CH638502A5 - Process for preparing novel 1-(4-phenoxyphenyl)-1,3,5-triazine derivatives - Google Patents

Abstract

Novel 1-(4-phenoxyphenyl)-1,3,5-triazines of the formula <IMAGE> in which R<1> and R<3> can be identical or different and represent hydrogen, alkyl, alkyloxy, halogen, or an optionally substituted sulphamoyl radical, R<2> represents haloalkylthio, haloalkylsulphinyl or haloalkylsulphonyl, R<4> represents hydrogen, alkyl, alkenyl or alkynyl, R<5> represents alkyl, as well as their physiologically tolerated salts, are prepared. These compounds are obtained by reacting compounds of the formula <IMAGE> with corresponding bis-(chlorocarbonyl)amines. The novel compounds may be used as active compounds in coccidiosis agents.

Description

The present invention relates to a process for the preparation of new 1- (4-phenoxyphenyl) -1, 3,5-triazine derivatives which can be used as medicaments, in particular as coccidiostats.

It has already become known that l- (4-phenoxyphenyl) -l, 3,5-triazines have an action against poultry and mammalian coccidiosis (DOS nos. 2313721, 2413722).

It has now surprisingly been found that the new l- (4-phenoxyphenyl) -l, 3,5-triazine derivatives of the formula

O1 R5

CFjS

CH3

C1-C0-N-C0-C1 -2HC1

NH-CS-NH,

S H

(i)

3rd

638 502

In the formulas mentioned, the alkyl R1, R3, R4 or R5 is straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of optionally substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl may be mentioned.

In the formulas, the alkenyl R4 is straight-chain or branched alkenyl with preferably 2 to 6, in particular 2 to 4, carbon atoms. Examples include substituted ethenyl, propenyl- (1), propenyl- (2) and butenyl- (3).

In the formulas, the alkynyl R4 is straight-chain or branched alkynyl having preferably 2 to 6, in particular 2 to 4, carbon atoms. Substituted ethynyl, propynyl- (1), propynyl- (2) and butynyl- (3) may be mentioned as examples.

In the formulas, the alkoxy R1 or R3 is straight-chain or branched alkoxy having preferably 1 to 6, in particular 1 to 4, carbon atoms. Substituted methoxy, ethoxy, n- and i-propoxy and n-, i-butoxy may be mentioned as examples.

In the formulas, halogen R1 or R3 is fluorine, chlorine,

Bromine and iodine, especially chlorine and bromine.

In the formulas, haloalkylthio is R2, haloalkylthio having preferably 1 to 4, in particular 1 or 2, carbon atoms and preferably 1 to 5, in particular 1 to 3, identical or different halogen atoms, fluorine, chlorine and bromine, in particular fluorine and chlorine, preferably being halogen atoms . Examples include trifluoromethylthio, chlorodifluoromethylthio, bromomethylthio, 2,2,2-trifluoroethylthio and pentafluoroethylthio.

In the formulas, the haloalkylsulfinyl R2 is haloalkylsulfinyl, preferably having 1 to 4, in particular 1 or 2, carbon atoms and preferably 1 to 5, in particular 1 to 3, identical or different halogen atoms, fluorine, chlorine and bromine preferably being the halogen atoms, especially fluorine and chlorine. Examples include trifluoromethylsulfinyl, chlorodifluoromethylsulfinyl, bromomethylsulfinyl, 2,2,2-trifluoroethylsulfinyl and pentafluoroethylsulfinyl.

In the formulas, haloalkylsulfonyl R2 is haloalkylsulfonyl having preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3, identical or different halogen atoms, fluorine, chlorine and bromine, in particular, being preferred as halogen atoms Fluorine and chlorine are available. Examples include trifluoromethylsulfonyl, chlorodifluoromethylsulfonyl, bromomethylsulfonyl, 2,2,2-trifluoroethylsulfonyl and pentafluoroethylsulfonyl.

In the formulas, optionally substituted sulfamoyl R1 and / or R3 is preferably one of the following radicals: S02NH2, S02NH-CH3, S02N (CH3) 2, S02NH-C2H5, S02-N (C2Hs) 2,

S02NQ, S02NO. S02N VD O, SO ^ NNH,

S02-N ^^ N-CH3.

Some of the bis (chlorocarbonyl) amines of the general formula VI which can be used in the process according to the invention are already known (cf. article in "Synthesis" 1970, pp. 542-543) and, if not yet known, can be obtained from ring-shaped diacyl disulfides and chlorination in inert organic solvents, preferably in carbon tetrachloride.

Suitable diluents are all organic solvents which are preferably inert for these reactions.

In addition to pyridine, these preferably include aromatic hydrocarbons such as benzene, toluene, xylene, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene and ethers such as tetrahydrofuran and dioxane.

The hydrochloric acid possibly formed during the reaction escapes in gaseous form or can be bound by organic or inorganic acid acceptors. Acid acceptors preferably include tertiary organic bases such as triethylamine, pyridine and others. or inorganic bases such as alkali or alkaline earth carbonates.

The reaction temperatures can be varied within a wide range for the above-mentioned reaction. Generally one works between about 0 and about 150 ° C, preferably between 20 ° C and 100 ° C.

In the above reaction, the reaction can be carried out at normal pressure or at elevated pressure. Generally one works at normal pressure.

When carrying out the process according to the invention, the substances involved in the reaction are preferably used in molar amounts.

The new active ingredients - and their salts - have strong coccidio-cide effects. They are highly effective against poultry coccidia, e.g. Eimeria tenella (appendix coccidiosis of the chicken), E. acervulina, E. brunetti, E. maxima,

E. mitis, E. mivati, E. necatrix and E. praccox (small intestine ocidiosis / chicken). The preparations can also be used for the prophylaxis and treatment of coccidiosis infections of other types of poultry. The new active ingredients are also characterized by their very strong effectiveness in coccidial infections in mammals, e.g. rabbits (E. stiedaejhebercoccidiosis, E. magna, E. media, E. irresidua, E. per / oraws / intestinal coccidiosis), sheep, cattle and other pets, including dogs and cats, and laboratory animals such as the white mouse (E. falciformis) and the rat.

Efficacy against toxoplasmosis was also found. In the case of this infection, the compounds can be used both for the treatment of cats in question as separators from the infectious stages (oocysts) and for the treatment of the sick person. Coccidia infections can lead to severe losses in domestic animals and are particularly common in the rearing of poultry and mammals, e.g. Cattle, sheep, rabbits and dogs are a real problem. The effects of coccidiosis known so far are usually limited to a few types of poultry. The treatment and prophylaxis of mammalian coccidiosis has so far been a largely unsolved problem.

The new active ingredients can be converted in a known manner into the customary formulations, such as premixes for administration with the feed, tablets, dragées, capsules, suspensions and syrups.

Although the compounds for combating coccidiosis are usually administered most expediently in or with the feed or in drinking water, the compounds can also be administered to individual animals in the form of tablets, medicinal drinks, capsules or the like, or by injection or by pouring on (pour on ) are administered.

An active ingredient-containing feed is usually prepared with the new compounds in such a way that about 5 to 5000, preferably about 5 to 250 ppm of active ingredient with a nutritionally balanced animal feed, e.g. be thoroughly mixed with the chick feed described in the following example.

When a concentrate or premix is to be prepared which is ultimately to be diluted in the feed to the above values, generally about 1 to 30%, preferably about 10 to 20% by weight of active ingredient is used with an edible organic or inorganic carrier, e.g. Corn meal or corn and soybean meal or mineral salts containing a small amount of an edible dusting oil, e.g. Contain corn oil or soybean mixed. The premix thus obtained can then be added to the whole poultry feed prior to administration.

The following composition can be used as an example of the use of the substances which can be produced according to the invention in poultry feed:

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

638 502

4th

52.0000%

Grain forage

17.9980%

Soybean meal

5.0000%

Corn gluten feed

5.0000%

Whole flour

3.0000%

Fish meal

3.0000%

Tapioca flour

3.0000%

Lucerne grass green flour

2.0000%

Wheat germ, crushed

2.0000%

Soybean oil

1.6000%

Fish bone meal

1.5000%

Whey powder

1.4000%

carbonated lime

1.0000%

phosphoric acid lime

1.0000%

molasses

0.5000%

Brewer's yeast

0.0020%

l- [3,5-dichloro-4- (4'-trifluoromethylthiophenoxy) -

phenyl] -3-methyl-4,6-dioxo-2-thioxohexahydro-

1,3,5-triazine

100.0000%

Such feed is suitable for both curative and prophylactic use.

The chemotherapeutic agent can be used for individual treatment either as such or in combination with pharmaceutically acceptable carriers. Dosage forms in combination with various inert carriers are tablets, capsules, dragées, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Like. Such carriers include solid diluents or fillers, a sterile aqueous medium and various non-toxic organic solvents and the like. Like. Of course, the tablets for oral administration u. Like. Be provided with sweetener additive and the like. In the aforementioned case, the therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range mentioned above.

In the case of oral use, tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch and the like. Like., And binders such as polyvinyl pyrrolidone, gelatin and the like. Like. included. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs which are intended for oral applications, the active ingredient can be used with various flavor enhancers, colorants, emulsifiers and / or together with diluents such as water, ethanol, propylene glycol, glycerol and similar compounds or combinations of this type Find use.

In the case of parenteral use, solutions of the active ingredient in sesame or peanut oil or in aqueous propylene glycol or N, N-dimethylformamide can be used.

The new compounds can also be contained in capsules, tablets, lozenges, dragées, ampoules, etc. in the form of dosage units, each dosage unit being adapted to deliver a single dose of the active ingredient.

The powder and pour on formulations can be obtained using suitable solid or liquid carriers.

The new active ingredients can be used in the usual way, in particular they are intended for application with the feed. But you can also e.g. in the treatment of mammalian coccidiosis and toxoplasmosis are administered orally, parenterally and dermally in the above-mentioned formulations.

Dosages for practice in the treatment and prophylaxis of poultry coccidiosis, especially the coccidiosis of chickens, ducks, geese and turkeys, admixtures of 5 to 100, preferably 10 to 100 ppm, to the feed in question, which in special cases due to good tolerance can be increased. The dose can be reduced by combination with imidazole-4,5-dicarboxamide or sulfonamides, e.g. The p-aminobenzenesulfonamides of 2-amino-4,6-dimethylpyrimidine, 2-aminoquinoxaline, 2-amino-5-methoxy-pyrimidine and 2-amino-4-methylpyrimidine can be achieved because of the potentiating effect .

For individual treatment e.g. in mammalian coccidiosis or in toxoplasmosis, it has proven advantageous to administer amounts of from about 5 to about 250 mg / kg of body weight per day for effective results. Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight of the test animal or the type of application route, but also on the basis of the animal type and its individual behavior towards the medication or the type of formulation and the time or Interval at which the administration takes place. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses throughout the day. The same dosage range is provided for application in human medicine. The other statements above also apply mutatis mutandis.

The compounds which can be prepared according to the invention are notable for a high activity against poultry and mammalian coccidia which are comparable to those of known commercial preparations - such as e.g. that of 1 - [(4-amino-2-propyl-5-pyrimidinyl) methyl] -2-picolinium chloride hydrochloride - is far superior.

The coccidiocidal activity of two compounds obtained according to the invention is exemplified in Table 1 in comparison to 1 - [(4-amino-2-propyl-5-pyrimidyl) methyl] -2-picolinium chloride hydrochloride (= P). Eimeria tenella (appendix coccidiosis / chicken) is listed as an example of the effectiveness on poultry coccidin.

E.g. 11 d old chickens infected with 30,000 sporulated oocysts from Eimeria tenella, the causative agent of appendicitis, 30 to 70% of the animals die from the untreated controls. The surviving chicks excrete 300,000 to 500,000 oocysts per gram (OpG) of faeces daily from the 7th to the 9th day after infection. In the course of the disease, there is a considerable impairment in weight gain and severe, macroscopically recognizable pathological changes in the appendix that lead to heavy bleeding. When tested for activity against E. tenella, the compounds according to the invention were administered from 3 d before infection to 9 d after infection (end of test) with the feed.

The number of oocysts was determined with the help of the McMaster chamber (see Engelbrecht et al., "Parasitological Working Methods in Medicine and Veterinary Medicine", p. 172, Akademie-Verlag Berlin [1965]).

The macroscopically recognizable infection-related damage is classified into 0 = no damage or blood excretion, + = slight damage or blood excretion, + + = moderate damage or blood excretion, + + + = severe damage or blood excretion. The impairment in weight development is determined by weighing the test animals at the beginning and end of the test and compared with that of uninfected, untreated control animals.

(Table at the end of the patent)

Manufacturing example

Cl.

CF3 SO;

Cl-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

638 502

8.9 g (20 mmol) of N- [3,5-dichloro-4- (4'-trifluoromethyisulfonylphenoxy) phenyl] thiourea are suspended in 150 ml of absolute toluene. At 0 to 5 ° C, 3.3 g (21 mmol) of N-methylbis (chlorocarbonyl) amine are added dropwise with stirring. The mixture is stirred at 20 ° C. for 30 minutes, slowly heated to boiling and boiled for 60 minutes. The precipitate obtained is brought into solution by adding 50 ml of absolute toluene. It is boiled for a further 30 min,

Table 1

Comparison of the action of new compounds l- [3,5-dichloro-4- (4'-trifluoromethylsulfonylphenoxy) phenyl] -3-methyl-4,6-dioxo-2-thioxohexahydro-l, 3,5-tria: in and l - [3,5-dichloro-4- (4'-trifluoromethylthiophenoxy) phenyl] -3-methyl-4,6-dioxo-2-thioxohexahydro-1,3,5-triazine with that of l - [(4-amino -2-propyl-5-pyrimidinyl) methylJ-2-picolinium chloride hydrochloride (= P)

criteria

Dose 50 ppm in the feed

Dose 25 ppm in the feed

Dose 10 ppm in the feed

Infected untreated control

H

No. 2

first. Beis 10

P-

P

H

No. 2

first. Beis 10

P-

P

H

No. 2

first. Beis 10

P-

P

Death rate

0/3

0/3

0/5

0/3

0/3

0/6

0/3

0/3

1/3

2/6

Oocyst excretion (%) for the untreated infected control

0

0

46

0

0

75

0

1

82

100

Weight gain (%) for uninfected, untreated control

97

95

63

107

92

90

105

97

25th

38

Excretion of blood with the faeces *

0

0

+

0

0

+ 4 "

0

0

+ +

-f- -} - ~ \ -

Macroscopic section finding *

0

0

+ +

0

0

+ +

0

0

+ + +

+ + +

* The pathological changes caused by infection or the strength of the blood excretion are designated as follows: + + + = strong + + = moderate + = slight 0 = no changes cool and narrowed. The mixture is stirred with about 200 ml of ether; the precipitate obtained is filtered off and washed with ether. The precipitate is stirred with 300 ml of ether, filtered off with suction, washed with ether and 2.8 g (26.6% of theory) of l- [3,5-dichloro-4- (4'-trifluoromethylsulfonylphenoxy) phenyl] -3 are obtained -methyl-2,4-dioxo-6-thioxohexahydro-l, 3,5-triazine, mp. 206 C.

R

Claims (2)

638 502 2nd PATENT CLAIMS 1. Process for the preparation of new l- (4-phenoxyphenyl) -l, 3,5-triazines of the formula **> (I) in which R1 and R3 can be the same or different and stand for hydrogen and substance, alkyl, alkoxy, halogen or an optionally substituted sulfamoyl radical, R2 represents haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl, R4 represents hydrogen, alkyl, alkenyl or alkynyl, 20 R5 represents alkyl, and their physiologically tolerable salts, characterized in that compounds of the formula in which R1 and R3 can be the same or different and represent hydrogen, alkyl, alkoxy, halogen or an optionally substituted sulfamoyl radical, R2 represents haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl, R4 represents hydrogen, alkyl, alkenyl or alkynyl, R5 represents alkyl, and their physiologically tolerable salts, have an excellent action against poultry and mammalian coccidiosis. The new compounds of formula I are prepared according to the invention by using compounds of the formula R3 s (,,) -NH-C-NH-R4 -NH-C-NH-R in which R1, R2, R3 and R4 have the meaning given above, with bis (chlorocarbonyl) amines of the formula O (II) R5-N \ C-Cl (VI), C-Cl o in which R1, R2, R3 and R4 have the meaning given above, with bis (chlorocarbonyl) amines of the formula O R5-N \ C-Cl (VI) C-Cl o 35 and the compounds obtained are converted into their physiologically compatible salts, if appropriate. 2. The method according to claim 1, characterized in that the reaction is carried out in the presence of acid binders. 50 reacted, if appropriate in the presence of acid binders. Compounds obtained can be converted into the corresponding salts by reaction with acids. Surprisingly, the l- (4-phenoxyphenyl) -l, 3,5-triazines which can be prepared according to the invention show a better action against poultry and mammalian coccidiosis than the l- (4-phenoxyphenyl) -l, 3,5-triazinetriones and the previously described Commercially available substances known from the prior art, such as 3,5-dinitrotoluyl-amide, 1 - [(4-amino-2-propyl-5-pyrimidinyl) methyl] -2-picolinium chloride hydrochloride, 3,5-dichloro-2 , 6-dimethylpyridon-4 and the complex of 4,4'-di (nitrophenyl) urea and 4,6-dimethyl-2-hydroxypyrimidine. In addition, they are characterized by the fact that they act against both poultry and mammalian coccidiosis. This range of action is not known from commercially available coccidiosis agents. If you use e.g. N- [3-ethoxy-4- (4'-trifluoromethylthiophene-oxy) phenyl] thiourea and N-methylbis (chlorocarbonyl) amine as starting materials, the course of the reaction can be represented by the following formula: