CS196280B2 - Method of producing 2-alkoxycarbonyl-amino-5/6/-phenylsulphonyl- oxybenzimidazoles - Google Patents

Description

The invention relates to a process for the preparation of 2-alkoxycarbonylamino-5 (6) -phenylsulfonyloxybenzimidazoles having anthelmintic effects.

2-alkoxycarbonylaminobenzimidazolyl derivatives with alkyl radicals, acyl radicals, phenoxy and phenylthio groups at 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 relates to the anthelmintically active 2-alkoxycarbonylamino-5 (6) -phenylsulfonylpxybenzimidazoles of formula (1),

R 1 represents an alkyl radical having 1 to 4 carbon atoms;

R 2 and R 5 are each independently hydrogen, C 1 -C 4 alkoxy, halogen, trifluoromethyl, C 1 -C 4 alkyl or cyano; As alkyl radicals in R 1, R 2 and R 3 suitable are: methyl, ethyl, propyl, isopropyl butyl, sec-butyl, tert-butyl. As alkoxy groups in R2. and R 3 are: methoxy, e, thoxy, propoxy, isopropoxy. As halogen atoms in the substituents R? and R 3 are: fluorine, chlorine, bromine and iodine.

Particularly preferred are compounds of formula 1 wherein R 1 is methyl, ethyl, propyl or butyl ^; R2 is hydrogen or chlorine and R3 is hydrogen, chlorine or trifluoromethyl.

The present invention provides a process for the preparation of 2-alkoxycarbonylamino-5 (6) -phenylsulphonyloxybenzimidazoles of formula 1, wherein R 1, R 2 and R 5 are hydrogen; are as defined above, characterized in that the 6-phenylenediamine derivative of the general formula 2 is:

v. R2 and R3 have the same meaning as in formula i, react with an N-dichloromethylenecarbamic ester of formula 5, (5)

R 1 has the same meaning as in Formula 1,. . conveniently at a temperature between -10 and +40 ° C and in the presence of a base.

The reaction sequence can be illustrated by the following reaction scheme:

Cl

C = N-OR ₁ (5)

. · V - (ή} '. -J *'. / '·: ..; Z +, _t ú'čéIěm .reakce implementation of the _invention, are reacted advantageously 1 mol of derivative of formula fenylendlaminu-2 in the presence of' 2 mol of base with 1 mol of N-dichloromethylenecarbamic acid ester of formula 5.

Suitable bases are alkali metal 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.

Esters of acid. The N-dichloromethylenecarbamates 5 can be prepared according to the procedure described in DOS 1,932,297 from the known dichloromethylenecarbamic acid chloride with 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 the N-dichloromethylenecarbamic acid esters of formula 5 include: methyl, ethyl, isopropyl, propyl, n-butyl and sec-butyl N-dichloromethylenecarbate.

The reaction temperatures can be varied within a wide range. In general, it is operated in the range between -10 and 60 ° C, preferably between 0 and 30 ^b C.

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

Benzenesulfonic acid 3,4-diaminophenyl ester,

3.4- diaminophenyl ester ·

4-chlorobenzenesulfonic acid,

3.4- dia'minophenyl ester

3-chlorobenzenesulfonic acid,

3.4- diaihinophenyl ester

2-chlorobenzenesulfonic acids,

3.4- diaminophenyl ester

2,5-dichlorobenzenesulfonate. acids,

3.4- diaminophenyl ester

3.5- dlchlorobenzenesulfonic acids,

3.4- dlaminophenyl ester

4-bromobenzenesulfonic acid,

3.4- diaminophenyl ester

3-bromobenzenesulfonic acids,

3.4- diaminophenyl ester

2- brQ.Menzenesulfonic acids,

3.4-: diamnophenyl ester

4-methylbenzenesulfonic acid,

3.4- diaminophenyl ester

3-Methylbenzene-ulphonic acid,

2-methylbenzenesulfonic acid 3,4-diaminophenyl ester. 3,4-diaminophenyl ester

4-tert-butylbenzenesulfonic acid,

3.4- diaminophenyl ester

2,4-dimethylbenzenesulfonic acid; 3,4-aminoamino ester · ·? ....

2-chloro-4-methylbenzenesulfonic acid; _; acids;

3.4-, dlaminophenyl ester / - /

2-Chloro, 6-methylbenzenesulfonic acid. , acids,

3,4-diaminophenylestex * 3-chloro-4-methylbenzenesulfonic acid,

St. ....

3.4- diaminophenyl ester

3-chloro-6-methylbenzenesulfonic acid,

3,4-diaminophenyl ester

4-chloro-2-methylbenzenesulfonic acid,

3.4- diaminophenyl ester

4-chloro-3-methylbenzenesulfonic acid.

... V. . .

3.4- diaminophenylether

4-chloro-3,5'-diethylbenzenesulfonic acid,

3,4-diaminophenyl ester

3-trifluoromethylbenzenesulfonic acid,

3,4-diaminophenyl ester.

4-methoxybenzenesulfonic acids,

3,4-diaminophenyl ester

3-methoxybenzenesulfonic acids,

3,4-diaminophenyl 2-methoxybenzenesulfonic acid ester,

3.4- dianiinophenyl ester

4-Propoxybenzenesulfonic acids

3.4- diaminophenyl ester. , \

4-isopropoxybenzenesulfonic acid,

4-butoxybenzenesulfonic acid 3,4-diaminophenyl ester,

4-Isobutoxybenzenesulfonic acid 3,4-diaminophenyl ester.

The following compounds are preferably obtained by the process according to the invention:

2-methoxycarbonyl-5 (6) -phenylsulfonyloxybenzimidazole,.

2-methoxycarbonyl-5 (6) - (4-chlorophenylsulfonyloxy) benzimidazole;

2-methoxycarbonyl-5 (6 '- (3-chlorophenylsulfonyloxy) benzimidazole).

2-methoxycarbonyl-5 (6) - (2-chlorophenylsulfonyloxy) benzimidazole,. \

2-Methoxycarbonyl-5 (6) - (2,5-dichlorophenylsulfonyloxy) -benzzimidazole, 1'-.

2-methoxycarbonyl-5 (6) - (3,5-dichlorophenylsulphonyloxy) benzimidazole,

2-methoxycarbonyl-5 (6) - (4-bromophenylsulfonyloxy-benzimidazole),

2-methoxycarbonyl-5 (8J- (3-bromophenylsulfonyloxy) -benzzimidazole,

2-Methoxycarbonyl-5 (6) - (2-bromophenylsulfonyloxy) benzimidazole;

2-methoxycarbonyl-5 (6) - (4-methylphenylsulfonynyloxy) benzenidazole,

1ΘΘ280

2-methoxycarbonyl-5 (6) - ¹ *

- (3-methylferiylsulfonyloxy) - benzimidazole;

2-methoxycarbonyl-5 (B) -

- (2-methylphenylsulfonyloxy) -. benzimidazole,

2-Niutlioxycarbonyl-5 (6J- ··. ···

- (4-tert-Butylphenylsulfonyloxy) benzimidazole, -, - - - 1,2-Methoxycarbonyl-5- (6- (2-chloro-4-methylphenylsulfonyloxy)) - ¹ benzimidazole;

2-methoxycarbonyl-5 (6) - < - & gt ^{; ? t}

- (2-Chloro-6-methyl-phenylsulfonyloxy) -. Benzimidazole,

..... - '! · · Ν · ί-. ·;

2-methoxycarbonyl-5 (6) -; ·,. ^{! l!}

- (3-chloro-4-methylphenylsulfonyloxy) benzimidazole, '·'. '·· <: ··:. · ^R

2-methoxycarbonyl-5 (6) - (3-chloro-β-methylsulfonyloxy) benzimidazole, '

2-methoxycarbonyl-5 (6) - - -

(4-chloro-3-methylphenylsulfonyloxy) benzimidazole,

2-methoxycarbonyl-5 (6) - (4-chloro-3-methylphenylsulffortyl) benzimidazole;

2-Methoxycarbonyl (5 ' ^{, 6} '):

- (4-chloro-3,5-dimethylsulfonyloxy) - ^'' ./ benzimidazole. '<< - <. , · ¹ ·· ·

2-methoxycarbonyi-5 '(6) - ’’

- (3-Trifluoromethylsulfonyloxy) ^-1- benzimidazole,

2-methoxycarbonyl-5 (8) - (4-methoxyphenylsulfonyloxy) benzimidazole; '·· .... 1. 2 ', 2-methoxycarbonyl-5 (8) -1';

- (3-methoxyphenylsulphinyl onyloxy) benzimidazole, ^'\ ·' ^r! .

2-methoxycarbonyl-5 (8): - ': ⁴ '

- (2-methoxyphenylsulfonyloxy) - benzimidazole,

Z-methoxycarbonyl-S (R) - (4-propoxyphenylsulfonyloxy) benzimidazole,

2-methoxycarbonyl-5 (8) - N- (4-isopropoxyphenylsulfonyloxy) benzimidazole,

2-methoxycarbonyl-5- (6- (4-butoxyphenylsulfonyloxy) -4-benzimidazole),

2-methoxycarbonyl-5 (R) - (4-isobutoxyphenylsulfonyl) -benzimidazole;

2-ethoxycarbonylamino-5 (8)

-phenylsulfonyloxybenzimldazole,

2-propoxycarbonylhihp 4 (8) -. · ~

-phenylsulfonyloxybenzimidazpl,

2 isopropóxykarbonylátnitip> 5: f6) ./ ¹ '-fenylsulfonyloxybenzimldazol,

2-butoxycycloboramidin-5-g)

-phenylsulfonyloxybenzimidazole,

2-isobutoxycarbamino-5 (8) -phenylsulphonyloxybenzimazole; ,. f, ·

2-tert-Butoxycarbonylamino-5 (8) -phenylsulfonyloxybenzimidazol.

The o-phenylenediamine derivative of formula (2), which serves as the starting material, is obtained by reduction of the corresponding aminonitrile derivative of formula (12) in which RR and R R have the same meaning as in Formula 1. The reduction can be carried out, for example (methanol) or dimethylformamide at temperatures between 20 and 60 ° C or by the action of reducing agents such as sodium dithionite. ··· ' ¹ ··; ·

The amine nitro derivatives of formula 12 are obtained by substituting benzenesulfonic acid chloride of formula 13; in which / ^ žf '&.' R MAK same higher-known · as in formula 1 is reacted with 3-nitro-4-aminophenol 'Formula 14 in an inert solvent. · And>' ^v-!: A base / 'as the' three * ethylamine.

2-Alkoxycarbonylamino-5 (6) -phenylsulfonyloxybenzimidazoles according to; invention. are valuable chemotherapeutic agents and are useful for combating parasitic diseases in humans and animals.

The active compounds according to the invention are particularly effective against a large number of helminths, such as, for example, Haemonchus, Trichlostrongylus, Ostertagiaj, Stronglyoidesj, Cooperia. ' ^r ' toothworm (Ghabertia) ', ¹ toothworm (Oesophagostonum), - ¹ ' wormwood (Hyostrongylus), hookworm (Ancylostomaj; ' ⁴ ' roundworm (Askařis) and roup (Heterakis).

Especially pronounced is the efficacy of the compounds according to the invention against gastric and intestinal attack, especially ruminants. The infestation of animals by these parasites leads to great economic damage, with the result that the active substances have a particular use. in veterinary medicine.

The active substances of the formula I are, according to the nature of the nar

IQ paddings are administered at doses between 0.5 and 50 mg per kg body weight for 1 to 14 days. . .,

For oral administration, tablets, coated tablets, capsules, powders, granules or pastes which contain active substances together with customary auxiliaries and carriers such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatin are suitable. , calcium carbonate, finely divided 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. acids. Other suitable suspensions are aqueous suspensions which are prepared using ethoxylated sorbitan fatty acid esters, 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 medicines. For the purpose of human medicines, the active compound concentration is between 20 and 80% by weight.

In order to determine the effect of the compounds of the invention, chemotherapeutic experiments were carried out on lambs weighing approximately 30 kg, to which the larvae of Haemonchus contortus and Trichostrortgylus colubriformis were experimentally applied for infection. The test animals were kept in boxes that were thoroughly cleaned daily. At the end of 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 g of feces was determined by the modified McMaster method according to Wetzel (Tlerarztzsche Umschau, 6, 209-210 (1951)). treatment of sheep (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 the day 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 not only excellent in oral administration, but also in parenteral administration at doses up to 2 mg / kg. Thereby they are far superior to comparable benzimidazole derivatives, in particular all known 5 (6) -substituted 2-benzimidazole carbamates.

The preparation of the compounds of the invention is explained in more detail in the following examples. Temperatures are given in degrees Celsius. He did

26.4 g of benzenesulfonic acid 3,4-diaminophenyl ester, 20.2 g of triethylamine and 300 ml of chloroform are mixed and mixed with this mixture ^; A solution of 15.6 g of N-dichloromethylenecarbamic acid methyl ester in 50 ml of chloroform is added thereto at a temperature of not more than 20 ° C. The reaction mixture was stirred for an additional 1 hour, the precipitate was filtered off and then washed with chloroform. .

For purification, the crude product is recrystallized from a mixture of glacial acetic acid and methanol and after filtration the product is washed and dried. The yield of 2-methoxycarbonylamino-5 (6) -phenylsulfonyloxybenzimidazole is 5 g with a decomposition point of 242 ° C.

Benzenesulfonic acid 3,4-diaminophenyl ester is prepared by hydrogenating 17.5 g of benzenesulfonic acid 3-nitro-4-aminophenyl ester in 200 ml of dimethylformamide using a special nickel catalyst (so-called tubular catalyst) at room temperature using hydrogen overpressure. 5 MPa. Then, the catalyst is filtered off and the solvent is removed in vacuo. The residue is benzenesulfonic acid 3,4-diamino-phenyl ester, and is used for cyclization directly without further purification.

To prepare benzenesulfonic acid 3-nitro-4-aminophenyl ester, they are mixed

15.4 g of 3-nitro-4-aminophenol in 100 ml of acetone with 14 ml of triethylamine are added dropwise with stirring at an internal temperature not exceeding 20 ° C in an ice bath, 17.6 g of benzenesulphonic acid chloride dissolved in 30 ml. ml of acetones. After stirring at room temperature for 3 hours, the triethylamine hydrochloride was filtered off and the filtrate was evaporated to dryness. The residue is stirred with 50 ml of methanol and the product is filtered off. After washing with methanol and drying, 18.2 g of benzenesulfonic acid 3-nitro-4-aminophenyl ester of melting point 140 DEG C. is obtained.

The following compounds were prepared in an analogous manner using appropriately modified starting materials:

2) 3-Trifluoromethylbenzenesulfonic acid 3-nitro-4-aminophenyl ester (m.p. 131 degrees Celsius); and

3-Trifluoromethylbenzenesulfonic acid 3,4-diaminophenyl ester yields 2-methoxycarbonylamino-5 (6) - (3-trifluoromethylphenylsulfonyloxy) benzimidazole, m.p. 215 DEG C. (dec.);

3) through 3-trifluoromethylbenzenesulfonic acid 3-nitro-4-aminophenyl ester (m.p. 131 degrees Celsius); and

188

3-Trifluoromethylbenzenesulfonic acid 3,4-diaminophenyl ester: r. 2-isopropoxycarbonylamino-5 (6) - (3-trifluoromethylphenylsulfonyloxy) benzimidazole of melting point 205 DEG C. (decomposition);

4)

0 methylbenzenesulfonic acid (m.p. 131 degrees Celsius) a

3-Trifluoromethyl-benzo-3,4-diamino-phenyl ester. of zensulfonic acid gave 2-isobutoxycarbonylamino-5 (6) - (3-trifluoromethylphenylsulfonyloxy) benzimidazole, m.p. 243 DEG C. (decomposition).

via 3-Trifluoro-3-nitro-4-amindophenyl ester

Claims (1)

OF THE INVENTION A process for the preparation of 2-alkoxycarbonylamino-5 (6) -phenylsulphonyloxybenzylbidazoles of the formula 1, NH-C00fi HJ in which R1 represents an alkyl radical having from 1 to 4 carbon atoms; R 2 and R 5 are each independently hydrogen, C 1 -C 4 alkoxy, halogen, trifluoromethyl, C 1 -C 4 alkyl or cyano, characterized in that the o-phenylenediamine derivative of the formula (2) is: R2 and R3 have the same meaning as in formula 1, react with an N-dichloromethylenecarbamic acid ester of formula 5, Cl., ·. /. R1-O-C-N = C II .. \ O Cl (5) in which R1 is as defined above. Xsverografia, n. P., Plant 7, Most