of administration of the active compounds can easily be decided by anyone skilled in the art , on the basis of his expert knowledge.

The strong anti-microbial activity of the compounds of the invention is demonstrated by the following in vitro and in vivo experiments, l) In vitro experiments 100 γ/ml of the compounds according to the invention are dissolved in Mueller-Hinton nutrient solution, with addition of 0.1$ of glucose. The nutrient solution contains 1 to 2 10^ microbes per ml. The mixture is incubated in glass test tubes for 24 hours at 37°C and after this time the degree of turbidity is determined. If the mixture shows no turbidity after this treatment, the compound tested is considered to be effective against the particular pathogen.

On using the compounds from Examples 1, 2 and 3, the mixtures containing the following microbes remained free of turbidity: Escherichia coll A 261 Le A 14 681-RTF - y( - Escherichia coli 14 Escherichia coli 0165 Proteus vulgaris 1017 Klebsiella K 10 Klebsiella K 63 Salmonella species Shigella species .

Enterobacter species Neisseria catarrhalis species Diplococcus pneumoniae species Streptococcus pyogenes Enterococcus species Lactobacillus species Serratia species Proteus indole-negative, species Proteus indole-positive, species Pasteurella pseudotuberculosis Brucela species Haemophilus in luenzae 281 Bordetella bronchiseptica Bacteroides species Staphylococcus aureus 133 Pseudomonas aeruginosa W Pseudomonas aeruginosa B Aeromonas hydrophila species Oorynebacterium diphtheriae ravis Oorynebacterium pyogenes M Clostridium botulinium Clostridium tetani Borrelia species The compounds of Examples 1 and 2 show minimum in- 681-RTF - g - r hibitory concentrations of 32 γ/ml of nutrient medium in the series dilution test, Jensse egg medium, 37°C, against Mycobacterium tuberculosis . 2) In vivo experiments 12 white mice of strain CF^, which had been infected intraperitoneally each with about 1.5*10 Staphyloccus aureus organisms, were treated 30 minutes after the infection with 50 mg/kg of the compound from Example 2 in a single oral dose. All animals survived the infection after 24 hours.

Of 12 un-treated control animals, no animals survived after 24 hours.

The production of the compounds according to the invention is illustrated by the following Examples 1 - 9.

Example 1 About 9 g (0.3 mol) of gaseous methylamine are passed, over the course of.1.5 hours, into a suspension of 20.4 g (0.1 mol) of 2-oxo-[l,2,4-oxa-diazolo(2,3T3,4)benzo~l,2,4-triazine]-5-N-oxide in 120 ml of ethanol. An exothermic reaction takes place and produces a violet solution from which, after about 2 hours, the methylammonium salt of l1-[l,4-dioxo-benzo-l,2,4-triazin-3-yl]-3 '-methylurea precipitates l'-[l,4-diDXo-benzo-l,2,4-triazin-3-yl]-3'-methylurea is liberated from the ammonium salt by adding about 12 g (0.2 mol) of acetic acid.

Yield, 19 g (81# of theory) of l'-[l,4-dioxo-benzo- 1, 2,4-triazin-3-yl]-3'-methylurea in the form of yellow-brown Le A 14 681-RTF crystals which after purification by boiling in alcohol at 213-215°C, with decomposition.

Analysis σαΗαΝς0, (235) Calculated : G 46.0% H 3.8% N 29.7% Pound: C 46.070 H 3.8% N 29.2% Example 2 Gaseous ammonia is passed into a suspension of 20.4g (0.1 mol) of 2-oxo-[l,2,4-oxadiazolo(2,3-3,4)-benzo-l,2,4-triazine]-5-N-oxide in 100 ml of dimethylformamide for 30 minutes. The reaction temperature is kept at 25 to 30°C by cooling with ice. Thereafter the mixture is stirred for a further 2 hours and the new precipitate formed is then filtered off. Treatment of the red-brown product with water-acetic acid gives l,4-dioxo-benzo-l,2,4-triazin-3-yl-urea in the form of yellow-brown crystals which, after purification by boiling with ethanol, melt at 2l6°C with decomposition. Yield 17 g (77% of theory).

Analysis: (221) Calculated: C 43.4% H 3.2% N 31.6% Pound: C 43.2% H 3.7% N 31.7 Example 3 9.4 g (0.2 mol) of ethanolamine are added dropwise at 20 to 25°C, with slight cooling, to a suspension of 20.4 g Le A 14 681-RTF -^2tf - (0.1 mol) of 2-oxo-[l,2,4-oxadiazolo(2,3-3,4)-benzo-l,2,4-triazine]-5-N-oxide in 180 ml of dimethylformamide. A clear solution is formed, from which a precipitate separates after a few minutes. This is filtered off after 4 hours, and dissolved in water. On neutralising the aqueous solution with acetic acid, 18 g (68$ of theory) of red-brown crystals of l'-tl^-dioxo-benzo-l^^-triazin-^-yll-^'-l -hydroxy-ethyl]-urea precipitate; after recrystallisation from dimethylformamide , the product melts at 191 to 192°C, with decomposition.

Analysis: σι0ΗιιΝ5° (265^ Calculated: 0 45.3 H 4. $ N 26.4$ Pound: C 45.4$ H 4.3$ N 26.5$ The l,4-dioxo-benzo-l,2,4-triazin-3-yl-ureas of the general formula: listed in the table which follows were produced as described in Examples 1 to 3 from the corresponding compounds of the general formula (II) and the amino compounds indicated.

LB A 14 681-RTF The production of the starting compounds of the general formula (II) is illustrated in the following Example A.

Example A ■ - ' 35.6 g (0.2 mol) of 3-amino-benzo-l,2,4-triazine-l,4-di-N-oxide are dissolved in 200 ml of toluene. A vigorous stream of phosgene is passed into this suspension at 90°C. After 4 hours, the reaction product is filtered off and 34 g (84 of theory) of 2-oxo-l,2,4-oxadiazolo-(2, 3-a)-benzo-triazine-5-N-oxide are obtained as yellow-brown crystals which after recrystallisation from acetonitrile melt at 262°C, with decomposition.

The production of the starting compounds of the formula (IV) is illustrated in the following Example B.

Example B 13*6 g (0.1 mol) of benzofuroxane are suspended in a mixture of 40 ml of methanol and 40 ml of H20 at room temperature (approx. 20°C) and 17.2 g (0.2 mol) of disodium cyanamide are added in portions. The temperature rises to about 50 - 60°C and the solution turns blue-violet. The mixture is stirred for a further 40 minutes at about 60°C and the precipitate which has separated out is then filtered off the mother liquor. The precipitate is dissolved in water, the solution is filtered and the filtrate is acidified Le A 14 681-RTF - ,2? - with acetic acid. 12.5 g of 3-amino-l,2f4-benzo-triazine-l,4 di-N-oxide (71 of theory) then separate out in the form of red-golden crystals which melt at 220°C, with decomposition.

The remaining starting. compounds and their precursors for the process according to the invention, of the general formulae (II) and (IV), are obtainable analogously.

Le A 14 681-RTF

Claims (1)

1. 43613/ 3 What we claim is:- 1. Compounds - which are 1,4-dioxo-benzo-l, 2, 4-triazin-5-yl ureas of the following general formula:- in which 1 2 X and X are hydrogen atoms ; R"'" is hydrogen or lower alkyl 2 . . R is hydrogen, lower alkyl optionally substituted with hydroxy^ or cyclo lower alkyl; or 1 2 . R and R together with, the amide nitrogen atom between them form a saturated heterocyclic ring, optionally interrupted by an oxygen heteroatom. 1 2 2. Compounds according to claim 1 m which R aid R together with the amide nitrogen atom between them form a 5- or 6-membered " heterocyclic ring. 3. Compounds according to claim 2 in which the ring is 6-membered and contains a hetero- radical in the para- position relative to the amide nitrogen atom "between R1 and R2. 4y The compound of the formula:- 0 0 :5l.. The compound of the formula:- 43613/2 0 compound of the formula:- The The conroound of the formula: 0 0 The compound of the formula :- The compound of the formula 43613/2 The compound of the formula: 12. The compound of the formula:- 13. A process for the production of a compound according -to any of claims 1 to ,12 in which a compound of the general formula:- is reacted with an amino compound of the general formula:- _ - — - [in which general formulae II and III R and R are as defined in claim 1] , at temperatures between 0 and 150°C. 14. A process according to claim 13 in which the reaction is carried out at 20 to 80 °C. 15. A process according to claim 13 or 14 in which 2 to 5 moles of the compound of general formula III are employed per mole of the compound of general formula II. 16. A process for the production of compounds according to any of claims 1 to 12 substantially as hereinbefore described 43613/2 in any of the Examples. ^ 17. Compounds according to any of claims 1 to 12 whenever^ produced by a process according to any of claims 13 to 16. 18. A pharmaceutical composition containing as an active ingredient a compound according to any of claims 1 to 12 and 17 in admixture with a solid or liquid diluent or carrier 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. 19. A pharmaceutical composition containing as an active ingredient a compound according to any of claims 1 to 12 and 17 in the form of a sterile or isotonic aqueous solution. 20. A composition according to claim 18 or 19 containing from 0.5 to 95% of active ingredient, by weight. 21. A medicament in dosage unit form comprising a compound according to any of claims 1 to 12 and 17 either alone or in admixture with a diluent. 22. A medicament in the form of tablets, pills, dragees, capsules, ampoules or suppositories comprising a compound according to any of claims 1 to 12 and 17 either alone or in admixture with a diluent. 23. A medicament according to claim 21 or 22 substantially as hereinbefore described. 24. A method of combating microbial infections in non-human animals, or of enhancing the growth rate of animals, comprising administering to the animals an active compound according to any of claims 1 to 12 and 17 either alone or in admixture with a diluent or in the form of a medicament according to claim 21, 22 or 23. 25. A method according to claim 24 for combating microbial infections in which the active compound is administered in 43613/2 an amount of 25 to 75 mg/kg body weight per day. 26. A method according to claim 24 for combating microbial infections in which the active compound is administered locally as a pharmaceutical composition containing 0.01 to 10 weight % of the said active compound. 27. A method according to claim 24 for enhancing the growth rate of animals comprising administering the active compound to the animals mixed with fodder or drinking water. 28. A method according to claim 24 substantially as hereinbefore described. 29. Medicated fodder for domestic animals comprising an animal foodstuff and a compound of any of claims 1 to 12 and 17. HE:mr