DE2734224A1 - Alkyl-tetra:hydro-triazino-benzimidazole carboxylate(s) - as anthelmintics in humans and animals, esp. effective against liver fluke - Google Patents

Abstract

1,3,5 -triazino- 1,2-a benzimidazole-1-carbox- ylic acid alkyl esters of formula (I) are new. In (I) R' is 1-4c alkyl; R2 and R3 are each H, OH, 1-4C alkoxy, halogen, CF3, 1-4C alkyl, carb-(1-4C) alkoxy or CN; R4 is 1-18C alkyl, 3-18C alkenyl, 3-12C cycloalkyl (opt. substd. by alkyl or OH), tricyclo 5,2,1,02,6 -decyl, benzyl, phenylethyl, phenylpropyl, furfuryl or bicycloheptylmethyl; and X is -OSO2- or -SO2O-. (I) are chemotherapeutic agents, effective against helminths, esp. treimatodes, cestodes and namtodes. (I) are esp. effective against liver fluke in partic. the large liver leach fasciola hepatica, a parasite in domestic animals such as sheep and cattle. (I) can be used as anti-helmintics to treat worm infections in animals and humans. Suitable doses are 0.1-5.0 mg/kg s.c. and 0.5-50 mg/kg p.o.

Description

The substitution of the benzimidazole ring by the phenyl-X group in the 8-position, as with the starting materials used

ten benzimidazole carbamates of the formula (2) cannot be defined; it can also involve substitution in the 7-position. Even with the raw materials are manufactured according to DT-OS 24 41 201 and 24 41 202, means the corresponding 5 (6) substitution of tautomeric substances.

The invention also relates to a process for the preparation of 1,2,3,4-tetrahydro- / 1,3,5 7-triazino-t 1,2-a 7benzimidazole-1-carboxylic acid alkyl esters of the formula (1), characterized in that that a benzimidazole carbamate of the formula (2), with an amine of the formula H2N-R4 and formaldehyde, the groups R1, R2, R3, R4 and X having the meaning given for formula (1).

An advantageous embodiment of the method is that the benzimidazole (2) is suspended or dissolved in a solvent, the equimolar The amount of amine is added and, with stirring, the 2-fold molar to 4-fold molar amount aqueous formaldehyde solution added. One works at a temperature between 0 ° and 800 C, preferably between 20 and 40 ° C, but the temperature range is not critical. The reaction product is generally in solution and can in this Solution of any undissolved benzimidazole of formula (2) still present, e.g. by filtration. By concentrating the solution and treating the Residue with an inert solvent such as gasoline or by reprecipitation, e.g. from methylene chloride-nenæin, the triazino-benzimidazole (1) can be isolated in pure form will.

The reaction also takes place when a deficit of formaldehyde is used with formation of the end product I.

As the solvent for the reaction are particularly moderate or weak polar solvents, preferably those with low boiling points, can be used, such as methylene chloride, chloroform, carbon tetrachloride, benzene; Ethers such as diethyl ether, Diisopropyl ether and tetrahydrofuran; Esters such as methyl acetate and ethyl acetate. Chloroform or methylene chloride is preferably used.

The new compounds of formula (1) according to the invention are valuable Chemotherapy drugs. They work against helminths, especially trematodes, cestodes and nematodes. Their effectiveness against liver fluke, e.g. against the large liver fluke Fasciola hepatica, which like a parasite of farm animals Sheep and cattle is widespread. Grazing animals are common with tapeworms and particularly affected by nematodes.

Contamination of a herd with these helminths leads to sensitive ones economic damage. That is why a specific therapeutic agent comes against that named three helminth groups are of considerable importance.

The subject of the invention are therefore also anthelmintically effective Means containing the active ingredients of the formula (1), and the use of the active ingredients of formula (1) for combating worm diseases in humans and animals.

The anthelmintic effect of the compound of the formula (1) is shown in experiments on laboratory animals or domestic animals. The active ingredients are once or in a large number of small doses, if necessary spread over several days, together with a suitable pharmaceutical solvent or carrier substance orally or subcutaneously applied. The type of application is to be selected depending on the situation. The application concentration is in the range of 0.1-5.0 mg / kg body weight subcutaneously or 0.5-50 mg / kg body weight orally.

Solid forms of administration such as tablets, Dragees, powders, granules or mixtures of the active ingredients with feed are preferred; Potions can also be used.

For subcutaneous administration, liquid preparations such as Emulsions, suspensions and solutions of the active ingredients. For the production this Preparations come from the usual, physiologically harmless auxiliaries and carriers in question like talc, lactose, magnesium stearate for the solids or water, Paraffin oil or polyalcohols such as polyethylene glycol for the liquid preparations.

To determine the anthelmintic effect of the compounds of the Formula (1), chemotherapeutic studies were carried out on approx.

25 - 30 kg heavy sheep, which either artificially with 250 metacercariae of Fasciola hepatica or with larvae of gastrointestinal strongyles, mainly Haemonchus contortus and Trichostrongylus colubriformis, infected orally had been. At the end of the prepatency period (time between infection and sexual maturity the parasites with the beginning of excretion of eggs or larvae) became the parasite infestation secured by fecal examinations. In the case of the liver fluke infection, the qualitative-quantitative production of eggs after Telemann enrichment (German Medical Weekly 34: 1510, 1908). The number of eggs per gram of faeces of gastrointestinal strongyles was carried out using the modified McMaster method according to Wetzel (Tierärztliche Umschau 6, 209, (1951)). Immediately afterwards the treatment of the sheep (in general 3 - 4 animals per active ingredient, at least 2). The animals were given orally or subcutaneously a suspension of different amounts of active ingredient in 10 ml of a 1% Tylose suspension applied. On the 7th, 14th and 28th day after the treatment was again the number of eggs according to the procedure given above per gram of faeces and their percentage decrease compared to the initial value calculated before treatment. With some compounds were also with the Fasciola infestation An additional test technique was used: After the prepatent period had ended an artificial bile duct was created in Fasciola-positive sheep, the at the exit of the gallbladder contained a sieve so that those killed after the treatment Liver fluke could be caught in the gallbladder. Four to seven days after after the treatment, the sheep which had been operated on and then treated were killed dead liver fluke in the gallbladder and possibly still present in the liver living liver fluke were counted and of the total worm burden the percentage of those killed Parasites calculated.

The table below shows the effects of compounds Formula (1) and of known comparative products.

2-Acetoxy-4-chloro-3,5-diiodobenzanilide served as comparison products (Clioxanide) and 5,5'-dichloro-2,2'-dihydroxy-3,3'-dinitr biphenyl (Nic lofolan) as well as methyl 5-butyl-2-benzimidazole carbamate (parbendazole) and methyl 5-benzoyl-2-benzimidazole carbamate (Mebendazole).

The tetrahydrotriazino-benzimidazoles according to the invention are superior mostly in several, but at least in one of the following points: 1. minor Dosage (dose curativa minima / D.c.m.) 2. better effectiveness (effect) 3. wider Spectrum 4. Major chemotherapeutic index (The chemotherapeutic index gives the quotient of dose tolerata maxima and dose curativa minima).

Table: Chemotherapeutic examinations (> 90% reduction in worm burden) Host animal: Shaft Parasite: Liver fluke (Fasciola hepatica) Gastrointestinal strongyles (Ostertagia, Haemonchus, Trichostrongylus, Chargertia) Dose: mg / kg body weight, oral Substance Laberegel / Sheep Gastrointestinal Strongyles / Sheep Chemotherapeutic adult immature adult immature index (8w old) (3d and 10d old) Connection according to Example 1 <7.5 10.0 <7.5 <7.5> 16 2-acetoxy-4-chloro 3,5-diiodobenzanilide 10 - 15 [40] no effect 4 - 6 [2.5] 5,5'-dichloro-2,2'- dihyroxy-3,3'-dinitro- 3 [6] no effect 4 [2] biphenyl Methyl-5-butyl-2-benz- no effect 15> 15 4 imidazole carbamate benzimidazole caramate 100 not specified 15>15> 20 Example 1: 3-Cyclohexyl-8-phenoxysulfonyl-1,2, 3, 4-tetrahydro-s3-] -triazino-t1,2-a] benzimidazole-1-carboxylic acid methyl ester 61 g of 2-methoxyearbonylamino-5-phenoxysulfonyl-benzimidazole become suspended in 300 ml of methylene chloride and treated with 2 ml of triethylamine. Then 18 g of cyclohexylamine and 33 g of 35 percent strength are added dropwise at 300 in the course of 2 hours. aqueous formalin solution too. Then 50 g of anhydrous magnesium sulfate are added. After stirring for four hours, a further 6 ml of formalin solution are added. After a total of 6 hours, the magnesium sulfate is suctioned off. The filtrate is concentrated s. With 300 ml of petroleum ether, 69 g of product with a melting point of 49-1500 are precipitated; based on the starting benzimidazole, this corresponds to a yield of 83%.

Repeated reprecipitation from dichloromethane / cyclohexane and cleaning with activated charcoal the melting point can be increased to 151-152 °.

*) the liquid Further compounds of the formula (1) with R1 = CH3 were prepared in the same way and are listed in Table 1 Tab. 1: R2 R2 4 No. R3 »~ b 2 C6H5-O-SO2- - (CH2) IICH3 104-1050 3 C6H5-O-SO2- - (CH2) 17CH3 88-900 4 F3C SO SO2 - (CH2) 11CH3 102-1040 5 F3C-O-S02-Q 151 to 151 - 1530 6 F3CS02-O- - (CH2) 11CH3 oily 7 7 j F3C t -5 ° 2- ° - to | oily

Claims (4)

1,2,3,4-Tetrahydro- [1,3,5] -triazino- [1,2-a] -benzimidazole-1-carboxylic acid alkyl esterR Process for their preparation, their use for combating helminths and agents suitable therefor. 1. Triazinobenzimidazoles of the formula (1) in which R1 is alkyl with 1-4 carbon atoms, R2 and R3 are each independently hydrogen, hydroxyl, alkoxy with 1-4 carbon atoms, halogen, trifluoromethyl]., alkyl with 1-4 carbon atoms, carbalkoxy with 1 - 4 carbon atoms in the alkoxy radical or CN, X the group -O-SO2- or -SO2-O- and R4 an optionally branched alkyl group with 1 - 18 carbon atoms, an optionally branched alkenyl group with 3 to 18 carbon atoms, a cycloalkyl group with 3 to 12 carbon atoms, which in turn can be substituted by alkyl groups or OH, denote the groups tricyclo- / 5,2,1,02'67-decyl, benzyl, phenylethyl, phenylpropyl, furfuryl or bicycloheptyl-methyl. 2. Process for the preparation of triazinobenzimidazoles of the formula (1) in claim 1, characterized in that one e benzimidazole carbamate of the formula (2) with an amine of the formula H2N-R4 and formaldehyde, where R¹, R², R³, R4 and X have the meaning given for formula (1) in claim 1. 3. Anthelmintic agents containing a substance of formula (1) in claim 1. 4. Use of a substance of the formula (1) in claim 1 for combating of helminths. 2-Carbalkoxy-amino-benzimidazole derivatives with phenoxy-sulfonyl groups or phenylsulfonyloxy groups in the 5 (6) position are according to DT-OS 2,441,201 and 2 441 202 known as Antheirnbthica. There are also 5 (6) -substituted benzimidazole derivatives with fused-on hexahydrotriazine ring according to DT-OS 2 452 365 known. The invention relates to new 1,2,3,4-tetrahydro- [1 1,3,5 ~ 7-triazine2- [1,2-a] -benzimidazole-1-carboxylic acid alkyl esters of the formula (1) in which R1 is alkyl with 1 - 4 carbon atoms, R2 and R3 are each independently hydrogen, hydroxyl, alkoxy with 1 - 4 carbon atoms, halogen such as fluorine, chlorine, bromine, iodine, trifluoromethyl, alkyl with 1 - 4 carbon atoms Atoms, carbalkoxy with 1-4 carbon atoms in the alkoxy radical or CN, X the group -O-SO2- or -SO2-O- and R4 an optionally branched alkyl group with 1-18 carbon atoms, an optionally branched alkenyl group with 3 up to 18 carbon atoms, a cycloalkyl group with 3 to 12 carbon atoms, which in turn can be substituted by alkyl groups or OH, the group tricyclo- / 5,2,1,02,67-decyl, benzyl, phenylethyl, phenylpropyl, furfuryl or Bicycloheptyl-methyl- mean. Preference is given to compounds of the formula (1) in which R1 is methyl, R2 is hydrogen and R³ is hydrogen, chlorine, bromine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy mean, where R³ is particularly preferably in the 3-position of the phenyl ring, and in R4 cycloalkyl with 4 to 7 carbon atoms, in particular with 6 carbon atoms, or alkyl with 4 to 18 carbon atoms.