CH619938A5 - Process for the preparation of 2-carbalkoxyamino-5(6)-phenyl-sulphonyloxybenzimidazoles - Google Patents

Description

619938

2nd

PATENT CLAIM Process for the preparation of 2-carbalkoxyamino-5 (6) - phenylsulfonyloxy-benzimidazoles of the formula I.

R3

S02 - o

\

'C-NH-COOR.

(I),

(III),

io wherein X is fluorine, chlorine or bromine, in the presence of a base.

wherein

R! Alkyl of 1 to 4 carbon atoms; and R2 and R3 each independently of one another are hydrogen, hydroxy, alkoxy having 1 to 4 carbon atoms, halogen, trifluoromethyl, alkyl having 1 to 4 carbon atoms, carbalkoxy having 1 to 4 carbon atoms in the alkoxy radical or CN

mean, characterized in that a 2-carb-alkoxyamino-5 (6) -hydroxy-benzimidazole of the formula II

C-NH-COOR.

(II)

with a benzenesulfonic acid halide of the formula III

+

15 2-carbalkoxyamino-benzimidazolyl derivatives with alkyl, acyl, phenoxy and phenylthio radicals in the 5 (6) position are known as anthelmintics [P. Actor et al., Nature 215 (1967) 321; furthermore DE-OSen 2 029 637, 2 164 690 and 2 363 348].

The subject of the invention is therefore the method defined in patent claim 20.

The reaction is preferably carried out using benzenesulfonic acid chlorides of the formula III.

If Rls R2 and R3 are alkyl radicals, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and 25 tert-butyl are suitable for this purpose; when R2 and Ra are alkoxy, methoxy, ethoxy, propoxy, isopropoxy and butoxy are suitable. If R2 and R3 stand for halogen atoms, these can be fluorine, chlorine, bromine or iodine atoms. If R2 and R3 are carbalkoxy groups, 30 carbomethoxy, carbethoxy, carbopropoxy and carbobutoxy are suitable.

Compounds of the formula I in which

Rj is methyl, ethyl, propyl or butyl;

35 R2 hydrogen or chlorine; and R3 is hydrogen, chlorine or trifluoromethyl.

The course of the reaction can be represented by the following scheme:

C-NH-C00R,

(III)

(II)

C-NH-COOR,

(I) •

When carrying out the reaction, the procedure is expediently such that a 2-carbalkoxyamino-5 (6) -hydroxy-benzimidazole of the formula II is suspended in an aprotic solvent which contains a tertiary amine and added to this suspension with stirring a solution of a benzene

3rd

619938

Adds sulfonic acid halide of the formula III dropwise. The mixture is expediently stirred until the reaction has ended, the end point being expediently determined by means of thin-layer chromatography.

Examples of suitable 2-carbalkoxyamino-5 (6) -hydroxy-benzimidazoles of the formula II are the following:

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

2-carboethoxyamino-5 (6) -hydroxy-benzimidazole

2-carbisopropoxyamino-5 (6) -hydroxy-benzimidazole

2-carbobutoxyamino-5 (6) -hydroxy-benzimidazole

2-carbisobutoxyamino-5 (6) -hydroxy-benzimidazole

2-carbo-tert-butoxyamino-5 (6) -hydroxy-benzimidazole.

Examples of suitable aprotic solvents are:

Acetone, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethylformamide, dimethyl sulfoxide, tetramethyl urea and similar dipolar aprotic solvents.

Suitable bases are alkali or alkaline earth metal hydroxides, carbonates and bicarbonates as well as tertiary organic bases, e.g. Sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine, pyridine and methyl-substituted pyridines.

Examples of suitable benzenesulfonic acid halides of the formula III are:

Benzenesulfonic acid chloride 4-chloro-benzenesulfonic acid chloride

3-chloro-benzenesulfonic acid chloride

2-chlorobenzenesulfonic 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-methylbenzenesulfonic acid chloride

3-methyl-benzenesulfonic acid chloride 2-methyl-benzenesulfonic acid chloride

4-tert-butyl-benzenesulfonic acid chloride 2,4-dimethyl-benzenesulfonic 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 2-methoxy-benzenesulfonic acid chloride

4-propoxy-benzenesulfonic acid chloride 4-isopropoxy-benzenesulfonic acid chloride 4-butoxy-benzenesulfonic acid chloride 4-isobutoxy-benzenesulfonic acid chloride.

Temperatures in the range from 0 to 60 ° C., preferably between 15 and 30 ° C., are recommended for carrying out the reaction. The rate of conversion depends on the reactivity of the benzenesulfonic acid chloride used and can vary from a few hours to the duration of a day.

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

The reaction products can be isolated from the reaction mixture by filtration. In this way the following 3 connections are obtained:

2-carbomethoxyamino-5 (6) -phenylsulfonyloxy-benzimidazole 2-carbomethoxyamino-5 (6) - (4-chlorophenylsulfonyloxy) -benz-imidazole m 2-carbomethoxyamino-5 (6) - (3-chlorophenylsulfonyloxy) - -benzimidazole

2-carbomethoxyamino-5 (6) - (2-chlorophenylsulfony.loxy) benzimidazole

2-carbomethoxyamino-5 (6) - (2,5-dichlorophenylsulfonyloxy) -15 -benzimidazole 2-carbomethoxyamino-5 (6) - (3,4-dichlorophenylsulfonyloxy) benzimidazole

2-carbomethoxyamino-5 (6) - (3,5-dichlorophenylsulfonyloxy) benzimidazole

20 2-Carbomethoxyamino-5 (6) - (4-bromophenylsulfonyloxy) benzimidazole

2-carbomethoxyamino-5 (6) - (3-bromophenylsulfonyloxy) benzimidazole

2-carbomethoxyamino-5 (6) - (2-bromo-phenylsulfonyloxy) -25 -benzimidazole

2-carbomethoxyamino-5 (6) - (4-methylphenylsulfonyloxy) benzimidazole

2-carbomethoxyamino-5 (6) - (3-methylphenylsulfonyloxy) benzimidazole

30 2-Carbomethoxyamino-5 (6) - (2-methylphenyisulfonyloxy) benzimidazole

2-carbomethoxyamino-5 (6) - (4-tert-butylphenylsulfonyloxy) benzimidazole

2-Carbomethoxyamino-5 (6) - (2-chloro-4-methylphenylsulfo-35 nyloxy) benzimidazole

2-carbomethoxyamino-5 (6) - (2-chloro-6-methylphenylsulfonyl-

oxy) benzimidazole 2-carbomethoxyamino-5 (6) - (3-chloro-4-methylphenylsulfonyloxy) benzimidazole 40 2-carbomethoxyamino-5 (6) - (3-chloro-6-methylphenylsulfonyloxy) ) -benzimidazole 2-carbomethoxyamino-5 (6) - (4-chloro-2-methylphenylsulfonyl-

oxy) benzimidazole 2-carbomethoxyamino-5 (6) - (4-chloro-3-methylphenylsulfonyl-45 oxy) benzimidazole 2-carbomethoxyamino-5 (6) - (4-chloro-3,5-dimethylphenylsulfo -

nyloxy) -benzimidazole 2-carbomethoxyamino-5 (6) - (3-trifluoromethyl-phenylsulfonyl-oxy) -benzimidazole so 2-carbomethoxyamino-5 (6) - (4-methoxy-phenyIsulfonyIoxy) - benzimidazole

2-carbomethoxyamino-5 (6) - (3-methoxyphenylsulfonyloxy) benzimidazole

2-Carbomethoxyamino-5 (6) - (2-methoxy-phenylsulfonyloxy) -55 -benzimidazole

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

2-carbomethoxyamino-5 (6) - (4-isopropoxyphenylsulfonyloxy) benzimidazole

60 2-Carbomethoxyamino-5 (6) - (4-butoxy-phenylsulfonyloxy) benzimidazole

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

2-Carbäthoxyamino-5 (6) -phenylsulfonyloxy-benzimidazole 65 2-Carbopropoxyamino-5 (6) -phenylsulfonyloxy-benzimidazole 2-Carbisopropoxyamino-5 (6) -phenylsulfonyloxy-benzimidazole 2-Carbobutoxyamino-5 (6) -phenyl-2-phenol-2-phenol -Carbisobutoxyamino-5 (6) -phenylsulfonyloxy-benzimidazole

619938

4th

2-carbo-tert-butoxyamino-5 (6) -phenyIsulfonyloxy-benz-

imidazole.

The 2-carbalkoxyamino - 5 (6) -hydroxy-benzimidazoles of the formula II which serve as starting material can be prepared by known processes, cf. DE-OS 2 164 690. You can proceed in such a way that 3-nitro-4-amino-phenol is reacted with benzoyl chloride to give benzoic acid-3-nitro-4-amino-phenyl ester, this with Raney nickel for 3,4-di -amino derivative hydrogenated, the latter is reacted with S-methylthiourea carboxylate to give 2-carbalkoxyamino-5-benzoyloxy-benzimide-azole and this is converted into the hydroxy compound of the formula II using dilute sodium hydroxide solution.

The 2-carbalkoxyamino - 5 (6) -phenylsulfonyloxy-benzimidazoles obtainable according to the invention are valuable chemotherapeutic agents and are suitable for combating parasitic diseases in humans and animals, such as helminths and liver fluke.

They are particularly effective against a large number of helminths, e.g. Haemonchus, Trichostrongylus, Ostertagia, Strongyloides, Cooperia, Chabertia, Oesophagostomum, Hyostrongylus, Ankylostoma, Askaris and Heterakis. The effectiveness against gastrointestinal tract - strongylides, which mainly affect ruminants - is particularly pronounced. The infestation of the animals by these parasites leads to great economic damage, which is why the compounds obtainable according to the invention are used in particular in veterinary medicinal products.

Depending on the situation, the active compounds of the formula I are administered in doses between 0.5 and 50 mg per kg of body weight for 1 to 14 days.

For oral administration, tablets, dragees, capsules, powders, granules or pastes are considered, which contain the active ingredients together with customary auxiliaries or carriers, such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely divided silica, carboxymethyl cellulose or similar substances.

Solutions are possible for parenteral administration, e.g. oily solutions which are produced 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 suitable, which are prepared using ethoxylated sorbitan fatty acid esters, optionally with the addition of thickeners, such as polyethylene glycol or carboxymethyl cellulose.

The concentrations of the active substances obtainable according to the invention in the preparations produced therewith are preferably between 2 and 20% by weight for use as veterinary medicinal products, and for the use as human medicinal products the concentrations of the active substances are preferably between 20 and 80% by weight.

To determine the effect of the compounds obtainable according to the invention, chemotherapeutic tests were carried out on sheep lambs weighing approximately 30 kg, which had been experimentally infected with larvae of Haemonchus contor-tus or Trichostrongylus colubriformis. The test animals were kept in tiled boxes, which were cleaned thoroughly every day. After the prepatence period (time between infection and sexual maturity of the parasites with the beginning of the excretion of eggs or larvae), the egg count per gram of faeces was determined in the modified McMaster method according to Wet-zel [Veterinary Review 6 (1951) 209 to 210]. Immediately afterwards, the sheep were treated (generally 4 to 8 animals per active ingredient, but at least 2). The doses of the process products were applied to the animals as a suspension in 10 ml of a 1% tylose suspension. On the 7th, 14th and 28th day after the treatment, the number of eggs per gram of faeces was again determined according to the above-mentioned method and their percentage decrease compared to the starting value before the treatment was calculated.

The table below shows the effects of some compounds of formula I in these experiments.

TABLE

connection

dosage

Acceptance based on the example of the egg number

1

5 mg / kg

> 95%

2nd

5 mg / kg

90%

7

5 mg / kg

100%

9

5 mg / kg

100%

11

5 mg / kg

> 95%

12

5 mg / kg

> 95%

The process products are not only excellently effective when administered orally, but also act parenterally in doses down to 2 mg / kg. They are thus far superior to comparable benzimidazole derivatives, in particular to 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 are added. With vigorous stirring, a solution of 4.4 g of benzenesulfonyl chloride in 20 ml of acetone is added dropwise at room temperature and the mixture is stirred for 10 hours, the consistency of the suspension changing significantly. It initially becomes thin and gradually thick again. After cooling, the solid constituents are filtered off, washed successively with acetone, water and methanol and dried on the steam bath.

For purification, the crude product is recrystallized from glacial acetic acid / methanol. The yield of 2-carbomethoxy-amino-5 (6) -phenylsulfonyloxy-benzimidazole is 6.2 g from the 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 ethyl acetate and 1 ml of glacial acetic acid as eluent shows that the stain of the starting material has disappeared and that of the reaction product with a higher Rt value has replaced it.

Analogous are shown using equivalent amounts of the corresponding benzenesulfonic acid chlorides from 5.15 g of 2-carbomethoxyamino-5 (6) -hydroxy-benzimidazole and

2) 5.3 g of 4-chloro-benzenesulfonic acid chloride

6.8 g of 2-carbomethoxyamino-5 (6) - (4-chlorophenylsulfonyloxy) benzimidazole, mp. 230 ° C. (dec.)

3) 5.3 g of 3-chlorobenzenesulfonic acid chloride

6.8 g of 2-carbomethoxyamino-5 (6) - (3-chlorophenylsulfonyloxy) benzimidazole, mp. 250 ° C. (dec.)

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

7.4 g of 2-carbomethoxyamino-5 (6) - (3,4-dichlorophenylsulfonyloxy) benzimidazole, mp. 255 ° C. (dec.)

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

619938

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

7.3 g 2-carbomethoxyamino-5 (6) - (3,5-dichlorophenyl-

sulfonyloxy) benzimidazole, mp. 280 ° C. (dec.)

6) 6.4 g of 3-bromo-benzenesulfonic acid chloride

7.6 g 2-carbomethoxyamino-5 (6) - (3-bromo-phenyl-

sulfonyloxy) benzimidazole, mp 242 ° C. (dec.)

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

6.4 g of 2-carbomethoxyamino-5 (6) - (4-methylphenyI-

sulfonyIoxy) -benzimidazole, mp. 237 ° C (dec.)

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

6.4 g of 2-carbomethoxyamino-5 (6) - (3-methylphenylsulfonyloxy) benzimidazole, mp. 250 ° C. (dec.)

9) 6.1 g of 3-trifluoromethyl-benzoisulfonic acid chloride 7.4 g of 2-carbomethoxyamino-5 (6) - (3-trifluoromethyl-

-phenylsulfonyloxy) -benzimidazole, mp. 215 ° C (dec.)

Using 6.1 g of 3-trifluoromethyl-benzenesulfonic acid chloride and

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

7.7 g of 2-carbäthoxyamino-5 (6) - (3-trifluoromethyl-phe-

nylsulfonyloxy) benzimidazole, mp. 227 ° C (dec.)

11) 5.9 g of 2-carbisopropoxyamino-5 (6) -hydroxy-benzimide-

azole

8.0 g of 2-carbisopropoxyamino-5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) benzimidazole, mp. 205 ° C. (dec.).

12) 6.2 g of 2-carbisobutoxyamino-5 (6) -hydroxy-benzimide-

azole

8.2 g 2-carbisobutoxyamino-5 (6) - (3-trifhiormethyl-

-phenylsulfonyloxy) -benzimidazole, mp. 243 ° C s (dec.)

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

6.7 g of 2-carbomethoxyamino-5 (6) - (3-cyano-phenyl-sulfonyloxy) -benzimidazole, mp. 275 ° C io (dec.)

To prepare the 2-carbomethoxyamino-5 (6) -hydroxy-benzimidazole used as starting material, 56 g of S-methylthiourea sulfate in 90 ml of water are mixed with 26 ml of 15 chloroformate and 116 g of 25% sodium hydroxide solution are added dropwise at a temperature below 20 ° C. The mixture is stirred for a further half hour and then a solution is added which has been obtained from hydrogenation of 51.6 g of 3-nitro-4-aminophenyl benzoate in 250 ml of glacial acetic acid with Raney-20 nickel and filtration from the catalyst. 300 ml of glacial acetic acid, 100 ml of water and 100 ml of methanol are added and the mixture is boiled under reflux for 2 hours. After cooling, the precipitated 2-carbomethoxyamino - 5 (6) -benzoyloxy-benzimidazole is isolated in a yield of 41 g 25 with mp. 280 ° C (dec.).

The 2-carbomethoxyamino-5 (6) -benzoyloxy-benzimidazole thus obtained is stirred in a mixture of 400 ml of methanol and 400 ml of 2N sodium hydroxide solution for 5 minutes, the solution is filtered, neutralized with glacial acetic acid and concentrated in vacuo. 30 The residue is mixed with 100 ml of water, the precipitated solid is suction filtered 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 of mp 305 ° C. (dec.) Are obtained.

35

V