NO763196L - PROCEDURE FOR THE PREPARATION OF ANTELMINTIC ACTIVE 2-CARBALCOXYAMINO-5 (6) -PHENYL-SULPHONYLOXY-BENZIMIDAZOLES. - Google Patents

Description

Process for the production of anthelminthically active 2-carbalkoxyamino-5-(6)-phenyl-sulfonyloxy-benzimidazoles.

2-Carbaloxy-amino-benzimidazolyl derivatives with alkyl, acyl, phenoxy and phenylthioesters in the 5(6) position are known as antelmintica (P. Actor et al., Nature 215, 321 (1967), DOS 2,029,637, DOS 2,164,690, DOS 2,363,348).

The object of the invention is a method for the production of anthelminthically active 2-carbaloxyamino-5(6)-phenyl-sulfonyloxy-benzimidazole with formula (1)

wherein R means alkyl with 1 to 4 C atoms, R 2 and R each independently means hydrogen, hydroxyl, alkoxy with 1 to 4 C atoms, halogen, trifluoromethyl, alkyl with 1 to 4 C atoms, carboxyl with 1 to 4 C atoms in the alkoxy radical or CN, the method being characterized by a 2-carbaloxyamine-5(6)-hydroxy-benzimidazole of formula (2), in which has the same meaning as above, is reacted in the presence of a base with a benzenesulfonic acid halide of formula (3 )

in which R2 and R3 have the same meaning as above and X means fluorine, chlorine or bromine. For the reaction, benzenesulfonic acid chloride with formula (3) is preferred.

As alkyl residues for the substituents R^, and R^ the following come into consideration: methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl, tertiary-butyl. The following methoxy, ethoxy, propoxy, isopropoxy and butoxy are considered as alkoxy groups for the substituents R^ and R^. As a halogen atom for the substituents R 2 and R 2 the following are considered: fluorine, chlorine, bromine and iodine. Carbomethoxy groups for the substituents R 2 and R 4 come into consideration: carbomethoxy, carbethoxy, carbopropoxy or carbobutoxy.

Particularly preferred are compounds of formula (1), in which R₂ means methyl, ethyl, propyl or butyl, R₂ means hydrogen or chlorine and R₂ means hydrogen, chlorine or trifluoromethyl.

The course of the reaction can be reproduced with the following form

To carry out the reaction, a 2-carbalkoxy-amino-5(6)-hydroxy-benzimidazole of formula (2) is suspended in an aprotic solvent with a tertiary amine and a solution of benzylene sulfonic acid halides of formula (3) is added dropwise while stirring. The mixture is stirred until the turnover is finished, the time being determined appropriately with the help of a

thin layer chromatic control.

As 2-carbalkoxyamino-5(6)-hydroxy-benzimidazole with formula (2) it is mentioned, for example

2-carbomethoxyamino-2(6)-hydroxy-benzimidazole 2-carboethoxy-ino-5(6)-hydroxy-benzimidazole

2-carbisopropoxyamino-5(6)-hydroxy-benzimidazole 2-carbobutoxyamino-5(6)-hydroxy-benzimidazole 2-carbisobutoxyamino-5(6)-hydroxy-benzimidazole 2- carbotert.butoxyamino-5(6)-hydroxy-benzimidazole

Acetone, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethylformamide, dimethylsulfoxide, tetramethylurea and similar dipolar, aprotic solvents should be mentioned as aprotic solvents.

Bases include alkali or alkaline earth 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.

As benzenesulfonic acid halides with formula (3) come into consideration, for example:

benzenesulfonic acid chloride

4-chloro-benzenesulfonic acid chloride

3-chloro-benzenesulfonic acid chloride

2-chloro-benzenesulfonic acid chloride

2,5-dichlorobenzenesulfonic acid chloride

3.4-Dichlorobenzenesulfonic acid chloride

3.5-Dichlorobenzenesulfonic acid chloride

4-bromo-benzenesulfonic acid chloride

3-bromo-benzenesulfonic acid chloride

2-bromo-benzenesulfonic acid chloride

4- Methyl-benzenesulfonic acid chloride

3- methyl-benzenesulfonic acid chloride

2-methyl-benzenesulfonic acid chloride

4-tert.butyl-benzenesulfonic acid chloride

2,4-dimethylbenzenesulfonic acid chloride

2-chloro-4-methyl-benzenesulfonic acid chloride

2-chloro-6-methyl-benzenesulfonic acid chloride

3-chloro-4-methyl-benzenesulfonic acid chloride

3-chloro-6-methyl-benzenesulfonic acid chloride

4-chloro-2-methyl-benzenesulfonic acid chloride

4-chloro-3-methyl-benzenesulfonic acid chloride

4-chloro-3,5-dimethyl-benzenesulfonic acid chloride

3-trifluoromethyl-benzenesulfonic acid chloride

4- methoxy-benzenesulfonic acid chloride

3-Methoxy-benzenesulfonic acid chloride

3-Methoxy-benzenesulfonic acid chloride

4- propoxy-benzenesulfonic acid chloride

4-isopropoxy-benzenesulfonic acid chloride

4-butoxy-benzenesulfonic acid chloride

4-isobutoxy-benzenesulfonic acid chloride

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

The progress of the reaction can be monitored by thin-layer chromatographic control, using silica gel as an adsorbent and mixtures of chloroform, ethyl acetate and glacial acetic acid as eluent, preferably in a ratio of 10:10:1.

The reaction products are isolated by filtration from the reaction mixture. One thus obtains: 2-carbomethoxyamino-5(6)-phenylsulfonyloxy-benzimidazole 2-carbomethoxyamino-5(6)-(4-chloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-(3-chloro-phenylsulfonyloxy) -benzimidazole 2-carbomethoxyamino-5(6)-(2-chloro-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(2,5-dichloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-(3,4-dichloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-( 3,5-dichloro-phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-(4-bromo-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(3-bromo-phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-(2-bromo-phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-(4-methyl- phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-(3-methyl-phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-(2-methyl-phenylsulfonyloxy)-benzimidazole 2-carbomethoxyamino-5(6)-( 4-tert.butyl-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(2-chloro-4-methyl-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(2-chloro-6-methyl-phenylsulfonyloxy)benzimidazole

2-carbomethoxyamino-5(6)-(3-chloro-4-methyl-phenylsulfonyloxy)-benz-imidazole

2-carbomethoxyamino-5(6)-(3-chloro-6-methyl-phenylsulfonyloxy)benzimidazole

2-carbomethoxyamino-5(6)-(4-chloro-2-methyl-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(4-chloro-3-methyl-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(4-chloro-3,5-dimethyl-phenylsulfonyloxy-benzimidazole

2-carbomethoxyamino-5 (6)-(3-trifluoromethyl-phenylsulfonyloxy)-benz-;imidaz".Q.l7J::L

2-carbomethoxyamino-5(6)-(4-methoxy-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(2-methoxy-phenylsulfonyloxy)-benzimidazole

2-Carbomethoxyamino-5(6)-(4-propoxy-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(4-isopropoxy-phenylsulfonyloxy)-benzimidazole

2-Carbomethoxyamino-5(6)-(4-butoxy-phenylsulfonyloxy)-benzimidazole

2-carbomethoxyamino-5(6)-(4-isobutoxy-phenylsulfonyloxy)-benzimidazole

2-Carbethoxyamino-5(6)-phenylsulfonyloxy-benzimidazole 2-Carbopropoxy-5(6)-phenylsulfonyloxy-benzimidazole 2-Carbisopropoxyamino-5(6)-phenylsulfonyloxy-benzimidazole 2-Carbobutoxyamino-5(6)-phenylsulfonyloxy-benzimidazole 2- carbisobutoxyamino-5(6)-phenylsulfonyloxy-benzimidazole 2- carbotert.butoxyamino-5(6)-phenylsulfonyloxy-benzimidazole

2-carbaloxyamino-5(6)-hydroxy-benzimidazole with formula (2) which is produced according to known methods/ - compared to DOS 2,164,690 serves as starting material. Thus, 3-nitro-4-amino-phenol is converted with benzoyl chloride into benzoic acid 3-nitro-4-amino-phenol ester, this compound is hydrogenated with Raney nickel to the 3,4-diamino derivative and this is reacted with S-methyl- thiourea carboxylate to 2-carbaloxyamino-5-benzoyloxy-benzimidazole, from which with diluted caustic soda the hydroxy compound with formula (2) is obtained.

The 2-carbaloxyamino-5(6)-phenylsulfonyloxy-benzi-imidazole according to the invention are valuable chemotherapeutics and are suitable for combating parasitic diseases in humans and animals such as from helminths and liver leeches.

They are particularly effective for a large number of helminths, e.g. Haemonchus, Trichostrongylus, Ostertagia, Strongyloides, Cooperia, Chabertia, Oesophagostomum, Hyostron-gylus, Ankylostoma, Askaris and Heterakis. Particularly pronounced is the effect against gastrointestinal Strongylides, of which above all ruminants are attacked. The animals' attack by these parasites leads to great economic damage, where the compounds according to the invention find special use in veterinary medicines.

Active substances with formula (1) are administered, depending on the situation of the case, in dosages between 0.5 and 50 mg per kg of body weight for 1 to 14 days.

For oral application, tablets, dragees, capsules, powders, granules or pastes containing the active substances together with usual auxiliary or carrier substances such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatins, calcium carbonate, finely divided silicic acid, carboxymethyl cellulose or similar substances.

For parenteral application solutions are considered, e.g. oily solutions that are prepared using sesame oil, castor oil or synthetic triglycerides, optionally with the addition of tocopherol as an antioxidant and/or using surfactants such as sorbitan fatty acid esters. In addition, aqueous suspensions are taken into account which are produced using . ethoxylated sorbitan fatty acid esters, optionally with the addition of thickeners, such as polyethylene glycol or carboxymethyl cellulose.

The concentration of the active substances according to the invention in the thus prepared preparations is preferably for use as a veterinary medicine between 2 and 20% by weight, for use as a human medicine the concentration of the active substances is preferably between 20 and 80% by weight.

In order to determine the effect of the compounds according to the invention, chromatographic examinations of approx. 30 kg sheep lambs, which had been experimentally infected with larvae of Trichostrongylus colubriformis resp. Haemonchus contortus. The experimental animals were kept in tiled boxes which were thoroughly cleaned daily. After the course of the prepatent period (the time between infection and sexual maturity after the parasite with the beginning of excretion of eggs or larvae) was determined according to the modified McMaster method according to Wetzel (Tierårztliche Umschau 6, 209 - 210 (1951)) egg numbers per grams of stool. Immediately thereafter, the sheep were treated (usually 4 to 8 animals per active substance, at least 2, however). The animals were administered the dosages of the process products as a suspension in each time 10 ml of a 1% tylose suspension. Every time on

on the 7th, 14th and 28th day after the treatment, it was again according to the above procedure. f estimated numbers per Gr. faeces and its percentage decrease are calculated compared to the starting value before treatment.

The table below reproduces the effect of some compounds according to the invention in these experiments.

The method products are not only excellently effective orally applied, but also work parenterally in dosages down to 2 mg/kg. Thus, they are far superior to comparable benzimidazole derivatives, especially all known 5(6)-substituted 2-benzimidazole carbamates.

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 are 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, as the consistency of the suspension clearly changes. It first becomes runny and then gradually thickens. After cooling, the solid components are filtered off, washed in sequence with acetone, water and methanol and dried in a steam bath.

For purification, the crude product is recrystallized from glacial acetic acid/methanol. The yield of 2-carbomethoxyamino-5(6)-phenylsulfonyl-oxy-benzimidazole amounts to 6.2 g of decomposition point 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 eluent shows that the stain of the starting material has disappeared and in its place there is this of the production product with a higher R F- value.

Analogously, using equivalent amounts of the corresponding benzenesulfonic acid chlorides, 5.15 g of 2-carbomethoxyamino-5(6)-hydroxy-benzimidazole and 2) 5.3 g of 4-chlorobenzenesulfonic acid chloride will be obtained

6.8 g of 2-carbomethoxyamino-5(6)-(4-chloro-phenylsulfonyloxy)-benzimidazole with melting point 230°C (under decomposition)

3) Get 5.3 g of 3-chloro-benzenesulfonic acid chloride

6.8 g of 2-carbomethoxyamino-5(6)-(3-chloro-phenylsulfonyloxy)-benzimidazole with melting point 250°C (under decomposition)

4) Get 6.15 g of 3,4-dichlorobenzenesulfonic acid chloride

7.4 g of 2-carbomethoxyamino-5(6)-(3,4-dichloro-phenylsulfonyloxy)-benzimidazole with melting point 255°C (under decomposition)

5) Get 6.15 g of 3,5-dichlorobenzenesulfonic acid chloride

7.3 g of 2-carbomethoxyamino-5(6)-(3,5-dichloro-phenylsulfonyl-oxy)-benzimidazole. with melting point 280°C (under decomposition).

6) Get 6.4 g of 3-bromobenzenesulfonic acid chloride

7.6 g of 2-carbomethoxyamino-5(6)-(3-bromo-phenylsulfonyloxy)-benzimidazole with melting point 242°C (under decomposition).

7) Get 4.8 g of 4-methyl-benzenesulfonic acid chloride

6.4 g of 2-carbomethoxyamino-5(6)-(4-methyl-phenylsulfonyloxy)-benzimidazole with melting point 237°C (under decomposition).

8) Get 4.8 g of 3-methyl-benzenesulfonic acid chloride

6.4 g of 2-carbomethoxyamino-5(6)-(3-methyl-phenylsulfonyloxy)-benzimidazole with melting point 250°C (under decomposition).

9) Get 6.1 g of 3-trifluoromethyl-benzenesulfonic acid chloride

7.4 g of 2-carbomethoxyamino-5(6)-(3-trifluoromethyl-phenylsulfonyl-oxy)-benzimidazole with melting point 215°C (under decomposition).

One will, using 6.1 g of 3-trifluoromethyl-benzenesulfonic acid chloride and

10) 5.5 g of 2-carbethoxyamino-5(6)-hydroxy-benzimidazole get

7.7 g of 2-carbethoxyamino-5(6)-(3-trifluoromethyl-phenylsulfonyl-oxy)-benzimidazole with a melting point of 227°C (below

cleavage).

11) 5.9 g of 2-carbispropoxyamino-5(6)-hydroxy-benzimidazole obtain 8.0 g of 2-carbispropoxyamino-5(6)-(3-trifluoromethyl-phenylsulfonyloxy)-benzimidazole with a melting point of 205°C (below

cleavage)

12) 6.2 g of 2-carbisbutoxyamino-5(6)-hydroxy-benzimidazole obtain 8.2 g of 2-carbisbutoxyamino-5(6)-(3-trifluoromethyl-phenylsulfonyloxy)-benzimidazole with a melting point of 243°C (below

cleavage)

13) Get 5.1 g of 3-cyano-benzosulfonic acid chloride

6.7 g of 2-carbomethoxyamino-5(6)-(3-cyano-phenylsulfonyloxy)-benzimidazole with melting point 275°C (under decomposition)

For the preparation of the 2-carbomethoxy-amino-5(6)-hydroxy-benzimidazole used as starting material, 56 g of S-methylthiourea sulphate is mixed in 90 ml of water with 26 ml of chloroformic acid methyl ester and at a temperature below 20°C, 116 g of 25% ig sodium lye. Stirring is continued for half an hour and a solution is then added which had been prepared by hydrogenating 51.6 g of benzoic acid 3-nitro-4-amino-phenyl ester in 250 ml of glacial acetic acid with Raney nickel and filtering off the catalyst. 300 ml of glacial acetic acid, 100 ml of water and 100 ml of methanol are added and boiled for 2 hours under reflux. After cooling, the precipitated 2-carbomethoxyamino-5(6)-benzoyloxy-benzimidazole is isolated in a yield of 41 g with a melting point of 280°C (under decomposition).

The 2-carbomethoxyamino-5(6)-benzoyl-oxy-benzimidazole thus formed is stirred for 5 minutes in a mixture of 400 ml of methanol and 400 ml of 2N caustic soda, the solution is filtered, neutralized with glacial acetic acid and evaporated in vacuo. The residue is mixed with 100 ml of water, the precipitated solid is sucked off and washed out with methanol and diisopropyl ether. After recrystallization from glacial acetic acid/methanol 1:1, 21 g of 2-carbomethoxyamino-5(6)-hydroxy-benzimidazole with a melting point of 305°C (under decomposition) is obtained.

Claims (1)

Process for the preparation of 2-carbalkoxy-amino-5(6)-phenyl-sulfonyloxy-benzimidazoles with formula (1) in which R^ means alkyl of 1 to 4 C atoms, R^ and R^ each independently of the other means hydrogen, hydroxyl, alkoxy of 1 to 4 C atoms, halogen, trifluoromethyl, alkyl of 1 to 4 C atoms, carbaloxy with 1 to 4 C atoms in the alkoxy residue or CN, characterized in that a 2-carbalkoxyamino-5(6)- hydroxybenzimidazole of formula (2) wherein R1 has the same meaning as in formula (1) is reacted in the presence of a base with a benzenesulfonic acid halide of formula (3) wherein R2 and R3 have the same meaning as in formula (1) and X means fluorine, chlorine or bromine.