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
__< / 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 PachThe 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
FIELD: organic chemistry, agriculture and veterinary.
SUBSTANCE: invention relates to triazine derivatives of formula I
wherein R1 is thienyl substituted with phenyl substituted with C1-C6-haloalkyl or C1-C6-haloalkoxy; or phenyl optionally substituted with one or two halogen, C1-C6-alkyl, C1-C6-haloalkoxy, substituted C2-C6-alkenyl, etc; or unsubstituted or monosubstituted phenoxy, wherein substituent is selected from group containing halogen, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-haloalkoxy; R2 is hydrogen or optionally substituted C1-C6-alkyl, wherein substituent is selected from group containing NO2 and C1-C6-alkylthio; A is direct bond; R5 is C1-C6-alkyl; R6 is hydrogen, C1-C6-alkyl or -C(=O)-R5; X1 is halogen and C1-C6-alkyl; X2 and X3 independently hydrogen, halogen and C1-C6-alkyl; with the proviso, that radical A-R1 and phenyl group are not in vicinal position relatively to one another in triazine ring; X1 is not Cl or F when X2 and X3 are hydrogen and R1 is phenyl, 2-fluorophenyl, p-fluorophenyl or 3-chlorophenyl. Also disclosed are composition containing compound of formula I as active ingredient and method for controlling of pests and ticks. Said method includes treating of pests and ticks or occupation places thereof with compound of formula I.
EFFECT: compounds and compositions with high controlling activity in regard to parasites on plants and warm-blooded animals.
5 cl, 9 tbl, 9 ex
FIELD: organic chemistry.
SUBSTANCE: invention relates to new ionic liquids designated for using in electrochemical cells and in organic synthesis. Invention describes ionic liquids of the general formula: K+A- (I) wherein K+ represents one of cations of the group consisting of the following formulae: wherein R1-R5 can be similar or different and can be bound to one another by a simple or double bond also, and each of them separately or in common can represent the following values: hydrogen atom (H), halogen atom, (C1-C8)-alkyl radical that can be partially or completely substituted with the following groups but preferably with fluorine atom (F), chlorine atom (Cl), N-[CnF(2n+1-x)Hx]2, O-[CnF(2n+1-x)Hx], SO2-[CnF(2n+1-x)Hx] or CnF(2n+1-x)Hx wherein 1 < n < 6 and 0 < x < 2n+1; A- means anion taken among the group consisting of [PFx(CyF(2y+1-z)Hz)6-x]- wherein 1 ≤ x ≤ 6, 1 ≤ y ≤ 8 and 0 ≤ z ≤ 2y+1. Invention provides the development of ionic liquids showing broad range of liquid state, high thermal resistance and low corrosive activity.
EFFECT: improved and valuable properties of ionic liquids.
FIELD: organic chemistry, medicine, neurology, pharmacy.
SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
32 cl, 10 tbl, 129 ex
FIELD: organic chemistry, pharmaceuticals.
SUBSTANCE: invention relates to heterocyclic compounds of general formula I with PGl2 receptor agonist activity. In formula R1 and R2 represent independently optionally substituted phenyl; Y represents N, N-O or CR5; Z represents N or CR6; A represents NR7; D represents alkylene or alkenylene; or A and D may together form divalent group; E represents phenylene or direct bond, or D and E may together form divalent group; G represents O, S, SO, SO2; R3 and R4 represent hydrogen atom or alkyl; Q represents carboxyl, alkoxycarboxyl, tetrazolyl, carbamoyl or -CONH-SO-R10 group. Prostaglandin I2(PGl2) is potent inhibitor of platelet aggregation and may be effectively used in treatment of vascular diseases, arteriosclerosis, hypertension, etc.
EFFECT: new compounds and drugs for platelet aggregation inhibition and treatment of vascular and other diseases.
15 cl, 3 tbl, 109 ex
SUBSTANCE: invention relates to a process for the preparation of (2-hydroxynaphthalen-1-yl) azine of general formula I where interaction of 2-naphthol with (A), or unsubstituted pyrimidine (b), or 3.6-diphenyl-1,2,4-triazine (c) in a trifluoroacetic acid medium which is reacted with unsubstituted quinazoline, which is then evaporated and the residue is treated with potassium hexacyanoferrate in an alkaline medium.
EFFECT: new method for obtaining this compound with high yields is proposed, without the use of additional reagents, which allows to lower the process temperature to room temperature.