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GB1562935A - Substituted paminophenyl-as-triazinediones process for their preparation and compositions containing them - Google Patents

Substituted paminophenyl-as-triazinediones process for their preparation and compositions containing them Download PDF

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GB1562935A
GB1562935A GB6959/77A GB695977A GB1562935A GB 1562935 A GB1562935 A GB 1562935A GB 6959/77 A GB6959/77 A GB 6959/77A GB 695977 A GB695977 A GB 695977A GB 1562935 A GB1562935 A GB 1562935A
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triazine
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nitrophenyl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones

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Description

(54) SUBSTITUTED P-AMINOPHENYL-AS-TRIAZINEDIONES.
PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM (71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt/Main 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to substituted pantinophenyl-as-triazinediones, a process for their preparation and to compositions containing them.
2-Aryl-as-triazinediones having coccidiostatic properties and the manufacture thereof have been described in German Offenlegungsschriften Nos. 2,149,645, 2,358,851 and 2,423,972.
The present invention provides substituted 2-(4anmaophenyl)-2HAH-1,2,4-tri- azine-3,5-diones of the general formula
in which each of R' and R2 is a halogen atom, such as a fluorine, chlorine, bromine or iodine atom, an alkyl group having 1 to 4 carbon atoms or trifluoromethyl, and R may also be a hydrogen atom.
The present invention also provides a process for the preparation of these sub- stituted 4-aminophenyl-as-triazinediones which comprises decarboxylating a compound of the formula
in which R' and R2 have the meanings given above and Y is NH, or NO, and, if Y is NO,, reducing the resulting compound of the formula
in which Y is NO2.
The decarboxylation of the compounds of formula (II) may be carried out by heating them to a temperature of from 110 to 300"C, preferably from 140 to 280"C.
Heating may be carried out either in the dry state or in a liquid which boils at a high temperature and which is inert under the reaction conditions, for example, ethylene glycol, toluene, xylene, quinoline, or a mixture of diphenyl or diphenyl oxide, optionally in the presence of an auxiliary agent which catalyses the decarboxylation. As auxiliary agents there may be mentioned mercapto-carboxylic acids preferably having from 2 to 8 carbon atoms, more preferably mercaptoacetic acid. The molar ratio of mercaptocarboxylic acid to 6-carboxy-1,2,4-triazinedione of the formula II may be from 0.1 to 1 to 10 to 1. The duration of the decarboxylation depends on the specific reaction conditions and is from 10 minutes to 30 hours.
The reduction of the nitro group in those compounds of the formula (111), in which Y is NO2, is carried out suitably with catalytically activated hydrogen, optionally under elevated pressure, in a polar aprotic solvent, preferably in dimethylformamide, or in a protic solvent, preferably in an alcohol, such as methanol or ethanol.
As the catalyst there may be used Raney nickel. Raney cobalt or a metal of the 8th group of the Periodic System or the oxides thereof, especially palladium black or platinum oxide. The temperature may be from 10 to 40"C.
The preparation of the compounds of the formula (II) is advantageously carried out (a) by reacting a substituted phenyldiazonium salt of the general formula
in which R1 and R2 have the meanings given above and Y' is NH2, NO2 or NH-acyl preferably with from 2 to 8 carbon atoms, more preferably from 2 to 4 carbon atoms, and X- is the anion of an acid, preferably a sulfate, chloride, bromide, tetrachlorozincate or tetrafluoroborate, with a compound of the formula R'H,O-NH-CO-OR4 (V) in which R3 is CN or CO--NHH-COOR and R' is an alkyl group having from 1 to 4 carbon atoms, preferably ethyl, to form a phenylhydrazone of the formula
in which Y', R1, R2, Rz and R( have the meanings given above, (b) by cyclizing the resulting phenyl-hydrazone with a basic catalyst at an elevated temperature to give a substituted 2H,4H-1,2,Striazine-3,5-dione of the formula
in which Y', R', R2, and R3 have the meanings given above, and (c) by hydrolysing the resulting dione of the formula (VII) by adding a strong acid or base at an elevated temperature to form a 6-carboxy-1,2,4-triazine- dione of the formula (II).
The reaction of a diazonium salt of the formula (IV) in step (a) is carried out in a solvent or mixture of solvents, advantageously in a protic solvent, preferably in water or glacial acetic add or a mixture thereof, at a temperature of from 0 to 300C, preferably from 10 to 20"C, at a pH of from 4 to 12, preferably from 4 to 8. Examples of diazonium salts of the formula (IV) are: 4-Amino-3-chlorophenyldiazonium salt, 4-amino-3,Sdichlorophenyldiazonium salt, 4-amino-3-bromophenyldiazonium salt, 4-amino-3-bromo-5-chlorophenyldiazonium salt, 3-chloroXnitro-phenyldiazonillm salt, 3,5-dichloroXnitrophenyldiazonium salt, 3-methylinitrophenyldiazonium salt, 3,5-dimethyl4-nitrophenyldiazonium salt, 3,5-diethyl-4-nitrophenyldiazonium salt, 4-amino3,5-bis-trifluoromethylphenyldiazonium salt, 4amino3-fiuorophenyldiazonium salt.
The reaction is advantageously carried out in the presence of a base, such as an acetate, carbonate or hydroxide of an alkali metal or alkaline earth metal or of a tertiary amine, such as pyridine or triethylamine.
Depending on the conditions, the reaction time is from 1 hour to 22 hours. The compounds of the formula (VI) are isolated by filtering off the precipitated reaction product, optionally after adding water.
The cyclization of the phenyl hydrazone of the formula (VI) according to step (b) is carried out in a solvent or mixture of solvents, preferably in a protic solvent, especially glacial acetic acid or water or a mixture thereof, advantageously in the presence of a base, such as an acetate, carbonate or hydroxide of an alkali metal or alkaline earth metal, or of a tertiary amine, such as pyridine or triethylamine. The cyclization is carried out at an elevated temperature, preferably at from 80 and 160 C, and advantageously at the reflux temperature of the solvent mixture used. The reaction time is from 1 hour to 5 hours, preferably from 2 to 4 hours. The dione of the formula (VII) is isolated by filtration after dilution of the reaction mixture with water.
The hydrolysis of the compounds of the formula (VII) is carried out advantage- ously in an aqueous mineral acid, such as hydrochloric acid, sulfuric acid or phos phoric acid, or in a mixture of sulfuric acid, acetic acid and water. It is also possible to saponify the compounds with hydroxides of alkali metals or alkaline earth metals.
The hydrolysis is carried out at an elevated temperature, preferably at from 80 to 160"C, and advantageously at the reflux temperature of the solvent mixture used. The reaction time is from 1 hour to 3 hours.
The preparation of the compounds of formula (II) via the steps (a), (b) and (c) may be simplified in such a manner that it is carried out without isolating the inter neediate product of the formula (VII), optionally also without isolation of the inter miate product of the formula (V').
The compounds of the formula (I) are pharmaceutically active compounds and also intermediates for the synthesis of other pharmaceutically active compounds. They show a pronounced action against protozoa, especially against coccidia Together with a high effectiveness they show an excellent compatibility. They are therefore suitable especially for the therapy and prophylaxis of coccidiosis in domestic animals, for example in poultry, such as chickens and turkeys.
In principle, the compounds of the formula (I) may be administered as such.
However, it is preferred to use the active compound in admixture with a suitable carrier material. As carrier material, there may be used the common feedstuff mixtures.
In this case, an active ingredient of the formula (I) is mixed with the feed in a concen tratiort of from 5 to 300 pprn, preferably from 15 to 100 ppm, by weight.
The present invention also provides pharmaceutical compositions for preventing or combating diseases caused by protozoa, which comprise as active ingredient a com pound of the formula (I) in admixture or conjunction with a pharmaceutically suitable carrier.
The present invention also provides a method for treating disease caused by protozoa which comprises administering to a host animal other than a human being a compound of the formula (I).
The following Examples illustrate the invention.
EXAMPLE 1 (a) 2-(4-Amino-3,5-dichlorophenyl-N,N'-bis(ethoxycarbonyl)rnalonamidehydrazono 23.2 Grams of 4amino-3,5-dichlorophenyldiazonium chloride as the zinc chloride double salt, 19.6 g of N,N'-bis(ethoxycarbonyl)malonamide and 13 g of sodium acetate in 350 ml of water are stirred at room temperature for 22 hours and are subsequently mixed with 1 liter of water. The precipitate is suction filtered off and is washed with water. The product may be dissolved and recrystallized from glacial acetic acid.
Melting point 204"C.
Another method of preparation is effected via the chloride of the diazoniurn compound: 88.5 Grams of 1P-diamino-2,6-dichlorobenzene are dissolved in a cold state in 1.75 1 of water and 127 mi of concentrated hydrochloric acid and diazotized at a temperature of from 5 to 10CC with a solution of 34.5 g of sodium nitrite in 150 ml of water.
After adding a mixture of 135 g of N,N'-bis(ethoxycarbonyl)malonamide and 102.5 g of sodium acetate portionwise, the reaction mixture is stirred for 1 hour, the precipitate is suction-filtered off and is washed several times with water The product may be recrystallized from glacial acetic acid.
Melting point 204"C.
(b) 2-(4-Amino-3,5dichloropbenyl)-6-ethoxycarbonylcarbamoyl 1,2,4-triazine-2-(4-Amino-3,5-dichlorophenyl)-6-ethoxycarbonyl-carbarnoyl-1,2,4-t}iazine- 2-(4-Amino-3,5dichloropbenyl)-6-ethoxycarbonylcarbamoyl 1,2,4-triazine-2-(4-Amino-3,5-dichlorophenyl)-6-ethoxycarbonyl-carbarnoyl-1,2,4-t}iazine- 3,5(2H,4H)-dione 62.5 Grams of 2-(4-arnino-3,5-dichlorophenylhydrazono)-N,N'-bis(ethoxycarbonyl)-2-(4-aniino-3,Sdichlorophenylhydrazono)-N,N'-bis(ethoxycarbonyl)- 2-(4-arnino-3,5-dichlorophenylhydrazono)-N,N'-bis(ethoxycarbonyl)-2-(4-aniino-3,Sdichlorophenylhydrazono)-N,N'-bis(ethoxycarbonyl)- malonamide in 700 ml of glacial acetic acid are kept under reflux with 12 g of sodium acetate for 2 hours. Upon cooling, crystals are obtained which are filtered off with suction and which can be recrystallized from a mixture of ethanol and water.
Melting point 223"C.223 C. 223"C.223 C.
c) 2-(4-Amino-3,5-dichlorophenyl)6carboxy-1,2,4-triazine-3,5-(2N,4N)-dione 2-(4Amino3,5-dichlorophenyl)6carboxy 1,2,4triazine-3,5-(211AH)dione 2-(4-Amino-3,5-dichlorophenyl)6carboxy-1,2,4-triazine-3,5-(2N,4N)-dione 2-(4Amino3,5-dichlorophenyl)6carboxy 1,2,4triazine-3,5-(211AH)dione of the formula II 34.4 Grams of 2 < 4amino-3,5-dichlorophenyl)-6-ethoxycarbonylcarbamoyl- 1,2,4-2 < 4-amino-3,5-dichlorophenyl)-6-ethoxycarbonylcarbarnoyl-1,2,4- 2 < 4amino-3,5-dichlorophenyl)-6-ethoxycarbonylcarbamoyl- 1,2,4-2 < 4-amino-3,5-dichlorophenyl)-6-ethoxycarbonylcarbarnoyl-1,2,4- triazine-3,5-(2H,4H)-dione in 440 ml of glacial acetic acid are kept under reflux with 22.0 ml of water/22.0 ml of concentrated sulfuric acid for 2 hours, are cooled, stirred with 33.5 g of sodium hydroxide until everything is dissolved, and the acetic acid is eliminated in vacuo. The residue is boiled in 500 ml of water, is clarified with animal charcoal, the substance is precipitated with 250 ml of 2N hydrochloric acid, filtered off with suction and washed with water until neutral.
Melting point 233"C.233 C. 233"C.233 C.
d) 2-(4-Amino-3,5-dichlorophenyl)-1,2,4-triazine-3,5-(2H,4H)-dione2-(4Amino-3,5-lichiorophenyl)-1,2A-triazine-3,5211AH) < iione 2-(4-Amino-3,5-dichlorophenyl)-1,2,4-triazine-3,5-(2H,4H)-dione2-(4Amino-3,5-lichiorophenyl)-1,2A-triazine-3,5211AH) < iione of the formula I 11.7 Grams of 2 - (4 - amino - 3,5 - dichlorophenyl) - 6 - carboxy - 1,2,4 - triazine - 3,5 - (2H,4H) - dione are stirred under reflux in 120 ml of a mixture of 73.5% of diphenyl ether and 26.5 of diphenyl. The precipitate obtained when cooling is suction-filtered, washed several times with ether and dried at the air. The product can be recrystallized from glacial acetic acid.
Melting point 232--233'C.232-233C. 232--233'C.232-233C.
In a manner analogous to the process of Example 1, the following compounds are prepared: EXAMPLE 2 a) From 4 - amino - 3 - bromophenyldiazonium salt and N,N'-bis(ethoxy carbonyl)malonamide, 2 - (4 - amino - - 3 - bromophenylhydrazono) - N,N' - bis(ethoxycarbonyl)malonamide ; b) from 2 - (4 - amino - 3 - bromophenylhydrazono) - N,N' - bis(ethoxy carbonyl)malonamide, 2 - (4 - amino - 3 - bromophenyl) - 6 - ethoxycarbonyl carbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione; c) from 2 - (4 - amino - 3 - bromophenyl) - 6 - ethoxycarbonylcarbamoyl 1,2,4 - triazine -triazine triazine -triazine 3,5 (211,411) - dione, 2-(4-amino-3-bromophenyl)-6-carboxy- 1,2,4-triazine-3,5(2H,4H)-dione; d) from 2 - (4 - amino - 3 - bromophenyl) - 6 - carboxy - 1,2,4 - triazine 3,5 (2H,4H) - dione, 2-(4-amino-3-bromopheWnyl)-1,2,4-triazine-3,52-(4-arnino-3-bromophenyl)- 1,2,triazine-3,5 2-(4-amino-3-bromopheWnyl)-1,2,4-triazine-3,52-(4-arnino-3-bromophenyl)- 1,2,triazine-3,5 (2H,4H) dione.
EXAMPLE 3 a) From 4 - amino - 3 - bromo - 5 - chiorophenyldiazonium salt and N,N' - bis (ethoxycarbonyl)malonamide, 2 - (4 - amino - 3 - bromo - 5 - chlorophenyl hydrazono) - N,N' - bis(ethoxycarbonyl)malonamide; b) from 2 - (4 - amino - 3 - bromo - 5 - chlorophenylhydrazono) - N,N' - bis (ethoxycarbonyl)malonamide, 2 - (4 - amino - 3 - bromo - 5 - chlorophenyl) - 6 - ethoxycarbonylcarbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione; c) from 2 - (4 - amino - 3 - bromo - 5 - chlorophenyl) - 6 - ethoxycarbonyl carbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione, 2-(4-amino-3-bromo-5- chlorophenyl)6-carboxy- 1,2,4triazine-3,5chlorophenyl)-6-carboxy-1,2,4-triazine-3,5 chlorophenyl)6-carboxy- 1,2,4triazine-3,5chlorophenyl)-6-carboxy-1,2,4-triazine-3,5 (2H,4H)-dione; d) from 2 - (4 - amino - 3 - bromo - 5 - chlorophenyl) - 6 - carboxy - 1,2,4 triazine - 3,5 (211,4)?) - dione, 2-(4-amino-3-bromo-5-chlorophenyl)-1,2,4-2-(4amin3-bromo-5-chlorophenyl)-1,2,4- 2-(4-amino-3-bromo-5-chlorophenyl)-1,2,4-2-(4amin3-bromo-5-chlorophenyl)-1,2,4- triazine-3,5 (2H,4H)-dione.
EXAMPLE 4 a) From 4 - amino - 3 - fluorophenyldiazonium salt and N,N' - bis(ethoxy carbonyl)malonamide, 2 - (4 - amino - 3 - fluorophenylhydrazono) - N,N' bis(ethoxycarbonyl)malonamide; b) from 2 - (4 - amino - 3 - fluorophenyihydrazono) - N,N' - bis(ethoxycar bonyl)malonamide, 2- (4 - amino - 3 - fluorophenyl) - 6 - ethoxycarbonyl carbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione; c) from 2 - (4 - amino - 3 - fluorophenyl) - 6 - ethoxycarbonylcarbamoyl 1,2,4 - triazine - 3,5 - (2H,4H) - dione,- (211,411) - dione, - (2H,4H) - dione,- (211,411) - dione, 2-(4-anuno-3-fluorophenyl)6car- boxy-1,2,4-triazine-3,5 (2H,4H)-dione; d) from 2 - (4 - amino - 3 - fluorophenyl) - 6 - carboxy - 1,2,4 - triazine - 3,5 (2H,4H) - dione, 2-(4-amino-3-fluorophenyl)-1,2,4-triazine-3,5 2-(4-amino-3-fluorophenyl)-1,2,4-triazine-3,5 (2H,4H)-dione.
EXAMPLE 5 a) From 4 - amino - 3,5 - bis - trffluoromethylphenyldiazoulum salt N,N' - his- (ethoxycarbonyl)malonamide, and 2 - [4 - amino - 3,5 - bis - (trifluoro methyl) - phenylhydrazonoj - N,N' - bis(ethoxycarbonyl)malonamide; b) from 2 - [4 - amino - 3,5 - bis - (trifluoromethyl) - phenyThydrazono] N,N' - bis(ethoxycarbonyl)malonamide, 2 - [4 - amino - 3,5 - bis - (trifluoro methyl) - phenyl j - 6 - ethoxycarbonylcarbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione; c) from 2 - [4 - amino - 3,5 - bis - (trifluoromethyl) - phenyl] - 6 - ethoxy carbonylcarbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione, 2 - [4 - arnino - 3,5 - bis - (trifluoromethyl) - phenyl] - 6 - carboxy - 1,2,4 - triazine - 3,5 (2H,4H) - dione; d) from 2 - [4 - amino - 3,5 - bis - (trifluoromethyl) - phenyl] - 6 - carboxy 1,2,4 - triazine - 3,5 (2H,4H) - dione, 2-[4-arnino-3,5-bis-(trifluoromethyl)-2- [amino-3,5-bis-(trifluoromethyl) 2-[4-arnino-3,5-bis-(trifluoromethyl)-2- [amino-3,5-bis-(trifluoromethyl) phenyl]-1,2,4-triazine-3,5 (2H,4H)-dione.
EXAMPLE 6 a) 2-(3-Methyl-4-nitrophenylhydrazono)-N,N'-bis(ethoxycarbonyl)malonamide2-(3-MethylA-nitrophenylhydrazono)-N,N'-bis(ethoxycarbonyl)malonainide 2-(3-Methyl-4-nitrophenylhydrazono)-N,N'-bis(ethoxycarbonyl)malonamide2-(3-MethylA-nitrophenylhydrazono)-N,N'-bis(ethoxycarbonyl)malonainide At a temperature in the range of from 5 to 10 C, 17.3 g of sodium nitrite dissolved in 25 ml of water are added dropwise to 15.2 g of 3-arninoSnitrotoluene, 28 ml of concentrated hydrochloric acid in 350 ml of glacial acetic acid. After 15 minutes a mixture of 27 g of N,N'-bis(ethoxvcarbonyl)malonamide and 20.5 g of sodium acetate is added portionwise, while stirring, and the whole is continued to be stirred for 1 hour at room temperature. After adding 500 ml of water and stirring for another hour, the precipitate is filtered off with suction, is washed several times with water and dried over potassium hydroxide. The product may be recrystallized from dioxan.
Melting point 199 C.
b) Z-(3-Methylinitrophenyl)+ethoxycarbonylcarbatnoyl-1,2,4-triazine-3,52-(3-Methylnitrophenyl)thoxycarbonylcarbamoyl 1,2,4triazine-3,5 Z-(3-Methylinitrophenyl)+ethoxycarbonylcarbatnoyl-1,2,4-triazine-3,52-(3-Methylnitrophenyl)thoxycarbonylcarbamoyl 1,2,4triazine-3,5 (ZH,4H)-dione 62.5 Grams of 2-(3-methylXnitrophenylhydrazonofN,N'-bis(ethoxycarbonyl)^ malonamide in 760 ml of glacial acetic acid are kept with 12.5 g of sodium acetate for 2 hours under reflux. The crystals precipitated after cooling are filtered off with suction, washed with water until neutral and dried at the air.
Melting point 236"C.
c) 2 < 3-Methylffinitrophenyl)+carboxy-1,2,Striazine-3,5-23 MethylAnitrophenyl)6carboxy-1,2,triazine-3,5- 2 < 3-Methylffinitrophenyl)+carboxy-1,2,Striazine-3,5-23 MethylAnitrophenyl)6carboxy-1,2,triazine-3,5- (2H4H)-dione(2H,4H)-dione (2H4H)-dione(2H,4H)-dione 33.2 Grams of 2-(3-methyl-4-nitrophenyl)-6ethoxycarbonylcarbamoyl-1,2,4-tri- azine-3,5 (2H,4H)-dione in 450 ml of glacial acetic acid are kept under reflux with 23 ml of water/23 ml of concentrated sulfuric acid for 2 hours. After cooling, 500 ml of water are stirred into the mixture, after 1 hour the precipitate is filtered off with suction, washed with water and recrystallized from water.
Melting point 1790C.
d) 2-(3-Methylnitropheny11,2,triazine3,5 2-(3-Methylnitropheny11,2,triazine3,5 (2H,4H)-dione 5 Grams of 2-(3-methyl4-nitrophenyl)-6-carboxy- 1,2,etriazine-3,5 (U-i,4N)-dione(2H,4$-dione (U-i,4N)-dione(2H,4$-dione are introduced, while stirring, into 50 ml of a mixture of 73.5 % of diphenyloxide and 26.5 % of diphenyl under reflux. The crystals precipitating when cooling are filtered off with suction and washed several times with diethylether. The product may be recrystal lized from glacial acetic acid.
Melting point 218"C.218 C. 218"C.218 C.
e) 2-(4-Amino-3-methylphenyl 1 ,2,4triazine-3,52-(4-Amino-3-methylphenylkl,2,4-triazine-3,5 2-(4-Amino-3-methylphenyl 1 ,2,4triazine-3,52-(4-Amino-3-methylphenylkl,2,4-triazine-3,5 (2H,4H)dione 24.2 Grams of 2-(3-methylinitrophenyl)-1,2,4-triazine-3,5 (2H,4H)-dione are hydrogenated in 500 ml of dimethylformamide with Raney nickel at room temperature in a shaking flask. The catalyst is filtered off with suction, washed with DMF, the filtrate is concentrated in vxuo, the oily residue is dissolved, while being heated, in 200 ml of 1N hydrochloric acid, is filtered with charcoal, and the solution is adjusted to a pH value of 4 by means of saturated sodium acetate solution. The crystals having precipitated in the refrigerator are filtered off with suction, washed 5 times with water and dried.
Melting point 177 to 178 C.
In an analogous manner, the following compounds are obtained from the corresponding starting compounds: EXAMPLE 7 a) From 3,5 - dimethyl - 4 - nitro - phenyldiazonium salt and N,N' - bis (ethoxycarbonyl)malonamide, 2 - (3,5 - dimethyl - 4 - nitrophenylEydrazono) N,N' - bis(ethoxycarbonyl)malonamide; b) from 2 - (3,5 - dimethyl - 4 - nitrophenylhydrazono) - N,N' - bis(ethoxy carbonyl)malonamide, 2 - (3,5 - dimethyl - 4 - nitrophenyl) - 6 - ethoxy carbonyl - carbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione;(211,411) - dione; (2H,4H) - dione;(211,411) - dione; c) from 2 - (3,5 - dimethyl - 4 - nitrophenyl) -6- ethoxycarbonyl - carbamoyl 1,2,4 - triazine - 3,5 (211,411) - dione, 2 - (3,5 - dnnethyl - 4 -- dione, 2 - (3,5 - dimethyl - 4 - - dione, 2 - (3,5 - dnnethyl - 4 -- dione, 2 - (3,5 - dimethyl - 4 - nitrophenyl) 6 - carboxy - 1,2,4 - triazine - 3,5 (211,411)triazine - 3,5 (2H,4H) triazine - 3,5 (211,411)triazine - 3,5 (2H,4H) - dione; d) from 2 - (3,5 - dimethyl - 4 - nitrophenyl) - 6 - carboxy - 1,2,4 - triazine 3,5 (2H,4H) - dione, 2 - (3,5 - dimethyl - 4 - nitrophenyl) - 1,2,4 - triazine 3,5 (2H,4H) - dione;3,5 (211,411) - dione; 3,5 (2H,4H) - dione;3,5 (211,411) - dione; e) from 2 - (3,5 - dimethyl - 4 - nitrophenyl) - 1,2,4 - triazine - 3,5 (2H,4H) dione, 2 - (4 - amino - 3,5 - dimethylphenyl) - 1,2,4 - triazine -triazine triazine -triazine 3,5 (2H,4H) - dione.
EXAMPLE 8 a) From 3,5 - diethyl - 4 - nitrophenyldiazonium salt and N,N' - bis(ethoxy carbonyl)malonamide, 2 - (3,5 - diethyl - 4 - nitrophenylhydrazono) - N,N' - bis(ethoxycarbonyl)malonamide; b) from 2 - (3,5 - diethyl - 4 - nitrophenylhydrazono) - N,N' - bis(ethoxy carbonyl)malonamide, 2 - (3,5 - diethyl - 4 - nitrophenyl) - 6 - ethoxy carbonyl - carbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dionea c) from 2 - (3,5 - diethyl - 4 - nitrophenyl) - 6 - ethoxycarbonyl - carbamoyl 1,2,4 - triazine - 3,5 - (2H,4H) - dione,- (211,411) - dione, - (2H,4H) - dione,- (211,411) - dione, 2-(3,5Ziethylinitrophenyl)62-(3,5 < liethylnitrophenyl)6 2-(3,5Ziethylinitrophenyl)62-(3,5 < liethylnitrophenyl)6 carboxy-l,Z,4-triazine-3,5 (2H,4H)-dione;(2H,4H)dione; (2H,4H)-dione;(2H,4H)dione; d) from 2 - (3,5 - diethyl - 4 - nitrophenyl) - 6 - carboxy - 1,2,4 - triazine 3,5 (211,411) - dione, 2 - (3,5 - diethyl - 4 - nitrophenyl) 1,2,4 - triazine 3,5 (2H,4H) - dione; e) from 2 - (3,5 - diethyl - 4 - nitrophenyl) - 1,2,4 - triazine - 3,5 (2H,4H) dione, 2 - (3,5 - diethyl - 4 - aminophenyl) - 1,2,4 - triazine- 3,5 - (2H,4H) - dione.
EXAMPLE 9 a) From 3 - chloro - 4 - nitrophenyldiazonium salt and N,N' - bis(ethoxy carbonyl)malonamide, 2 - (3 - chloro - 4 - nitrophenylhydrazono) - N,N' - bis(ethoxycarbonyl)malonamide, melting point 207"C; b) from 2 (3 - chloro - 4 - nitrophenylhydrazono) - N,N' - bis(ethoxycarbonyl) malonamide, 2 - (3 - chloro - 4 - nitrophenyl) - 6 - ethoxycarbonylcarba moyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione; melting point 234"C; c) from 2 - (3 - chloro - 4 - nitrophenyl) - 6 - ethoxycarbonylcarbamoyl 1,2,4 - triazine - 3,5 (2H,4H) - dione, 2 - (3 - chloro - 4 - nitrophenyl) - 6 - carboxy - 1,2,4 - triazine - 3,5 (2H,4N) - dione, melting point 263"C; d) from 2 - (3 - chloro - 4 - nitrophenyl) - 6 - carboxy - 1,2,4 - triazine - 3,5 (2H,4H) - dione, 2 - (3 - chloro - 4 - nitrophenyl) - 1,2,4 - triazine - 3,5 (2H,4H) - dione, melting point 184"C.184 C. 184"C.184 C.
Another method of decarboxylation is described below 15.2 Grams of 2 - (3 - chloro - 4 - nitrophenyl - 6 - carboxy - 1,2,4 - triazine 3,5 (2H,4H) - dione are kept under reflux for 16 hours in 50 ml of xylene with 4 ml of mercaptoacetic acid. After cooling, the solid matter is filtered off with suction and is recrystallized from glacial acetic acid. Melting point 184"C.
e) From 2 - (3 - chloro - 4 - nitrophenyl) - 1,2,4 - triazine - 3,5 (2H,4H) dione, 2 - (4 - amino - 3 - chlorophenyl) - 1,2,4 - triazine - 3,5 - (2H,4H) * dione, melting point 2010C.
EXAMPLE 10 a) From 3,5 - dichloro - 4 - nitrophenyldiazonium salt and N,N' - bis(ethoxy- carbonyl)malonamide, 2 - (3,5 - dichioro -4 - nitrophenylhydrazono) - N,N' bis(ethoxycarbonyl)malonamide; b) from 2 - (3,5 - dichloro - 4 - nitrophenylhydrazono) - N,N' - bis(ethoxy carbenyl)malonamide, 2 - (3,5 - dichloro - 4 - nitrophenyl) - 6 - ethoxy carbonyl - carbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione; c) from 2 - (3,5 - dichloro - 4 - nitrophenyl) - 6 - ethoxycarbonyl - carbamoyl

Claims (7)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    EXAMPLE 10 a) From 3,5 - dichloro - 4 - nitrophenyldiazonium salt and N,N' - bis(ethoxy- carbonyl)malonamide, 2 - (3,5 - dichioro -4 - nitrophenylhydrazono) - N,N' bis(ethoxycarbonyl)malonamide; b) from 2 - (3,5 - dichloro - 4 - nitrophenylhydrazono) - N,N' - bis(ethoxy carbenyl)malonamide, 2 - (3,5 - dichloro - 4 - nitrophenyl) - 6 - ethoxy carbonyl - carbamoyl - 1,2,4 - triazine - 3,5 (2H,4H) - dione;
    c) from 2 - (3,5 - dichloro - 4 - nitrophenyl) - 6 - ethoxycarbonyl - carbamoyl 1,2,4 - triazine - 3,5 (2H,4H) - dione, 2 - (3,5 - dichloro - 4 - nitrophenyl) 6 - carboxy - 1,2,4 - triazine 3,5 (2H,4H) - dione; d) from 2 - (3,5 - dichioro - 4 - nitrophenyl) - 6 - carboxy - 1,2,4 - triazine 3,5 (2H,4H) - dione, 2 - (3,5 - dichloro - 4 - nitrophenyl) - 1,2,4 - triazine 3,5 (2H,4H) - dione; e) from 2 - (3,5 - dichloro - 4 - nitrophenyl) - 1,2,4 - triazine - 3,5 (2H,4H) dione, 2 - (4 - amino - 3,5 - dichlorophenyl) - 1,2,4 - triazine - 3,5 (211,4)?) - dione, melting point 232 to 233"C.
    WHAT WE CLAIM IS:1. A compound of the general formula
    in which R1 is a hydrogen atom, a halogen atoms an alkyl group having from 1 to 4 carbon atoms or a trifluoromethyl group, and R2 is a halogen atom, an alkyl group having from 1 to 4 carbon atoms or a trffluoromethyl group.
  2. 2. A process for the preparation of a compound according to claim 1 which cob Drises decarboxvlating a compound of the formula
    in which R1 and R2 have the meanings specified in claim 1 and Y is NH, or NO, and, if Y is NO2, reducing the resulting compound of the formula
    in which Y is NO2.
  3. 3. A process according to claim 2 carried out substantially as described in any one of Examples 1 to 10 herein.
  4. 4. A compound according to claim 1 whenever prepared by a process according to claim 2 or claim 3.
  5. 5. A pharmaceutical composition, which comprises as active ingredient a compound according to claim 1, in admixture or conjunction with a pharmaceutically suitable carrier.
  6. 6. An animal feedstuff which contains a compound according to claim 1.
  7. 7. A method for treating diseases caused by protozoa which comprises administering to a host animal other than a human being a compound according to claim 1.
GB6959/77A 1976-02-20 1977-02-18 Substituted paminophenyl-as-triazinediones process for their preparation and compositions containing them Expired GB1562935A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0576251A1 (en) * 1992-06-25 1993-12-29 Suntory Limited Substituted 1,2,4-triazine-3,5-dione derivatives and drug compositions containing them, particularly for coccidiosis treatment
EP0648760A3 (en) * 1993-10-15 1995-06-28 Takeda Chemical Industries Ltd Triazine derivatives, process for their preparation and their use.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT346271B (en) * 1977-02-25 1978-11-10 Poensgen & Sulzmann Gmbh Geb CONTINUOUS DRUM MACHINE FOR TREATMENT OF TEXTILE GOODS
DE3408924A1 (en) * 1984-03-12 1985-09-26 Hoechst Ag, 6230 Frankfurt SUBSTITUTED 2-PHENYL-HEXAHYDRO-1,2,4-TRIAZINE-3,5-DIONE, METHOD FOR THE PRODUCTION THEREOF, MEANS CONTAINING IT AND THEIR USE
AU578708B2 (en) * 1984-06-12 1988-11-03 Fmc Corporation Herbicidal 2-aryl-1,2,4-triazine-3,5(2h,4h)-diones and sulfuranalogs thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0576251A1 (en) * 1992-06-25 1993-12-29 Suntory Limited Substituted 1,2,4-triazine-3,5-dione derivatives and drug compositions containing them, particularly for coccidiosis treatment
US5424310A (en) * 1992-06-25 1995-06-13 Suntory Limited Substituted 1,2,4-triazine-3,5-dione derivative and anticoccidial drug composition containing the same as active component
EP0648760A3 (en) * 1993-10-15 1995-06-28 Takeda Chemical Industries Ltd Triazine derivatives, process for their preparation and their use.
CN1062861C (en) * 1993-10-15 2001-03-07 武田药品工业株式会社 Triazine derivatives, production and use thereof

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