JPS624388B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 1-(4-phenoxy-phenyl)-1,3,5-triazine derivatives, several processes for their preparation and their use as medicaments, in particular as coccidiostatic agents. 1-(4-phenoxy-phenyl)-1, 3, 5
- Triazines have already been shown to have an action against sporodiasis in poultry and mammals (German patent application no.
2313721 and 2413722). The present invention is based on the formula In the formula, R ¹ represents halogen, R ² represents trifluoromethylthio or trifluoromethylsulfonyl, R ³ represents halogen or C _1-4 -alkyl, R ⁴ represents C _1-4 -alkyl, 1-(4-phenoxy-phenyl)-1, 3, 5
- Triazine derivatives and salts thereof are provided. Surprisingly, the compounds of the invention (ie compounds of formula () and salts thereof) have a significant effect against sporodiasis in poultry and mammals. Among the compounds of the present invention that are salts, pharmaceutically acceptable salts are most important and preferred. Furthermore, the compound of the present invention is In the formula, R ¹ , R ² , R ³ and R ⁴ have the above meanings. In the formula, R ⁶ represents a halogen atom, an alkoxy group or an aryloxy group. Wherein R ¹ , R ² , R ³ and R ⁴ have the above meanings, the substituted 1,3,5-triazine derivative of is optionally isolated and obtained, or (b) formula () , where R ¹ , R ² , R ³ and R ⁴ have the above meanings, a compound of formula (), where R ¹ , R ² , R ³ and R ⁴ have the above meanings optionally in the presence of an acid binder, the formula In the formula, R ⁷ represents hydrogen, which is obtained when reacting with bis-(chlorocarbonyl)-amine. In either case, the resulting product can be converted into a salt by treatment with a base. Surprisingly, the 1-(4-phenoxy-phenyl)-1,3,5-triazine in the present invention is Against sporodiosis in poultry and mammals,
The previously defined 1-(4-phenoxy-phenyl)-1,3,5-triazine-trione and the commercially available substances known in the art, such as 3,5-dinitrotolylamide, 1-[(4-
amino-2-propyl-5-pyrimidinyl)-methyl]-2-picolinium chloride hydrochloride,
3,5-dichloro-2,6-dimethylpyrido-4
-one and 4,4'-di-(nitro-phenyl)-
It exhibits a stronger effect than the complex of urea and 4,6-dimethyl-2-hydroxy-pyrimidine. In addition, the compounds are also distinguished by their activity against both poultry and mammalian sporodiasis. This breadth of action is unknown among currently commercially available drugs against sporodiasis. In method (a), N-[3,5-dichloro-4-
When (4'-trifluoromethylthio-phenoxy)-phenyl]-N'-methyl-thiourea and chlorocarbonyl isocyanate are used, the reaction process can be illustrated by the following reaction equation: When N-[3-ethoxy-4-(4'-trifluoromethylthio-phenoxy)-phenyl]-thiourea and bis-(chlorocarbonyl)-amine are used as starting materials in process (b), the reaction The process can be illustrated by the following reaction equation: C _1-4 -alkyl in R ³ and R ⁴ of the formula is straight-chain or branched alkyl. Examples which may be mentioned are methyl, ethyl, n- and isopropyl and n-, iso- and t-butyl. The alkoxy group in R ⁶ of the formula is preferably straight-chain or branched alkoxy of 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. Examples which may be mentioned are optionally substituted methoxy, ethoxy, n- and isopropoxy and n- and isobutoxy. Halogen in the formula and in R ¹ , R ³ and R ⁶ can be fluorine, chlorine, bromine or iodine, especially chlorine and bromine. In the formula, the aryloxy group as R ⁶ is preferably phenoxy. The substituted thiourea of the formula used as starting material is largely unknown; however, following methods known per se, (a) the substituted 4-aminodiphenyl ether is dissolved in an inert solvent. (b) ammonia or a substituted amine and the corresponding substituted 4-isothiocyanate- (c) the substituted p-hydroxyphenol-thiourea in an aprotic solvent such as dimethyl sulfoxide, dimethylformamide or hexamethylphosphoric triamide. can be prepared by condensation reaction with an activated halogen aromatic compound at a temperature between 20°C and 150°C in the presence of a base such as sodium hydride, potassium hydroxide, potassium carbonate, etc. Generally, by choosing the amount of solvent appropriately, the reaction products will crystallize out when the solution is cooled. The literature on the mutual production of urea from amines and isocyanates is: Methoden der Org.
Chemie (Methods of Organic Chemistry)
(Houben-Weyl), 4th edition, Volume 157-158.
page. As examples of starting compounds of the general formula used in the process according to the invention, the following may be mentioned:
N-[3-morpholinosulfonyl-4-(4'-trifluoromethylthio-phenoxy)-phenyl]-
N'-methyl-thiourea, N-[3-chloro-5-
Methyl-4-(4'-trifluoromethylthio-phenoxy)-phenyl]-N'-methyl-thiourea, N-[3-chloro-4-(4'-trifluoromethylsulfonyl-phenoxy)-phenyl]-
N'-Methyl-thiourea, N-[3,5-dimethyl-4-(4'-trifluoromethylthio-phenoxy)-phenyl]-N'-methyl-thiourea, N-
[3-ethoxy-4-(4'-trifluoromethylsulfonyl-phenoxy)-phenyl]-N'-methyl-thiourea, N-[3-ethoxy-4-(4'-trifluoromethylthio-phenoxy)- phenyl]-thiourea and N-[3-chloro-4-(4'trifluoromethylthio-phenoxy)-phenyl]-N'-allyl-thiourea. General formula () which can be used in method (b) according to the invention
Some bis-(chlorocarbonyl)-amines are already known (Synthesis 1970 , 542-
(see page 543), if these are not known, the compounds are prepared in a similar manner from cyclic diacyl disulfides by chlorination in an inert organic solvent, preferably carbon tetrachloride. be able to. Diluents that can be used in the reaction of thiourea of formula () with carbonyl isocyanate of formula () (method a) and the reaction of bis-(chlorocarbonyl)-amine of formula () (method b) are suitable for these reactions. All inert organic solvents that are inert against In addition to pyridine, these solvents preferably include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, and ethers such as tetrahydrofuran and dioxane. Hydrochloric acid that may be formed during the reaction can be released as a gas or can be combined with an organic or inorganic acid acceptor. Acid acceptors preferably include tertiary organic bases such as triethylamine, pyridine, etc., or inorganic bases such as alkali metal carbonates or alkaline earth metal carbonates. The reaction temperatures for the above reaction steps can vary within a wide range. Generally the reaction is carried out at 0°C and about
It is carried out between 150°C, preferably between 20°C and 100°C. In the above reaction steps, the reaction can be carried out under normal pressure or elevated pressure. Generally this reaction is carried out under normal pressure. When carrying out the method according to the invention, the substances participating in the reaction are preferably used in equimolar amounts. The new active compounds and their salts have strong coccidiocidal actions. The compound is effective against coccidia in poultry, such as Eimeria tenella (chicken vermiform sporodiasis), Eimeria acervulina (E.
acervulina), Eimeria brunetsutei (E.
brunetti), Eimeria Maxima (E.
maxima), E.mitis, E.mivati, Eimeria
E.necatrix and Eimeria
Highly active against E. praecox (small intestinal/hen sporodiasis). The compounds can also be used for the prevention and treatment of coccygeal infections in other species of poultry. In addition, the novel active compounds can also be used in mammals such as rabbits [Eimeria
E.stiedae/hepatic sporodiasis, E.magna, E.media, E.irresidua and E.perforans/intestinal It is extremely effective in cases of coccid infections in sheep, cattle and other livestock including dogs and cats, and in laboratory animals such as white mice (E. falciformis) and rats. It is characterized by its high activity. In addition, it was found to be active against toxoplasmosis. In the case of this infection, the compounds can be used both in treating cats that react to the feces of the infected stage (oocysts) and in treating infected humans. Coccyx infections are a real problem that causes great damage in livestock and occurs particularly in poultry and mammals, such as cattle, sheep, rabbits and dogs. In most cases, the effects of conventionally known drugs against sporodiasis are
It was limited to a few types of poultry. Conventional treatment and prevention of sporodiasis in mammals still leaves many unanswered questions. The compounds of the invention are typically administered in or with feed or in drinking water. The invention therefore includes compounds according to the invention and nutritional substances such as oil cake, grains (e.g. barley), fish meal, soybean meal,
Includes medicated feeds consisting of extracted sugar beet chips, fresh preserved feed, hay or skimmed milk. The compound can also be administered to individual animals in the form of tablets, drinks, capsules, etc., or by injection, or a solution of the compound can be poured into the animal. Using the compounds according to the invention, the active compound-containing feed may be sufficient as an animal feed nutritionally averaged from about 5 to 5000, preferably about 5 to 250 ppm, of the active compound, such as the cow feed described in the following example. It is manufactured by mixing with. If it is desired to produce concentrates or premixes which are ultimately diluted in the feed to the above values, generally about 1 to 30% by weight of active compound, preferably about 10 to 20%
% by weight of edible organic or inorganic excipients, such as corn flour or corn and soybean flour,
Alternatively, it is mixed with an inorganic salt containing a small amount of an edible powdered inhibiting oil, such as corn oil or soybean oil.
The premix thus obtained can then be added to the complete poultry diet before administration. The following compositions are examples of the use of the substances of the invention in poultry feed: Milled grain feed 52.0000% Milled soybean 17.9980% Corn gluten feed 5.0000% Wheat whole meal 5.0000% Fish meal 3.0000% Tapioca flour 3.0000% Fresh Purple horse palm powder 3.0000% Crushed wheat germ 2.0000% Soybean oil 2.0000% Fish bone meal 1.6000% Milk powder 1.5000% Carbonized feed lime 1.4000% Feed lime phosphate 1.0000% Molasses 1.0000% Brewer's yeast 0.5000% 1- [3,5-dichloro-4-(4'-trifluoromethylthio-phenoxy)-phenyl]-3-methyl-4,6-dioxo-2-thioxo-hexahydro-1,35-triazine 0.0020% 100.0000% Such feed is suitable for both therapeutic and prophylactic applications. The compounds according to the invention are used as active ingredients in a mixture with a liquid diluent other than a solvent, with a molecular weight of less than 200 (preferably less than 350), unless a solid or liquefied gaseous diluent or a surfactant is present. It can be included as a pharmaceutical preparation. Furthermore, the compounds according to the invention can be incorporated as active ingredients in the form of sterile or isotonic aqueous solutions to form pharmaceutical preparations. The compounds according to the invention can also be made into medicaments in the form of dosage units consisting of the compounds alone or in admixture with diluents. The present invention also provides a medicament in the form of a tablet (including lozenges and granules), a pill, a capsule, a pill, an ampoule or a suppository, comprising the compound. As used herein, "drug" refers to a physically separate and integral part suitable for pharmaceutical administration. As used herein, "drug in dosage unit form" refers to the daily dosage or multiple (up to 4 times) or means physically separate, integral parts suitable for pharmaceutical administration, each containing a submultiple (up to 1/40). Depending on whether the drug comprises a daily dosage or, for example, 1/2, 1/3 or 1/4 of a daily dosage, the drug is administered once or, for example, twice a day, respectively. 3 or 4
It will be time. Pharmaceutical compositions include, for example, the form of ointments, gels, liniments, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powders. You can take it. Diluents used in adapted pharmaceutical compositions (e.g. granules) for shaping into tablets, dragees, capsules and pills include: (a) fillers and extenders, e.g. starches; , sugar, mannitol and silicic acid; (b) binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; (c) wetting agents such as glycerin; (d)
Disintegrants such as agar, calcium carbonate and sodium bicarbonate; (e) Dissolution retarders such as paraffin;
(f) resorption enhancers, such as quaternary ammonium compounds; (g) surfactants, such as cetyl alcohol, glycerin monostearate; (h) adsorption carriers, such as kaolin and bentonite; (i) lubricants, such as talc. , calcium stearate and magnesium stearate and solid polyethylene glycol. Tablets, dragees, capsules and pills prepared from the pharmaceutical compositions may contain conventional coatings, envelopes and protective matrices, and they may contain opacifying agents. They can be constructed to release the active ingredient only or preferably in a specific part of the intestinal tract, possibly over a prolonged period of time. Coatings, envelopes and protective matrices can be made of polymeric materials or waxes, for example. The active ingredient can also be made into microcapsules together with one or more of the above diluents. Diluents used in pharmaceutical compositions suitable for shaping into suppositories include, for example, common water-soluble or water-insoluble diluents such as polyethylene glycols and fats such as cocoa oil and higher esters such as C _16
-C14 -alcohols by fatty acids]) or mixtures of these diluents. Pharmaceutical compositions which are ointments, liniments, creams and gels may, for example, contain common diluents such as animal and vegetable fats, waxes, paraffin, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids. , talc and zinc oxide or mixtures of these substances. Pharmaceutical compositions that are powders and sprays can, for example, contain the common diluents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Aerosol sprays can include, for example, common propellant bases such as chlorofluorohydrocarbons. Pharmaceutical compositions which are solutions and emulsions may contain, for example, the usual diluents (excluding, of course, the above-mentioned solvents with a molecular weight below 200, unless surfactants are present), such as solvents, solubilizers and emulsifiers. specific examples of such diluents include water,
Ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,
Fatty acid esters of 1,3-butylene glycol, dimethylformamide, oils (eg peanut oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol, or mixtures thereof. For parenteral administration, solutions and emulsions should be sterile and suitably blood isotonic. For pharmaceutical compositions that are suspensions, common diluents,
Liquid diluents such as water, ethyl alcohol, propylene glycol, surfactants such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters,
Microcrystalline cellulose, aluminum metahydroxide,
Bentonite, agar and tragacanth or mixtures thereof can be included. All pharmaceutical compositions can also contain coloring agents and preservatives, as well as aroma and flavor additives (eg oil of quince and eucalyptus) and sweetening agents (eg saccharin). The pharmaceutical composition preferably contains from about 0.1 to 99.5% by weight, more preferably from about 0.5 to 95% by weight of active ingredient, based on the weight of the total composition. In addition to the compounds according to the invention, the pharmaceutical compositions and medicaments described above may also contain other pharmaceutically active compounds. The composition can also contain more than one of the compounds according to the invention. Any diluent in the drug can be any diluent mentioned above for drug compositions. Such drugs have a molecular weight of 200 as the sole diluent.
Smaller solvents can be included. The separate integral parts that make up the drug are generally adapted for pharmaceutical administration by reason of their shape or packaging and can be, for example: tablets (including lozenges and granules), pills, dragees, Capsules, suppositories and ampoules. Some of these forms can provide sustained release of the active ingredient. Some, such as capsules, contain a protective envelope that physically separates and brings together the drug portions. A suitable daily dosage for administration of the drug is 250 mg to 25 g of active ingredient. The above pharmaceutical preparations and drugs are manufactured by methods known in the art, for example by mixing the active ingredients and diluent(s) to form a pharmaceutical composition (e.g. granules) and then This is done by forming the composition into a medicament (for example, a tablet). Furthermore, the compounds of the present invention can be administered to humans and non-human animals either alone or as a mixture with a diluent, or in the form of the above-mentioned drugs to control (including prevention, relief and treatment) the above-mentioned diseases in the animals. can do. It is contemplated that the active compounds may be administered orally, parenterally (eg, intramuscularly, intraperitoneally or intravenously), rectally or topically. However, preferably the compound is administered with the animal feed. In the treatment and prevention of sporomiasis in poultry, especially in hens, ducks, birds and turkeys, the dosage that can be used in practice is 5 to 100 ppm, preferably 10 to 100 ppm of the feed. a mixture; in special cases, for better tolerability, this amount can be increased. Dosage reduction may be due to idazole-4,5-dicarboxylic acid amide or sulfonamide, e.g. 2-amino-
p of 4,6-dimethylpyrimidine, 2-amino-quinoxaline, 2-amino-5-methoxy-pyrimidine and 2-amino-4-methyl-pyrimidine
-amino-benzenesulfonamide, since they have a synergistic effect. For example, for the individual treatment of sporodiasis or toxoplasmosis in mammals, it has been found advantageous to administer doses of 5 to about 250 mg/Kg body weight/day to obtain effective results. . However, sometimes it is necessary to deviate from the above dosages,
In particular, this will depend on the weight of the animal being treated or the nature of the route of administration, but also on the quality of the composition and the timing or interval of administration, depending on the type of animal and its individual response to the drug. Thus, in some cases it may be sufficient to use less than the above-mentioned minimum amount, whereas in other cases the above limit may have to be exceeded. When administering a large amount, it may be considered to divide the dose into several doses a day. A similar dosage range is contemplated for human pharmaceutical administration. The general meanings of the other interpretations above also apply. The compound of the present invention is characterized by having a high degree of activity against cocci in poultry and mammals, and the compound can be used in known commercially available compositions such as 1-[(4-amino-2-propyl- It is far superior to 5-pyrimidinyl)-methyl]-picolinium chloride hydrochloride. As an example, Table 1 shows the coccicidal activity of two types of compounds in the present invention. A comparison with P) is shown. As an example of activity against cocci in poultry, fowl coccycetes (wormoids/sporodiasis of hens) are shown. For example, if an 11-day-old chicken is infected with 30,000 spore oocysts of chicken coccyx, the pathogenic bacteria for worm-like sporodiasis, 30 to 70
% of animals died. Surviving chickens were infected 7 to 7 days after infection.
From the 9th day, 300,000~ per gram of feces per day
Excreted 500,000 oocysts (OPG). During the disease, weight gain was markedly impaired, macroscopically detectable pathological changes appeared in the vermiform processes, and provoking profuse hemorrhage. When testing activity against chicken ballworms, the compounds of the present invention were administered together with feed from 3 days before infection to 9 days after infection (end of experiment). The number of oocysts was determined using a McMaster chamber (as described in Parasitolo by Engelbrecht et al.
gische Arbeitsmethoden in Medizin und
Veterina¨rmedizin (Parasitological Methods in
Medicine and Veterinary Medicine), p. 172,
See Akademie-Verlag Berlin (1965)]. Macroscopically detectable damage due to infection was classified as follows: 0 = no damage or no blood drainage, + = slight damage or blood drainage, ++ = moderate damage and blood drainage, +++ = damage. Or excessive blood excretion. Experimental animals were weighed at the beginning and end of the experiment to determine loss in weight gain and compared to uninfected, untreated control animals.

[Table] Manufacturing Examples Example 1 N-[3-chloro-5-methyl-4 with melting point 223°C
-(4′-trifluoromethylsulfonyl-phenoxy)-phenyl]-N′-methyl-thiourea 4.38 g
(10 mmol) was suspended in 60 ml of anhydrous toluene,
1.27 g (12 mmol) of chlorocarbonyl isocyanate dissolved in 5 ml of anhydrous toluene was added dropwise at 20° C. with stirring. Crystals separated immediately from the resulting solution. The mixture was boiled for 30 minutes and the crystals were separated hot and washed with toluene and ether. Yield: 1-[3-chloro-5-methyl-4-(4'-trifluoromethylsulfonyl-) with a melting point of 274°C.
phenoxy)-phenyl]-3-methyl-4,6
-dioxo-2-thioxo-hexahydro-
3.6 g of 1,3,5-triazine (theoretical amount of 71
%). After concentrating the liquid under vacuum and stirring with isopropanol, a further 0.7 g of product with a melting point of 273 DEG C. were obtained, which increased the yield to 97% of theory. The following compounds were produced in the same manner as above. Example 2 1-[3,5-dichloro-4-(4'-trifluoromethylsulfonyl-phenoxy)-phenyl]-
3-Methyl-4,6-dioxo-2-thioxo-
Hexahydro-1,3,5-triazine, melting point
271℃. Example 3 1-[3-chloro-5-methyl-4-(4'-trifluoromethylthio-phenoxy)-phenyl]-
3-Methyl-4,6-dioxo-2-thioxo-
Hexahydro-1,3,5-triazine, melting point
222℃. Example 4 1-[3,5-dichloro-4-(4'-trifluoromethylthio-phenoxy)-phenyl]-3-methyl-4,6-dioxo-2-thioxo-hexahydro-1,3,5- Triazine, melting point 321°C.

Claims (1)

[Claims] 1 formula In the formula, R ¹ represents halogen, R ² represents trifluoromethylthio or trifluoromethylsulfonyl, R ³ represents halogen or C _1-4 -alkyl, R ⁴ represents C _1-4 -alkyl, 1-(4-phenoxy-phenyl)-1, 3, 5
-Triazines or their salts. 2 formulas, In the formula, R ¹ represents halogen, R ² represents trifluoromethylthio or trifluoromethylsulfonyl, R ³ represents halogen or C _1-4 -alkyl, R ⁴ represents C _1-4 -alkyl, The compound with the formula, wherein R ⁶ represents a halogen atom, an alkoxy group or an aryloxy group, and consists of reacting with a substituted carbonyl isocyanate of and optionally isolating the product or converting it into a salt by optionally treating with a base. formula In the formula, R ¹ , R ² , R ³ and R ⁴ have the above meanings, and 1-(4-phenoxy-phenyl)-1.3.5
- A method for producing triazine or its salt. 3 formulas In the formula, R ¹ represents halogen, R ² represents trifluoromethylthio or trifluoromethylsulfonyl, R ³ represents halogen or C _1-4 -alkyl, and R ⁴ represents C _1-4 -alkyl. The compound, optionally in the presence of an acid binder, has the formula A formula consisting of reacting with a bis-(chlorocarbonyl)-amine, in which R ⁷ represents hydrogen, and optionally treating the product with a base to convert it into a salt. In the formula, R ¹ , R ² , R ³ and R ⁴ have the above meanings, and 1-(4-phenoxy-phenyl)-1.3.5
- A method for producing triazine or its salt. 4 formula In the formula, R ¹ represents halogen, R ² represents trifluoromethylthio or trifluoromethylsulfonyl, R ³ represents halogen or C _1-4 -alkyl, R ⁴ represents C _1-4 -alkyl, 1-(4-phenoxy-phenyl)-1, 3, 5
- A sporodiasis control agent characterized by containing triazine or a salt thereof as an active ingredient. 5. Patents containing the active ingredient in a mixture with a solid or liquefied gaseous diluent or, unless a surfactant is present, with a gaseous diluent other than a solvent with a molecular weight less than 200. The pesticidal agent according to claim 4. 6. The pesticidal agent according to claim 5, which comprises the active ingredient in the form of a sterile or isotonic aqueous solution. 7. The pesticidal agent according to claim 5 or 6, containing 0.5 to 95% by weight of the active ingredient. 8. The pesticidal agent according to claim 5, which is in a dosage unit form. 9. The pesticidal agent according to claim 5, which is in the form of a tablet, pill, dragee, capsule, ampoule, or suppository. 10 formula In the formula, R ¹ represents halogen, R ² represents trifluoromethylthio or trifluoromethylsulfonyl, R ³ represents halogen or C _1-4 -alkyl, and R ⁴ represents C _1-4 -alkyl. 1-(4-phenoxy-phenyl)-1, 3, 5
- Sporidia control feed consisting of triazine or its salt and nutrients.