CS196284B2 - Method of producing phenylesters of 2-alkoxycarbonyl aminobenzimidazol-5/6/-ylsulphonic acid - Google Patents

Description

The present invention relates to a process for the preparation of 2-alkoxycarbonylaminobenzimidazol-5 (6) -ylsulfonic acid phenyl esters which are useful as anthelmintically active substances.

2-alkoxycarbonylaminobenzimidazole derivatives with alkyl, acyl, phenoxy residues and phenylthio groups in the 5-position (6) are already known as anthelmintics [P. Actor et al., Nature 215, 321 (1967), DOS 2,029,637, DOS 2,164,690, DOS 2,363,348].

The present invention provides anthelmintically active 2-alkoxycarbonylaminobenzimidazolyl-5 (6) -sulfonic acid phenyl esters of Formula 1

in which

R1 is C1-C4alkyl,

R 2 and R 5 are each independently hydrogen, C 1 -C 4 alkoxy, halogen, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl. up to 4 carbon atoms in the alkoxy or cyano group.

Suitable alkyl radicals in the substituents R1, R2 and R3 are: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl. suitable alkoxy groups in R2 and R5 are: methoxy, ethoxy, propoxy, isopropoxy and butoxy. Possible halogen atoms in the substituents R2 and R3 are: fluorine, chlorine, bromine and iodine. Suitable alkoxycarbonyl groups in substituents R2 and R3 are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl.

Particularly preferred are compounds of formula 1 wherein R 1 is methyl, R 2 is hydrogen and R 5 is hydrogen, chlorine, bromine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, with R 5 being particularly preferred at the 3-position of the phenyl ring.

The present invention provides a process for the preparation of 2-alkoxycarbonylaminobenzimidazol-5 (6) -ylsulphonic acid phenyl esters of formula (1), wherein R 1, R 2 and R 5 are as defined above, comprising: a .beta.-phenylenediamine derivative of the formula

in which

R2 and R3 are as defined above, reacted with the N-dichloromethylene carbamate 5

Cl ./

R1-O-C-N = 'C'

o Cl (5) in which

R 1 is as defined above, at a temperature between -10 and +40 ° C in the presence of a base.

The course of reactions can be illustrated by the following reaction schemes:

in

Cl

C18 (2) +; > ^C = NC - OR _n O (57

•IN

C-NH-COOP.

'and/

H

In order to carry out the reaction according to the invention, 1 mol of the o-phenylenediamine derivative of the formula 2 is expediently reacted in the presence. 2 moles of base with 1 mol of N-dichloromethylcarbamate of formula 5.

Suitable bases are alkali or alkaline-earth metal hydroxides, carbonates and acid carbonates or tertiary organic bases. Examples include: sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, triethylamine, pyridine and methyl-substituted. pyridines.

The N-dichloromethylene carbamates of formula 5 can be prepared according to the procedure described in DOS 1932 297 from the known dichloromethylene carbamic acid chloride and alcohols in the presence of an inert organic solvent such as ether, dioxane, tetrahydrofuran, benzene, toluene at temperatures between 0 and 40 ° C.

Examples of N-dichloromethylenecarbamates of formula 5 include: methyl, ethyl, isopropyl, propyl, n-butyl and sec-butyl N-dichloromethylenecarbamate.

The reaction temperatures can be varied within a wide range. In general, a range between -10 and 60 ° C, preferably between 0 and 00 ° C, is possible.

Examples of suitable o-phenylenediamine derivatives of formula (2) are:

3,4-diaminobenzenesulfonic acid phenyl ester,

3,4-diaminobenzenesulfonic acid 4-chlorophenyl ester,

3-Chlorophenyl 3,4-diaminobenzenesulfonic acid ester

3,4-diaminobenzenesulfonic acid 2-chlorophenyl ester,

2,5-Dichlorophenyl ester of 3,4-diaminobenzenesulfonic acid,

3,4-diaminobenzenesulfonic acid 3,5-dichlorophenyl ester,

3,4-diaminobenzenesulfonic acid 4-bromophenyl ester, as follows:

3-Bromophenyl 3,4-diaminobenzenesulfonic acid ester

3,4-diaminobenzenesulfonic acid 2-bromophenyl ester,

3,4-diaminobenzenesulfonic acid 4-methylphenyl ester,

3,4-diaminobenzenesulfonic acid methylphenyl ester,

3,4-diaminobenzenesulfonic acid 2-methylphenyl ester,

3,4-diaminabenzenesulfonic acid 4-tert-butylphenyl ester;

3,4-diaminobenzenesulfonic acid 2,4-dimethylphenyl ester,

3,4-diaminobenzenesulfonic acid 2-chloro-4-methylphenyl ester;

3,4-diaminobenzenesulfonic acid 2-chloro-6-methylphenyl ester;

3-Chloro-4-methylphenyl ether of 3,4-diaminobenzenesulfonic acid,

3,4-diaminoben-, zensulfonic acid 3-chloro-6-methylphenyl ester '

3,4-diaminobenzenesulfonic acid 3-chloro-4-carbethoxyphenyl ester,

4-chloro-2-methylphenyl ether 3,4-diamino. benzenesulfonic acids,

3,4-diaminobenzenesulfonic acid 4-chloro-3-methylphenyl ester,

3,4-diaminobenzenesulfonic acid 4-chloro-3,5-dimethylphenyl ester,

3,4-diaminobenzenesulfonic acid 3,5-bistrlfluoromethylphenyl ester,

3,4-diaminobenzenesulfonic acid 4-methoxyphenyl ester,.

3,4-diamino-benzenesulfonic acid 3-methoxyphenyl ester,

3,4-diaminobenzenesulfonic acid 2-methoxyphenyl ester,

3,4-diaminobenzenesulfonic acid 4-propoxyphenyl ester,

3,4-diaminobenzenesulfonic acid 4-isopropoxyphenyl ester,

3,4-diaminobenzenesulfonic acid 4-butoxyphenyl ester a

3,4-diaminobenzenesulfonic acid 4-isobutoxyphenyl ester.

The following compounds are obtained in this way:

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester

2-Methoxycarbonylamino-5-benzimidazole-1-phosphonic acid 4-chlorophenyl ester,

3-Chlorophenyl 2-methoxycarbonylamino-5-benzimidazolesulfonic acid ester,

2-Methoxycarbonyl-5-benzimidazolesulfonic acid 2-chlorophenyl ester,

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid, 2,5-dichlorophenyl ester,

3,5-Dichlorophenyl 2-methoxycarbonylamino-5-benzimidazolesulfonic acid ester,

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 4-bromophenyl ester;

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 3-bromophenyl ester,

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 2-bromophenyl ester,

4-Methylphenyl ester of 2-methoxycarbonylamino-5-benzimidazolesulfonic acid,

3-Methoxyphenyl ester of 2-methoxycarbonylamino-5-benzimidazolesulfonic acid,

2-methylphenyl ester. 2-methoxycarbonylamino-5-benzimidazolesulfonic acid,

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 4- tert -butyl phenyl ester,

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 2,4-dimethylphenyl ester,

2-Chloro-4-methylphenyl 2-methoxycarbonylamino-5-benzimidazole-3-sulfonic acid ester,

2-Methoxy-2-chloro-6-methyl-phenyl ester. carbonylamino-5-benzimidazolesulfonic acid,

3-Chloro-4-methylphenyl 2-methoxycarbonylamino-5-benzimidazol-sulfonic acid ester,

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 3-chloro-6-methylphenyl ester,

3-Chloro-4-carbethoxyphenyl 2-methoxycarbonylamino-5-benzimidazolylphosphonic acid ester,

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 4-chloro-2-methylphenyl ester,

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 4-chloro-3-methylphenyl ester,

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 4-chloro-3,5-dimethylphenyl ester,

3,5-bistrifluoromethylphenyl 2-methoxycarbonylamino-5-benzimidazolesulfonic acid ester,

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 4-methoxyphenyl ester,

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 3-methoxyphenyl ester,

9 6 284

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 2-methoxyphenyl ester,

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 4-propoxyphenyl ester,

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 4-isopropoxyphenyl ester,

2-methoxycarbonylamino-5-benzimidazolesulfonic acid 4-butoxyphenyl ester,

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 4-isobutoxyphenyl ester, 2-ethoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester, 2-propoxycarbonylamino-phenyl ester.

-5-benzimidazolesulfonic acid, 2-isopropoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester, 2-isobutoxycarbonylamino-5-benzimidazole sulfonic acid phenyl ester, 2-butoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester, and 2-tert-butoxy-2-tert-butoxyxyl ester.

The o-phenylenediamine derivative of formula 2, which serves as the starting material for the reaction according to the invention, is obtained by reduction of the corresponding amino nitro derivative of formula 12 in which R 2 and R 3 have the same meaning as in formula 1. solvents such as methanol or dimethylformamide at temperatures between 20 and 60 ° C or treatment with reducing agents such as sodium dithionite.

The aminonitroderivatives of formula 12 are obtained by reacting the corresponding chloronitroderivatives of formula 13 in which R 2 and R 3 have the same meaning as in formula 1 with ammonia in a suitable solvent such as dioxane or methanol at elevated temperature and elevated pressure. The chloro-derivatives of formula 13 are obtained by reacting 3-nitro-4-chlorobenzenesulfonic acid chloride of formula 15 with a phenol of formula 14 in which R 2 and R 3 have the same meaning as in formula 1 in an inert solvent in the presence of a base , such as triethylamine.

The 2-alkoxycarbonylaminobenzimidazol-5 (6-ylsulfonic acid) phenyl esters of the present invention are valuable chemotherapeutic agents and are useful in combating parasitic diseases in humans and animals, such as helminths and liver fluke.

The active compounds according to the invention are particularly effective against a large number of helminths, such as the Haemonchus, Trichostrongylus, Ostertagiaj, Strongyloidesj, Cooperia, Oesophagostomum, Oesophagostomum. (Hyostrongylus), hookworm (Ancylostomaj, roundworm (Askaris) and roup (Heterakis)) The activity of the compounds according to the invention against the gastric and intestinal tract infestation, especially ruminants, is particularly pronounced. wherein the compounds of the invention find particular use in veterinary medicine.

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

For oral administration, tablets, coated tablets, capsules, powders, granules or pastes which contain the active substances together with customary excipients and carriers such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatin, calcium carbonate are suitable. , finely dispersed silicic acid, carboxymethylcellulose or the like.

For parenteral administration, suitable solutions are, for example, oily solutions which are prepared using sesame oil, castor oil or synthetic triglycerides, optionally with the addition of tocopherol as an antioxidant and / or with surfactants such as sorbitan fatty acid esters. . In addition, aqueous suspensions are prepared which are prepared using ethoxylated esters of sorbitan fatty acids, optionally with the addition of thickeners, such as polyethylene glycol or carboxymethylcellulose.

The concentrations of the active compounds according to the invention in the preparations prepared from these compounds are suitably between 2 and 20% by weight for veterinary purposes. For the purpose of human medicines, the concentration of the active ingredients is between 20 and 80% by weight.

In order to investigate the effect of the compounds of the invention, chemotherapeutic experiments were carried out on lambs weighing about 30 kg, which were injected experimentally with larvae of Haemonchus. After the pre-retention period (time between infection and sexual maturity of parasites beginning with the elimination of eggs or larvae), the number of eggs per 1 was determined by a modified McMaster procedure according to Wetzel [Tierarztliche Umschau, 6, 209-210 (1951)]. Immediately thereafter, sheep were treated (generally 4 to 8 animals per active ingredient, but at least 2 animals) The animals were dosed with the compounds of the invention in the form of a suspension, each in 10 ml of a 1% tylose suspension.

On 7, 14 and 28 days after treatment, the number of eggs per g of faeces was again determined as above and the percentage reduction compared to the pre-treatment baseline was calculated.

The compounds of the invention are excellent not only for oral administration, but also for parenteral administration at doses up to 2 mg / kg. This far exceeds comparable benzimidazole derivatives, in particular 19-8 284, to all known 5 (6) -substituted 2-benzimidazoicarbamates. _Ř

The preparation of the compounds of the invention is illustrated by the following examples. Temperatures are given in degrees Celsius.

Example 1 - ·.

26.4 g of 3,4-diaminobenzenesulfonic acid phenyl ester, 20.2 g of triethylamine and 300 ml of chloroform are mixed and a solution of 15.6 g of N-dichloromethylenecarbamic acid methyl ester in 50 ml of chloroform is slowly added with stirring. Not more than 20 ° C. The reaction mixture was stirred for 1 hour, the precipitate was filtered off and washed with chloroform.

For purification, the crude product was dissolved in dioxarium, the solution was filtered through charcoal, and water was added to the filtrate. After filtration, washing and drying, 2 g of 2-methoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester of decomposition temperature 242 DEG C. is obtained.

The 3,4-diaminohenzenesulfonic acid phenyl ester is prepared by hydrogenating 27 g of 3-nitro-4-aminobenzenesulfonic acid phenyl ester in 300 ml of methyl glycol in the presence of Raney nickel at atmospheric pressure and room temperature. The catalyst was filtered off and the filtrate was concentrated to give 3,4-diaminobenzenesulfonic acid phenyl ester as a crude product. This product is 25 g of a dark oil which can be used directly for cyclization.

In order to prepare phenyl 3-nitro-4-aminobenzenesulfonic acid phenyl ester 54 g, 3 ^j nitro-4-methylphenyl ester in 500 ml maintains. dioxane at a pressure of 0.5 MPa of ammonia gas for 5 hours at 50 ° C and then the solvent is removed in vacuo. 200 ml of a mixture of equal parts of methanol and water were added to the residue, after which a solid precipitate formed after a short time and was filtered off.

Recrystallization several times from methanol and then benzene gave 28 g of 3-nitro-4-aminobenzenesulfonic acid phenyl ester, m.p. 104 ° C.

3-Nitro-4-chlorobenzenesulfonic acid phenyl ester is obtained by taking 51 g of chloride

3-Nitro-4-chlorobenzenesulfonic acid is mixed with 18.8 g of phenol in 120 ml of acetone and 28 ml of triethylamine are added dropwise while cooling at an internal temperature not exceeding 10 ° C. The mixture was stirred for several hours at room temperature, and then water was added, leaving an oil which was treated with ether.

After recrystallization from methanol, 54 g of 3-nitro-4-chlorobenzenesulfonic acid phenyl ester, m.p. 71 DEG C., precipitated.

The following compounds are obtained in an analogous manner using appropriately modified starting materials:

2.

through 3-nitro-4-chlorobenzenesulfonic acid 3-chlorophenyl ester (m.p. 68 ° C); and

3-chiurfenster. 3-nitro-4-aminoben-1-zensulfonic acid (m.p. 138 DEG C.); .

3,4-diaminohenzenesulfonic acid 3-chlorophenyl ester, m.p. 84 DEG C., gives 2-methoxycarbonylamino-5-benzimidazolesulfoic acid 3-chlorophenyl ester (m.p. 234 DEG C.) (decomp.); ...

3. via 3-nitro-4-chlorobenzenesulfonic acid 3-bromophenyl ester (m.p. 72 ° C); and

3-Nitro-4-chlorobenzenesulfonic acid 3-bromophenyl ester (m.p. 141 ° C); and

3,4-diaminobenzenesulfonic acid 3-bromophenyl ester (m.p. 94 ° C) gave 2-methoxycarbonylamino-5-benzimidazolesulfonic acid 3-bromophenyl ester (m.p. 242 ° C) (dec.);

4. '. - via 3-nitro-4-chlorobenzenesulfonic acid 3-methylphenyl ester (m.p. 60 ° C); and

3-Nitro-4-aminobenzenesulfonic acid 3-methylphenyl ester (m.p. 138 ° C); and

3,4-diaminobenzenesulfonic acid 3-methylphenyl ester (m.p. 84 ° C) gave 2-methoxycarbonylamino-S-benzimidazolesulfonic acid 3-methylphenyl ester (mp 234 ° C) (dec.);

5.

via 3-nitro-4-chlorobenzenesulfonic acid 3-methoxyphenyl ester (oil);

3-Nitro-4-aminobenzenesulfonic acid 3-methoxyphenyl ester (m.p. 116 ° C); and

3,4-diaminobenzenesulfonic acid 3-methoxyphenyl ester (oil) gave 2-methoxycarbonylamino-5-benzimidazolesulfonic acid 3-methoxyphenyl ester (m.p. 227 ° C) (dec.);

6.

via 3-nitro-4-chlorobenzenesulfonic acid 3-ethoxyphanyl ester (oil);

3-Nitro-4-aminobenzenesulfonic acid 3-ethoxyphenyl ester (m.p. 86 ° C); and

3,4-diaminobenzenesulfonic acid 3-ethoxyphenyl ester (oil) gave 2-methoxycarbonylamino-5-benzimidazolesulfonic acid 3-ethoxyphenyl ester (m.p. 212 DEG C.) (decomposition);

7.

via 3-nitro-4-chlorobenzenesulfonic acid 3-trifluoromethylphenyl ester (m.p. 65 °)

Celsius) a

3-Nitro-4-aminobenzenesulfonic acid 3-trifluoromethylphenyl ester (m.p. 132 ° C); and

3-Trifluoromethylphenyl ester of 3,4-diaminobenzenesulfonic acid gave 2-methoxycarbonylamino-5-henzimidazolesulfonic acid 3-trifluoromethylphenyl ester (m.p. 250 ° C) (dec.).

Claims (1)

VYNALEZU , ... pSEDMET Process for the preparation of 2-alkoxycarbonylaminobenzimidazol-5 (6) -ylsulfonic acid phenyl esters in which: R 1 represents an alkyl radical having 1 to 4 carbon atoms, R @ 2 and R @ 3 are each independently hydrogen, (C1 -C4) alkoxy, halogen, trifluoromethyl, alkyl (C1 -C4), (C1 -C4) alkoxycarbonyl or cyano, characterized in that: 2. A method according to claim 1, wherein the o-phenylenedlamine derivative of formula (2) is: R 2 and R 3 are as defined above, reacted with an N-dichloromethylenecarbamic acid ester of formula 5 Cl / R1-O-C-N = C (5) in which R1 is as defined above.