CH558367A - Substd phenyl thioureas - as anthelmintics - Google Patents

Abstract

Cpds. (I) and their salts. (where R is H, Hal, OH, NO2, COOH, COOAlkyl, 1-4C alkyl, -alkoxy or -alkylthio, NH2NH alkyl, N(alkyl)2, acylamino, AlkylOCONH- or SO2NH2; R2 is H, Hal NO2, 1-4C alkyl, COOAlkyl or COOH; R2 is HaHalo, NO2 or COOH; R4 and R5 are 1-4C alkyl or together form a 2-6C polymethylene chain where one CH2 may be replaced by N-R; R is H 1-4C alkyl or -hydroxyalkyl, Ph or PhCH2; and X is O, S, SO2 or NH) are prepd. by methods for forming thiourea or cpds. (I) are converted into other derivs. (e.g. NO2 NH2, NHAcyl-NH2 etc). Thus, 4-nitro-4-isothiocyanodiphenylamine with Ba2NH gives (I R = NO2R2=R3=H, X=NH,R4=R5=Bu).

Description

  

  
 



   The present invention relates to a process for the preparation of new thioureas which can be used to control parasitic helminths.



   The new thioureas correspond to formula I:
EMI1.1

In this formula: Rl denotes hydrogen, hydroxyl, alkyl, alkoxy, alkylthio, alkoxycarbonyl, carboxyl, amines, alkylamino, dialkylamino, acylamino, halogen, nitro or sulfamoyl, each with 1 to 4 carbon atoms per alkyl group,
R2 is hydrogen, alkyl, alkoxycarbonyl with 1 to 4 carbon atoms per alkyl group, carboxyl, halogen or nitro,
R3 hydrogen, carboxyl, halogen or nitro,
R4 and R5 together form a polyethylene bridge with 3 to 6 methylene groups, one of which is replaced by the group N-R, in which R is alkyl, hydroxyalkyl with 1 to 4 carbon atoms per alkyl group,

   Phenyl or benzyl and
X is oxygen, sulfur, sulfonyl or the imino group.



   As already mentioned, in this formula alkyl, represented by the symbols R1, R2 and R, is to be understood as meaning straight-chain or branched alkyl radicals with 1 to 4 carbon atoms, e.g. Methyl, ethyl, n-propyi, isopropyl or one of the 4 isomeric butyl radicals Such alkyl radicals also form the alkyl part of an ali represented by R1: oxy, alkylthio, alkylamino, dialkylamino and alkoxycarbonyl radical. Alkanoyl radicals, e.g. Acetyl, propionyl, butyryl, valeryl, isobutyryl etc. are to be understood as acyl substituents of an acylamino group R1.



   A heterocycle formed by the radicals R4 and R5, the adjacent nitrogen atom and the group N-R preferably has 5-7 ring members. Such heterocycles are, for example, N-methyl-piperazine and N-phenyl-piperazine. The radical R, as an alkyl radical, has the same meanings as were given above for the radicals R1 and R2. Halogen is to be understood as meaning fluorine, chlorine, bromine and iodine, but preferably chlorine and bromine.



   The new thioureas of the formula I are prepared according to the invention by adding an isothiocyanate of the formula II:
EMI1.2
   in which R1, R2, Rs and X have the meaning given under formula I, with an amine of formula III:
EMI1.3
   in whichever R4 and R5 have the meanings given under formula 1, converts and, if desired, compounds obtained in which R1 denotes a nitro group by reduction and compounds in which R1 denotes an acylamino or alkoxycarbonylamino group by hydrolysis into compounds of the formula I, in which R denotes the amino group. The hydrolytic cleavage of lower alkoxycarbonyl groups or

  Acyl groups are preferably carried out in an alkaline medium, for example by heating the compounds obtained in aqueous alkali metal hydroxide solutions.



   The new thioureas of the formula I, in which one of the symbols R1 and R3 has a Sul> substituent capable of salt formation, eg. an alkyl or dialkylamino group or the carboxyl group can be converted into the corresponding salts with acids or bases which are non-toxic to the human and animal organism. Inorganic and organic acids, such as e.g. Hydrogen halides, sulfuric acid, phosphoric acids, acetic acid, aminoacetic acid, butyric acid, lauric acid, stearic acid, oxalic acid, adipic acid, maleic acid, tartaric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. are possible.

  Alkali metal and alkaline earth metal hydroxides and alkanolates, and also quaternary ammonium bases and ammonium salts, are preferably used as bases.



   For the preparation of quaternary ammonium salts, the new thioureas of the formula I, in which R1 is a dialkylamino group, can be treated with customary quaternizing agents, such as e.g. Alkyl halides, dialcyl sulfates, toluenesulfonic acid esters, etc. are converted into the corresponding ammonium salts. If the anion of the quaternary salts obtained is toxic to the human and animal organism, it can be exchanged for a non-toxic anion by reaction with non-toxic acids.



   The process according to the invention is expediently carried out in the presence of organic solvents and / or diluents which are inert towards the reactants. As inert organic solvents, aromatic hydrocarbons, for example benzene, toluene, and aliphatic and aromatic halogenated hydrocarbons, such as methylene chloride, chloroform, chlorobenzene, and ethers and ethereal compounds, such as diethyl ether, dioxane, and N-alkylated acid amides, such as dimethylformamide , and mixtures of such solvents with one another, optionally also water or mixtures of such solvents with water, can be used.



   The isothiocyanates of the formula II used as starting materials are prepared according to the process of Swiss Patent No. 470 846 and Belgian Patent No. 736010 by reacting an amine with a compound capable of introducing the thiocarbonyl group.



   The following example illustrates the preparation of the new thioureas of formula I.

 

   example
To a solution of 10 g of 4-nitro-4'-isothiocyano-diphenylamine in 80 ml of toluene, 3.75 g of N-methylpiperazine are added dropwise at a temperature of 50 ° C. and with stirring.



  After 3 hours of stirring at 50 ° C., the resulting precipitate is filtered off. Recrystallization of the crude product from methanol gives 9.5 g of 4-nitro4'-N- (methylpiperazinyl) thiocarb onylamino-diphenylamine with a melting point of 191-196 ° C.



   Further thioureas, which were prepared according to the method described in the example, can be found in the table below.



   The temperatures are given in degrees Celsius.



      Sclunelz connection points: in degrees
Celsius 4-methoxy-4 '- (N-methylpiperazinylpthiocarbo- 138-140 nilamino-diphenyl ether 4-methyl-4' - (N-methylpiperazinyl) -thiocarbonyl-134-137 amino-diphenyl ether 4-nitro-4 '- (N- methylpiperazinyl) thiocarbonyl 168-169 amino diphenyl ether 4-bromo-4'4N-methylpiperazinyL) thiocarbonyl 151-152 amino diphenyl ether methylthio-4 '- (N-methylpiperazinyi) 4hiccar1 164-166 nylamino-diphenylamine 4-ethyl -4 '- (N-methylpiperazinyl) -thiocarbonyl- 150152 amino-diphenylamine 4-chloro-4' - (N-methylpiperazinyl) -thiocarbonyl- 165-167 amino-diphenylamine 4-nitro-4 '- (N-methylpiperazinyl) - thlocarbonyl

   191-196 aminodiphenylamine 4-chloro-3'-carboxy- (N-methylpiperazinyl, -thio-188-190 carbonylamino-diphenylamine
The new thioureas of the formula I are suitable for combating parasitic helminths and their stages of development. Of the endoparasites that infest domestic and farm animals, the parasitic helminths are particularly dangerous pests. In infested animals, in addition to slowed growth, diseases caused by helminth infestation are often found, which the animals die of. It is therefore of great importance to develop agents which, on the one hand, prevent the infestation of such endoparasites prophylactically, but on the other hand also have a good anthropogenic effect with a broad spectrum of activity.

  However, the previously known ureas and thioureas with anthelmintic action are unsatisfactory, be it that they have an inadequate action in the tolerated doses, in therapeutically effective doses they show undesirable side effects or have too narrow a spectrum of action.



   Urea, such as 3, 5-bistrifluoromethyl-4'-nitro-diphenylurea and 3, 5,3'-trifluoromethyidiphenylurea (both compounds are from Belgian patent no.



  616 735, the former mentioned in the examples of this patent) also show a good effectiveness, but have a strong irritant effect in the application concentrations, which was shown in the extremely thin feces in chickens and diarrhea in sheep and horses. For example, the thioureas known from British Patent No. 956 520, the 3,3 ', 5-tris-trifluoromethyl-diphenyl; -thiourea and the N- (3,5-bis-trifluoromethyl-phenyi) -N'- (3'chlorphenyl) -thiourea in a concentration of 100 mg / kg body weight against Ascaridia galli in chickens and oxyurs in mice, no effect , at 500 mg / kg body weight already severe toxic side effects.



   The thioureas of the formula I accessible according to the invention are not toxic in the normal use concentrations (compare the experiments below). They are very well tolerated by pets and farm animals and have a broad spectrum of activity. The new active ingredients fe are particularly for combating parasitic nematodes (e.g. Ascaridae, Trichostrongylidae, Ancylostomatidae), cestodes (e.g. Taeniidae, Anoplocephalidae, Hymenolepidae) and trematodes (e.g. Fasciolidae) in domestic and farm animals such as cattle, sheep, goats, and horses , Pigs, cats, dogs and poultry.



   The new active ingredients can be administered to the animals either orally or abomasal directly, as a single dose or repeatedly, in the form of solutions, emulsions, suspensions (drench), powders, tablets, boluses and capsules. With a prolonged administration, a better effect is achieved in some cases or one can manage with lower total doses. The active ingredients or mixtures containing them can also be added to the feed or the drinkings, or be contained in so-called feed premixes.



   The application forms are prepared using, for example, customary solid carriers, such as kaolin, talc, bentonite, table salt, calcium phosphate, carbohydrates, cellulose powder, cottonseed flour, carboaxe, gelatin, or idleness such as water, if desired with the addition of surface-active substances such as ionic or nonionic Dispersants, as well as oils and other solvents that are harmless to the animal organism. If the anthelmintic agents are in the form of feed concentrates, for example performance feed, feed grain or protein concentrates serve as carrier substances.

  In addition to the active ingredients, such feed concentrates can also contain additives, vitamins, antibiotics, chemotherapeutics, bacteriostatics, fungistats, coccidiostats, hormone preparations, substances with an anabolic effect or other substances that promote growth, influence the meat quality of slaughtered animals or are otherwise useful for the organism.



   Suitable dosage unit forms for oral use such as dragees, tablets, preferably contain 100-500 mg of the active ingredient according to the invention, namely 20 to 80% of a compound of the general formula I. For their preparation, the active ingredient is combined e.g. with solid, powdery carriers such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, also laminari; apowder or citrus pulp powder, cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to tablets or dragees Kernels.

  The latter is coated, for example, with concentrated sugar solutions, which e.g. Arabic gum, talc and / or titanium dioxide, or a lacquer dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, e.g. for labeling different doses of active ingredients.



   Determination of the anthelmintic effect on chickens infected with Ascaridia galli.

 

   Chicks 1-3 days old were artificially infected with eggs of Ascaridia galli (roundworms). Groups of 5 chickens were used per experiment. 4 to 5 weeks after the establishment, the animals were given the active ingredients once per day on 3 consecutive days.



  Infested chickens that were not medicated served as controls.



   Evaluation:
The number of Ascaridi galli rejected per test group in the course of 5 days after the first administration of the active substance was determined daily and the number still found in the intestine during dissection on the 5th day of the test was also determined. The number of worm-free chickens was also determined.



   Number of Ascaridia galli from 5
Daily dose of chickens Number of active substance mg / kg during the experiments with the uterus-free general
Body duration rejected Section chickens Condition weight absolute in% of the pre
Number Total number found 4-methoxy-4 '- (N-methylpiperazinyl) - 750 125 100 0 5 good -thiocarbonylamino-diphenyl ether 4-nitro-4' - (N-methylpiperazinyl) - 750 125 100 0 5 good -thiocarbonylamino-diphenyl ether 4 -Methylthio-4 '- (N-methylpiperazinyl) - 750 83 95 4 3 good -thiocarbonylamino-diphenylamine 4-ethyl-4' - (N-methylpiperazinyl) - 750 191 100 0 3 good -thiocarbonylamino-diphenylamine 4-chloro-4 '- (N-methylpiperazinyl) - 750

   136 100 0 5 good thiocarbonylaminodiphenylamine
Experiments on rats infected with Fasciola hepatica
White laboratory rats are artificially infected with liver eggs (Fasciola hepatica). After the preparation time has elapsed, the infestation of the rats by liver fluke is detected by means of 3 independent faecal analyzes.



   In each experiment, 4 infected rats are treated with the active ingredient, which is applied in the form of a suspension by gastric tube, once a day on 3 consecutive days. In the 3rd to 5th week after administration of the active ingredient, a faecal analysis is carried out once a week for the content of liver jelly eggs. At the end of the 5th week after the start of the experiment, the test animals are sacrificed and examined for any liver flukes that are still present.



   Daily dose of faeces control for egg release Number of active substance in the liver in mg / kg 3 times body-body before after after regardless of condition weight medication medication section condition 4-methoxy-4 '- (N-methylpiperazi- 200 positive negative 2-0-1 -0 good nyl) -thiocarbonylami.no-diphenyl-ether 4-methylthio-4 '- (N-methylpipera- 200 positive negative 0-0 good zinvl) -thiocarbonylamino-diphenyi- amine 4-ethyl-4' - (N- methylpiperazinyl) - 200 positive negative 0-0-0-0 good -thiocarbonylamino-diphenylamine 4-chloro-4 '- (N-methylpiperazinyl) - 200 positive negative 0-0-0-0 good -thiocarbonylamino-diphenylamine
Experiments on mice infected by Hymenolepis nana
The active ingredients were in the form of a suspension via nasogastric tube

   administered to white mice artificially infected with Hymenolepis nana. 5 animals were used per experiment. The active substances were administered to each group of animals once a day for 3 consecutive days. The animals were then sacrificed and dissected on the 8th day after the start of treatment.



   The evaluation was carried out after dissection of the test animals by counting the tapeworms in the intestine.



  Untreated mice infected simultaneously and in the same way served as controls.



   The mice tolerated the agents without symptoms.



   Infestation of
Daily dose 5 infestation of the active ingredient mg / kg search control animals
Body animals at both secuon weight of
Section 4-nitro-4 '- (N-methylpi- 75Q 0-0-al-1 0-4-13-13-23 perazinyl) -thiocarbonyl aminodiphenyl ether 4-methylthio-4' - (N-me-750 0-0-0-0-0 11-13-16-23-32 thylpiperazinyl) -thiocarbonylamino-diphenylamine 4-chloro-4 '- (N-methylpi- 750 4-0-0-2-6 0- 6-7-8-9 perazinyl) thiocarbonylamino-diphenylamine
Experiments on oxyur-infested mice
The active ingredients were administered in the form of a suspension by gastric tube to white mice infected with mouse oxyurs. 5 animals were used per experiment.

  The active ingredients were administered to each group of animals once a day for 3 consecutive days.



   The daily dose per animal was 750 mg of active ingredient per kg / body weight.



   The animals were then sacrificed and dissected on the 6th day after the start of treatment. The evaluation took place after dissection of the test animals by counting the mouse oxides in the intestine. Untreated mice infected in the same way served as controls.



   The mice tolerated the agents without symptoms.



     
Daily dose infestation of the
Daily dose mg / kg 5 The infestation of the active ingredient mg / kg suclnti ere control animals
Body at the weight of the section 4-methoxy-4 '- (N-methyl- 750 0-0-0- 3/1 / 1-3 / 2 / 3piperazinyl) -thiocarb- 0/2 / 2- 7 / 3 / L-8/8 / 4onylamino-diphenylether 0/2/3 19/4/8 4-Nitro-4 '- (N-methyl- 750 0-0-1- 5/9 / 8-6 / 5 / 5piperazinyl) thiocarb- l / lL-3 9/9 / 10-13 / 2/2 onylamino-diphenyl ether -20/10/9 4-methylthio-4 '- (N-me-750 0-0-0-0 -0 5/4 / 4-6 / 3 / 3thylpiperazinyl) -thio- 10/5 / 4carbonylamino-diphenyl- 12/12 / 10- amine 17/9/7 4-ethyl-4 '- (N-methyl-750 1 / 3L- 3/1 / 1-3 / 2 / 3- piperazinyl) -thiocarb- 0 0-0 0/1 7 / 3L- 8/8 / 4- onylamino-diphenyl- 19/4/8 amine 4- Chlorine-4 '- (N-methyl-750 1-0-0-0-0

   3/1 / 1-3 / 2 / 3piperazinyl) -thiocarb- 7 / 3L-8/8 / onylamino-diphenyl- 19/4/8 amine L = adult forms 1 = juvenile forms + = animal dead
Work-up forms of the new thioureas of the general formula I are described below. Parts mean parts by weight.



   Active ingredient concentrates in paste form:
Such semi-solid or oily active ingredient concentrates have, for example, the following composition: a) 40 parts of active ingredient of the formula I.
10 parts Bolus alba
2 parts of sodium lignosulfonate, 0.2 parts of sodium benzoate
1.0 part carboxymethyl cellulose
46.8 parts of water b) 30 parts of active substance of the formula I.
70 parts of arachidoel
The active ingredients are finely ground with the carriers, distribution agents and other additives (particle size 5-10 microns).



   The homogeneous concentrates obtained are administered to pets and farm animals using a drenching pistol. These concentrates are used for the temporary deworming of livestock, for example for deworming a by Haemonchus spp., Trichostrongylus spp. etc., infested flock of sheep.



   Powder concentrates:
The following substances are used to produce a) 50% and b) 25% powder concentrate: a) 50 parts of the active substance of formula 1
3 parts of polyoxyethylene sorbitan monooleate
3 parts of lignin sulfonic acid sodium salt
44 parts of Bolus alba b) 25 parts of active ingredient of Formula 1
3 parts of polyvinylpyrrolidone
3 parts of dodecylbenzenesulfonate
39 parts of diatomaceous earth
30 parts of Bolus alba
The specified active ingredients are absorbed onto the carrier substances, for example as acetone solutions.

 

  The dispersants and wetting agents are then added and the concentrate is ground until it is homogeneous. Such powder concentrates can be added to the feed, added to conventional feed premixes or diluted with water to make ready-to-drink drinkers. In addition, these powder concentrates can be enclosed in gelatine capsules directly, for example administered to dogs, or incorporated into feed, tabletted (feed pellets).

 

Claims (1)

PATENT CLAIM I Process for the preparation of new thioureas of formula 1: EMI5.1 in the R1 is hydrogen, hydroxyl, alkyl, alkoxy, alkylthio, alkoxycarbonyl, carboxyl, amino, alkylamino, dialkylamino, acylamino, halogen, nitro or sulfamoyl, each with 1 to 4 carbon atoms per alkyl group, R2 hydrogen, alkyl, alkoxycarbonyl with 1 to 4 carbon atoms per alkyl group, carboxyl, halogen or nitro, R3 hydrogen, carboxyl, halogen or nitro, R4 and R5 together form a polymethylene bridge with 3 to 6 methylene groups, one of which is replaced by the group N-R, in which R is alkyl, hydroxyalkyl with 1 to 4 carbon atoms per alkyl group, phenyl or benzyl and X denotes oxygen, sulfur, sulfonyl or the imino group, characterized in that an isothiocyanate of the formula II EMI5.2 in the R1, R2, R3 and X have the meanings given under formula I, with an amine of formula III: EMI5.3 in which R4 and R5 have the meanings given under formula I, to form a compound of formula I. SUBCLAIMS 1. Process according to claim I, characterized in that an end product of the formula I in which R is an acylamino group is hydrolyzed. 2. Process according to claim I, characterized in that an end product of the formula I in which R1 is a nitro group is reduced. 3. The method according to claim I, characterized in that an ena; toff of the formula I, in which one of the symbols R1 and R3 represents a substituent capable of salt formation, with a base or acid which is non-toxic to the human and animal organism appropriate salt transferred. PATENT CLAIM II Use of a compound of formula I prepared according to claim I, in which R1 represents a dialkylamino group, characterized in that the dialkylamino group is converted into the corresponding quaternary salt with a quaternizing agent. Note from the Federal Office for Intellectual Property: If parts of the description are not in accordance with the definition of the invention given in the patent claim, it should be remembered that according to Art. 51 of the Patent Act, the patent claim is decisive for the material scope of the patent.