CH630079A5 - Process for the preparation of 1-(4-phenoxyphenyl)-1,3,5-triazine derivatives - Google Patents

Description

630079

2nd

PATENT CLAIMS 1. Process for the preparation of new l- (4-phenoxyphenyl) -1,3,5-triazines of the formula

R

(I A)

(I A)

R

10th

R

produces and with a compound of formula

R5-Z

(V)

in which R1 and R3 can be the same or different and is in which Z represents halogen,

for hydrogen, alkyl, alkoxy, halogen or a given gene optionally converted into the corresponding salts.

if substituted sulfamoyl radical, R2 is haloalkyl

thio, haloalkylsulfinyl or haloalkylsulfonyl, R4

represents hydrogen, alkyl, alkenyl or alkynyl, and their physiologically tolerable salts, characterized in that 20

that you have compounds of the formula

The present invention relates to processes 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) -1,3,5-triazines have an action against poultry and mammalian coccidiosis (DOS 2 313 721, DOS 2413 722). It has now surprisingly been found that the new l- (4-phe-

(II)

noxy-phenylH, 3,5-triazine derivatives of the formula

30th

\\ 4

v-NH-C-NH-R

R

N> = 0

^> - \ s

(I)

R

in which R6 represents a halogen atom, an alkoxy group or an aryloxy group, is reacted and any compounds obtained are converted into the corresponding salts.

2. Process for the preparation of new l- (4-phenoxyphenyl) -1,3,5-triazines of the formula

(I B)

in which R1 and R3 can be the same or different and 45 represents hydrogen, alkyl, alkoxy, halogen or an optionally substituted sulfamoy radical, R2 represents haloalkyl-thio, haloalkylsulfinyl or haloalkylsulfonyl, R4 and R5 can be the same or different and represent hydrogen, Alkyl, alkenyl or alkynyl, as well as their physiologically compatible salts, have an excellent action against poultry and mammalian coccidiosis.

The process according to the invention for the preparation of new compounds of the formula

55

60

in which R1 and R3 can be the same or different and represent hydrogen, alkyl, alkoxy, halogen or an optionally substituted sulfamoyrest, R2 represents haloalkyl-thio, haloalkylsulfinyl or haloalkysulfonyl, R4 represents hydrogen, alkyl, alkenyl or alkynyl, R3 represents Alkyl, alkenyl or alkynyl, and their physiologically tolerable salts, characterized in that, according to the process of claim 1, a compound of the formula

(I A)

65

R

is characterized in that compounds of the formula

3rd

630079

R

R3

-NH-C-NH-R

(II)

wherein R1, R2, R3 and R4 are defined above R5 is different from hydrogen, are prepared according to the invention by, as described above, first by producing a compound of formula IA and then with a compound of formula

R5-Z

(V)

in which R1, R2, R3 and R4 have the meaning given above, with a substituted carbonyl isocyanate of the formula

10th

R -C-N = C = 0

n o

(III)

in which R6 represents a halogen atom, an alkoxy group or an aryloxy group, is reacted and any compounds obtained are converted into the corresponding salts.

New compounds of the formula

20th

25th

(I B)

where Z is halogen, reacted and the compounds obtained, if appropriate, converted into the corresponding salts.

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-triazine already described previously trione and the commercially available substances known from the prior art, such as 3,5-dinitrotolylamide, l - [(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- (nitro-phenyl) urea and 4,6-dimethyl-2-hydroxy-pyrimidine.

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- [3,5-dichloro-4- (4'-trifluoromethylthio-phenoxy) -phenyl] -N'-methyl-thiourea and chlorocarbonyl isocyanate and methyl iodide as alkylating agents, the course of the reaction can be represented by the following formula:

C1-C0-N = C = 0

-HCl

+ CH, J

-HJ

Clv_ Vn'CH3

):O

CK,

In the formulas given, the alkyl is R1, R3, R4 or, if substituted, ethynyl, propynyl- (l), propynyl- (2) and buti-

R5 preferably called straight-chain or branched alkyl with 1 to nyl- (3).

6, in particular 1 to 4 carbon atoms. Examples are in the formulas as alkoxy R1, R3, R6, preferably optionally substituted methyl, ethyl, n.- and i.-propyl, n.-, straight-chain or branched alkoxy with 1 to 6, in particular i.- and t .- Butyl called. 60 of them 1 to 4 carbon atoms. As an example,

In the formulas the alkenyl R4 or R5 is preferably substituted methoxy, ethoxy, n.- and i.-propoxy and n.-,

straight-chain or branched alkenyl with 2 to 6, in particular called i.-butoxy.

their 2 to 4 carbon atoms. Examples are given in the formulas as halogen R1, R3, R6 or Z,

if substituted ethenyl, propenyl (1), propenyl (2) and butylene fluorine, chlorine, bromine and iodine, especially chlorine and nyl- (3). 65 bromine.

In the formulas, preferably R4 or R5 is alkynyl.

their 2 to 4 carbon atoms. Examples are given atoms and 1 to 5, in particular 1 to 3 identical or different

630079

halogen atoms, the halogen atoms being preferably fluorine, chlorine and bromine, in particular fluorine and chlorine. Examples include trifluoromethylthio, chlorodifluoromethylthio, bromomethylthio, 2,2,2-trifluoroethylthio and pentafluoroethylthio.

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

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

In the formulas, the optionally substituted sulfamoyl is R1 and / or R3, preferably one of the following radicals: SO2NH2, SO2NH-CH3, S02N (CH3) 2, SO2NH-C2H5, SO2-

N (C2H5) 2, SO2 NQ, SChN ^, SO2NO SOzN ^ NH, s ° 2-nO-CH,

In formula III, aryloxy R6 is preferably phe-roxy.

The substituted thio-ureas of the formula II used as starting materials are largely unknown, but can be easily prepared by methods known per se by a) either substituting 4-aminodiphenyl ethers with the corresponding substituted isothiocyanates in inert solvents at temperatures between 0 ° C. and 100 ° C, or in reverse order b) ammonia or substituted amines with the corresponding substituted 4-isothiocyanato-diphenyl ethers can react with one another under the same conditions,

or by c) substituted p-hydroxy-phenylthioureas with activated halogen aromatics in aprotic solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide in the presence of bases such as sodium hydride, potassium hydroxide, potassium carbonate and others. condensed at temperatures between 20 ° C and 150 ° C.

If the amount of solvent is appropriately dimensioned, the reaction products generally crystallize when the solution is cooled. Literature for the mutual representation of ureas from amines and isocyanates: Methods of Org. Chemie (Houben-Weyl) IV. Edition, Vol. VIII, pp. 157-158.

The following may be mentioned as examples of the starting compounds of the general formula II used in the process according to the invention:

N- {3-morpholinosulfonyl-4- (4'-trifluoromethylthio-phenoxy) phenyl] -N'-methylthiourea

N- [3-chloro-5-methyl-4- (4'-trifluoromethylthiophenoxy> phenyl] -N'-methylthiourea

N- £ 3-chloro-4- (4'-trifluoromethylsulfonylphenoxy) phenyl] -N'-methylthiourea

N- [3,5-Dimethyl-4- (4 '-trifluoromethylthio-phenoxy) phenyl] -N' -methylthiourea

N- [3-ethoxy-4- (4'-trifluoromethylsulfonylphenoxy) phenyl] -N'-methylthiourea

N- [3-ethoxy-4- (4'-trifluoromethylIthio-phenoxy) phenyl] thio-urea

N- [3-chloro-4- (4'-trifluoromethylthio-phenoxy) phenyl] -N'-allyl thiourea

Suitable diluents for the reaction of the thioureas of the formula (II) with carbonyl isocyanates of the formula (III) and the 1,3,5-triazine derivatives of the formula (IA) with compounds of the formula Z are all organic solvents which are 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 stages. Generally one works between about 0 ° C and about 150 ° C, preferably between 20 ° C and 100 ° C.

The reaction can be carried out in the above-mentioned reaction stages at normal pressure or at elevated pressure. Generally one works at normal pressure.

When carrying out the processes 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 coccidiocidal effects. They are highly effective against poultry coccidia such as Eimeria tenella (appendix coccidiosis of the chicken), E. acervulina, E. brunetti, E. maxima, E. mitis, E. mivati, E. necatrix and E. praccox (small intestine coccidiosis / chicken): The preparations can also be used for prophylaxis and treatment of other domestic poultry coccidiosis infections. The new active ingredients are also characterized by their very strong effectiveness in coccidial infections in mammals, e.g. rabbits (E. stiedae / liver coccidiosis, E. magna, E. media, E. irresidua, E. perforans / 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 excretors from the infectious stages (oocysts) and for the treatment of the sick person. Cocci-sien infections can lead to severe losses in pets and are particularly common in the rearing of poultry and mammals such as e.g. Cattle, sheep, rabbits and dogs pose a real problem. The effects of the 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 into the customary formulations in a known manner, such as premixes for administration with the feed, tablets, dragées, capsules, suspensions and syrups.

Although the compounds for controlling coccidiosis are usually most conveniently administered in or with the feed or in the drinking water, the compounds can also be administered to individual animals in the form of tablets, medicine troughs, capsules or the like or by injection or by pouring on will.

A feed containing active substance is usually prepared with the new compounds in such a way that about 5-5000, 4

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

preferably about 5-250 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 is an example of the use of the substances produced according to the invention in poultry feed:

52.0000% feed grain meal 17.9980% soy meal 5.0000% corn gluten feed 5.0000% whole wheat flour 3.0000% fish meal 3.0000% tapioca meal 3.0000% alfalfa grass green meal 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% 1 - [3,5-dichloro-4- (4 '-trifluoromethylthiophenoxy) phenyl] -3-methyl-4,6-dioxo-2-thioxo-hexahydro-1,3,5-triazine

100.0000%

Such a 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, dragees, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, a sterile aqueous medium, and various non-toxic organic solvents and the like. Of course, the tablets and the like which are suitable for oral administration can be provided with a sweetener additive and the like. In the aforementioned case, the therapeutically active compound should be present in a concentration of about 0.5-90% 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 citrite, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch and the like, and binders such as polyvinylpyrrolidone, gelatin and the like. 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 combined with various flavor enhancers, colorings, emulsifiers and / or together with Verdün630079

agents such as water, ethanol, propylene glycol, glycerin and similar compounds or combinations of this type are used.

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, dragees, ampoules, etc. in the form of dosage units, each dosage unit being adapted to provide a single dose of the active ingredient.

The powder and pour on formulations can be prepared 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 coccidiosis of chickens, ducks, geese and turkeys, are admixed with 5-100 ppm, preferably 10-100 ppm, to the feed, which in special cases can be increased due to the good tolerance. The dose can be reduced by combination with imidazole-4,5-dicarboxamide or sulfonamides, e.g. The p-amino-benzenesulfonamides of 2-amino-4,6-dimethylpyrimidine, 2-aminoquinoxaline, 2-amino-5-methoxypyrimidine and 2-amino-4-methylpyrimidine can be achieved because they are potentiating Effectiveness comes.

For individual treatment e.g. in mammalian coccidiosis or toxoplasmosis, it has been found to be advantageous to administer amounts of about 5 to about 250 mg / kg of body weight per day for effective results. Nevertheless, it may be necessary to deviate from the quantities 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 accordingly.

The compounds which can be prepared according to the invention are notable for high activity against poultry and mammalian coccidia, which is comparable to that of known commercial preparations - such as e.g. that of l - [(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-day-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 divorced 300,000 to between 7 and 9 days after infection

5

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

630079 6

500,000 oocysts per gram (OpG) of faeces. In the course of the macroscopically recognizable infection-related damage

Illness leads to considerable impairment. Classifications are classified in 0 = no damage or

the weight gain and excessive macroscopic recognition - blood excretion, + = weak damage or blood loss

visible pathological changes to the appendix that lead to divorce, + + = moderate damage or blood excretion, heavy bleeding. When testing for effectiveness 5 + + + = severe damage or blood excretion. The leg

compared to E. tenella, the connection according to the invention of the weight development was determined by weighing the fertilizers from 3 days before the infection to 9 days after the test animals at the beginning and end of the test and

Infection (end of experiment) administered with the feed. compared to that of uninfected untreated contact

The oocyst number was trolled using the McMaster chamber.

determined (see Engelbrecht et al., Parasitological Working Methods in Medicine and Veterinary Medicine, p. 172,

Akademie Verlag Berlin (1965)).

Table 1

Comparison of the effect of Preparation Examples No. 2 and No. 10 with that of H (4-amino-2-propyl-5-pyrimidinyl) methyl} 2-picolinium chloride hydrochloride (= P)

criteria

Dose 50 ppm in the feed

Dose 25 ppm in the feed

10 ppm in the feed

infected

Mfr.

Ex.

Mfr.

Ex.

Mfr.

Ex.

untreated

No. 2

10th

P

No. 2

10th

P

No. 2

10th

P

control

Death rate

0/3

0/3

0/5

0/3

0/3

0/6

0/3

0/3

1/3

2/6

Oocyst excretion

in% of the untreated,

infected control

0

0

46%

0

0

75%

0

1%

82%

100

Weight gain in%

to the not infected

untreated

control

97%

95

63%

107%

92%

90%

105%

97%

25%

38

Blood excretion with

the feces *

0

0

+

0

0

+ +

0

0

+ +

+ + +

more macroscopic

Section finding *

0

0

+ +

0

0

+ +

0

0

+ + +

+ + +

* the pathological changes caused by infection or + + + = strong + + = moderate + = slight 0 = none The strength of the blood excretion are changes as follows

40

Production Examples Example 1

4.38 g (10 moles) of N- [3-chloro-5-methyl-4- (4'-trifluoromethyl-sulfo-Example 2

nyl-phenoxy> phenyl] -N'-methyl-thiourea of mp 223 ° C. 55 l- {3,5-dichloro-4- (4'-trifluoromethylsulfonyl-phenoxy) -phe-

are suspended in 60 ml of absolute toluene and at 20 ° C nyl] -3-methyl4,6-dioxo-2-thioxo-hexahydro-l, 3,5-triazine, mp.

with stirring with 1.27 g (12 m mol) of chlorocarbonyl isocyanate 271 ° C.

dissolved in 5 ml of absolute toluene added dropwise. A crystallizate soon separates from the resulting solution. It is boiled for 30 minutes, suction filtered while hot and with toluene and 60 example 3

Ether washed. l- [3-Morpholinosulfonyl4- (4'-trifluoromethylthio-phenoxy) -

Mp 274 ° C, yield: 3.6 g of l- [3-chloro-5-methyl4- (4'-trifluorophenyl} -3-methyl4,6-dioxo-2-thioxo-hexahydro-l, 3.5 -triazine,

methylsulfonylphenoxy) phenyl] -3-methyl4,6-dioxo-2-thioxo- mp. 271 ° C.

hexahydro-l, 3,5-triazine (71% of theory).

After concentration in vacuo and 65

Mix with isopropanol and obtain a further 0.7 g of mp. 273 ° C.- Example 4

ten, which increases the yield to 97% of theory. l- [3-chloro4- (4'-trifluoromethylthio-phenoxy) phenyl] -3-me-

The following compounds were obtained analogously: thyl4,6-dioxo-2-thioxo-hexahydro-l, 3,5-triazine, mp. 255 ° C.

Example 6

7 630079

Example 5 Example 10

l- [3-chloro4- (4'-trifluoromethylsulfonylphenoxy) phenyl] -3- l- [3,5-dichloro4- {4'-trifluoromethylthio-phenoxy) phenyl] -3-

methyl4,6-dioxo-2-thioxo-Jiexahydro-l, 3,5-triazine, mp. methyl4,6-dioxo-2-thioxo-hexahydro-l, 3,5-triazine, mp.

294 ° C. 321 ° C.

5

Example 11

'Tror0 ^ - .l .t_ Q l- [3-Methyl4- (4'-trifluoromethylthio-phenoxy) phenyl> 3-me-

SS "1 * Th: thylth ^ phenoxy> phenyl> 3-thl4Vdioxo2-thioxo-hexahydro-l, 3,5-triazine, mp. 243 ° C. Methyl4,6-dioxo-2-thioxo-hexahydro-l, 3, 5-triazine, mp JJ

304 ° C io Example 12

l- [3-Methyl4- (4'-trifluoromethylsulfonylphenoxy> phenyl] -3-example 7 methyl4,6-dioco-2-thioxo-hexahydro-l, 3,5-triazine, mp.

l- [3-Chloro-5-methyl4- (4'-trifluoromethylthio-phenoxy) -phe- 255 ° C.

nyl] -3-methyl4,6-dioxo-2-thioxo-hexahydro-l, 3,5-triazine, mp.

222 ° C. 15 Example 13

l- [3-ethoxy4- (4'-trifluoromethylsulfonylphenoxy) phenyl> 3-methyl4,6-dioxo-2-thioxo-hexahydro-l, 3,5-triazine, mp. Example 8 218 ° C

l- [3-ethoxy4- {4'-trifluoromethylthio-phenoxy) phenyl] -3-methyl4,6-dioxo-2-thioxo-hexahydro-l, 3,5-triazine, mp. 2Q ß; Spjei

294 ^ l- [3-chloro4- <4'-trifluoromethylthiophenoxy> phenyl] -3-allyl-

4,6-dioxo-2-thioxo-hexahydro-l, 3,5-triazine, mp. 149 ° C.

Example 9

l- [3,5-Dimethyl4- (4'trifluoromethylsulfonyl-phenoxy) -phe- Example 15 nyl] -3-methyl4,6-dioxo-2-thioxo-hexahydro-l, 3,5-triazine, mp. 25 l- [3-ethoxy4- (4'-trifluoromethylthiophenoxy) phenyl> 2.4-228 ° C. dioxo-6-thioxo-hexahydro-1,3,5-triazine, mp. 261 ° C.