IL32603A - Isothiocyano-diphenylamines,their preparation and anthelminthics compositions containing them - Google Patents

Description

AGRIPAT 8.A* New isothiocyano-diphenylamines , processes for their production and use thereof as antihelminthics The present invention concerns new isothiocyano-diphenylamines and processes for the production of these new compounds, as well as the use of the new compounds for the control of parasitic helminths.

Among endoparasites which occur in warm-blooded animals, helminths are those which cause the greatest damage. Thus animals attacked by them, for example, not only show retarded growth, but often injuries occur which can result in the death of the animals. It is, therefore, of great importance to develop agents which are suitable for combating helminths in all stages of their development and for preventing infestation by these parasites.

Although there are a number of substances known having anthel-minthic properties, they are often not wholly satisfactory, be it that their action is insufficient when applied in toxicologi-cally tolerable doses, or that when applied in therapeutically effective doses undesirable side effects appear, or that they show only a very specific range of action.

In the present description, the term "helminths" refers to nematodes, cestodes and trematodes, i.e. to worms which infest the gastrointestinal tract, the liver and other organs.

The novel anthelminthically active isothiocyano-diphenyl As an alkyl or alkenyl radical, in the above formula are meant straight chain or branched chain radicals, for example the following: methyl, ethyl, n^-propyl, isopropyl, n-butyl, iso-butyl, ter -butyl, sec-butyl and pentyl radioals, as well as allyl, methallyl, propenyl, ieopropenyl and butenyl radicals. A dialkylamino radical H1 has* in straight chains, 1 to 5 and in branched chains 3 to 5 carbon atoms. Alkenyloxy radicals have in straight (Jains 2 to 5 and in branched chains 3 to 5 carbon atoms.

As alkanoyl radicals R^ is for example the following: the formyl, acetyl, propionyl, butyryl, valeryl, isobutyryl and isovaleryl radicals. Such alkanoyljadicals preferably also form the alkanoyl ladical of an alkanoylamino group. In an alkoxy-carbonyl radical, the alkoxy moiety has at most 5 carbon atoms in a straight or branched chain.

Preferred compounds of the formula I are those in which R represents hydrogen represents hydrogen, chlorine, bromi nit o, alkoxy of at most 5, in particular 1 or 2;carbon atoms or alkylthio with at most 5» in particular 1 or 2, carbon atoms* Rg represents hydrogen, alkyl of at most 5» in particular 1 or 2, carbon atoms or isothio cyano, and represents hydrogen or oarboxy, and wherein any isothiocyano group must be in m- or p-position to the -NH-bridge, and when ^ and ^ are hydrogen* and 2 is isothiocyano, the latter must be in m-position to he -HH-bridge.

The isothiocyano-diphenylamines of formula I are produced according to the invention by reacting an amino-diphenylamine of the formula II: alkyl represents a lower alkyl . radical having- at most 4 carbon . .· atoms , and :.· ' ' ..·, ·.."· . '■ m represents the integer 1 or 2, or · : . · · " ' c) pentathio-dipercarbonic acid-bis-(trihalogenoalkyl) esters The processes are preferably performed in the presence of. solvents or diluents' hich are inert towards the reaction . ·■ - . . . . , . ' . . . components. ' - ' , For the process according to the invention, as.thiocar-bonic acid derivatives mentioned under (a), either thiophosgene, optionally in the presence of an acid-binding agent and at. temperatures ranging between 0 and 75°C, >'or N,N-diethylthiocarba-moyl chloride at temperatures between 40 and 200°C are used.

The thioca bonyl group is introduced by known methods: reactions of amines with thiophosgene (a) are described in Houben eyl 4th Ed. , Vol. 9, page.867 (1955) the use of acid-binding agents is described by O.E.: Schultz in Arch. Pharm. 295, 146-151, (1962); the reaction of amines with Ν,Ν-diethylthiocarbamoyl chloride (a) is described in the Journal org. Chem. 30, 2465· (1965), with bis-thiocarbamoyl sulfides (b) by F.H. Marquardt in Helv. chim. Acta 49., .1716 (1966),' and those with pentathio-dipercarbonic acid-bis- (trihalogenoalkyl). esters '(c) "by R. Gottfried in Angew. Chemi 7_8, 985 (1966). ' · . " ' ■ ' The new isothiocyano-diphenylamines of Formula I, where-' . in R. ,. R and R, have the meaning given for Formula I with the . ! exception that nitro,. carboxy and trifluoro ethyi must be at a ' j ring not bearing an amino group, are. also obtained by reactin : ; a diphenylamine of Formula II, in which ^, '2 and ^ have the | i meanin s iven for Formula II with th x hydrogen chloride in a solvent which is inert towards the reaction components, preferably in an aromatic hydrocarbon or halo-hydrocarbon; e) with benzoyl isothiocyanate into the corresponding thiourea and this is then decomposed by heating, in the presence of a solvent which is inert towards the reaction components, preferably in an aromatic hydrocarbon or halohydrocarbon , or in the presence of acids or acid anhydrides; f) with carbon disulfide in the presence of an inorganic base or a tertiary amine into the corresponding dithiocarbamic acid salts and then splitting off the mercapto moiety therefrom.

For the reactions mentioned under (d) and (e), chloro-benzene is preferably used as solvent, other suitable solvents are, however, also dichlorobenzene , toluene, xylenes, cumene, etc. Process (d) is performed according to British patent No. 1,099,768, by saturating the solution of the diphenylamine with hydrogen chloride gas, then adding the ammonium thiocyanate and refluxing for several hours under continual introduction of hydrogen chloride. The thermal decomposition of thioureas (e) is performed in the manner described by J.N.Baxter et al. in J.Chem.Soc. (1956), page 659 ff. The thioureas are produced according to Org. Synthesis III 735 (1955). As inorganic bases for the production of dithiocarbamic acid salts (f), for example, the hydroxides, oxides and carbonates of alkali metals and alkal earth metals as well as ammonium hydroxide are used; as tertiar amines, for example, trialkyl amines, pyridine bases, etc., are used. The stripping off of the mercapto moiety can be performed oxidativel with metal salts British atent No 793 802 Dutch 32603/2 ,J wherein R, ^6 an0 ^ have' ΐηδ same meaning as above, and the -NCS group at ring B and any isothiocyano grou R2 are in m- or p-position to the bridge -NR- when R is hydorgen and any isothiocyano group R2 is in m- or p-position to the Y-H- group; with a compound of Formula V: R Z · · (V) '" wherein R^ has the meanings given for Formula III, and ^ Z represents chlorine, bromine or iodine, o in stoichiometrical amounts, calculated on hydrox 1 and/or mercapto groups' (-Y-H) . For the production of compounds of Formula III in which R^ represents an alkyl radical, instead of a compound of Formula V, a dialkyl sulfate can also be employed. The performance of this modification of the process is carried out in the 5 manner described in German patent No. 852,087; The starting amino-diphenylamines of Formula II wherein R represents an alkyl or alkenyl radical with at most 3 carbon wherein R^ R2 and R3 are as defined under Formula I, preferably in the presence of an acid binding agent and of a solvent inert towards •the reactants, with a compound of Formula VII R - E (VII) wherein R has the meaning given above and E represents a halogen atom or an or arylsulfonyloxy-group and reducing by methods known per se the so. obtained N-alkyl- or N-alkenyl-nitrodiphenylamine to the N-alkyl- or N-alkenyl -amino - diphenylamines , for instance, not only by means of molecular hydrogen, but also by means of nascent hydrogen, formed,, e.g. in a solution or suspension of the nitro-diphenylamine . Moreover, the reaction may be performed also by means of hydrogenatio catalyst such as e.g. Raney-nickel , and Raney-cobalt . Nitro-diphenylamines of Formula VI are in part known and in part new compounds. As far as they are new, they may be prepared according to Houben- Weyl 11/1, page 242 or F. Ullmann, Ber. 41, 3744-3755 (1908).

The novel isothiocyano-diphenylamines of Formula I wherein one of the symbols R-^ and R^ represent a tertiary amino group be converted into the corresponding salts ·■ or acids that are non-toxic for human and animal organisms. Suitable acids are inorganic and organic acids such as, for example, hydro halic acids, sulfuric acid, phosphoric acids, acetic acid, amino- sulfonic acid and p-toluene sulfonic acid, or for the production !· . of quaternary salts and they can be converted with the usual quaternizing agents such as alkyl halides, dialkyl sulf ates, toluene sulfonic acid esters, etc. , into the corresponding quaternary ammonium salts. If the anion of the quaternary salt is toxic for the animal organism, it can be exchanged for a nontoxic anion by reacting with a non-toxic acid.

The amines serving as starting materials can be employed in the form of the free bases and also as acid addition salts, especially those from mineral acids. Examples of suitable inert, organic solvents that can be employed in the process according to the invention are the following: aliphatic or aromatic hydrocarbons, aliphatic and aromatic halohydro-carbons, ether and ether-type compounds, water or mixtures of such solvents with water.

The isothiocyano-diphenyl amines ■ according to the invention, and their salts, including the quaternary salts, possess decided anthelmintic, properties. The new active substances are especially suited for combating parasitic nematodes: such as ascaridae, trichostrongylidae , strongylidae , ancylostomatidae ; cestodes: such as taeniidae, anoplocephalidae ; trematodes: such as fasciolidae; in pets and domestic animals such as cattle, sheep, goats, horses pigs, cats, dogs and poultry.

The active substances can be administered to helminth-infested animals or to animals to be protected against helminths dose or repeatedly, the single dosage, depending on the type of animal, preferably, between 25 and 1000 mg per kg bodyweight.

In some cases better results are obtained or the total amount required for a cure can be decreased by protracted administration. The concentration in which the active substances in the form of such agents are added, e.g. to feeds or liquids given to animals are between 0.05 and VL by weight.

The novel isothiocyano-diphenyl amines and their salts which are non-toxic for the organism, can be administered to the animals perorally- or via the abomasum in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boluses and capsules.

To prepare the forms of application listed above, conventional solid carriers can be used such as kaolin, talcum, bentoriite, sodium chloride, calcium phosphate s carbohydrates, cellulose powder, cottonseed meal, carbowaxes, gelatins, or liquids such as water, if desired with the addition of surface active substances such as ionic or non-ionic dispersing agents, and also oils and other solvents which are well tolerated by the animal organism. When the anthelmintic ·. agents are in the form of feed concentrates, carriers which can be used are, for example, formulated foods, grain feeds or protein concentrates. Such feed concentrates can also contain, in addition to the active substan ces, other additives , e . g. -vitamins , antibiotic, chemotherapeu i , bacteriostatic, fungistatic and coccidiostatic substances, hormone preparations, substances having an anabolic activity or other substances which promote growth, influence the quality, of the meat of fat stock animals or are useful to the animal or Some tests to determine the anthelmintic: activity of the new isothiocyano-diphenylamines of the general Formula I are described below.

Determination of the anthelmintic , action on chickens infested with Ascaridia galli 1 to 3 day-old chicks were artificially infested with eggs of Ascaridia galli . Groups of 5 chicks each were used for each test. 4 to 5 weeks after infestation, the active substances were administered to the animals in a single dose per day on 3 consecutive days. Infested chickens that had not been treated served as controls.

Evaluation: The number of Ascaridia galli eliminated by each test group during 5 days after the first administration of the active substance was determined daily and in addition the number of worms still found in the intestine after' dissection on the 5th day. Furthermore, the number of chickens free from worms was determined .

Daily (lumber of Ascaridia gal i from 5 Number 3eneral dosage chi ckens ■ of siorm- con¬ A c t i v e s u b s t a n c e o/kg f ree dition body el iai nate i during the found chickens weioht L.est at dissection absolute in % of the number total number 4-chl oro- ' -carboxy-4'-i sot iocyano-di phenyl affli ne 500' ! 100 0 5 good 3-methyl - 1 -i sothi ocyano-di pheny 1 ami ne 500 353 100 0 5 good -ni tro-4'-isoth i ocyano-di phenyl amine 500 εο • 100 0 5 good 4-methy 1 -4 '-i sothi ocyano-di phenyl amine 500 " 72 100 0 5 good 4-tert-buty 1 - '-i sothi ocyano-di henyl -amine 500 65.. 100 0 5 good 4-me thy 1-3-i sothi ocyano-di henyl amine 500 199 100 0 5 good 4-hydroxy- -i sothi ocyano-di phen l ami ne 500 119 "86 19 3 good 4-chloro-4'-i sothi ocyano-di phenyl amine 500 37 100 0 5 good 3-i sothi ocyano-di phenyl amine 500 169: 100 0 5 good 4-tr,ethoxy-4'-i sothi ocyano-di pheny 1 amine 500 86 100 0 5 good 4-methy lthio-4'-i sothi ocyano-di phenyl -aniine 750 1 3 100 0 5 good N-al lyl-4-chl oro-4'-i sothi ocyano-di pheny 1-amine 750 211 98 4 4 good 3, 4-di methyl -V-i sothi ocyano-di phenyl amine 750 106 100 0 5 good 3-trif luoromethyl -3' -i sothi ocyano-di -phenylaiiiine 170 168 98 2 3 good 4-bromo-4 '-i sothi ocyano-d i phenylamine 750 164 100 0 5 good 3-nitro-4'-i sothi ocyano-di pheny la mine 600 104 100 0 5 good 3, V-di i sothi ocyano-di phenyl amine 750 137 100 0 5 good Tests on mice infested with Hymenolepis nana The active substances, in the form of a suspension, were administered via an esophagal syringe to white mice which had been infested with Hymenolepis nana. Five animals were used for each test. The active substances were administered once a day to each test animal on 3 consecutive days. The animals were then killed and dissected on the 8th day after the beginning of the treatment.

The results were evaluated after dissection of the test animals by counting the number of tape worms in the intestines. Untreated mice, which had been infested in the same way and at the same time served as controls.

The agents were tolerated by the mice without any symptoms.

Daily Infestation Infestation of dosage of the test the control A c t i v e s u b s t a n c e mg/kg animals at animals at disbody dissection section weiqht 3-methyl-4' -i sothi ocyano-di phenylam ί ne 500 0-0-0-0-0 3-3-0-0-1 4-ni tro-4'-i sothi ocyano-di phenyl amine .750 0-0-1-0-0 4-5-1-11-2 4-methyl - 1 -i soth i ocyano-d i phen laroi ne 750 0-0-0-0-0 22-41-5-15-21 2-carboxy-3'-i sothi ocyano-di phenyl amine 400 0-0-0-0-0 · 8-0-23-4-5 4-chloro-4'-i sothi ocyano-di phenyl amine 750 0-0-0 -0-0 28-19-16-11-13 2-carbomethoxy-3'-i sothi ocyano-di phenyl amine 750 0-0-0-0-0 9-4-3-6-5 -methyl i o-3' -i sothi ocyano-di phenyl amine 750 0-0-0-0-0 4-6-2-4-7 4-meth l thio-4~ri sothi ocyano-di phenyl amine 750 0-0-0-0-0 4-5-2-4-7 3-c loro-V-i so thi ocyano-di phenyl amine 500 0-0-0-0-0 1 -3-21-9-8 3-ni tro-V-i so thi ocyano-di phenyl amine 750 0-0-0-0-0 3-5-4-4 A-acetamido-3 '-i so thi ocyano-di phenyl amine 750 0-0-0-0-0 3-5-4-4 3,4-- bis-i so thi ocyano-di henyl amine 750 0-0-0-0-0 3.5-4-4 N-n-propyl-4-n)ethoxy-4'-i sothi ocyano-di phenyl amine 750 0-0-0-0-0 3-4-5-6-9 N-al lyl- -methoxy- -i so thi ocyano-di phenyl a ine 750 0-0-0-0-2 3-4-5-6-9. -allyl-4-chlor-V-i so thi ocyano-di phenyl amine 750 0-0-0-0-0 3-8-12-16-15 Tests on rats infested with Fasciola hepatica White laboratory rats are infested with liver flukes (Fasciola hepatica). On completion of the prepatency period, th infestation of the rats by liver flukes is determined by three separate analyses of the faeces.

For each test 2 to 4 infested rats are treated once daily for three consecutive days with the active substance which is applied via an esophagal syringe in the form of a suspension. From the third to the fifth week after administration of the active substance, the faeces are analyzed once a week to determine whether they contain any eggs of liver flukes. At the end of the fifth week of the test, the test animals are killed and examined for the presence of liver flukes.

Daily Examination of faeces Number of General dosage for elimination of liver con- mg/kg of eggs 3 times flukes di tion A c t i v e s u b s t a n c e body after weight before after dissection edi cation medication 2, 4-d i ni tro- ' -i sothi ocyano-d i phenyl arc i ne 200 positive negative 0-0 good 3— me hy 1 - '-i sothi ocyano-di phenyl am in 50 positive negati ve 0-0 good 4-iiiethoxy-2-carboxy-5'-i sothi ocyano-dipheny lam ine 200 positive negative 0-0 good 4-ni tro-4 '-i sothi ocyano-di phenyl am ine 200 posi five negative 0-0 good 4-acety 1 ami no-4 '-ΐ sothi ocyano-dipheny lain ine 50 positive negative 0-0 good 4-methy 1 -4' -i sothi ocyano-di phenylamine 200 posi tive negative . 0-0 good 2-carboxy-3 ' -i soih i ocyano-di phenyl amine 100 positive negative 0-0 good 2-carboxy-4 ' -i sothi ocyano-di phenyl an i ne 50 positive negative 0-0 good 4-chloro-4'-i sothi ocyano-di phenyl ara ine 100 positi e negati ve 0-0-0-1 good 2-carboxy-3-i sothi ocyano-di phenyl am ine 100 posi tive negative 0-0-0-0 good '1-3 '-i sothi ocyano-di pheny larai ne 200. positi e negative 0-0-0-0 good 4— methyl th i o-41 -i sothi ocyano-d i phenyl ami ne 150 positi e negative 0-0-0-0 good N-al lyl-4-chl oro-4'-i sothi ocyano-di phenyl am ine 200 positive negative 0-0-0-2 good N-al lyl -4-methy 1-4' -i sothi ocyano-di phenyl amine 50 posi tive negative 0-0-0-0 good H-n-propyl-3-methox.y-V-i sothi ocyano-di phenyl am ine .200 positive negative 0-0-0-0 good N-al lyl -4-methy 1th i o- -i sothi ocyano-di henyl amine 150 positive negative 0-0-0-0 good 4-i sothi ocyanodi phenylamine 75 positi ve negati e 0-0-0-0 good 3-chloro-4!-i sothi ocyano-di henyl ara ine 100 posi tive negati ve 0-0-0-0 good 3-ni tro-4' -i sothi ocyano-di phenylamine 200 posi ti ve negative 0-0-0-2 good 4-d i methy 1 am ino-4'-i sothi ocyano-di phenyl am ine 100 positive negative 0-0-0-0 good 3, 4-di methyl -4 '-i sothi ocyano-di phenyl a ine 200 positive negative 0-0-0-0 good Tests on mice infested with, mouse oxyuridae The active substance was administered via an esophagal syringe in the form of a suspension to white mice which had been infested with mouse oxyuridae. 5 animals were used for each test. The active substances were administered to each test animal once daily for three consecutive days. The animals were then The results were evaluated after dissection of the test animals by counting the number of mouse o yuridae in the intestines. Untreated mice which had been infested in the same manner served as controls.

The agents were tolerated by the mice without any symptoms.

Daily length of infestation of Infestation of the dosage adminithe 5 test control animals at mg/kg stration animals at dissection A c t i ve s.u b s i a n c e body in days dissection »eight 3 -nethyl - '-i soth i ocyano-d i phenyl amine 500 3 0-0-0-0-0 5/L1-7/L-20/1- 0/L1-8/L1 4-ni tro- '-i sot i ocyano-di pheny Jami ne 750 3 0-0-0-0-0 9/U-25/L1-0/L- 0/L-4/L1 4-aethyl - '-i sothi ocyano-di phenyla ine 750 3 0-0-0-0-0 2-4-0-3/L-12/L 4-tert-butyl -i sothi ocyano-di phen lam i ne 750 3 0-0-0-0-0 2- -0-3/L-12/L 4-methyl -3' -i sothi ocyano-di henyl an ine 750 3 0-0-0-0-0 2- -0-3/L-12/L 4-chloro-4' -i sothi ocyano-di phenyl amine 750 3 0-0-0-0-0 12/L /1-0-9-4/L -methoxy-4'-i sothi ocyano-di phenyl am ine 750 1 0-0-0-0-0 4-7-12-10-24 2-carbomethoxy-3 sothi ocyano-di phenyl amine 750 3 0-Λ-0-0-0 4/L-4/L1-5/L1- 7/L1-4/L1 4-methy 1 th i o-3 '-i soth i ocyano-d i phenyl am i ne 750 3 0-0-0-0-0 82/1-35/1-45/1- 5/M/L1 4-methyl thio-4'-i sothi ocyano-di pheny lam ine 750 3 0-0-0-0-0 82/1-36/1-45/1- 5/1-4/L1 3-ch loro- -i sothi ocyano-di pheny lam i ne 500 3 0-0-0-0-0 O-O/L-2-1-1 3-ni tro- -i sothi ocyano-di phenyl am ine 750 3 0-0-0-0-0 3/L1-3/1-0-8/1 -acetami do-3 ' -i sothi ocyano-di pheny lam ine 750 3 0-2L-3-0-0 3/L1-3/1-0-8/1 3,4* — d i i sothi ocyano-di phenyl amine 750 3 0-0-0-2L-0 3/L 1-2/1 -0-8/1 N-n-propyl-4-methoxy- '-i sothi ocyano-di pheny lam ine 750 3 0-0-0-0-0 4/L-4/L1-5/U- 7/L1-4/L1 iJ-allyl-'i-methoxy-V-i sothi ocyano-di pheny lam ine 750 3 0-0-0-0-0 4/L-4/L1-5/L1- 7/L1-4/L1 H-allyl-4-chloro-V-i sothi ocyano-di phenyl amine 750 3 0-0-0-0-101 4/L-4/L1-5/L1- 7/L1-4/L1 N-n-propy 1 -3-me thoxy-4 ' -i so th i ocyano-d i pheny 1 - 750 3 0-0-0-0-1 L' 15/L1-20/L-28/L1-amine 60/L-40 4-e t hyl - ' -i sot i ocyano-di pheny lam ine 250 3 0-0-0-0-0 15/L1-20/L-28/L1- 60/L-40 4- i th l - '-i s t i n - i h n i 7 3 -0- - -0 15 L1-20 L-28 L Daily " length of Infestation of Infestation of the dosage adminithe 5 test control animals at A c t i v e s u b s t a n c e ■iiig/ko stration aninals at di ssection body in days dissection weight 4-al lyloxy-V-i sothi ocyano-di phenyl amine 750 3 0-0-0-0-0 ■ 15/L 1 -20/L-28/L Ί - oOLAO f 1 'joronethy. -chl oro-4 ' -i sothi ocyano-di -phenyl aiiiine 750 3 0-0-0-0-0 8-10-11-12-13/1 A-bromo-A 1 -i sothi ocyano-di phenyl arai ne 750 3 0-0-0-0-0 4/L1/5/U-7/L1- 12/L1-24/L1 4-nethoxy-3'-i sothi ocyano-di henyl amine 750 3 0-0-0-0-0 3/L-12/L-15/L- 16/L1-28/L1 presence of old larvae presence of young larvae The following examples illustrate the process according to the invention. Where not stated otherwise, "parts" are expressed by weight. The temperatures are given in degrees centi grade.

Example 1 A solution of 16.1 parts of 4-chloro-4' -a inodiphenyl-amine in 100 parts by volume of dioxane is added dropwise to an emulsion of 9.6 parts. of thiophosgene in 100 parts ^by volume of ice water, and stirred for 14 hours at room temperature. The resulting precipitate is washed well with water, and after drying in vacuo is recrystallized from ether/petroleum ether. 14 Parts of 4-chloro-4' -isothiocyano-diphenylamine , m.p. 110-112°, are obtained.

Example 2 A solution of 19.8 parts of 3-methyl-4 ' aminodiphenyl-amine in 300 parts by volume of ether is added dropwise to an emulsion of 12.6 parts of thiophosgene in 150 parts by volume of ice water. After stirring for 8 hours at room temperature, the layers are separated, the organic phase is dried over potassium carbonate, filtered, concentrated, and the oil remaining is distilled in high vacuum. 11 Parts of 3-methy1-4' -isothiocyano-diphenylamine , b.p. 169- 73°/0.002 Torr, distill.

Example 3 At -10°, first 68 parts by volume of absolute triethyl-amine and then 9.7 parts by volume of carbon diexide are added dropwise, in such a manner that the internal temperature does not exceed 0°, to 32 parts of 4-methyl- ' -aminodiphenylamine in 80 parts by volume of absolute ether.

After stirring for 18 hours at room temperature, 15.1 of absolute ether are added dropwise. (Internal temperature 0 to 10°, time of addition: 45 min.) Stirring is then continued for another 18 hours, the ethereal solution is decanted, and the residue is extracted 3 more times with 100 parts by volume each of ether. The combined ether extracts are concentrated and the remaining 4-methyl-41 -isothiocyano-diphenylamine distills at 181-183°/0.02 Torr. Melting point of the distilled product: 64-66°.

Example 4 44 Parts of thiophosgene in 50 parts by volume of chloroform are added dropwise to a solution of 73 parts of 4-methylthio-4' -aminodiphenyl amine in 300 parts by volume of chloroform and 63.5 parts of sodium bicarbonate in 1000 parts by volume of water. After completion of the addition, stirring is continued for 6 hours at room temperature, the layers are separated, the chloroform solution is dried over magnesium sulfate, filtered and concentrated. The residue is dissolved in alcohol, and the 4-methylthio-4 '-isothiocyano-diphenylamine , .p. 87-91°, is precipitated by the addition of water. Yield: 65 parts.

Example 5 24.4 Parts of thiophosgene in 250 parts by volume of ether are added dropwise to a well-stirred suspension of 39 parts of 4-hydroxy-4' -amino-diphenylamine and 40 parts of sodium bicarbonate in 200 parts by volume of ice water. After completion of the addition, stirring is continued for 8 hours at room temerature, the la ers are then separated, the or anic phase is residue is recrystallized from toluene. 16.8 Parts of 4-hydroxy- 4' -isothiocyano-diphenylamine , m.p. 118-120°, are obtained. 12.8 •Parts thereof are refluxed with 7.5 parts of potassium carbonate in 40 parts by volume of acetone for 30 minutes with stirring; then 15.2 parts of allyl bromide are added dropwise with cooling. After refluxing for 18 hours, the reaction mixture is filtered, the filtrate is completely concentrated, and the residue is re-crystallized from ether/petroleum ether to which animal charcoal has been added. 11 Parts of 4-allyloxy-4' -isothiocyano-diphenylamine, m.p. 62-64°, are obtained.

Example 6 7.4 Parts of benzoyl chloride are added dropwise to a solution of 4 parts of ammonium thiocyanate in 20 parts by volume of acetone. The mixture is refluxed and, while hot, treated with a solution of 11.5 parts of 4 ' -amino-4-methylthio-diphenylamine in 20 parts by volume of acetone. The reaction mixture is then poured with stirring into 300 parts by volume of water, and treated with 150 parts by volume of 30 % aqueous sodium hydroxide solution, and then refluxed. After the mixture has cooled, it is neutralized with hydrochlorid acid, while cooling with ice, and the resulting precipitate is removed by suction. The resulting 1-N- (4' -methylthiophenyl) -4-amino-phenyl-thiourea is dried and then refluxed for 10 hours in 100 parts by volume of chlorobenzene The solvent is then removed by distillation and the residue is recrystallized from ethanol/water . The 4' -isothiocyano-4-methyl- thio-diphenylamine has a melting point of 87-91°. The mixed melting point with the compound obtained according to Example 4 Example 7 a) 17.7 Parts of —nitro-4-aminodiphenylamine in 200 parts by volume of ice water are treated with 9.7 parts of thiophosgene and stirred for 12 hours at room temperature. The resulting dark yellow precipitate is separated by filtration, dried in vacuum at 70° and recrystallized from acetone. 11.7 Parts of 4-nitro-4' -isothiocyano-diphenylamine, m.p. 204-206°, are obtained b) A suspension of 29.9 parts of 4-nitro-4' -aminodiphenyl-amine and 30.7 parts of bis-diethyl-thiocarbamoyl disulfide (tetra ethyl thiuramdisulfide) in 500 parts by volume of chlorobenzene is saturated with hydrogen chloride gas at room temperature, while excluding atmospheric moisture; then it is stirred for 4 hours at reflux, filtered hot, the separated warm "' " organic layer is extracted with warm water, then dried over calcium chloride, filtered and concentrated. The crystalline residue is recrystallized from acetone/toluene to which animal charcoal has been added, whereby 10 parts of 4-nitro-4' -isothiocyano-diphenylamine , m.p. 202-205°, are obtained. The mixed melting point with a sample of the substance obtained according to (a) shows no depression. c) 11.45 Parts of 4-nitro-4' -aminodiphenylamine and 7.95 parts of N, -diethyl-thiocarbamoyl chloride are refluxed for 6.5 hours with 150 parts by volume of chlorobenzene. After removal of the solvent by distillation, the crystalline residue is dispersed in ethyl acetate/water, the layers are separated, the organic extract is dried over potassium carbonate, filtered and concentrated. The crystalline residue which remains is recrystallized according to Example 6 b) from acetone/toluene, identical melting point and mixed melting point, are obtained. d) A solution of 11.5 parts of 4-nitro-4' -amino-diphenyl-amine in 100 parts by volume of chlorobenzene (anhydrous) is saturated with dry hydrogen chloride gas, then treated with 5 parts of ammonium thiocyanate and refluxed for 6 hours with continual introduction of hydrogen chloride gas. The undissolved portions are removed by filtration and the filtrate is concentrated to dryness in vacuum. The crystalline residue is re-crystallized from acetone/toluene. The 4-nitro-4' -isothiocyano-diphenylamine , m.p, 204-206°, is obtained; the mixed melting point with the substance obtained according to (a) shows no depression.

Example 8 46 Parts of 4-methoxy-4' -nitro-diphenylamine are refluxed for 15 minutes while stirring. with 40 parts of finely pulverized potassium hydroxide in 400 parts by volume of acetone. A solution of 26.6 parts of allyl bromide in 35 parts by volume of acetone is then carefully added dropwise at room temperature. Then the mixture is refluxed for 90 minutes while stirring and subsequently concentrated by evaporation. The residue is digested with water, filtered and, after drying, recrystallized from ethyl acetate/petroleum ether. 55 Parts of N-allyl-4-methoxy-4' -nitro-diphenylamine , m.p. 81-82°, are obtained, which are reduced in dioxane with Raney nickel to N-n-propyl-4-methoxy-4' -amino-diphenylamine , 13 Parts of the latter product in 200 parts by volume of of the addition, the mixture is stirred for 8 hours at room temperature. The organic phase is separated, dried over potassium carbonate, filtered, concentrated by evaporation, and the remaining oil is distilled under high vacuum. The resulting N-n-propyl-4-methoxy-4' -isothiocyano-diphenylamine has a boiling point of 185-188°/0.1 Torr.

Example 9 23 Parts of 4-methoxy- 1 -nitro-diphenylamine are refluxed for 15 minutes while stirring with 20 parts of finely pulverized potassium hydroxide in 200 parts by volume of acetone. 30 Parts by volume of dimethyl sulfate are carefully added dropx^ise at room temperature, and the reaction mixture is refluxed for 90 minutes while stirring and then concentrated by evaporation. The residual N-methyl-4-methoxy- 1 -nitro-diphenylamine, which after recrystallization has a melting point of 125-126° is reduced in dioxane with Raney nickel to N-methyl-4-methoxy-4' -amino-di-phenylamine, m.p. 76-79°. 11 Parts of the latter in 200 parts by volume of ether are added dropwise to an emulsion of 6.5 parts of thiophosgene in 100 parts by volume of ice water. After completion of the addition, the mixture is stirred for 8 hours at room temperature. The organic phase is separated, dried over potassium carbonate, filtered and concentrated by evaporation. The residual N-methyl-4-methoxy-4' -isothiocyano-diphenylamine has, after recrystallization from benzene/petroleum ether a melting point of 73-75°.

The following isothiocyano-diphenylamines of the Formula I are also produced according to the preceding examples: T a b l e Melting points o. Compounds: Boiling points refraccion ndice s 6 4-acetylamino-4 ' -isothiocyano-diphenylamine 164-165° 7 4-acetylamino- 1 -isothiocyano-diphenylamine 152-155° 8 2-carbomethoxy-4' -isothiocyano-diphenylamine 95- 98° 9 2-carbomethoxy~3 ' -isothiocyano-diphenylamine 45- 47° o 3,4' -diisothiocyano-diphenylamine 108-111° 1 4~dime hylamino- 1 -isothiocyano-diphenylamine 115-120° 2 3- rifluoromethyl-31 -isothiocyano-diphenylamine 156-160° 0.2 Torr 3 4-trimethylammonio-4 ' -isothiocyano-diphenylamine- iodide 186-189° 4 3-trifluoromethyl-4-chloro-4' -isothiocyano-diphenylamine 87- 92° 5 3, -dimethyl-4 ' -isothiocyano-diphenylamine 92- 93° 6 4-hydroxy-41 -isothiocyano-diphenylamine 118-120° 7 3- isothiocyano-diphenylamine 212°/0.1 Torr 8 4-isothiocyano-diphenylamine- 73- 74° 9 4-methoxy-4' -isothiocyano-diphenylamine 55- 57° o 4-methoxy-2' -carboxy-5' -isothiocyano-diphenylamine 198-203° 1 4-faromo-4' -isothiocyano-diphenylamine 111-114° 2 4-valeryl-4' -isothiocyano-diphenylamine. 132-135° 3 4-cyano-4' -isothiocyano-diphenylamine 185-186° 4 4-dimethylaminoethoxy-4 ' -isothiocyano-diphenylamine 117-120° 5 3-trifluoromethy1-4^-isothiocyano-diphenylamine 77- 79° 6 N-allyl-4-chloro-41 -isothiocyano-diphenylamine 179-181° 7 2Q N-allyl-4-methyl-4' -isothiocyano-diphenylamine nj .1.6742 No. Compounds : Melting poii Boiling poii refraction 5ndi 71 j4-valeryloxy-4 ' -isothiocyano-diphenylamine 72 -dimethyl ——3-isothiocyano-diphenylamine The following non limitative examples are given for the production of forms of application of anthelmintically. ■ effectiv veterinary-medical preparations and feed additives. Parts are given therein by weight.

Example 73 A dispersable powder is produced by thoroughly milling and mixing 50 parts of 4-nitro-4 ' -isothiocyano-diphenylamine , 1 part of a condensation product obtained from ethylene oxide and the condensation product of propylene oxide and. propylene glycol having a molecular weight of about 2000 (e.g. the commercially available "Pluronic L 61"), 5 parts of the ammonium salt of a sulfonated naphthalene sulfonic acid-phenol-formalde- hyde condensate ..(e . g. , the commercially available "Irgatan AG . 1") and 44 parts of kaolin.

A dispersable powder is also obtained when 50 parts of 4-chloro-4' -isothiocyano-diphenylamine, 1 part of a condensation product obtained from ethylene oxide and the condensation product of propylene oxide and propylene glycol having a molecular of sodium aluminium silicate are used.

These dispersable powders can be mixed with liquid or pulpy feeds for administration to pets and domestic animals .

Example 74 2 Parts of 4-nitro- ' -isothiocyano-diphenylamine are thoroughly mixed with 2 parts of a condensation product obtained from ' ethylene oxide and the condensation product of propylene oxide and propylene glycol (e.g. the commercially available "Pluronic L 64") and 96 parts of glycolmonoethyl ether to form an emulsion concentrate, which can be dispersed in any concentration desired, e.g. in water or milk, for administration to pets and domestic animals.

Exam 1e 75 40 Parts of 4-methyl-4' -isothiocyano-diphenylamine are thoroughly mixed with 2.5 parts of sodium lignin sulfonate, 0.3: parts of sodium benzoate, 10 parts of glycerol and 47.2 parts of distilled water to form a paste, which can be mixed with liquid or pulpy feeds for administration to pets and domestic animals.

Example 76 , Parts of 4-nitro- 1 - isothiocyano-diphenylamine are thoroughly mixed with 15 parts of molasses, 5 parts of pulverised bran. The obtained mixture is shaped by means of a press into briquets which can be added to the feed.

In the above Examples 73 to 76 the active substance of Formula I can be replaced by any of the compounds disclosed in the Examples 1 to 9 or in the table.

Claims (1)

1. a) a thiocarbonic acid derivative of the formula : Hal - C Y H wherein Hal represents chlorine or bromine, Y represents chlorine, bromine or a dialkylamino. group, or b) a sulfide of the formula: alkyl alkyl alkyl alkyl wherein alkyl represents an alkyl radical having at most 4 carbon atoms and m represents the integer 1 or 2, or c) a pentathio-dipercarbonic acid-halogenoalkyl ester. 15. Process according to Claim 1 , which comprises reacting a diphenylamine of Formula II, in which R-^, R,' ^ and R^ have the ,that meanings given for Formula II with the exception nitro, tri- fluoromethyl and carboxy, must be at a ring not bearing an amino group, with d) ammonium thiocyanate in the presence of hydrogen chlorid in a solvent which is inert towards the reaction components, or e) benzoyl-isothiocyanate into the corresponding thiourea and decomposing this by heating in the presence of a solvent which is iner towards the reaction components, or of acids 16. Process according to Claim 14, which comprises using an aromatic hydrocarbon or halohydrooarbon as inert solvent. 17. Process for the p reduction of isothiocyano-diphenyiaminee o the general formula wherein R and Rg have the same meaning as in Claim 1; ft is an alkyl or aUcenyl ^radical tf.th at most 5 carbon 4 atoms or a dlalkylamlnoalkyl radical with at most 6 carbon atoms; Y is oxygen or sulfur; and Rg is hydrogen, chlorine or nitre; and the -NC3 group at ring B and any isothiocyano group Rg being in m- or p-position to the -BE-brldge when R is hydrogen; and any isothiocyano group R« is n m~ or p-positioit¾ to the Y-H group; which comprises reacting an isothiocyano-diphenylamine of the formula IV: wherein R, Rg, Rg and Y have the same meaning as above, and the -JSfCS group at ring B and any Isothiocyano group Rg are in m- or p-position to the bridge -NR- when R is hydroge and any isothiocyano group Rg is in m- or p-position to the Y-H- group; with a compound of formula V 32603/2 (v) wherein R^ has the meanings given for formula III* and Z represents chlorine,* bromine or iodine, in stoichio-metrical amounts, ejaculated roh hydroxyl and/or mercapto groups (-Y-H). ' 18 i Process according to Claims 14 to 17§ which comprises converting the end products of formula I in which R^ represents a dialJsylamino group with acids that are non-toxic for human and animal organisms, into the corresponding salts. 19. Process according to Claims 14 t to 17, which comprises converting the end products of formula I in. which R^ represents a quaternizable amino roup, with a qu*ernizin agent into the corresponding quaternary salts. 20. Anthelmintic compositions for veterinary medical purposes comprising as active ingredient at least one isothiocyano diphenylamine of the formula I in Claim 1 and/or at least one non-toxic salt of a compound of formula I which is capable of salt formation, in admixture with physiologically inert carrier and/or dispersing agent. 21. Veterinary-medical anthelminthlc compositions for combatting helminths in domestic and farm animals, comprising an isothiocyano-diphenylamine of the formula I in Claim 1 and/or a non-toxic salt of such a compound, in admixture with a feedstuff for such animals and/or physiologically inert carrier and or a dis ersin a ent.