5,6-dihydro-2-(substituted phenyl)-1,2,4-triazine-3,5-(2h,4h)- diones with protivooksidantnoj and coccidiostatics activity

 

(57) Abstract:

Usage: in veterinary medicine, in particular as substances with protivooksidantnoj and coccidiostatics activity. The inventive product - 5,6-dihydro-2-(substituted phenyl)-1,2,4-triazine-3,5-[2H, 4H] -dione total f-ly I , where R1- C1-C4-alkyl; R2is cyano or carboxyl; R3- Galois or C1-C4-alkyl; R4is hydrogen or halogen, R5- halogen or C1-C4-alkoxygroup. Reagent 1: the corresponding unsaturated 1,2,4-triazine f-crystals 2 . Reagent 2: hydrogen. Reaction conditions: the hydrogenation is carried out in the presence of a hydrogenation catalyst. 3 table.

The invention relates to new chemical compounds having valuable pharmaceutical properties, and relates to 5,6-dihydro-2- (substituted phenyl)-1,2,4-triazine - 3,5-[2H, 4H] -diones with protivooksidantnoj and coccidiostatics activity. Known 2-phenyl-asymmetric. the triazine-3,5-[2H, 4H] -diones used to combat coccidiosis (see U.S. patent 3912723).

Compounds according to the invention have higher activity than the known compounds. Thus, the object of the invention is 5,6-dihydro-2- (R2the cyano group or a COOH group;

R3- halogen or alkyl WITH1-C4;

R4is halogen or hydrogen;

R5halogen or (C1-C4) alkyloxy group having protivooksidantnoj and coccidiostatics activity.

In the above definitions, the term "halogen" is a generic term for fluorine, chlorine, bromine and iodine; the term "C1-C4-alkyl" includes saturated hydrocarbon radicals, straight and branched chain with a number of 1-4 carbon atoms, for example methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, etc.

The compounds of formula I can be obtained using a reduction reaction of the corresponding 1,2,4-triazine - 3,5-(2H, 4H)-dione of formula II

Reaction recovery

__< / BR>
This reduction may be appropriate made known methods of transformation of 1,2,4-triazine-3,5 (2H,4H)-dione in 5,6-dihydro-1,2,4-triazine-3,5 (2H,4H)-diNovo part of the molecule.

This reduction may be, for example, carried out by bringing into contact of the source material of the formula (II) with hydrogen in the presence of an appropriate catalyst, for example, Westlaw by bringing in the interaction of the starting material of formula (II) with zinc in acetic acid or tin chloride (II) in hydrochloric acid, optionally in the presence of inert in this reaction, an organic solvent or a mixture of such solvents, for example a lower alcohol, e.g. methanol or ethanol; hydrocarbons, for example, methylbenzol or xylene; a ketone, e.g. 2-propanone, 1-butanone; simple ether, such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane; ether complex, for example, ethyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide; pyridine; acetic acid. To accelerate the reaction can be applied fever.

Considering their extremely high activity in the fight against coccidian, the compounds according to the invention is very suitable to destroy or prevent the growth coccidia warm-blooded animals. Therefore, the compounds of formula I are particularly suitable as protivooksidantnymi agents, as well as coccidiostatics.

Thanks useful protivooksidantnymi and coccidiostatics properties of the compounds according to the invention can be introduced in conjunction with any solid, semi-solid or liquid diluent or carrier, as described above. In addition, thanks to the useful coccidiostatic activity of the compounds according to the invention can Pach

The examples given to explain the invention in no way limit its scope.

In the absence of other instructions, all parts are given by weight.

A) Obtaining intermediate compounds.

P R I m e R 1. 66 hours of concentrated sulfuric acid added in portions over 5 min 10 h 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazine-2(3H)- yl)benzoylacetonitrile at 60aboutC. Upon completion of the addition stirring is continued for 1.5 h at 90aboutC. After cooling, the reaction mixture is poured into ice water. The product is filtered, washed with water and treated with a small amount of warm N,N-dimethylformamide to homogeneity. The mixture is cooled to room temperature, add 48 hours of methanol and crystallized product. It is filtered off, washed with methanol and dried in vacuum to obtain 9,8 h (92,2% ) of 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4-(4,5 - dihydro-3,5-dioxo-1,2,4-triazine - 2(3H)-yl)benzoylacetate; so pl. 276,4aboutC.

P R I m m e R 2. A mixture of 13.2 h 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4- (4,5-dihydro-3,5-dioxo-1,2,4 - triazine-2(3H)-yl)benzoylacetate, 648 hours of concentrated hydrochloric acid and 200 hours of acetic acid is stirred with reflux in techera sodium hydroxide the resulting solution was acidified with concentrated hydrochloric acid. The product is filtered and purified by the method of column chromatography on silica gel using as eluent a mixture of methylbenzol, tetrahydrofuran and acetic acid (70:30:1 by volume). Pure fractions are collected and the eluent is evaporated, get to 3.8 hours (27,8%) of 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4- (4,5-dihydro-3,5-dioxo - 1,2,4-triazine-2(3H)-yl) benzooxazol acid; so pl. to 219.5 aboutC.

P R I m e R 3. a) To a stirred mixture of 4 h 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo - 1,2,4-triazine-2(3H)-yl)benzoylacetonitrile, 1,4 including potassium carbonate and 22.5 h N,N-dimethylformamide add 2,84 hours of iodomethane at room temperature. The reaction mixture was stirred for 1.5 hours at 40aboutC. After evaporation in vacuo the residue is dissolved in water. Precipitated precipitated product is filtered off and washed with water. After crystallization from acetonitrile, the product is filtered off, washed with 2,2'-oxybisethane and dried, receive 2.5 hours (59,2%) of 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4- (4,5-dihydro-4-methyl-3,5 - dioxo-1,2,4-triazine - 2(3H)-yl)benzoylacetonitrile; so pl. 159,7aboutC.

b) When the temperature of the back of the fridge stirred solution of 20.2 hours 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4- (4,5-dihydro-4-methyl-3,5 - dioxo-1,2,4-triazine-2(3H)-yl)- benzo is ing the mixture is stirred for 3 h at the temperature of the back of the refrigerator, then concentrated to 1/20 of the volume and the concentrate was stirred in water. The precipitated product is washed with water after filtration and dissolved in trichloromethane. Residual water is removed, the organic layer dried, filtered and evaporated. The remainder of the double cleanse method column chromatography on silica gel using trichloromethane as eluent. Pure fractions are collected, the eluent is evaporated to obtain a 20.3 hours (99.8 per cent) of 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4-(3,4,5,6-tetrahydro - 4-methyl-3,5-dioxo-1,2,4 - triazine-2(1H)-yl)benzooxazol acid.

C) Obtaining the target compounds

P R I m e R 4. To a stirred solution of 1.5 hours 2,6-dichloro - alpha<N> -(4-chlorophenyl)-4-(4,5-dihydro-3,5 - dioxo-1,2,4-triazine-2(3H)- yl)-benzooxazol acid in 100 hours of acetic acid under boiling under reflux add 3 hours zinc. The stirring is continued for 30 minutes at boiling temperature under reflux. Zinc salts are filtered and the filtrate evaporated. The residue is washed with water, after which the solid product is filtered off and dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The solution is dried, filtered and evaporated. The residue is washed with ethyl acetate and 2,2'-oxybisethane and dried, obtaining 0,98 part (67,2%),2about(Compound I).

P R I m e R 5. To stir the mixture for 1.5 h 2-chloro-4-(4,5-dihydro-3,5-dioxo - 1,2,4-triazine-2(3H)-yl)- alpha<N> -(4-forfinal)- alpha<N> -methyl-benzoylacetonitrile and 75 h of acetic acid under boiling under reflux portions add 3 hours zinc for 30 minutes After complete addition, stirring is continued for 3 hours at the boil under reflux. The reaction mixture is filtered while hot and the filtrate was concentrated in vacuo to one tenth of its volume. To the concentrate water is added. The precipitated product is filtered off and purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated in vacuum. The residue is crystallized from acetonitrile. The product is filtered off, washed with 2,2-oxybisethanol and dried to obtain 0.8 part (53,6% of 2-chloro - alpha<N> -(4-forfinal)-alpha<N> -methyl-4-(3,4,5,6-tetrahydro - 3,5-dioxo-1,2,4-triazine-2(1H)- yl)-benzoylacetonitrile; so pl. 122,5about(Compound 2).

P R I m e R 6. According to the methods of examples 4 and 5, using the appropriate starting materials, the following compounds are presented in table. 1.

C) Farmakologiya cyclododecene salts, from the obtained substitution reactions of metal salts or amines and their possible stereochemical isomeric forms prove the data obtained in the following experiments. These data are shown only to illustrate valuable Antiprotozoal properties of all compounds covered by this invention, and in no way limit the present invention or scope susceptible protozoa, either by volume formula I

P R I m e R 7. The test anticoccidials effectiveness against Eimeria tenella.

Hisex Chicks received commercial basic diet that does not contain coccidiostatics agent. 18-day-old Chicks were divided into groups of two or chicken. Water was supplied automatically and contains the drug food was given as needed, from the date of introduction of infection (day 0) to the seventh (exclusively) days after the introduction of infection. Food containing no drug was given according to the needs of two groups, each consisting of 4 birds, to control uninfected and infected chickens.

Food that does not contain a medicinal product is a commercial basic diet that does not contain coccidiostatics agent. Pixellogo mixing the latter with a certain amount of the test compound.

At day 0 birds infected orally 105sporulirovannyh the oocyst of Eimeria tenella. On the 5th day evaluation of faeces according to the following scale:

0 = no blood stains

1 = 1-2 spots of blood

2 = 3-5 spots of blood

3 = more than 5 spots of blood.

On the 7th day determine the production of oocysts by collecting faeces and counting the number of oocysts per 1 g of faeces (o/g) and birds weighed.

In table. 2 in the third column presents the average relative increase in the weight percentage compared to control uninfected chickens. In the fourth column presents the average score of faeces, and the fifth - the average number of oocysts.

The data obtained in the test for Eimeria tenella, are presented in table. 3.

Compounds 3, 4, 5 obtained according to the invention.

Compounds I, II and III are structurally closest compounds of U.S. patent 3912723.

5,6-Dihydro-2-(substituted phenyl)-1,2,4-triazine-3,5-(2H, 4H)-diones of General formula

< / BR>
where R1is hydrogen, C1-C4-alkyl;

R2is cyano or the group-COOH;

R3- halogen or C1-C4-alkyl;

R4is halogen or hydrogen;

R5- halogen or C1-C4-Alki

 

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Ionic liquids ii // 2272043

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