Derivatives of triazine, methods for their production, antiprotozoal composition, additive in food animals, the method of inhibiting protozoa animals

 

(57) Abstract:

Describes the new triazine derivatives of General formula I, where the values of A, X, R1-R6specified in paragraph (1 formulas, which are useful for combating parasitic protozoan pathogens, in particular the coccidia and the like, and Antiprotozoal composition containing any of them. Also describes the methods for their preparation, additive in food animals, the method of inhibiting protozoa animals. 7 C. and 21 C.p. f-crystals, 3 PL.

The invention relates to new triazine derivative or salts thereof and their use. More specifically, the invention relates to new triazine derivative or their salts, which are useful for combating parasitic protozoan pathogens, in particular the coccidia and the like, and Antiprotozoal composition containing any of them.

Parasitic pathogens protozoa are parasites of a wide range of animals, including mammals, birds, fish and insects. Parasitic protozoa usually settle in the internal organs or external bodies, such as the skin and eyes of an animal host. As such, these parasites cause serious puritanicalness damage. Coccidiosis, which is one of the diseases that cause the most serious economic damage when breeding animals, mainly is caused by several species of protozoa of the genus Eimeria, such as E. tenella, E. necatrix, E. acervulira, E. maxima, E. brunetti and E. mivati.

For example, E. tenella parasitizes on the inner walls of the intestine, such as the cecum, and often causes fatal damage to the animal to the owner. Thus, infection with E. tenella causes several symptoms, such as extensive erosion, inflammation and intestinal bleeding caused by protozoa, blood stagnation in the caecum and, therefore, anemia, stunted growth or death of an animal host.

Endoparasiticides simplest normally transferred orally and as coccidosis, in particular, even intensive disinfection solution of bichromate of potash does not allow you to kill oocysts. Moreover, because their life cycle is so short as 7 days, each associated with large-scale livestock farming, is the face of the outbreak and spread of disease without effective proteomes.

As for fish, an ectoparasitic protozoa are a serious problem of interest. Their sometimes fatal. In large-scale fisheries parasitic protozoa are spread among all of the fish farms and the ultimate economic losses are much greater than they could provide.

A similar situation prevails for insects. Taking as an example bees, parasitic protozoa, presents Nosema apis, do the most damage to the culture of bees worldwide. Nosema apis destroys the internal organs with the weakening of bee-master, and, thus, the bee-master and the corresponding decrease in resistance tends to death from various other diseases.

There were proposed several drugs against parasitic protozoa, but most of them are limited in the rate and spectrum of activity and even already known simple with acquired resistance to certain drugs. In addition, the weak activity of these drugs requires large doses, so that none of them is satisfactory, both from an economic and environmental point of view. Therefore, the development of drugs that can be widely used with sufficient effectiveness to combat these parasites in animals, poultry, fish and insects, Serie, is the quiet have anticoccidial activity /J. Med. Chem. 22, 1483 /1979//, and were received and tested some derivatives of 6-azauracil. However, it was found that these compounds are teratogenic and may not, therefore, find application in this area. As compounds which overcome the problems associated with teratogenicity, using 1,2,4-triazinone in some European countries, Australia and Hungary, or South Africa, as anticoccidial drugs. However, since these compounds remain in the body for a long time, their use is strongly restricted and even banned in lot of countries, including Japan.

From the point of view of the above, the authors of the present invention conducted a study and found that the number of new triazine derivatives possess excellent activity against parasitic protozoa. In addition, an intensive search has led them to the discovery that these series of derivatives are suitable for combating a wide range of parasitic protozoa found in cultivated and farmed animals, such as mammals, birds, fish and insects, in conditions of normal animal husbandry and breeding, they are viscotoxin drugs existed before.

This invention is made based on the data above.

The present invention relates to:

/1/ triazine derivative of the formula

< / BR>
where ring A represents an optionally substituted aromatic group;

X represents an oxygen atom or sulfur;

R1and R6each independently represents a hydrogen atom or optionally substituted hydrocarbon residue or heterocyclic group, which may be linked through a heteroatom;

R2and R3each independently represents a hydrogen atom, a halogen atom or a group attached through a carbon atom, oxygen, or sulfur, or, taken together, are = S;

R4and R5each independently represents a hydrogen atom, a halogen atom or a group attached through a carbon atom, oxygen, nitrogen or sulfur: R1and R2and R5and R6each contact together with the formation of the chemical bond; provided that when ring A represents A phenyl group containing at least a halogen atom in position 2 or 4, and X represents an oxygen atom, R5and R6not associated with bond formation or its salts;

/2/ Ashe /1/, and physiologically acceptable carrier, excipient and diluent;

/3/ stern, possessing activity, which includes triazine derivatives or their salts, as mentioned above, and

/4/ the way of cultivation and breeding of animals, which includes the introduction of an effective amount of triazine derivatives or the above-mentioned salts. The present invention also relates to /5/ way to obtain derivatives of triazine or Antiprotozoal composition.

Regarding the above formulas optional substituted aromatic group, ring A includes 5-6-membered Homo - or heteroaromatic group which may have one or more substituents.

Carbocycle specified optionally substituted homoeopathically group may be, for example, benzene.

Heteroaromatic group include 5 - or 6-membered unsaturated heterocyclic group containing 1 to 4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, in addition to at least one carbon atom, for example 5-membered heterocyclic group containing 1 to 4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, in addition to at least one carbon atom, such, 4 - or 5-thiazolidine, 3-, 4 - or 5-pyrazolinone, 2-, 4 - or 5-imidazolidinyl, 3-, 4 - or 5-isoxazolyl, 3-, 4 - or 5-isothiazolinone, 3 - or 5-/1,2,4-oxadiazolidine/, 1,3,4-oxadiazolyl, 3 - or 5-/1,2,4-thiadiazolidine/, 1,3,4-thiadiazolyl, 4 - or 5-/1,2,3-thiadiazolidine/, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H - or 2H-tetrazolyl and so on, and 6-membered heterocyclic group containing 1-4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, in addition to at least one carbon atom, such as N-oxide-2-, 3 - or 4-peredelnye, 2-, 4 - or 5-pyrimidinyl, N-oxide-2-, 4 - or 5-pyrimidinyl, Oxymetazoline, dioxothiazolidine, perylene, tipirneni, 1,4-oxazinyl, 1,4-casinoline, 1,3-casinoline, triazinyl, oxothiazolidine, 3 - or 4-pyridazinyl, personilnya, N-oxide-3 - or 4-pyridazinyl and so on, Among them 6-membered heterocyclic group containing one heteroatom as a ring member, are preferred, and nitrogen-containing heterocyclic group are particularly desirable.

Such Homo - or heteroaromatic group may be substituted by 1 to 5 or preferably 1 to 3 substituted provisions, the following substituents, among the Druta.D.,

/2/ C2-4alkenyl, for example vinyl, 1-methylvinyl, 1-propenyl, allyl, etc. ,

/3/ C2-4-quinil, such as ethinyl, 1-PROPYNYL, propargyl and so on,

/4/ C3-6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on,

/5/ C5-7-cycloalkenyl, for example cyclopentenyl, cyclohexenyl and so on,

/6/ C7-11-aralkyl, for example benzyl, -methylbenzyl, phenethyl, and so forth,

/7/ phenyl,

/8/ C1-6-alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, out-butoxy, sec-butoxy, tert-butoxy and so on,

/9/ phenoxy,

/10/ C1-6-alkanoyl, for example formyl, acetyl, propionyl, n-butyryl, out-butyryl and so on,

/11/ benzoyl,

/12/ C1-6-alkanoyloxy, for example, formyloxy, atomic charges, propionyloxy, n-butyryloxy, out-butyryloxy, etc., benzoyloxy,

/13/ carboxyl,

/14/ C2-7-alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, ISO-propoxycarbonyl, n-butoxycarbonyl, isobutoxide, tert-butoxycarbonyl and so on,

/15/ carbarnoyl,

/16/ N-mono-C1-4-allylcarbamate, for example N-methylcarbamoyl, N-ethylcarbazole, N-propellerblades, N-isopropylcarbamate, N-butylcarbamoyl and so on,

/17/ N-di-C1-4-Ala is.,

/18/ cyclolinear, for example 1-aziridinyl, 1-azetidinone, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperidine, morpholinomethyl and so on,

/19/ halides such as F, Cl, Br, I, and so on,

/20/ mono-, di - or tri-halogen-C1-4-alkyl, such as chloromethyl, dichloromethyl, trifluoromethyl, triptorelin and so on,

/21/ oxo,

/22/ amidino,

/23/ imino,

/24/ optional protected amino /protected group for the amino group defined below/,

/25/ mono-C1-4-alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino and so on,

/26/ di-C1-4-alkylamino, for example dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino and so on,

/27/ 3-6-membered, cycloamino, which may contain from 1 to 3 heteroatoms, selected from among oxygen, sulfur, nitrogen and so on, in addition to at least one carbon atom and one nitrogen atom, such as aziridinyl, azetidin, pyrrolidinyl, pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino, morpholino, dihydropyridin, pyridyl, N-methylpiperazine, N-ethylpiperazine and so on,

/28/ C1-6-alcanada, such as formamido, acetamido, triptorelin, propionylcarnitine, for example, N-methylcarbamoyl, N-ethylcarbodiimide, N-propylenpipeline, N-isopropylcarbamate, N-butylcarbamoyl and so on,

/32/ N, N-di-C1-4-alkylcarboxylic, for example N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylamine, N,N-dibutylethanolamine etc.

/33/ C1-3-alkylenedioxy, for example, methylenedioxy, Ethylenedioxy and so on,

/34/ B/OH/2,

/35/ hydroxy,

/36/ epoxy /-O/,

/37/ nitro,

/38/ cyano,

/39/ mercapto,

/40/ sulfo,

/41/ sulfine,

/42/ phosphono,

/43/ dihydroxyphenyl,

/44/ sulfamoyl,

/45/ C1-6-monoalkylphenol, for example N-methylcarbamoyl, N-ethylsulfonyl, N-propylsulfonyl, N-isopropylamino, N-butylsulfonyl and so on,

/46/ di-C1-4-alkylsulfonyl, for example N,N-dimethylsulphamoyl, N,N-diethylcarbamoyl, N,N-dipropylamino, N,N-dibutylamino and so on,

/47/ C1-6-alkylthio, for example methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio and so on,

/48/ phenylthio,

/49/ C1-6-alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and so on,

/50/ phenylsulfinyl,

/51/ C1-6-alcalali and

/53/ 5 - or 6-membered heterocyclic group containing from 1 to 4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, in addition to at least one carbon atom, which may be connected through one or diatomic chain containing oxygen, sulfur, nitrogen, carbon atom or the like, for example 2 - or 3-thienyl, 2 - or 3-furyl, 2 - or 3-pyrrolyl, 2-, 3 - or 4 - pyridyl, 2-, 4 - or 5-oxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-imidazolyl, 3-, 4 - or 5-isoxazolyl, 3-, 4 - or 5-isothiazole, 3 - or 5-/1,2,4-oxadiazolyl/, 1,3,4-oxadiazolyl, 3 or 5/1,2,4-thiadiazolyl/, 1,3,4-thiadiazolyl, 4 - or 5-/1,2,3-thiadiazolyl/, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H - or 2H-tetrazolyl, N-oxide-2-, 3 - or 4-pyridyl, 2-, 4 - or 5-pyrimidinyl, N-oxide-2-, 4 - or 5-pyrimidinyl, accomidating, DIOXOLANYL, pyranyl, tiopronin, 1,4-oxazinyl, 1,4-thiazines, 1,3-thiazines, triazinyl, oxadiazolyl, 3 - or 4-pyridazinyl, pyrazinyl, N-hydroxy-3 - or 4-pyridazinyl etc.

Of the aforementioned groups, any group containing a carbon chain with two or more carbon atoms, or a cyclic group may be further substituted in the 1 or 2 substitutable position such groups substituents, as

/a/ halides such as Cl, F and so on,

/b/ g is but for example dimethylamino, diethylamino and so on,

/f/ halogen-C1-4-alkyl, such as chloromethyl, trifluoromethyl, triptorelin and so on,

/g/ C1-4-acyl such as formyl, acetyl, and so on,

/h/ hydroxy-C1-4-alkyl, for example hydroxymethyl, 2-hydroxyethyl, and so on,

/i/ C1-4-alkoxy-C1-4-alkyl, such as methoxymethyl, 2-ethoxyethyl and so on,

/j/ cyano,

/k/ tixo and

/1/ C1-4-alkylthio, for example methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio etc.

In addition, if the substitution takes place on two adjacent with each other, the atoms forming the ring, they can connect together to form a ring. Condensed ring, thus obtained, is 8-10-membered bicyclic ring, which includes bicyclic aryl group such as 1 - or 2-pentalene, 1 - or 2-indanyl /1H - or 2H-indenyl/ or 1 - or 2-Naftali, and bicyclic heterocyclic ring containing 1 to 4 heteroatoms, selected from among oxygen, sulfur, nitrogen atom, in addition to at least one carbon atom, such as indolyl, isoindolyl, benzofuran, benzothiophene, benzothiazole, benzoxazole, tetrazolo /1,5-b/ pyridazinyl, triazolo /4,5-b/ pyridinoline, 1,8-naphthylidine, purinol, pteridinyl, dibenzofurans, bromanil, benzoxazine or the like.

Among the above as examples of substituents of a halogen atom, optionally substituted alkyl, especially C1-4is an alkyl group, haloalkyl group or optionally substituted aralkyl, especially phenyl WITH1-4is an alkyl group, phenyl or heterocyclic group, which may be linked through a chain of 1 or 2 atoms, such as phenoxy, phenylthio, benzoyl, benzoyloxy, phenylsulfonyl, benzamide and heterocyclic group, optionally linked through a chain of 1 or 2 atoms are preferred.

With respect to the topology of the substitution of the benzene ring, for example, may be preferably substituted in position 3 and/or 5, more preferably may be substituted in position 4 in addition to the substitution at the 3 and/or 5 position, but it certainly does not exclude selection.

X represents an oxygen atom or sulfur and the oxygen atom is preferred.

When R1and R6are optionally substituted hydrocarbon residues, each of which can be linked through a heteroatom, the hydrocarbon residue includes the, exil, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and so on, C3-8-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., C2-10alkenyl, such as vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, 3-octenyl, and so on, C2-10-quinil, such as ethinyl, 2-PROPYNYL, 3-hexenyl etc., C3-10-cycloalkenyl, such as cyclopropyl, cyclopentyl, cyclohexenyl, and so on, C6-14-aryl, such as phenyl, naphthyl and so on, C7-16-aralkyl, such as benzyl, phenylethyl, etc., Among them, alkyl, aryl or kalkilya group are preferred. Hydrocarbon residue containing 1 to 7 carbon atoms, is preferred. Any of these hydrocarbon residues may contain 1 to 5 substituting groups in the substituted provisions, selected from

/1/ nitro,

/2/ hydroxy,

/3/ oxo,

/4/ thioxo,

/5/ cyano,

/6/ carbamoyl,

/7/ carboxyla,

/8/ C1-4-alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl and so on,

/9/ sulfo,

/10/ of Halogens such as F, Cl, Br, I, and so on,

/11/ C1-4lower alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, in-butoxy, t-butoxy and so on,

/12/ PV> lower alkylthio, for example methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and so on,

/15/ phenylthio,

/16/ C1-4lower alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl and so on,

/17/ C1-4lower alkylsulfonyl, for example methylsulfonyl, ethylsulfonyl and so on,

/18/ amino,

/19/ C1-6lower acylamino, for example acetylamino, propionamido and so on ,

/20/ mono - or di-C1-4-alkylamino, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino and so on,

/21/ C1-4the lower acyl such as formyl, acetyl, and so on,

/22/ benzoyl,

/23/ 5 - or 6-membered heterocyclic groups containing 1-4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, optionally at least one carbon atom, such as 2 - or 3-thienyl, 2 - or 3-furyl, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-imidazolyl, 1,2,3 - or 1,2,4-triazolyl, 1H, or 2H-tetrazolyl, 2-, 3 - or 4-pyridyl, 2-, 4 - or 5-pyrimidyl, 3 - or 4-pyridazinyl, hinely, ethanolic, indolyl, etc. which may be substituted by 1 to 4 substituents selected among the /a/ of Halogens, such as the th as o-, m - or p-chlorophenoxy, o-, m - or p-bromophenoxy and so on,

/24/ C1-10-haloalkyl, such as diformate, trifloromethyl, triptoreline, trichlorethyl etc.

In addition, if a hydrocarbon residue is cycloalkyl, cycloalkenyl, aryl or aralkyl, it may have 1-4 C1-4lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, etc. as deputies.

Examples of hydrocarbon residues of alkyl, aryl and kalkilya group are preferred. Hydrocarbon residue containing 1 to 8 atoms, is preferred.

The acyl group of the hydrocarbon residue represented by R1and R6includes a group containing General formula CORa, CONHRa, CSRaor CSNHRawhere Rarepresents hydrogen or the above-mentioned hydrocarbon group represented by the radicals R1or R6. Hydrocarbon group, Ramay have 1-2 substituents at substitutable position selected among the above groups from /1/ to /23/. Among them, C1-7-acyl group, where Rarepresents C1-6hydrocarbon group, such as C1-6is an alkyl group (for example, methyl, ethyl, etc. /, C2-6and the group /for example, cyclohexyl/, C3-6-cycloalkenyl group /for example, cyclohexenyl/ or phenyl is preferred.

Oxycarbonyl group of the hydrocarbon residue represented by R1or R6includes a group having the General formula COORawhere Rahas the same meaning as defined above. Hydrocarbon group, Ramay have 1 to 2 substituents at substitutable position selected from the group of the above examples from /1/ to /23/. Preferred among oxycarbonyl groups is a group, where Rarepresents C1-6hydrocarbon group, such as C1-6is an alkyl group (for example, methyl, ethyl, etc./, C2-6-Alchemilla group /for example vinyl/, C2-6-Alchemilla group /for example, etenil/, C3-6-cycloalkyl group /for example, cyclohexyl/, C3-6-cycloalkenyl group /for example, cyclohexenyl/or phenyl.

Optionally substituted heterocyclic group, which may be linked through a heteroatom, includes among others, 5-8-membered heterocyclic group or condensed heterocyclic group formed from them, containing 1 to 4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, the docking heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, optionally at least one carbon atom, such as 2-or 3-thienyl, 2 - or 3-furyl, 2 - or 3-pyrrolyl, 2-, 3 - or 4-pyridyl, 2-, 4 - or 5-oxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-imidazolyl, 3-, and 4 - or 5-isoxazolyl, 3-, 4 - or 5-isothiazole, 3 - or 5-/1,2,4-oxadiazolyl/, 1,3,4-oxadiazolyl, 3 - or 5-/1,2,4-thiadiazolyl/, 1,3,4-thiadiazolyl, 4 - or 5-/1, 2,3-thiadiazolyl/ 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2, 4-triazolyl, 1H - or 2H-tetrazolyl etc., 6-membered heterocyclic group containing 1 to 4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, in addition to at least one carbon atom, such as N-oxide - 2-, 3 - or 4-pyridyl, 2-, 4 - or 5-pyrimidyl, N-oxide-2-, 4 - or 5-pyrimidinyl, thiomorpholine, morpholine, accomidating, DIOXOLANYL, pyrrolidinyl, piperidinyl, pyranyl, tiopronin, 1,4-oxazinyl, 1,4-thiazines, 1,3-thiazines, piperazinil, triazinyl, oxadiazolyl, 3 - or 4-pyridazinyl, pyrazinyl, N-oxide-3 - or 4-pyridazinyl and so on, and bicyclic or tricyclic condensed heterocyclic group containing 1 to 4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, optionally at least one at radziner, benzimidazolyl, hinely, ethanolic, cinnoline, phthalazine, hintline, honokalani, indolizinyl, hinolinol, 1,8-naphthylidine, purinol, pteridinyl, dibenzofurans, carbazoles, arylidene, phenanthridines, bromanil, benzoxazines, phenazines, phenothiazines, phenoxazines, etc. Among them unfused heterocyclic ring, especially a 5 - or 6-membered ring is preferred. Any such heterocyclic groups may have 1 to 5 substituents selected from among such as

/1/ C1-4-alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butyl, t-butyl, and so on,

/2/ C2-4alkenyl, for example vinyl, 1-methylvinyl, 1-propenyl, allyl, and so on ,

/3/ C2-4-quinil, such as ethinyl, 1-PROPYNYL, propargyl and so on,

/4/ C3-6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on,

/5/ C5-7-cycloalkenyl, for example cyclopentenyl, cyclohexenyl and so on,

/6/ C7-11-aralkyl, for example benzyl methylbenzyl, penicil and so on,

/7/ phenyl,

/8/ C1-6-alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, in-butoxy, t-butoxy and so on,

/9/ phenoxy,

/10/ C1-6-alkanoyl, for example formyl, acetyl, propyloxy, propionyloxy, n-butyryloxy, isobutyryloxy and so on, benzoyloxy,

/13/ carboxyl,

/14/ C2-7-alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxide, t-butoxycarbonyl and so on,

/15/ carbarnoyl,

/16/ N-mono - C1-4-allylcarbamate, for example N-methylcarbamoyl, N-ethylcarbazole, N-propellerblades, N-isopropylcarbamate, N-butylcarbamoyl and so on,

/17/ N,N-di-C1-4-allylcarbamate, for example N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylacetamide, N,N-dibutylbarbituric and so on,

/18/ cyclolinear, for example 1-aziridinyl, 1-azetidinone, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazine, morpholinomethyl and so on,

/19/ halides such as F, Cl, Br, I, and so on,

/20/ mono-, di - or tri-halogen-C1-4-alkyl, such as chloromethyl, dichloromethyl, trifluoromethyl, triptorelin and so on,

/21/ oxo,

/22/ amidino,

/23/ imino,

/24/ amino,

/25/ mono-C1-4-alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino and so on,

/26/ di-C1-4-alkylamino, for example dimethylamino, diethylamino, dipropylamino, diisopropylamino, Deeb is the OST and the like, additionally, at least one carbon atom and one nitrogen atom, such as aziridinyl, azetidin, pyrrolidinyl, pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino, morpholino, dihydropyridin, pyridyl, N-methylpiperazine, N-ethylpiperazine and so on,

/28/ C1-6-alkanolamide, for example, formamido, acetamido, triptorelin, propionamido, butyramide, isobutyramide, and so on,

/29/ benzamido,

/30/ carbamoylating,

/31/ N-C1-4-alkylcarboxylic, for example N-methylcarbamoyl, N-ethylcarbodiimide, N-propylenpipeline, N-isopropylcarbamate, N-butylcarbamoyl and so on,

/32/ N, N-di-C1-4-alkylcarboxylic, for example N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylamine, N,N-dibutylethanolamine and so on,

/33/ C1-3-alkylenedioxy, for example, methylenedioxy, Ethylenedioxy and so on,

/34/ B/OH/2,

/35/ hydroxy,

/36/ epoxy/-O-/,

/37/ nitro,

/38/ cyano,

/39/ mercapto,

/40/ sulfo,

/41/ sulfine,

/42/ phosphono,

/43/ dihydroxyphenyl,

/44/ sulfamoyl,

/45/ C1-5-monoalkylphenol, for example N-methylcarbamoyl, N-ethylsulfonyl, N-propylsulfonyl, N-isopropylidenediphenol, N,N-dipropylamino, N,N-dibutylamino and so on,

/47/ C1-6-alkylthio, for example methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, in-butylthio, t-butylthio and so on,

/48/ phenylthio,

/49/ C1-6-alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and so on,

/50/ phenylsulfinyl,

/51/ C1-6-alkylsulfonyl, for example methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and so on, and

/52/ phenylsulfonyl.

Optionally substituted hydrocarbon residue or heterocyclic group, the above can be contacted via a heteroatom, such as, for example, the nitrogen atom of the amino group, substituted amino group (for example, amino, C1-4-alkylamino, hydroxyamino and so on/ or hydrazine, the sulfur atom of thiocarbonyl or sulfina or oxygen atom.

The preferred environment of the aforementioned optionally substituted hydrocarbon residue and heterocyclic groups, which can be contacted through the heteroatom are optionally substituted alkyl, aryl, aralkyl and optionally substituted nitrogen-containing heterocyclic group, which may be contacted through heteroatom, and more preferred is arborina group are also preferred.

Group linked through a carbon atom, oxygen or sulfur, presents R2and R3that include, among others,

/1/ cyano,

/2/ carboxy,

/3/ carbarnoyl,

/4/ mercapto,

/5/ hydroxy,

/6/ C1-4-alkyl, for example methyl, ethyl, propyl, isopropyl, and so on,

/7/ C1-6-alkylthio, for example methylthio and so on,

/8/ C7-11-aralkyl,

/9/ C2-4alkenyl, for example vinyl, 1-methylvinyl, 1-propenyl, allyl, alltel and so on,

/10/ C2-4-quinil, such as ethinyl, 1-PROPYNYL, propargyl and so on,

/11/ C1-6-alkoxy, for example methoxy, and so on,

/12/ C3-6-cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl and so on,

/13/ C6-10-aryl, for example phenyl, naphthyl etc., or

/14/ 5-7-membered heterocyclic group containing 1-4 atoms selected from among nitrogen, sulfur, oxygen and the like, optionally at least one carbon atom, such as pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, DIOXOLANYL, piperidino, morpholino, N-methylpiperazine, N-ethylpiperazine, dioxane, etc.

Among the above mentioned groups, the groups mentioned in the /6/ - /14/ m/BR> /b/ hydroxy,

/c/ oxo,

/d/ C1-4-alkoxy, for example methoxy, ethoxy and so on,

/e/ di-C1-4-alkylamino, for example dimethylamino, diethylamino and so on,

/f/ halogen-C1-4-alkyl, such as chloromethyl, trifluoromethyl, triptorelin and so on,

/g/ C1-4-acyl such as formyl, acetyl, and so on,

/h/ hydroxy-C1-4-alkyl, for example hydroxymethyl, 2-hydroxyethyl, and so on,

/i/ C1-4-alkoxy-C1-4-alkyl, such as methoxymethyl, 2-ethoxyethyl and so on,

/j/ thioxo,

/k/ a sulfide,

/1/ C3-6-cycloalkyl, such as cyclopropyl and so on, and

/m/ mercapto.

The halogen atom may be, for example, chlorine, bromine, fluorine or iodine.

Preferred among the above are the atoms of halogen and optionally substituted alkyl or aryl group, which may be linked through an oxygen atom or sulfur. Among alkyl group, a lower alkyl group with 1 to 4 carbon atoms is preferable, and phenyl is a preferred aryl group.

The group, linked through a carbon atom, a nitrogen, oxygen or sulfur, R4and R5includes

/1/ cyano,

/2/ carboxy,

/3/ carbarnoyl,

/4/ amino,

/5/ nitro,

/6/ hydroxy,
the sludge, for example vinyl, 1-methylvinyl, 1-propenyl, alkyl, alltel and so on,

/10/ C2-4-quinil, such as ethinyl, 1-PROPYNYL, propargyl and so on,

/11/ C3-6-cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl and so on,

/12/ C6-10-aryl, for example phenyl, naphthyl, etc., or

/13/ 5 - or 7-membered heterocyclic group containing 1-4 heteroatoms selected among nitrogen, sulfur, oxygen and the like, in addition to at least one carbon atom, such as pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, DIOXOLANYL, piperidino, morpholino, N-methylpiperazine, N-ethylpiperazine, doksany etc.

Among these groups the groups mentioned below /8/-/13/ can have 1 to 2 substituent in the substituted provisions, selected among

/a/ of Halogens, such as Cl, F and so on,

/b/ hydroxy,

/c/ oxo,

/d/ C1-4-alkoxy, for example methoxy, ethoxy and so on,

/e/ di-C1-4-alkylamino, for example dimethylamino, diethylamino and so on,

/f/ halogen-C1-4-alkyl, such as chloromethyl, trifluoromethyl, triptorelin and so on,

/g/ C1-4-acyl such as formyl, acetyl, and so on,

/h/ hydroxy-C1-4

Gasoil may be, for example, chlorine, bromine, fluorine or iodine.

Preferred among these groups are the halides and alkyl or aryl groups are optionally substituted and/or each linked through the nitrogen atom, oxygen or sulfur.

R1and R2or R5and R6each contact together with the formation of chemical bonds, i.e. the double bond between the carbon atom in position 5 and the nitrogen atom in position 4, or between the carbon atom in position 6 and the nitrogen atom in position 1 the triazine ring. The double bond between the 4 - and 5-positions and the same between the 1 - and 6-positions can compete, but it is preferable that from them there was only one, and more preferably, the double bond present between the 1 - and 6-positions.

If the triazine ring is tautomers, respectively, the tautomers also be submitted for consideration in connection with the triazine derivatives of this invention.

Among the triazine derivatives of the present invention, the compound of the formula or its salt are preferred

< / BR>
where R1, R2, R3; R4, R5and R6have the same mn of the forge group, which may contain a heteroatom, ring C represents an optionally substituted fenelonov group, Y represents a chemical bond, -O-, -S/O/mor optionally protected amino or optionally substituted divalent lower hydrocarbon atom, and m represents 0, 1 or 2.

Optionally substituted 5 - or 6-cleana cyclic group represented by ring B includes carbon rings as cycloalkyl, such as cyclopentyl or cyclohexyl, and so on, cycloalkenyl, such as 1-, 2 - or 3-cyclopentenyl, 1-, 2 - or 3-cyclohexenyl, and so on, phenyl or heteroaromatic group containing 1 to 4 heteroatoms, selected from among oxygen, sulfur, nitrogen and the like, in addition to at least one carbon atom, for example 2 - or 3-thienyl, 2 - or 3-furyl, 2 - or 3-pyrrolyl, 2-, 3 - or 4 - pyridyl, 2-, 4 - or 5-oxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-imidazolyl, 3-, 4 - or 5-isoxazolyl, 3-, 4 - or 5-isothiazole, 3 - or 5-/1,2,4-oxadiazolyl/, 1,3,4-oxadiazolyl, 3 - or 5-/1,2,4-thiadiazolyl/, 1,3,4-thiadiazolyl, 4 - or 5-/1,2,3-thiadiazolyl/, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H - or 2H-tetrazolyl, etc. N-oxide-2-, 3 - or 4-pyridyl, 2-, 4 - or 5-pyrimidinyl, N-oxide-2-, 4 - or 5-pyrimidinyl, accomidating, dioxothiazolidine, N-oxide-3 - or 4-pyridazinyl and so on, Among them 6-membered cyclic group, especially phenyl is preferred and 6-membered nitrogen-containing heterocyclic group are particularly desirable, if B represents a heterocyclic group.

This cyclic group may be substituted by 1 to 5 or preferably 1 to 3 substituted provisions, the following substituents among other

/1/ C1-4-alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and so on,

/2/ C1-4lower alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, n-butoxy, tert-butoxy and so on,

/3/ carboxy,

/4/ carbarnoyl,

/5/ the halides, e.g. F, Cl, Br, I, and so on,

/6/ the mono-, di - or triploid-C1-4-alkyl, such as chloromethyl, dichloromethyl, trifluoromethyl, triptorelin and so on,

/7/ amino,

/8/ -B/OH/2,

/9/ hydroxy,

/10/ nitro,

/11/ cyano,

/12/ mercapto,

/13/ sulfo,

/14/ sulfine,

/15/ and phospho

/16/ C1-4-acyl such as formyl, acetyl, etc.

The halogen atom, alkyl or haloalkyl group is preferred.

If deputies are on two adjacent to each other atoms,the ring B.

Optionally substituted phenyl group represented by the ring C may be substituted with 1 to 4, preferably 1 to 2 substituents, selected from those in the ring A. Among them, a halogen atom, alkyl, alkoxy or haloalkyl group is desirable.

Lower hydrocarbon residue represented by Y includes a hydrocarbon group with 1 to 6 carbon atoms, for example C1-4-alkylene, such as methylene, ethylene, propylene, trimethylene, tetramethylene etc., C2-6-albaniles, such as vinile, propylen, 1 - or 2-butylen, butadiene and so on, or C2-6-alkylidene, such as ethylidene, propylidene, butylidene etc.

These lower hydrocarbon groups are substituted by 1 to 4 substituents selected from

/1/ halides such as Cl, F and so on,

/2/ hydroxy,

/3/ oxo,

/4/ cyano,

/5/ C1-4-alkoxy, for example methoxy, ethoxy and so on,

/6/ mono - or di-C1-4-alkylamino, such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino and so on,

/7/ halogen-C1-4-alkyl, such as vermeil, foradil, chloromethyl, chloroethyl, methyl bromide, bromacil, trifluoromethyl, triptorelin, chlorpropyl and so on,

/8/ C1-4-acyl such as formyl, acetyl, xypropyl and so on,

/10/ C1-4-alkoxy-C1-4-alkyl, such as methoxymethyl, 2-ethoxyethyl, and so on,

/11/ C1-4-alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl and so on,

/12/ tixo and

/13/ C1-4-alkylthio, for example methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio etc.

Among them, a hydrocarbon group containing 1 to 2 carbon atoms in an unbranched chain, which connects the ring B, and C so that optionally substituted methylene, ethylene, vinile and ethynylene is preferred. In addition, C1-3-alkylene, C2-4-alkylene or C2-4-allenylidene, which may be optionally substituted 1 to 2 of the above substituents is the preferred option.

For example, the preferred option includes a methylene group, optionally substituted with chlorine, fluorine, stands, monitoroption, monochloromethyl, trifluoromethyl, hydroxy, carboxy, oxo, /for the formation of carbonyl groups, thioxo /for the formation of the thiocarbonyl group/ methoxycarbonyl, etoxycarbonyl, cyano or the like, ethylene group, neonatesultram, hydroxy, carboxy, cyano or the like, propylene group optionally independently substituted in position 2, 1 or 3 chlorine, fluorine, stands, monitoroption, monochloro, stands, trifluoromethyl, hydroxy, carboxy, oxo /to form, for example, ethylidenenorbornene, acetylation etc./, methoxy, ethoxy, methylthio, ethylthio, dimethylamine, diethylamine or similar, C2-4-alkynylamino group, optionally substituted with chlorine, fluorine, stands, monitoroption, monochloromethyl, hydroxy, carboxy, cyano, or the like independently at any substitutable position, and C2-4-alkylidene group, optionally substituted with chlorine, fluorine, oxo /to form, for example, formylmethylene, acetylation, methylcarbamoylmethyl etc./, hydroxy, methoxy, ethoxy, methylthio, dimethylamine, diethylamine or the like.

In the optionally protected amino group, Y is amino group can be protected by a group selected from

/1/ formyl,

/2/ C1-6-alkylsulphonyl, for example acetyl, ethyl, carbonyl, propellerblade, butylcarbamoyl, which can be substituted by halogen atoms such as Cl, Br, F and so on,

/3/ C6-10-arylcarbamoyl, such as phenylcarbinol, which may bicarbonat, propellerblades, butylcarbamoyl etc. or nitrogroup,

/4/ C1-6-allyloxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, which may be substituted by 1 to 3 halogen atoms such as Cl, Br, F, etc. , C1-6-alkylcarboxylic, such as methylcarbamyl, ethylcarbonate, propellerblades, butylcarbamoyl and so on, or nitrogroup,

/5/ C6-10-aryloxyalkyl, such as phenoxycarbonyl, which may be substituted by 1 to 3 halogen atoms such as Cl, Br, F, etc., C1-6-alkylcarboxylic, such as methylcarbamyl, ethylcarbonate, propellerblades, butylcarbamoyl and so on, or nitrogroup,

/6/ C7-10-aralkylamines, such as benzylcarbamoyl, phenylethylamine, which may be substituted by 1 to 3 halogen atoms such as Cl, Br, F, etc., C1-6-alkylcarboxylic, for example, methylcarbamyl, ethylcarbonate, propellerblades, butylcarbamoyl and so on, or nitrogroup,

/7/ trityl, which may be substituted by 1 to 3 halogen atoms such as Cl, Br, F, etc., C1-6-alkylcarboxylic, such as methylcarbamyl, ethylcarbonate, propellerblades, butylcarbamoyl and so on, or nitrogroup and

/8/ falola, which may be substituted by 1 to 3 halogen atoms such as Cl, Br and F, and so on, C1-6

However, any group can be used, because it can be chemically converted into the amino group of synthetically using conventional methods of organic chemistry or physiological way /for example, enzymatic legirovaniem or metabolism/.

Among the divalent groups represented by Y, -O-, -S-, or optionally substituted divalent C1-6hydrocarbon groups, especially unsubstituted C1-4-alkylene or C2-4-alkylidene group is preferred.

In the above formula, the preferred option R1and R6for each is a hydrogen atom or optionally substituted hydrocarbon residue, especially an alkyl, aryl or kalkilya group, which may be linked through a heteroatom.

In addition, hydrogen, C1-7-acyl group (for example, acetyl, benzyl, etc. /, C1-7-oxycarbonyl group /for example, methoxycarbonyl, hydroxycarbonyl and so on/ or optionally substituted alkyl, such as C1-4-alkyl, mono-, di - or triploid-C1-4alkyl, C1-4-alkylsulphonyl or the like, is preferable as R1.

In the above formula, R4and R5each preferably selected from among a hydrogen atom, halogen atom and optionally substituted alkyl or aryl group, more preferably hydrogen or optionally substituted C1-4is an alkyl group. In addition, at least one, especially both R4and R5may be preferably a hydrogen atom.

R6is preferably hydrogen IDN optionally substituted C1-4is an alkyl group, such as C1-4-alkyl, mono-, di - or triploid-C1-4-alkyl, C1-4-acyl, C1-4-alkylsulphonyl or the like.

Compounds in which R1and R

Salt of the triazine derivative according to this invention is preferably a physiologically acceptable salt for animals and as such includes salts with alkali metals such as sodium, potassium etc., salts with alkaline earth metals such as calcium and so on, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, etc. and salts with organic acids such as acetic acid, succinea acid, etc.

Derived triazine of this invention can be obtained, inter alia, as follows.

Response /a/

< / BR>
/where the ring A, X, R1, R2, R3, R4, R5and R6have the meanings defined here above: L represents hydrogen or an alkyl or aryl group,/.

The above reaction /a/ directed by cyclization of a derivative of hydrazine (2) to compounds of General formula (1).

This reaction is usually carried out in an inert solvent or in the absence of solvent, optionally in the presence of a Lewis acid or base Lewis. The reaction temperature is usually from about 60oto about 200oC and preferably from about 100oup to about 160oto be any reaction solvent, which is usually used in organic chemistry, for example, benzene, naphtha, benzene, toluene, xylene and methylene chloride, telengard, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, ethers (for example, disutility ether, glycol dimethyl ether, typically dimethyl ether, tetrahydrofuran, dioxane, etc. /, ketones, for example, methyl ethyl ketone, methylisobutylketone, methyl isobutyl ketone, etc. / ester complex /for example, ethyl acetate, etc./, NITRILES (for example, acetonitrile, propionitrile etc./, amides (for example, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide etc./, N-organic, dimethylsulfoxide, tetramethylarsonium, mercaptoacetate acid, pyridine, etc. This reaction can be carried out, if you remove a by-product, such as alcohol or water.

Reaction /b/

< / BR>
/where the ring A, R1- R4, L and X have the meanings as defined above/.

The above reaction /b/ includes the interaction of hydrazine (3) with a carboxylic acid derivative (4) with the formation of hydrazone derivatives (2a), followed by reduction with hydrazine derivatization (2).

The compound (2a), obtained by the interaction of the compound (3) connect the solvent, which can be used includes, among other hydrocarbons /for example, Noonan, Dean, dodecane, xylene, toluene, benzene, etc./, halogenated hydrocarbons (for example, chloroform, dichloromethane, tetrachlorocarbon, chlorobenzene, dichloroethane, etc./, alcohols (for example, diethylene glycol etc/ ethers /for example, monobutyl ether of diethylene glycol, disutility ether of diethylene glycol, etc./, dioxane, tetrahydrofuran, dimethylformamide, sulfoxidov and sulfones, such as dimethylsulfoxide, tetramethylarsonium and so on, This reaction can also be carried out in the presence of a Lewis acid or a dehydrating agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazole, and so on/.

This reaction can be carried out usually at a temperature ranging from about -10oC to about 150oC. In particular, the temperature region from about 10 to about 20oC is preferred, if you use a dehydrating agent, and from about 60 to about 110oC is preferred in other examples.

The reduction of compound (2a) can be achieved by processing (2a) in the presence of from about 1 to about 10 equivalents of catalyst /palladium, NaBH4, LiAlH4and so/ and in alcohol or water, the method Tamejiro Hiyama and other /Bull, Chem.Soc.Japan., 45, 1863-1866 /1972//.

Response /c/

< / BR>
/where the ring A, R1, R2, R3, R4, L and X have the same meanings as defined above; R7represents optionally protected amino group/.

The above reaction /c/ aimed at the cyclization of a derivative of procarbazine (5) for the synthesis of compounds of the present invention. The cyclization reaction is carried out in an inert solvent or in the absence of solvent, optionally in the presence of a Lewis acid or base Lewis. The reaction is usually carried out at a temperature ranging from about 0oC to 200oC. In particular, the reaction temperature is from about 5oto about 30ois preferred when using hydroxyl-containing activating agent /for example, triperoxonane anhydride, acetic anhydride, phosphorus oxychloride, etc./. If you do not use hydroxyl-containing activating agent, the reaction is carried out from about 100oto about 200oC, preferably from about 140oup to about 180oC. the solvent is usually used any inert organic solvent. Thus, such a solvent include aliphatic and aromatic hydrocarbons /for example, be the reed, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, etc/ ethers /for example, disutility ether, dimethylglycine ether, dimethyl ether of diglycol, tetrahydrofuran, dioxane, etc.,/, ketones (for example, methyl ethyl ketone, methylisobutylketone, methyl isobutyl ketone, etc./, esters (for example, ethyl acetate, etc./, NITRILES (for example, acetonitrile, propionitrile etc./, amides (for example, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide etc./, N-methyl-pyrrolidone, dimethyl sulfoxide, tetramethylarsonium, mercaptoacetate acid, pyridine, etc. To remove residual hydroxyl-containing activating agent after the reaction using an organic base, such as pyridine, triethylamine, dimethylpyridin, etc. or an inorganic base such as potassium hydroxide, sodium hydroxide, etc.

This reaction can be carried out in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide, carbonyldiimidazole etc.

Tetrahydrothiopyrano compound (1a), thus obtained, can be recovered in the manner described for the reaction of /b/, obtaining hexahydrotriazine compound (1b).

In addition, if ispolzot cyclization when heated in the same way, as the compound (5) for the synthesis of tetrahydrocanabinol compounds (1a). The cyclization reaction is usually carried out at a temperature of from about 60 to about 160oC, preferably from about 80oto about 120oC. This reaction can also be carried out with addition of a catalyst, so to speak in the presence of a Lewis acid or similar compounds /for example, epirate boron TRIFLUORIDE, methanesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid and so on/. In this reaction, the protecting group optionally protected amino group represented by R7is any group commonly used in organic chemistry /c.f.Shinjiken Koza Vol. 14, p. 2555, Edit.Nihon seikagakkai/.

The compound (6), where R7is amino, can be obtained by a method that includes dissolving N-alkyl-N-/2.2-delcochiacal/-N'-prilocaine in an aprotic solvent (for example, dimethylformamide, dimethyl sulfoxide, N-organic, etc./, adding finely ground (about 50 - 100 microns/ powder of potassium hydroxide or sodium hydroxide, then adding amineralo agent /for example, hydroxy-amino-O-sulfonic acid, 3-chloro-2-cyanopyridine amine, etc./ multiple portions at the Colo from 25 to about 30oC additionally for 2 hours, pouring the reaction mixture into ice water, neutralized mixture, diluted hydrochloric acid, and extracting it with chloroform.

N-alkyl-N-/2.2-delcochiacal/-N'-prilocaine can be obtained from a conventional reaction between phenylisocyanate and N-2,2-dialkoxybenzene.

The compound (6) in which R7represents a protected amino group, can be obtained following the reaction of /d/.

Response /d/

< / BR>
/where A, R1, R2, R3, R4, R7, L and X have the same meanings as defined above; R8represents a halogen atom or optionally protected C1-4-alkoxy /for example, halogen, C1-4-alkyl, etc./ or phenoxy and Z represents a halogen atom/.

The above reaction /d/ directed by amination, followed by acylation derivative of hydrazine in the presence of a base to obtain compound /6/. The reaction is usually carried out at a temperature of from about -5 to about 40oC, preferably from about 5 to about 10oC. Basis used here, includes an organic base such as pyridine, triethylamine, DBU, kallidin, 1,1,3,3-tetramethylguanidine etc.

As slitting, such a solvent includes aliphatic and aromatic hydrocarbons /for example, benzene, naphtha, benzene, toluene, xylene, etc./, halogenated hydrocarbon (for example, methylene chloride, telengard, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene etc/ ethers /for example, diotalevi ether, dimethyl ether glycol, dimethyl ether of diglycol, tetrahydrofuran, dioxane, etc. /, ketones (for example, methyl ethyl ketone, methylisobutylketone, methyl isobutyl ketone, etc. / ester complex /for example, ethyl acetate, etc./, the NITRILES (for example, acetonitrile, propionitrile etc./, amides (for example, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide etc./, N-organic, dimethylsulfoxide, tetramethylarsonium, mercaptoacetate acid, pyridine, etc.

Of the compounds of this invention, the compound in which the position of the 5 - presents = S, can be obtained by a method that includes heating 1,2,4-triazine-1,3-dinonogo connection /which can be in accordance with the method reported by Max W. Miller and others, J. Med.Chem. 22, 1483, 1979/ with Lawesson reagent or pentasulfide phosphorus in a solvent such as aliphatic or aromatic hydrocarbons, which may be optional is recklessly carbon, dichloroethane, chlorobenzene, o-dichlorobenzene and so on/ and others /for example, disutility ether, dimethyl ether glycol, dimethyl ether of diglycol, tetrahydrofuran, dioxane, etc., and ketones (for example, methyl ethyl ketone and so on/. Thus obtained 5-tion /=S/ can be restored using Raney Nickel to obtain 5-methylene compounds.

Connection /1/ and a physiologically acceptable salt of the present invention are suitable for combating parasitic protozoa, common in farmed and/or farmed animals, such as mammals, birds or insects, and show activity against some or all stages of growth of these pathogenic parasitic protozoa. In addition, these compounds show a sufficient effective activity within conventional doses against protozoa, which have resistance to known drugs. As a result, the morbidity and mortality of an animal host is reduced and therefore the efficiency of the production and reproduction of /for example, the efficiency of production of meat, milk, wool, hides and skins, eggs, honey, etc. as well as the efficiency of cultivation/ growing. In addition, the use of compounds of the present invention provides a chance to view the AK for example infection of coccidia.

Protozoal diseases that can be treated by the compounds of the present invention, include a wide range of these diseases. Thus, parasitic protozoa, which can be addressed include, among other Apicomplexa protozoa, in particular the family Eimeriidae, such as the genus Eimeria, such as E. acervulina, E. adenoides, E. alabamensis, E. arloingi, E. auburnensis, E. bovis, E. brunetti, E. canis, E. contorta, E. ellipsoidalis, E. farcimormis, E. gallopavonis, E. hagani, E. intestinalis, E. magna, E. maxima, E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E. piriformis, E. praecox, E. stiedai, E. suis, E. tenella, E. truncata, E. zuernii, and so on, genus Isospora, such as I. belli, I. canis, I. felis, I. rivolta, I. suis and so on , Toxoplasma gondii and the genus Cryptosporidium, particularly Cryptosporidium s. p., the family Sarcocystidae, for example S. suihominis and so on, genus Leucocystidae, for example L. Simandi, L. caulleryi, etc., family Plasmodiidae, such as P. berghei, P. falciparum, P. malariae, P. ovale, P. vivax and so on, the simplest subclass Piroplasmea, more specific genus Babesia, for example, B. argentina, B. bovis, B. canis, and so on, genus Theileria, for example, T. parva, and so on, Adeleina, Hepatozoon canis, etc.

In addition, protozoa taxonomically belong to Myxospora or Microspora, the easiest of the genus Glugea and among them may be mentioned the genus Nosema.

Connection /1/ and its physiologically acceptable salt can be used both prophylactically and therapeutically when s is, camel, Buffalo, donkey, rabbit, reindeer, mink, chinchilla, raccoon, mice, rats, Guinea pigs, Golden hamsters (golden hamster), dogs, cats, etc. / birds /such as chicken, quail, goose, Turkey, ducks, wild ducks, pigeons, etc./, river and sea fish /for example, carp, eel, rainbow trout, smelt, salmon, ruff, kambaloobraznykh, sea bream, sea bass, striped catfish and so on/ and even insects, such as bees.

Connection /1/ and its physiologically acceptable salt can be a security entered any of the above animal, either by itself or in various dosage forms according to the route of administration, which may be oral or parenteral. Dosage forms mentioned above can be obtained by known methods (for example, Japanese patent application, unverified publication N H5-1047, which corresponds to EP-A-476439, Japanese patent application, unverified publication H5 N-117250, which corresponds to EP-A-4570 15, Japanese patent application, unverified publication N H2-240003, which corresponds to EP-A-383285, Japanese patent application untested publication N S 62-61972, which corresponds to EP-A-215354 and so on/.

The compound of General formula /1/ or its physiologically terapevticheskii agents for protozoal diseases by mixing them with pharmaceutically acceptable additives(Oh), such as thinner and filler, if you want to compile Antiprotozoal compositions according to the known pharmaceutical methods, and then the introduction of food or drinking water for injection.

Antiprotozoal agent of the present invention receives, for example, by diluting the compounds of General formula /1/ or its physiologically acceptable salts independently or in a mixed state with a solid or liquid carrier used in undiluted form or stabilize it by covering and similar action for making powders, Farrukh Dustov, granules, tablets, solutions, emulsions, pastes, capsules, pre-obtained mixtures, injections and the like. Antiprotozoal agent of the present invention is also obtained by dispersing directly compounds of General formula /1/ or its physiologically acceptable salt in food, drink and the like, or by introducing them after dispersion in the carrier. The carrier can be any until it is physiologically harmless per se. The media, which has the function of food or food component, is preferred. Solid carriers include, for example, lactose, sucrose, starch, wheat flour, corn flour, bran, soy imuu flour, peanut flour, husk powder and calcium carbonate.

Examples of liquid carriers include water, physiological saline solutions and physiologically acceptable organic solvents. In addition, other suitable adjuvants such as emulsifiers, dispersing agents, suspendresume additives, wetting agents, thickeners, glioblastoma agents and solubilization, can be added in appropriate amounts. Next can be entered preservatives, fungicides, coloring agents, aromatic and antibacterial agents, antibiotics, enzyme preparations, lactobacilli drugs, antifebrile, analgesics, antiphlogistic and so on, and other agents against protozoal diseases can also be made in the composition, because they differ from the compounds of the present invention by the mechanism of action. In addition, various vitamins, mineral supplements and amino acids can be introduced.

Antiprotozoal agents of the present invention is administered to animals, such as mammals, bird, fish or insect, for the prevention and/or treatment of protozoal diseases. As in the cattle industry Pets usually are grown or reared in groups, this is possible infected individuals, the selected group or the entire group through food, drinking water or the like, if it is confirmed that some animals in the group affected protozoal disease.

Antiprotozoal composition of this invention may contain one or more types of the compound or salt of this invention. In addition, the composition may contain other medications to improve the General condition of the animals or medicines for the prevention or treatment of a specified disease. They can be used in combination with such drugs, if not expected negative influence or effect of dilution.

Antiprotozoal composition of this invention must contain connection /1/ or its physiologically acceptable salt in a concentration of from about 0.01 M. D. up to about 1%, preferably from about 0.1 M. D. up to about 0.1%. In that case, when the composition is prepared for an arbitrary dilution, it is prepared so that it contained the active drug in a concentration of from about 0.01 to about 90% or preferably from about 0.1 to about 30%.

Usually Antiprotozoal composition of this invention can be entered in a daily dose of from about 0.01 to about 50 mg/mg of body weight, preferably from about 0.1 to about 5 mg/kmouth to be added to the diet of the animal or food per connection /1/ or its salt, from about 0.01 to about 100 M. D., preferably from about 0.1 to about 50 memorial plaques Received the diet can be used both for therapeutic purposes and for preventive purposes. Such a diet can usually be obtained pre-concentrate or pre-mix containing from about 0.5 to about 30 wt.%, preferably from about 1 to about 20 wt.% connection /1/ or its salts with a mixture of a filler or a mixture of it with regular food. The filler mentioned above can be, for example, cornmeal or flour soybeans containing a small amount of some edible oils, prevents dusting, such as corn oil or soybean oil or mineral salt. The preliminary mixture is usually mixed with regular food animal for injection.

For the treatment or prevention of coccidia in poultry, particularly chickens, small birds of the pheasant family, ducks, wild ducks, geese and turkeys, usually administered from about 0.01 to about 100 M. D., preferably from about 0.1 to about 50 memorial plaques connection /1/ or its salt in the form of a pre-mixed product with the appropriate edible substances such as nutritious food. Medication may be up to is whether toxoplasmosis, connection /1/ or its physiologically acceptable salt is introduced in a daily dose of from about 0.5 to about 100 mg/kg body weight. Depending on the body weight of animals, therapeutic mode, view mode breeding, individual response to Antiprotozoal drug dosage forms or compositions, time and interval of administration and so over time, if necessary, to depart from the above dose rate. Thus, in some cases, can be effectively reduced dose, whereas in other cases it may be necessary high doses. For mass injection, the daily dose can be advantageously introduced separate doses.

Treatment of fish is carried out oral route, such as through food, or due to short-term "medicinal bath" method, which involves moving fish from commercial pond in a tank filled with a solution of drug /medicinal bath/ and keeping them there for a predefined time /a period of from several minutes to several hours.

However, seasonal or permanent treatment of the whole habitat /for example, pond, aquarium, tank or reservoir/ may also be performed.

In such with the Concentration of Antiprotozoal agent of this invention may be in the range from about 1 M. D. up to about 10 wt.% on volume. For treatment in "medicinal bath" or for treatment, covering habitat /treatment pond/ fish, preferably use solution Antiprotozoal drugs of this invention in a polar solvent or mixture of solvents, which may be diluted or suspended water.

For the preparation of the solution of compound /1/ or its physiologically acceptable salt is dissolved or suspended in a polar water-soluble environment. Preferably, after adding the connection, /1/ and/or physiologically acceptable salts diluent showed a pH in the region of 7 to 10, particularly in the area around 8 - 10.

Since the introduction of the compounds of this invention for combating parasitic protozoa is to reduce the risk associated with the illness, death, growth retardation and deterioration of the General condition, the invention is useful to prevent reduction of the yield of meat, milk, fur, eggs, honey, etc. However, the invention also provides a significant contribution to the safety of animal husbandry of ornamental animals and pet animals.

The following examples, examples, test examples and compositions are intended to describe e the practical formula of compound, obtained in the following examples, shown in table 3.

The test of example 1. The influence of biological test /1/.

Anticoccidial effect of the compounds of this invention was evaluated in chickens. Using 9-day-old male Chicks white Livorno in groups of 3 chicken, animals in all groups, except for the uninfected, untreated control groups were inoculated orally 5104sporulirovannyh the oocyst birds laboratory standard strain of Eimeria tenella. As medicine dry milled group of compounds of this invention was mixed with 31,3 M. D. standard main diet /SDL N 1: Nippon Haigo Shiryo Co., Ltd./ and the chickens were allowed freely to accept food for 9 consecutive days, starting 24 hours before infection and during 8 days after infection. During the feeding period was determined by the body weight of each chicken. In addition, the calculated amount of blood litter and the number of oocysts was adopted to assess anticoccidial effect of the medication. The results are shown in table 1. N compounds in table 1 corresponds to the N compounds in table 3.

From table 1 it is evident that compared with the uninfected group, under the connection of this invention has excellent anticoccidial activity.

Test example 2. The influence of biological test /2/.

Anticoccidial effect of the compounds of the invention were evaluated in the same manner as in example 1, the introduction of a standard diet containing 4 M. D. connection. The results are shown in table 2.

Comparative example 1.

3,5-Dichloro-4-/4'-chloro-1 - methoxycarbonyl/benzisothiazol.

In 100 ml of acetonitrile is dissolved 4,00 g p-chlorophenylacetic, of 4.54 g of 3,4,5-trichloronitromethane and 2,60 g of 1,1,3,3-tetramethylguanidine followed by boiling under reflux for 8 hours and concentrated to dryness. The residue is dissolved in 100 ml of toluene, washed with 100 ml of ice water and 100 ml of cold water, dried over MgSO4and concentrate. Then to concentrate add ethanol, and get 6,82 g in the form of crystals mentioned in the title compound, so pl. 92 - 93oC.

Comparative example 2.

3,5-Dichloro-4-/4'-chloro-1-methoxycarbonyl/benzylaniline.

In 50 ml of ethanol is dissolved 6.0 g of 3,5-dichloro-4-/4'-chloro-1-methoxycarbonyl/benzimidazole obtained according to comparative example 1, followed by addition of 5-fold molar amount of SnCl2and refluxed for 2 hours, sweat, after this, the solution is alkalinized by adding 10% NaOH. The extract is washed with water, dried over MgSO4and recrystallized from ethanol to obtain 5,12 g mentioned in the title compound, so pl. 151 - 152oC.

Comparative example 3.

3,5-Dichloro-4-/4'-chloro-1 - methoxycarbonyl/benzylpenicillin.

In a mixture of 100 ml of acetic acid and 30 ml of hydrochloric acid diluted to 5.00 g of 3,5-dichloro-4-/4'-chloro-1 - methoxycarbonyl/benzylaniline obtained according to comparative example 2, followed by adding 10 ml of 2-fold molar amount of a solution of sodium nitrate is added dropwise under stirring at 5 to 10oC.

After adding the solution interacts with a 10 - 20oC for 2 hours and then interacts with a 10 - 20oC for 2 hours after addition of 5-fold molar amount of SnCl2dissolved in 50 ml of hydrochloric acid dropwise with stirring at 5 to 10oC. Obtained in such a manner the crystals are suspended in ice-cold water and extracted with ethyl acetate. The extract is dried over MgSO4, concentrated and recrystallized with getting 4,20 g specified in the product name, so pl. 113 - 114oC.

Comparative example 4.

oC.

Comparative example 5.

4-/4'-Chloro-1-methoxycarbonyl/benzyl-3-triftormetilfullerenov.

Based on the 4-/4'-chloro-1-methoxycarbonyl/benzyl-3 - triptorelin obtained according to comparative example 4, in a manner analogous to comparative example 3, if not specified otherwise, get a connection so pl. 95 - 97oC.

Example 1.

2-/3,5-Dichlorophenyl/-5-methoxy-2,3-dihydro-1,2,4-triazine-3-one (compound No. 16).

In THF dissolved 2,77 g 2-/3,5-dichlorophenyl/-5 - chloro-2,3-dihydro-1,2,4-3-triazine-3-one followed by the addition of sodium methoxide in equimolar amounts to the original connection and the mixture is stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and to the residue is added ice-cold water. The resulting crystals are collected by filtration, dried and dissolved in 100 ml of chloroform. A solution of chloroform is dried over anhydrous magnesium sulfate, concentrated and cleaned chromatographytandem on column /Merck silica gel 60; dichloromethane: methanol = 10: 1/ obtain 0.4 g of white crystals /so pl. 164oC/.: C 44.1kHz; H 2,59; N 15,44.

Found: C 43,92; H 2,61; N 15,31.

NMR /CDCl3/ : 4.09 to /with, 3H/, 7,25 - of 7.48 /m 1H/, 7,51 to 7.75 /m, 2H/.

/Here and below, s - singlet, m - multiplet, t - triplet, br - broad, Hz - Hz/.

Example 2.

2-/3,5-dichloro-4-/4'-chloro-1-cyanobenzyl/phenyl/hexahydro - 1,2,4-triazine-3-one (compound N 38).

To 50 ml of dichloromethane add 2,07 g 2-/3,5-dichloro-4-/4'-chloro-1-cyanobenzyl/phenyl/-1-/2-hydroxyethyl/ procarbazine, and 2-fold molar amount of pyridine. The solution is cooled to 0 to 5oC and added dropwise an equimolar amount of triperoxonane anhydride under stirring. After adding a solution then the reaction is carried out under the same conditions for 1 hour. Then remove the dichloromethane concentration and added to the concentrate 50 ml of 1,4-dioxane. The mixture is refluxed for 4 hours, after which the solvent is distilled off and the residue is dissolved in chloroform. A solution of chloroform, washed with ice water, dried over anhydrous magnesium sulfate and concentrated. The residue is then cleaned by chromatographytandem on column /Merck silica gel 60; chloroform/ to obtain 0.1 g mentioned in the title compound as a white substance melting at 138 - 139

Found: C 51,53; H 3,36; N 14,14.

NMR /CDCl3/ : 3,00 - to 3.64 (m, 4H), 4,19 (m, J = 6 Hz, 1H), 5,69 (Shir. 1H), 6,09 (s, 1H), 7,29 (s, 4H), 7,92 (s, 2H).

Example 3.

2-/3,5-Dichloro-4-/4'-chloro-1 - cyanobenzyl/phenyl/-2,3,4,5 - tetrahydro - 1,2,4-triazine-3-one (compound No. 41).

On the basis of 2.0 g 2-/3,5-dichloro-4-/4'- chloro-1-cyanobenzyl/phenyl/-1- /2-hydroxymethylation/procarbazine get 0,38 g white mentioned in the title compound in a manner analogous to example 2, unless otherwise noted. So pl. 166 - 167oC.

The data of elemental analysis for C17H11Cl3N4O.

Calculated: C 51,86; H 2,82; N 14,23.

Found: C 51,60; H 2,87; N 13,93.

NMR /CDCl3/ : 4,00 - 4,20 (m, 2H), 6,14 (s, 1H), 6,45 (Shir. 1H), 7,15 (Shir. 1H), 7,30 (s, 4H), 7,72 (s, 2H).

Example 4.

2-/3,5-Dichloro-4-/4-chloro-1'- cyanobenzyl/phenyl/-4 - methylhexane-1,2,4-triazine-3-one (compound No. 40).

In 50 ml of dimethylformamide is dissolved 1.18 g of 1-methyl-1-/2.2-diatexites/-2-/3,5-dichloro-4-/4'-chloro-1 - cyanobenzyl/phenyl/procarbazine and conduct the reaction at 140 - 145oC with stirring for 2 hours. Then the reaction mixture is poured into 300 ml ice water and extracted with 200 ml of chloroform. The extract is dried over anhydrous magnesium sulfate, the chloroform conc/ to obtain 0.1 g specified in the product name, so pl. 137 - 138oC.

The data of elemental analysis for C18H15Cl3N4O.

Calculated: C 52,77; H 3,69; N 13,68.

Found: C 52,74; H 3,62; N 13,68.

NMR /CDCl3/ : 3,00 (s, 3H), 3,20 - of 3.60 (m, 4H), 4,25 (Shir. 1H), between 6.08 (s, 1H), 7,28 (s, 4H), 7,89 (s, 2H).

Example 5.

2-/3,5-Dichlorophenyl/-2,3,4,5-tetrahydro-1,2,4-triazine-3-one-5-tion (compound No. 7).

To 100 ml of toluene added 2.58 g of starting compound 3,5-dione, and 1/2 equivalent of Lawesson reagent and the mixture is refluxed for 5 hours. Then the reaction mixture is concentrated and cleaned chromatography on a column /Merck, silica gel 60, chloroform/ obtaining 0.9 g of light yellow crystals, so pl. 200 - 201oC.

The data of elemental analysis for C9H5Cl2N3OS.

Calculated: C 39,43; H 1,84; N 15,33.

Found: C 39,45; H 1,97; N 15,05.

NMR /CDCl3/ : to 7.67 (s, 3H), 7,84 (c, 1H), 13,80 (Shir. 1H).

Example 6/

2-/3,5-Dichlorophenyl/-2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound No. 1).

In 50 ml of ethanol is dissolved to 2.74 g of compound No. 7 obtained in example 5, with the subsequent addition of 10 equivalents of activated Raney Nickel. The mixture is stirred at room temperature for a STATCOM is dissolved in 100 ml of ethyl acetate. This solution was dehydrated over anhydrous magnesium sulfate, concentrated and the resulting red-brown oil clean chromatographic column /Merck, silica gel 60, chloroform/ obtaining 1.0 g mentioned in the title compounds as a pale yellow substance, so pl. 179 - 181oC.

The data of elemental analysis for C9H7Cl2N3O.

Calculated: C 44,29; H 2,89; N 17,22.

Found: C 44,59; H 2,98; N 17,41.

NMR /CDCl3/ : 4,05 - 4,20 (m, 2H), 6.30-in - 6,60 (width, 1H), 7,00 - 7,30 (m, 2H), 7,52 (g, J = 2 Hz, 2H).

Example 7.

2-/3,5-Dichlorophenyl/-5-phenyl-2,3-dihydro-1,2,4-triazine-3-one (compound No. 27).

In 50 ml of dioxane was dissolved in 2.20 g 2-/3,5-dichlorophenyl/procarbazine followed by the addition of 1.52 g phenylglyoxal monohydrate and the mixture is boiled for 5 hours under reflux. Then the reaction mixture was concentrated and the residue is recrystallized from acetonitrile to obtain 1,34 g mentioned in the title compound, so pl. 160 - 161oC.

The data of elemental analysis for C15H9Cl2N3O.

Calculated: C 56,63; H 2,85; N 13,21.

Found: C 56,52; H 2,78; N 13,34.

NMR /CDCl3/ : 7,38 (m, J = 2 Hz, 1H), 7,45 - of 7.70 (m, 3H), 7,75 (g, J = 2 Hz, 2H), 8,05 - 8,30 (m, 2H), 8,48 (get connection N 2 way similar to the method of example 2, unless otherwise noted, so pl. 120 - 122oC.

Example 9.

Based on 2-/3,5-dichlorophenyl/-1-/2-hydroxy-2-methylthioethyl/procarbazine get connection 3 in a manner analogous to the method of example 2, unless otherwise noted, so pl. 115 - 116oC.

Example 10.

Based on 2-/3,5-dichlorophenyl/-1-/2,2-dimethyldi-2-hydroxyethyl/ procarbazine obtain compound 4 in a manner analogous to example 4, if not mentioned specifically, so pl. 151 - 152oC.

Example 11.

On the basis of the connection 1 connection get 5 in a manner analogous to the method of example 7, so pl. 148 - 149oC.

Example 12.

Based on 2-/3,5-dichlorophenyl/-6-methyl-2,3,4,5-tetrahydro-1,2,4-triazine-3-one - 5-thione get connection 6 in a manner analogous to the method of example 6, if not mentioned specifically, so pl. 164 - 165oC.

Example 13.

Based on 2-/3,5-dichlorophenyl/-4-methylhexane - 1,2,4-triazine-3,5-dione get a connection 8 in a manner analogous to the method of example 5, if not mentioned specifically, so pl. 149 - 150oC.

Example 14.

Based on 2-/3,5-dichlorophenyl/-hexahydro-1,2,4-triazine-3,5-dione get a connection 9 in a manner analogous to the method of example 5, if n/2-hydroxy-2-phenetyl/procarbazine get the connection 10 way similar to the method of example 2, unless otherwise noted, so pl. 164 - 165oC.

Example 16.

Based on 2-/3,5-dichlorophenyl/-1-/2-hydroxy-2-penicilin/procarbazine get the connection 11 in a manner analogous to the method of example 2, unless otherwise noted, so pl. 139 - 140oC.

Example 17.

On the basis of the connection 8 get the connection 12 in a manner analogous to the method of example 6, if not mentioned specifically, so pl. 210 - 211oC.

Example 18.

Based on 2-/3,5-dichlorophenyl/-6-methylhexane-1,2,4-triazine-3-one-5-thione get the connection 13 in a manner analogous to the method of example 6, unless otherwise noted.

Example 19.

Using the mercaptan instead of sodium methoxide get the connection 14 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 190 - 191oC.

Example 20.

Using benzylmercaptan instead of sodium methoxide get the connection 15 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 152 - 153oC.

Example 21.

5-Chloro-2-/3,5-dichlorophenyl/-2,3 - dihydro-1,2,4-triazine-3-one (compound N 17).

In 30 ml of dichloromethane suspended 1,00 g 2-/3,5-dichlorophenyl/- 2,3,4,5-tetrahydro-1,2,4-Tria carbon and triphenylphosphine and refluxed for 12 hours. After the reaction, the obtained solution is cleaned chromatography on a column /Merck silica gel 60, dichloromethane-carbon tetrachloride = 2:1/, so pl. 148 - 149oC.

NMR /CDCl3/ : 7,42 (t, J = 2 Hz, 1H), 7,66 (d, J = 2 Hz, 2H), to $ 7.91 (s, 1H).

Example 22.

Using fluoride potassium instead of sodium methoxide, get the connection 18 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 93 - 95oC.

Example 23.

Using p-chlorothiophenol instead of sodium methoxide, get the connection 19 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 176 - 178oC.

Example 24.

Using t-butylmercaptan instead of sodium methoxide, get the connection 20 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 97 - 99oC.

Example 25.

Using t-piperonyl potassium instead of sodium methoxide, get the connection 21 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 91 - 92oC.

Example 26.

Using phenol instead of sodium methoxide, get the connection 22 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 126 - 127oC.

Example 27.

And what of iMER 1, if not mentioned specifically, so pl. 68 - 69oC.

Example 28.

Using 2-floridana instead of sodium methoxide, get a connection 24 in a manner analogous to the method of example 1, so pl. 110 - 111oC.

Example 29.

Using 2,2,2-triptoreline instead of sodium methoxide, get the connection 25 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 80 - 81oC.

Example 30.

Using 1,3-dimercaptopropane instead of sodium methoxide, get a connection 26 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 195 - 196oC.

Example 31.

Using 2-/3,5-dichlorophenyl/-5-chloro-2,3,4,5-tetrahydro - 1,2,4-triazine-3-one and using the mercaptan instead of sodium methoxide, get connection 3 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 115 - 116oC.

Example 32.

Using 2-/3,5-dichlorophenyl/-1-benzoylmethylene/polycarbon receive connection 27 in a manner analogous to the method of example 2, unless otherwise noted, so pl. 160 - 161oC.

Example 33.

Using 2-/3,5-dichlorophenyl/-1-benzoyl-1-phenylmethylene/ polycarbon receive connection 28 in a manner analogous to sporogenes/-5-chloro-1,2,3,6-tetrahydro - 1,2,4-triazine-3-one and using the mercaptan instead of sodium methoxide, get the connection 29 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 133 - 134oC.

Example 35.

Using 2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione, get the connection 30 in a manner analogous to the method of example 5, if not mentioned specifically, so pl. 183 - 184oC.

Example 36.

Based on 2-phenyl-5-chloro-2,3-dihydro-1,2,4-triazine-3-one and using methylmercaptan instead of sodium methoxide, get a connection 31 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 115 - 116oC.

Example 37.

Based on 2-phenyl-5-chloro-2,3-dihydro-1,2,4-triazine-3-she will be receiving a connection 32 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 102 - 103oC.

Example 38.

Using 2-/4-chlorophenyl/-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione, get a connection 33 in a manner analogous to the method of example 5, if not mentioned specifically, so pl. 198 - 199oC.

Example 39.

On the basis of 2-/4-chlorophenyl/-5-chloro-2,3-dihydro-1,2,4-triazine-3-one and using the mercaptan instead of sodium methoxide, get a connection 34 in a manner analogous to the method of example 1, so pl. 168 - 169oC.

Example 40.

Using 2-/4-PI is e specially stated, so pl. 151 - 152oC.

Example 41.

Using 2-/3,5-dichloro-4-/4'-chloro-1-cyanobenzyl/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione, get a connection 36 in a manner analogous to the method of example 5, if not mentioned specifically, so pl. 249 - 250oC.

Example 42.

Using 2-/3,5-dichloro-4-/4'-chloro-1-cyanobenzyl/phenyl/ hexahydro-1,2,4-triazine-3,5-dione, get a connection 37 in a manner analogous to the method of example 5, if not mentioned specifically, so pl. 215 - 216oC /decomposition/.

Example 43.

Using 2-/3,5-dichloro-4-/4'-chloro-1-cyanobenzyl/phenyl/4 - methyl-2,3,4,5-tetrahydro-1,2,4-triazine-3-one-5-tion, receive a connection 40 in a manner analogous to the method of example 5, if not mentioned specifically, so pl. 137 - 138oC.

Example 44.

Using 2-/3,5-dichloro-4-/4'-chloro-1-cyanobenzyl/phenyl/-5 - chloro-2,3-dihydro-1,2,4-triazine-3-one, get the connection 42 in a manner analogous to the method of example 1, if not mentioned specifically, so pl. 193 - 194oC.

Example 45.

The connection 36 is dissolved in THF and subjected to interaction with equimolar amounts of methyliodide getting connection 43, so pl. 204 - 205oC.

Example 46.

Compound 43 was dissolved in dichloromethane and subjected to cooperation">

2-/3,5-Dichlorophenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one /connection N 1/.

In 20 ml of acetonitrile is dissolved 1,77 g of 3,5-dichloropyridazine followed by the addition of 1.10 g of benzaldehyde is added dropwise with constant stirring at 10 - 20oC and obtain 2.70 g of the hydrazone. In 30 ml of acetonitrile is dissolved 1,33 g of hydrazone followed by a 3-fold molar amount of pyridine and 0.6-fold molar amount of trichloromethylcarbonate and added dropwise to the mixture with constant stirring at 0 to 10oC. After completion of addition, the solution dropwise, the mixture is stirred at 20 to 25oC for 1 hour.

In 30 ml of acetonitrile is dissolved 0,60 g dimethylacetate of aminoacetaldehyde and then adding the result of the above reaction solution with constant stirring at 5 to 10oC. After completion of addition, the solution dropwise, the reaction solution was stirred at 20 - 25oC for 3 hours. After the thus obtained concentrated solution was added ice water and extracted with 50 ml dichloromethane. After drying over anhydrous magnesium sulfate, the extract was concentrated and dried chromatographic column /Merck silica gel 60, chloroform/ obtaining 1,54 CLASS="ptx2">

In 20 ml of acetonitrile is dissolved in 1.00 g of thus obtained of procarbazine followed by heating the reaction at 50 - 60oC with 0.1 ml of concentrated hydrochloric acid for 20 minutes. After the reaction, the obtained crystals are collected by filtration and washed with water. Thus obtained crystals are recrystallized from ethyl acetate to obtain 0,72 g mentioned in the title compound, so pl. 179 - 181oC.

Example 48.

2-/3,5-Dichloro-4-/4-chlorophenylthio/ phenyl/-6-methyl-2,3,4,5 - tetrahydro - 1,2,4-triazine-3-one (compound No. 45).

After boiling under reflux to 1.60 g of 3,5-dichloro-4-/4-chlorophenylthio/phenylhydrazone and 0.9 g of N-acetylpenicillamine in 30 ml of toluene, add 0.8 g of diazabicyclo [5,4,0]-7-undecene and boil for more than 2 hours under reflux. After the reaction solution was concentrated, add ice water and extracted with 50 ml dichloromethane. After drying over anhydrous magnesium sulfate, the extract was concentrated to dryness and peeling chromatography on a column /Merck silica gel 60, chloroform/ to obtain 0.34 g mentioned in the title compounds as white matter, so pl. 258 - 259oC.

NMR /DMSO-d6/ : 3.04 from (s, 3H), 3,98 (Shir. g, J = 2 Hz, 2H), 7,22 (sq J = 8 Hz, the ro-1,2,4-triazine-3-one (compound N 46).

On the basis of 3,5-dichloro-4-/4-chlorbenzoyl/phenyl/hydrazine get mentioned in the title compound in a manner analogous to the method of example 48, unless otherwise stated, so pl. 257 - 259oC.

Example 50.

4-Acetyl-2-/3,5-dichloro-4-/4'-Chlorobenzyl/phenyl/-6-methyl-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound 47).

Specified in the title compound is obtained by acetylation of compound 46, obtained according to example 49 of acetic anhydride in toluene, so pl. 101 - 102oC.

Example 51.

2-(3,5-Dichlorophenyl)-1-methyl-hexahydro-1,2,4-triazine-3-one (compound No. 48).

The crystals obtained by the interaction of 1-aminoacetyl-1-methyl-2-(3,5-dichlorophenyl)hydrazine with phenylcarbamates in the presence of a base, dissolved in THF and subsequent recovery NaBH4obtaining specified in the connection name. So pl. 150 - 151oC.

Example 52.

6-Chloro-2-(3,5-dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazine-3 - tion (compound No. 49).

In 30 ml of dichloromethane is dissolved to 1.33 g of 1-(3,5-dichlorophenyl)-2-benzylideneacetone and 5-fold molar amount of pyridine, followed by addition of 2-fold molar amount of phosgene is added dropwise under stirring at 5 - Asa and add equimolar amount of cleaners containing hydrochloride salt of tipitina with stirring at 5 - 10oC. After 2 hours reaction, the reaction solution is washed with water and concentrated to dryness. The residue is dissolved in 30 ml of acetonitrile and subjected to interaction with 0.1 ml of concentrated hydrochloric acid at 50 - 60oC for 20 minutes to obtain 2-(3,5-dichlorophenyl)-hexahydro-1,2,4-triazine-6-it-thione. The compound obtained hairout known way of obtaining specified in the connection name. So pl. 207 - 208oC.

Example 53.

2-(3,5-Dichlorophenyl)-1.5-dimethylhexane-1,2,4-triazine-3-one (compound No. 50).

Interaction 1-/2-aminopropyl/-1-methyl-/3,5 - dichlorophenyl/hydrazine with phenylcarbamates in the presence of a base to receive specified in the title compound, so pl. 129 - 130oC.

Example 54.

2-/3,5-Dichlorophenyl/-1 methylhexane - 1,2,4-triazine-3,5-tion (compound No. 51).

Based on 1-/2-amino-ethyl/-2-/3,5-dichlorophenyl/methylhydrazine and thiophosgene get mentioned in the title compound in a manner analogous to the method of example 52, unless otherwise stated, so pl. 240 - 241oC.

Example 55.

2-/3-Chloro-4-/4'-chloro-1-cyanobenzyl/-5-were/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound No. 52).

On the basis of 3-chloro-4-/4'-chloro-1-cyanobenzyl/-5-METI the unless otherwise noted, so pl. 192 - 193oC.

Example 56.

2-/3-Chloro-4-/4'-chloro-1-cyanobenzyl/-5-were/hexahydro - 1,2,4-triazine-3-one (compound N 53).

Restoring the connection 52, obtained according to example 55, LiAlH4in THF receive specified in the title compound, so pl. 201 - 202oC.

Example 57.

2-/3-Chloro-4-/4'-chloro-1-cyanobenzyl/-5-were/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one-5-tion (compound No. 54).

On the basis of 2-/3-chloro-4-/4'-chloro-1-cyanobenzyl/-5-were/- 2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione get mentioned in the title compound in a manner analogous to the method of example 5, if not mentioned specifically, so pl. 234 - 236oC.

NMR /DMSO-d6/ : to 2.41 (s, 3H), 6,36 (s, 1H), 7,17 - of 7.70 (m, 6H), 7,87 (s, 1H), 13,86 (Shir. 1H).

Example 58.

2-/3-Chloro-4-/4'-chloro-1-cyanobenzyl/-5-were/hexahydro - 1,2,4-triazine-3-one-5-tion (compound No. 55).

Restoring the connection 54, obtained according to example 57, LiAlH4in THF receive specified in the title compound, so pl. 217 - 218oC.

Example 59.

2-/3,5-Dichloro-4-/4'-chloro-1-benzoyl/phenyl/-2,3,4,5-tetrahydro - 1,2,4-triazine-3-one (compound No. 56).

On the basis of 3,5-dichloro-4-/4-chlorbenzoyl/phenyl receive specified in n the tx2">

Example 60.

2-/3,5-Dichloro-4-/4'-chloro-1-hydroxybenzyl/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound No. 57).

Restoring the connection 56, obtained according to example 59, LiAlH4in THF receive specified in the title compound, so pl. 115 - 116oC.

Example 61.

2-/3-Chloro-4-/4'-chlorobenzoyl/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound N 58).

On the basis of 3-chloro-4-/4-chlorbenzoyl/phenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 158 - 159oC.

Example 62.

2-/3-Chloro-4-/4'-chloro-1-hydroxybenzyl/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound No. 59).

The connection 58, obtained according to example 61, restore LiAlH4in THF with obtaining mentioned in the title compound, so pl. 135 - 136oC.

Example 63.

2-/3,5-Dichloro-4-/4-chlorophenylthio/ phenyl/-2,3,4,5-tetrahydro - 1,2,4-triazine-3-one (compound N 60).

On the basis of 3,5-dichloro-4-/4-chlorophenylthio/phenyl/hydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 224 - 225oC.

Example 64.

2-/4-/4'-Chlorobenzyl/-3-glorf is and get listed in the name of the connection method, similar to the method of example 47, if not mentioned specifically, so pl. 196 - 197oC.

Example 65.

2-/3-Chloro-4-/2-chloropyridin-5-yl-cyanomethyl/-5-were/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound No. 62).

On the basis of 3-chloro-4-/2-chloropyridin-5-yl-cyanomethyl/-5 - methylphenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 211 - 212oC.

Example 66.

2-/3-Chloro-4-/2-chlorothiazole-5-yl-cyanomethyl/-5-were/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound No. 63).

On the basis of 3-chloro-4-/2-chlorothiazole-5-yl-cyanomethyl/-5 - methylphenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 238 - 239oC.

Example 67.

2-/3-Chloro-4-/1-Mei-2-yl-thio/-5-were/- 2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound N 64).

On the basis of 3-chloro-4-/1-Mei-2-yl-thio/-5-methylphenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 173 - 174oC.

Example 68.

2-/3,5-Dichloro-4-/4'-chloro-1-terbisil/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound N /DAST/, dissolved in 5 ml dropwise with constant stirring at about -50oC. After the reaction for 30 minutes under the same conditions, the reaction solution is further communicates at 20 - 25oC for 1 hour and the solution concentrated. The residue is cleaned chromatography on a column /Merck silica gel 60, chloroform/ obtaining 0,22 g mentioned in the title compound, so pl. 182 - 183oC.

NMR /CDCl3/ : 4.09 to (m, J = 2 Hz, 2H), 6,65 (Shir. 1H), 7,12 (m, J = 2 Hz, 1H), 7,22 (g, J = 46 Hz, 1H), 7,30 (c, 4H), to 7.67 (g, J = 2 Hz, 2H).

Example 69.

2-/3-Chloro-4-/4'-chloro-1-terbisil/phenyl/- 2,3,4,5-tetrahydro - 1,2,4-triazine-3-one (compound N 66).

On the basis of 2-/3-chloro-4-/4'-chloro-1-hydroxybenzyl/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-it gets mentioned in the title compound in a manner analogous to the method of example 68, if not mentioned specifically, so pl. 124 - 125oC.

Example 70.

2-/3,5-Dichloro-4-/4'-Chlorobenzyl/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound N 67).

On the basis of 3,5-dichloro-4-/4-chlorbenzyl/phenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 196 - 197oC.

Example 71.

2-/3,5-Dichloro-4-/4'-chlorophenylthio/phenyl/gaiam mentioned in the title compound, so pl. 242 - 243oC.

Example 72.

2-/4-/4'-Chlorobenzyl/-3-chlorophenyl/hexahydro - 1,2,4-triazine-3-one (compound No. 69).

The connection 61 restore LiAlH4in THF with obtaining mentioned in the title compound, so pl. 157 - 158oC.

Example 73.

2-/2-Chloro-4-triptorelin-6-yl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound N 70).

On the basis of 2-chloro-4-triftorperasin get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 197 - 198oC.

Example 74.

2-/2-Chloro-8-trifluoromethyl-pyridine-6-yl/hexahydro - 1,2,4-triazine-3-one (compound N 71).

The connection 70, obtained according to example 73, restore LiAlH4in THF with obtaining mentioned in the title compound, so pl. 191 - 192oC.

Example 75.

2-/3,5-Dichloro-4-/2-/4-chlorophenyl/-1-cyanoethyl/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound N 72).

On the basis of 3,5-dichloro-4-/2-/4-chlorophenyl/1-cyanoethyl/ phenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 213oC.

Example 76.

2-/3,5-Dichloro-4-/4'-chloro-1-methoxycarbonylbenzyl/ phenylhydrazine get listed in the name of the connection method, similar to the method of example 47, if not mentioned specifically, so pl. 206 - 207oC.

Example 77.

2-/3,5-Dichloro-4-/4'-chloro-1-hydroxymethylbenzene/phenyl/ hexagono-1,2,4-triazine-3-one (compound No. 88).

Connection 73, obtained according to example 76, restore LiAlH4in THF with obtaining mentioned in the title compound, so pl. 108 - 109oC.

NMR /CDCl3/ : 3,00 - 3,60 (width, 4H), 4,00 - 4,70 (Shir.m, 4H), 5,12 (m, 1H), 5,88 (Shir.with. 1H), 7,19 (s, 4H), 7,73 (s, 2H).

Example 78.

2-/3/Trifluoromethyl-4-/4'-chloro-1-methoxycarbonylbenzyl/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound N 74).

Based on 3-trifluoromethyl-4-/4'-chloro-1-methoxycarbonylbenzyl/ phenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 118 - 119oC.

Example 79.

2-/3-Chloro-4-/4'-Chlorobenzyl/-5-/were/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound No. 89).

On the basis of 3-chloro-4-/4-chlorbenzyl/-5-methylphenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 209 - 210oC.

Example 80.

2-/3-Chloro-4-/4'-Chlorobenzyl/ -5-were/hexahydro - 1,2,4-triazine-3-is getting mentioned in the title compound, so pl. 197 - 198oC.

Example 81.

2-/3-Chloro-4-/4'-chloro-1-terbisil/-5-were/hexahydro - 1,2,4-triazine-3-one (compound N 91).

On the basis of 3-chloro-4-/4'-chloro-1-terbisil/-5-methylphenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 160 - 161oC.

Example 82.

2-/3-Chloro-4-/4'-chlorophenoxy/-5-/were/hexahydro-1,2,4 - triazine-3-one (compound N 92).

On the basis of 3-chloro-4-/4'-chlorophenyl/-5-methylphenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, and restore LiAlH4in THF, unless otherwise stated, so pl. 188 - 189oC.

Example 83.

2-/3-Chloro-4-/4'-chlorobenzylthio/-5-/were/hexahydro - 1,2,4-triazine-3-one (compound No. 93).

On the basis of 3-chloro-4-/4'-chlorobenzylthio/-5-methylphenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 82, if not mentioned specifically, so pl. 165 - 167oC.

Example 84.

2-/3-Chloro-4-/2-/4-chlorophenyl/ -2-cyanovinylene/-5-were/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound No. 94).

On the basis of 3-chloro-4-/2-/4-chlorophenyl/-2-cyanovinylene/-5 - methylphenylhydrazine pl. 250 - 251oC.

Example 85.

2-/3-Trifluoromethyl/-4-/4'-chloro-1-hydroxymethylbenzene/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound # 95).

The connection 74, obtained in example 78, restore LiAlH4in THF with obtaining mentioned in the title compound, so pl. 76 - 77oC. Further recovery mentioned in the title compound is carried out in THF LiAlH4and get 2-/3-trifluoromethyl/ -4-/4'-chloro-1-hydroxymethylbenzene/ phenyl/hexahydro - 1,2,4-triazine-3-one (compound No. 77), so pl. 87 - 88oC.

Example 86.

2-/3,5-Dichloro-4-/4'-chloro-1-cyanobenzyl/phenyl/-6-methyl - 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound No. 39).

On the basis of 3,5-dichloro-4-/4'-chloro-1-cyanobenzyl/phenylhydrazine dissolved in toluene, is heated with acetylamino within 2 hours. After addition of equimolar amount of phenylcarbamate the resulting solution was then heated for 2 hours. After the reaction the solution is cooled and filtered to obtain specified in the connection name in the form of a crystal.

Example 87.

2-/3-Trifluoromethyl-4-/4'-chloro-1-formativeness/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound N 75).

Based on the connection 77 receive specified in n the tx2">

Example 88.

2-/3,5-Dichloro-4-/4'-chloro-1-methylthiotetrazole/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound N 96).

In methanol 2-/3,5-dichloro-4-/4-chloro-1-chloromethylbenzene/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one interacts with thiomethoxam sodium obtaining specified in the connection name.

Example 89.

2-/3,5-Dichloro-4-/4'-chloro-1-dimethylaminomethylphenol/ phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one (compound N 97).

2-/3,5-Dichloro-4-/4'-chloro-1-chloromethylbenzene/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one interacts in dimethylformamide solution of dimethylamine.

Example 90.

2-/3,5-Dichloro-4-/4'-chloro-1-trifloromethyl/ phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound No. 98).

On the basis of 3,5-dichloro-4- /4'-chloro-1-trifloromethyl/phenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47, unless otherwise stated.

Example 91.

2-/3,5-Dichloro-4-/4'-chloro-1-hydroxymethylbenzene/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound N 99).

On the basis of 3,5-dichloro-4-/4'-chloro-1-hydroxymethylbenzene/phenylhydrazine get mentioned in the title compound in a manner analogous to the method of example 47.

Based on 2-/ 3,5-dichloro-4- /4'-chloro-1-hydroxymethylbenzene/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one and get listed in the title compound in a manner analogous to the method of example 68.

Example 93.

2-/3,5-Dichloro-4-/4'-chloro-1-chloromethylbenzene/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound 101 N).

2-/3,5-Dichloro-4-/4'-chloro-1-hydroxymethylbenzene/phenyl/-2,3,4,5 - tetrahydro-1,2,4-triazine-3-one in toluene is heated with thionyl chloride and cleaned chromatography on a column of receipt specified in the connection name.

Example 94.

2-/3,5-Dichloro-4-/4'-chloro-1-methylbenzyl/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound No. 102).

2-/3,5-Dichloro-4-/4'-chloro-1-chloromethylbenzene/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one is dissolved in acetic acid and refluxed with 5-fold molar amount of zinc powder for 3 hours. After this, the solution is concentrated and add ice water to the obtained residue, and extracted with ethyl acetate. The extract is dried with magnesium sulfate, concentrated and cleaned chromatography on a column of receipt specified in the connection name.

Example 95.

2-/3,5-Dichloro-4-/4'-chloro-1-ethoxymethylene/phenyl/- 2,3,4,5-Tetra,4-triazine-3-one in methanol interacts with sodium methoxide to obtain specified in the connection name.

Example 96.

2-/3-Trifluoromethyl-4-/4'-chloro-1-methylbenzyl/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one (compound 104 N).

In acetic acid dissolve 2-/3-trifluoromethyl-4-/4'-chloro-1-methylbenzyl/phenyl/- 2,3,4,5-tetrahydro-1,2,4-triazine-3-one, followed by the addition of 5-fold molar amount of zinc powder and refluxed for 3 hours with heating. After adding ice water, the reaction solution is extracted with ethyl acetate. The extract is dried with magnesium sulfate and transferred to clean in a chromatographic column with a receipt in the name of the connection.

Example 97.

2-/4-/2-/4-Chlorophenyl/-1-cyanovinyl/ 3,5-dichlorophenyl/-4,5 - dihydro-1,2,4-triazine-3/2H/he (compound No. 87).

Based on 4-/2-/4-chlorophenyl/-1-cyanovinyl/-3,5 - dichloropyridazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 83 - 85oC.

H-NMR /CDCl3/ : 4,12 - 4,17 (2H, J = 21 Hz, m), of 5.83 ~ 5,86 (1H, J = 2,5 Hz, (g), 7,07 ~ 7,89 (8H, m).

Example 98.

2-/3,5-Dichloro-4-/5-trifluoromethyl-1,2,4-oxadiazol-3-ylmethyl/ phenyl/-4,5-dihydro-1,2,4-triazine-3/2H/he (compound No. 86).

On the basis of 3,5-dichloro-4-/5-trifluoromethyl-1,2,4-oxadiazol-3 - yl-m is e specially stated, so pl. 164 - 165oC.

Example 99.

2-/4-/4-Chloro-chloromethylbenzene/ -3-triptoreline/- 4,5-dihydro-1,2,4-triazine-3/2H/he (compound N 76).

On the basis of connection N 95 receive specified in the title compound in a manner analogous to the method of example 68, if not mentioned specifically, so pl. 157 - 158oC.

Example 100.

2-/3-Chloro-4/4-chloro-terbisil/-5-were/- 4,5-dihydro-1,2,4-triazine-3/2H/he (compound N 78).

On the basis of connection N 79 receive specified in the title compound in a manner analogous to the method of example 68, if not mentioned specifically, so pl. 141 - 142oC /decomposition/.

Example 101.

2-/3-Chloro-4/-4-chloro-hydroxybenzyl/ -5-were/- 1,4,5,6-tetrahydro-1,2,4-triazine-3/2H/he (compound No. 80).

On the basis of connection N 81 receive connection N 79 in a manner analogous to the method of example 60, unless otherwise stated, followed by the addition of excess sodium borate for connection N 80, so pl. 146 - 147oC.

Example 102.

2-/3-Chloro-4/4-chlorbenzoyl/ -5-were/-4,5-dihydro - 1,2,4-triazine-3/2H/he (compound N 81).

On the basis of 3-chloro-4-/4-chlorbenzoyl/-5-methylphenylhydrazine get mentioned in the title compound in a manner analogous to penzoil/-5-were/- 1,2,4-triazine-3/2H/-he-5-/4H/-tion (compound No. 82).

On the basis of 2-/3-chloro-4-/4-chlorbenzoyl/-5-were/-1,2,4 - triazine-3,5/2H, 4H/-Dion receive specified in the title compound in a manner analogous to the method of example 5, so pl. 104 - 106oC.

H-NMR /DMSO-d6/ : of 2.16 (3H, s), 7,60 ~ 7,89 (7H, m), 13,89 (1H, sh.-C.).

Example 104.

2-/3-Chloro-5-methyl-4-phenyl/ phenyl/-4,5-dihydro - 1,2,4-triazine-3/2H/he (compound No. 83).

On the basis of /3-chloro-5-methyl-4-phenyl/phenyl/hydrazine get mentioned in the title compound in a manner analogous to the method of example 47, if not mentioned specifically, so pl. 175 - 176oC.

The composition of example 1.

2-/3,5-Dichlorophenyl-5-methoxy - 2,3-dihydro-1,2,4-triazine-3-one (compound No. 16) 25 g pulverized through a sieve 355 μm intensively and uniformly mixed with 975 g low-fat rice bran /1:1/.

The composition of example 2.

2-/3,5-Dichlorophenyl-2,3,4,5-tetrahydro-1,2,4-triazine-3-one /connection N 1/ 5,0 g dissolved in 10 cm3methanol, followed by addition of 100 g of soya beans. After mixing, the mixture is dried in vacuum at 50oC for 10 hours. This mixture is crushed, passing through a sieve of 500 μm, and simultaneously mixed with 895 g of soy flour with obtaining the composition.

1. Derivatives of triazine of General formula

< / BR>
where Qty: (1) C1-4alkyl, (2) halogen, and (3) three-halogen-C1-4alkyl, and phenyl may be optionally substituted by (i) a phenyl which may be substituted with halogen, (ii) pyridium, which may be substituted with halogen, (iii) thiazolium, which may be substituted with halogen, (iv) imidazolium, which may be substituted C1-4the alkyl, or (v) oxadiazolyl, which can be substituted by three halogen - C1-4the alkyl and the above (i) phenyl, (ii) pyridyl, (iii) thiazolyl, (iv) imidazolyl or (v) oxadiazolyl may be linked via (a) -O-, (b) -S-, (c) - CH2S-, (d) -C(O)-, (e) C1-4alkylene, which may be substituted with halogen, C1-4by alkyl, hydroxy, cyano, C1-4alkoxy, CI-C1-4alkylamino, halo,-C1-4the alkyl, C1-4the acyl, hydroxy-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkoxy-carbonyl, or C1-4alkylation, or (f) C2-6albaniles, which may be substituted by cyano, or [2] pyridyl which may be substituted by three halogen - C1-4alkyl group or halogen;

X means an oxygen atom or sulfur;

R1means hydrogen, C1-4alkyl or the group-CORawhere Rameans C1-6alkyl;

R2means hydrogen, C1-4alkyl or C1-4al, 7-11phenylalkyl, phenoxy, phenylthio where specified alkoxy, alkylthio, phenylthio can have from one to three substituents selected from halogen, C3-6cycloalkyl or mercapto, or R2and R3taken together, form =S;

R4means hydrogen, halogen, C1-4alkyl or phenyl;

R5means hydrogen;

R6means hydrogen or C1-4alkyl

or R1and R2or R5and R6can be linked together with the formation of the chemical bond, provided that when ring a represents a phenyl group containing at least halogen atom in position 2 or 4, and X represents an oxygen atom, R5and R6together do not form a chemical bond,

or their pharmaceutically acceptable salts.

2. Derivatives of triazine under item 1, where the ring a represents phenyl which may be substituted by 1 or 2 substituents selected from the group comprising (1) C1-4alkyl, (2) halogen, and (3) three-halogen-C1-4alkyl, and phenyl may be optionally substituted by (i) a phenyl which may be substituted with halogen, (ii) pyridium, which may be substituted with halogen, (iii) thiazolium, which may be substituted with halogen, (iv) imidazolium, which can, and these (i) phenyl, (ii) pyridyl, (iii) thiazolyl, (iv) imidazolyl or (v) oxadiazolyl may be linked via (a) -O-, (b) -S-, (c) - CH2S-, (d) -C(O)-, (e) C1-4alkylene, which may be substituted with halogen, C1-4by alkyl, hydroxy, cyano, C1-4alkoxy, CI-C1-4alkylamino, halo,-C1-4the alkyl, C1-4the acyl, hydroxy-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkoxy-carbonyl, or C1-4allylthiourea, or (f) C2-6albaniles, which may be substituted by cyano,

or their pharmaceutically acceptable salts.

3. Derivatives of triazine under item 1, where the ring a is pyridyl which may be substituted Tagalog-C1-4alkyl group or halogen,

or their pharmaceutically acceptable salts.

4. Derivatives of triazine under item 1, where R1represents C1-4alkyl group, or their pharmaceutically acceptable salts.

5. Derivatives of triazine under item 1, where R2and R3represent each a hydrogen atom or a C1-4alkyl group,

or their pharmaceutically acceptable salts.

6. Derivatives of triazine under item 1, where R2and R3taken together, represent =S, or their pharmaceutically acceptable salts.


or their pharmaceutically acceptable salts.

8. Derivatives of triazine under item 1, where R6represents a hydrogen atom or a C1-4alkyl,

or their pharmaceutically acceptable salts.

9. Derivatives of triazine under item 1, where these triazine derivatives have the structure formula

< / BR>
where the ring is (i) phenyl which may be substituted with halogen, (ii) pyridyl which may be substituted with halogen, (iii) thiazolyl, which may be substituted with halogen, (iv) imidazolyl, which may be substituted C1-4the alkyl, or (v) oxadiazolyl, which can be substituted by three halogen-C1-4by alkyl;

the ring is phenylene which may be substituted by 1 or 2 substituents selected from the group comprising (1) C1-4alkyl, (2) halogen, and (3) three-halogen-C1-4alkyl;

Y represents (a) -O-, (b) -S-, (c) - CH2S-, (d) -C(O)-, (e) C1-4alkylene, which may be substituted with halogen, C1-4by alkyl, hydroxy, cyano, C1-4alkoxy, CI-C1-4alkylamino, halo,-C1-4the alkyl, C1-4the acyl, hydroxy-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkoxy-carbonyl, or C1-4allylthiourea, or (f) C2-6albaniles, which can be Zam
alkyl;

R2means hydrogen, C1-4alkyl or C1-4alkylthio;

R3means hydrogen, halogen, C1-4alkyl, C1-6alkylthio, C1-6alkoxy, phenyl, C7-11phenylalkyl, phenoxy, phenylthio where specified alkoxy, alkylthio, phenylthio can have from one to three substituents selected from halogen, C3-6cycloalkyl or mercapto, or R2and R3taken together, form =S;

R4means hydrogen, halogen, C1-4alkyl or phenyl;

R5means hydrogen;

R6means hydrogen or C1-4alkyl;

or R1and R2or R5and R6can be linked together with the formation of the chemical bond,

or their pharmaceutically acceptable salts.

10. Derivatives of triazine under item 9, where the ring is (i) phenyl which may be substituted with halogen, (ii) pyridyl which may be substituted with halogen, (iii) thiazolyl, which may be substituted with halogen, or (iv) imidazolyl, which may be substituted C1-4the alkyl,

or their pharmaceutically acceptable salts.

11. Derivatives of triazine under item 9 in which the ring b is phenyl which may be substituted by one to five halogen atoms,

astavliaut each atom of hydrogen or C1-4alkyl, R2represents a hydrogen atom; R3represents a hydrogen atom, halogen atom, or R2and R3taken together, represent =S,

or their pharmaceutically acceptable salts.

13. Derivatives of triazine under item 9, where R1represents hydrogen or C1-4alkyl group,

or their pharmaceutically acceptable salts.

14. Derivatives of triazine under item 9, where R1represents C1-4alkyl or the group CORawhere Rarepresents C1-4alkyl,

or their pharmaceutically acceptable salts.

15. Derivatives of triazine under item 9, where R3represents a hydrogen atom, a halogen atom, a C1-4alkylthio group or a C1-4alkoxygroup,

or their pharmaceutically acceptable salts.

16. Derivatives of triazine under item 9, where R2and R3are both hydrogen atoms, or their pharmaceutically acceptable salts.

17. Derivatives of triazine under item 9, where R4and R5are both hydrogen atoms, or their pharmaceutically acceptable salts.

18. Derivatives of triazine under item 9, where Y represents C1-4alkylene, which may be substituted with halogen, C1-4by alkyl, hydroxy, cyano, C1-4alkoxy, CI-C1-4the alkyl, C1-4alkoxy-carbonyl, or C1-4allylthiourea, or C2-6albaniles, which may be substituted by cyano,

or their pharmaceutically acceptable salts.

19. Derivatives of triazine under item 9, where R6is a hydrogen atom,

or their pharmaceutically acceptable salts.

20. Derivatives of triazine under item 1, which is 2-[3,5-dichloro-4-(4'-chloro-1-cyanobenzyl)phenyl] -2,3,4,5-tetrahydro-1,2,4-triazine-3-one,

or its pharmaceutically acceptable salt.

21. Antiprotozoal composition comprising a biologically active ingredient, characterized in that as a biologically active ingredient it contains an effective amount of a derivative of triazine under item 1

or its pharmaceutically acceptable salt.

22. The composition according to p. 21, wherein the protozoan pathogen is coccidia.

23. Additive in food animals in a pre-prepared mixture comprising a biologically active compound, characterized in that as biologically active compounds it contains an effective amount of a derivative of triazine under item 1

or its pharmaceutically acceptable salt.

24. Method of inhibiting protospatharius acceptable salt.

25. The method according to p. 24, characterized in that said animal is a bird.

26. A method of obtaining a triazine derivative of the formula I, as defined in paragraph 1, characterized in that carry out the cyclization of the compounds of formula

< / BR>
where L represents alkyl or aryl, and the other symbols have the meanings given in paragraph 1.

27. A method of obtaining a triazine derivative of the formula I, as defined in paragraph 1, characterized in that carry out the cyclization of the compounds of formula

< / BR>
where L represents alkyl or aryl, and the other symbols have the meanings given in paragraph 1,

to obtain the triazine derivatives of the formula

< / BR>
where each symbol has the meaning as defined in paragraph 1.

28. A method of obtaining a triazine derivative of the formula I, as defined in paragraph 1, characterized in that carry out the cyclization of the compounds of formula

< / BR>
where R7represents optionally protected amino group, L represents alkyl or aryl, and the other symbols have the meanings given in paragraph 1,

to obtain the triazine derivative of the formula

< / BR>
where each symbol has the meaning as defined in paragraph 1,

and then, if necessary, subjected derived triazine is I, defined in paragraph 1.

Priority points:

15.10.93 - p. 20;

19.09.94 - p. 18;

on the filing date of the application in the Russian Federation - other claims.

 

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