DK141550B - METHOD OF ANALOGY FOR THE PREPARATION OF ANTHELMINTIC ACTIVE 2-CARBALCOXYAMINO5 (6) -PHENYL-SULPHONYLOXY-BENZIMIDAZOLES - Google Patents

Description

(11) SUPPLY POWER 1 k 1 550 DENMARK (51) Int Cl3 c 07 D 235/32 (21) Application No. 4198/76 (22) Filed on 17 · 6βρ. 1976 Ηί8π (23) Ubed8e 17 # eep '^ 76

\ / (44) The claim made and, Q

the publication of the writ was published on 21 April. "9θϋ

DIRECTORATE OF

PATENT AND TRADEMARKET (30) Priority granted from it

19 · sep. 1975 # 2541752, DE

<71) HOECHST AKTIENGESELLSCHAFT, Brueningstrasse 45, 6230 Frankfurt / Main 80, m.

(72) Inventor: Heinz Loevie, Kelkheitn / Taunus, Berlin Ring 6, DE: Josef Urbanletz, SchwaTbacb / Taunus, -Am Sandring 4-4, DE: Dieter Duevtel, Hof «Heim / Taunus, Frankfurter Strasse 39 / DE: Reinhard Kirsch, ~ Niederjosbach / Taunus, Kurmainzerstrasse 10, DE.

(74) Plenipotentiary in the proceedings:

The engineering company Budde, Schou & Co._ (64) Analogous process for the preparation of anthelmintically active 2-carbalkoxyamino-5 (6) -phenylsulfonyloxy-benzimidazoles.

2-Carbalkoxy-amino-benzimidazolyl derivatives having alkyl, acyl, phenoxy and phenylthio groups in the 5 (6) position are known as anthelmintics (P.Actor et al., Nature 215, 321 (1967), German Publication No. Written Nos. 2,029,637, 2,164,690 and 2,363,348).

The invention relates to an analogous process for the preparation of novel anthelmintically active 2-carbalkoxyamino-S (6) -phenylsulfonyloxy-benzimidazoles of formula I

r2 S ° 20 0 (I)

IT H

Wherein R is an alkyl group of 1-4 carbon atoms and R and R are each

especially independently of one another, hydrogen atoms, hydroxy groups, alkoxy groups of 1-4 carbon atoms, halogen atoms, trifluoromethyl groups, alkyl groups of 1-4 carbon atoms, carbalkoxy groups of 1-4 carbon atoms in the alkoxy group or cyano groups, which process is characterized by a 2-carboxyalkyl 5 (6) -hydroxybenzimidazole of formula II

“'CO' *" '"

wherein R · * · has the same meaning as in Formula I, is reacted with a benzenesulfonic acid halide of Formula III

Wherein R and R have the same meaning as in formula I and X represents a fluorine, chlorine or bromine atom, in the presence of a base. For the reaction, benzene sulfonic acid chlorides of formula III are preferred.

12 3 Considering alkyl groups R, R and R are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl groups.

2 3 Considering alkoxy groups R and R come methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. Considering halogen atoms 2 3 R and R come fluorine, chlorine, bromine and iodine atoms. Considering that 2 3 carbalkoxy groups R and R come carbomethoxy, carbethoxy, carboprop oxy or carbobutoxy groups.

Particularly preferred are compounds of formula I wherein R 2 represents a methyl, ethyl, propyl or butyl group, R represents a 3 hydrogen atom or a chlorine atom, and R represents a hydrogen atom, a chlorine atom or a trifluoromethyl group.

The course of the reaction is shown by the following scheme 3 141550 + "iQ ^^ Sc-NH-COOR1 r3'2 I ^^ - ir ^ X> ^ ° no (>

H

To carry out the reaction, a 2-carbalkoxy-amino-5 (6) -hydroxy-benzimidazole of formula II is suspended in an aprotic solvent with a tertiary amine, and with stirring, a solution of a benzenesulfonic acid halide of formula III is added. The mixture is stirred until the reaction is complete, which time is conveniently determined by thin layer chromatographic control.

As aprotic solvents there may be mentioned acetone, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethylformamide, dimethylsulfoxide, tetramethylurea and the like, dipolar aprotic solvents.

Speaking as bases come alkali metal or alkaline earth metal * hydroxides, carbonates and hydrogen carbonates or tertiary organic bases. Examples include sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine, pyridine and methyl-substituted pyridines.

The temperature range of the reaction is between 0 and 60 ° C, preferably between 15 and 30 ° C. The rate of the reaction depends on the reactivity of the benzenesulfonic acid chloride used, so that the duration can vary from a few hours to a day.

The course of the reaction can be followed by thin layer chromatographic control, suitably using silica gel as the adsorbent and mixtures of chloroform, acetic acid ethyl ester and glacial acetic acid, preferably in the ratio of 10: 10: 1, as the solvent.

The reaction products are isolated from the reaction mixture by filtration.

4 141550

The 2-carbalkoxyamino-5 (6) -hydro-xybenzimidazole of formula II used as starting material is prepared by known methods (cf. German Publication No. 2,164,690). Thus, 3-nitro-4-aminophenol is reacted with benzoyl chloride to benzoic acid 3-nitro-4-amino-phenyl ester, this compound is hydrogenated with Raney nickel to 3,4-diamino derivatives and this is reacted with S-methyl thiourea carboxylate for 2-carbalkoxyamino-5-benzoyloxy-benzimidazole, of which the hydroxy compound of formula II is obtained with dilute sodium hydroxide solution.

The 2-carbalkoxyamino-5 (6) -phenylsulfonyloxy-benzimidazoles disclosed herein are valuable chemotherapeutics and are useful in the control of parasitic diseases in humans and animals, e.g. induced by helminther and livery. They are particularly effective against a large number of helminths, e.g. Haemonchus, Trichostrongylus, Ostertagia, Stron gyloides, Cooperia, Chabertia, Oesophagostomum, Hyostrongylus, Ankylostoma, Askaris and Heterakis. Particularly pronounced is the effect on gastrointestinal strongylids, which primarily attack ruminants.

Attacks on animals of these parasites lead to great economic damage, which is why the compounds in question are particularly useful in veterinary medicine.

The active substances of formula I are administered depending on the situation of the case in doses between 0.5 and 50 mg per day. kg body weight for 1-14 days.

In a comparison experiment, the closest of the known 5 (-6) -substituted 2-benzimidazole carbaminates, namely the so-called "Oxfendazole" which is 5 (6) -phenylsulfinyl-2-carbomethoxyaminobenzimidazole, and a number of the The following examples prepared compounds. The experiments were carried out in such a way that lamb received orally 200 metacercariae of Fasciola hepatica, and after the expiry of the prepathetic period, there was a headache to ensure that an infection had occurred. After treatment of the animals with the test compounds, the results were obtained by repeated faecal examinations and eventually by dissection. Listed below are the oral doses and the eradication of the parasites.

5 14155Ό

Conn. Fasciola / lamb Extinction according to. eg mgA <? Ρ · ο · ____% __ 1 1 x 50 100 2 1 x 50 100 3 1 x 50 100 4 1 x 30 100 5 1 x 50 100 6 1 x 30 80 7 1 x 50 100 8 1 x 50 100 9 1 x 10 100 10 1 x 30 100 11 1 x 30 100 12 _1 x 50_100_ "Oxfendazole" 1 x 30 0

The products of this invention are not only very effective in oral administration, but also act parenterally in doses of up to 2 mg / kg. Thus, they are far superior to comparable benzimidazole derivatives, especially all known 5 (6) -substituted 2-benzimidazole carbaminates.

Example 1.

5.15 g of 2-carbomethoxyamino-5 (6) -hydroxy-benzimidazole are suspended in 100 ml of acetone and 3.5 ml of triethylamine is added. With vigorous stirring, a solution of 4.4 g of benzenesulfonic acid chloride in 20 ml of acetone is added dropwise at room temperature and stirred for 10 hours, thereby changing the consistency of the suspension clearly. It first gets thin and then gradually thick again. After cooling, the solid components which are successively washed with acetone, water and methanol are filtered off and dried on a steam bath.

For purification, the crude product from glacial acetic acid / methanol is recrystallized. The yield of 2-carbomethoxyamino-5 (6) -phenylsulfonyloxy-benzimidazole is 6.2 g with a decomposition point of 242 ° C. The thin layer chromatographic control of the reaction mixture on silica gel with a mixture of 10 ml of chloroform, 10 ml of acetic acid ethyl ester and 1 ml of glacial acetic acid as a solvent 6

MlBffQ

shows that. the spot of the starting material has disappeared and the reaction product with a higher R

By analogy, equivalent amounts of the corresponding benzenesulfonic acid chlorides are prepared from 5.15 g of 2-carbomethoxyamino-5 (6) -hydroxy-benzimidazole and 2) 5.3 g of 4-chlorobenzene-sulfonic acid chloride 6.8 g of 2-carbomethoxyamino-5 ($) - (4-Chloro-phenylsulfonyloxy -) - benzimidazole, m.p. 230 ° C (dec.) 3) 5.3 g of 3-chlorobenzene sulfonic acid chloride 6.8 g of 2-carbomethoxyamino-5 (6) - (3-chloro-phenylsulfonyloxy) -benzimidazole, m.p. 250 ° (decomposition) 4) 6.15 g of 3,4-dichloro-benzenesulfonic acid chloride 7.4 g of 2-carbomethoxyamino-5 (6) - (3,4-dichloro-phenylsulfonyloxy) -benzimidazole, m.p. 255 ° C (dec.) 5) 6.15 3,5-Dichlorobenzene sulfonic acid chloride 7.3 g of 2-carbomethoxyamino-5 (6) - (3,5-dichlorophenylsulfonyloxy) -benzimidazole, m.p. 280 ° C (dec.) 6) 6.4 g of 3-bromo-benzenesulfonic acid chloride 7.6 g of 2-carbomethoxyamino-5 (6) - (3-bromo-phenylsulfonyloxy) -benzimidazole, m.p. 242 ° C (dec.) 7) 4.8 g of 4-methyl-benzenesulfonic acid chloride 6.4 g of 2-carbomethoxyamino-5 (6) - (4-methyl-phenylsulfonyloxy) -benzimidazole, m.p. 237 ° C (dec.) 8) 4.8 g of 3-methylbenzenesulfonic acid chloride 6.4 g of 2-carbomethoxyamino-5 (6) - (3-methyl-phenylsulfonyloxy) -benzimidazole, m.p. 250 g (decomposition) 9) 6.1 g of 3-trifluoromethyl-benzenesulfonic acid chloride 7.4 g of 2-carbomethoxyamino-5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) -benzimidazole, m.p. 215 ° C (decomposition) and using 6.1 g of 3-trifluoromethyl-benzenesulfonic acid chloride and 10) 5.5 g of 2-carbethoxyamino-5 (6) -hydroxy-benzimidazole 7.7 g of 2-carbethoxyamino-5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) -benzimidazole, m.p. 227 ° C (dec.) 11) 5.9 g of 2-carbisopropoxyamino-5 (6) -hydroxy-benzimidazole 8.0 g of 2-carbisopropoxyamino-5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) -benzimidazole, m.p. . 205 ° C (decomposition) 12) 6/2 g of 2-carbisobutoxyamino-5 (6) -hydroxy-benzimidazole 8.2 g of 2-carbisobutoxyamino-5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) -benzimidazole with m.p. 243 ° C (dec.) 13) 5.1 g of 3-cyano-benzosulfonic acid chloride 6.7 g of 2-carbomethoxyamino-5 (6) - (3-cyano-phenylsulfonyloxy) -benzimidazole, m.p. 275 ° C (dec.)

To prepare the starting material used 2-carbo-methoxyamino-5 (6) -hydroxy-benzimidazole, 56 g of S-methylthiourea sulfate is mixed in 90 ml of water with 26 ml of chloroformic acid methyl ester and 116 g is added dropwise 25% * sodium hydroxide solution. Stir for an additional 1/2 hour and then add a solution prepared by hydrogenation of 51.6 g of benzoic acid 3-nitro-4-amino-phenyl ester in 250 ml of glacial acetic acid with Raney nickel and filtration from the catalyst. Add 300 ml of glacial acetic acid, 100 ml of water and 100 ml of methanol and cook for 2 hours at reflux.

After cooling, the precipitated 2-carbomethoxyamino-5 (6) -benzoyl-oxy-benzimidazole is isolated in a yield of 41 g with a m.p. at 280 ° C (dec.).

The 2-carbomethoxyamino ~ 5 (6) -benzoyloxy-benzimldazole thus prepared is stirred in a mixture of 400 ml of methanol and 400 ml of 2N sodium hydroxide solution for 5 minutes and the solution is filtered, neutralized with glacial acetic acid and evaporated in vacuo. To the residue is added 100 ml of water and the precipitated solid is separated by suction and washed with methanol and diisopropyl ether. After recrystallization from glacial acetic acid / methanol in a 1: 1 ratio, 21 g of 2-carbomethoxyamino-5 (6) -hydroxy-benzimidazole are obtained, m.p. at 305 ° C (dec.).