CS196279B2 - Method of producing 2-alkoxycarbonylamino-5/6/-phenylsulphonyl oxybenzimidazoles - Google Patents

Description

benzimidazoles

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 (6) position are already known as anthelmintics (P. Actor et al., Nature 21S, 321 (1967); DOS 2 029 637; DOS 2 164 690; DOS 2,363,348).

The present invention relates to anthelmintyl-active 2-alkoxycarbonylamino-5 (6) -phenyl-sulfonyloxybenzimidazoles of the general formula

C 1 -C 4 alkyl or cyano.

Suitable alkyl radicals in R1, R2 and R5 are: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl. Possible alkoxy groups in the substituents R 2 and R 3 are: methoxy, ethoxy, propoxy, isopropoxy and butoxy. Possible halogen atoms in the substituents R2 and R3 are: fluorine, chlorine, bromine and iodine. .

Particularly preferred are compounds of formula 1 wherein R 1 is methyl, ethyl, propyl or butyl, R 2 is hydrogen or chloro, and R 3 is hydrogen, chloro, or trifluoromethyl. .

The present invention provides a process for the preparation of 2-alkoxycarbonylamimo-5 (6) -phenylsulfonyl-. oxybenzimidazoles of formula 1, wherein R1, R2 and R3 are as defined above, characterized in that the o-phenylenediamine derivative of formula 2 is

Ri is alkyl having 1 to 4 carbon atoms ^1,

R2 and R2 are each independently hydrogen, C1-C4alkoxy, halogen, trifluoromethyl,

(2) where '1'; · /.

-R 2 and -R 1 have the same meaning as c 1 ,; condensates with a cyanamide carboxylate of formula 4,. .. ...,.

7

NC — N — COOR1 '(4)

-v-which has. r ·. ·>; ' As defined in formula (1), in the range of pH from 1 to 6, preferably from 2 to 5; The reaction pattern can be illustrated by the following reaction scheme:

- ŇC-NCa + ofcoofy -—>

(10) (2) + (4) n-n-coo 2

H (4)

(d)

In carrying out the reaction according to the invention, the chloroformic acid ester of formula 10 is first added to the aqueous suspension of cyanamide in the form of a salt, preferably a calcium salt of formula 11, while maintaining the reaction temperature by cooling between 40 and 80 ° C.

Suitable chloroformic acid esters of formula (10) are, for example, the following. r - methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl ester. acids, chlorniacetic acid, butyl ester; chloroformic acid, isobutyl chloroformate, tert-butyl chloroformate.

After filtering off the precipitated dark by-products, a cyanamide carboxylate of formula 4 is obtained in the filtrate.

The o-phenylenediamine derivative of formula 2 is added to the cyanamide carboxylate thus obtained and the mixture is adjusted to a pH between 6 and 6, preferably between 2 and 4, by addition of a mineral acid, for example concentrated hydrochloric acid. The reaction mixture is conveniently maintained at temperatures between 30 and 100 ° C, depending on the reactivity of the o-phenylenediamine derivative for 30 minutes to 10 hours. After cooling the reaction mixture, the precipitated reaction product of formula 1 is isolated by filtration and washing.

The o-phenylenediamine derivatives of the formula 2 which are suitable are, for example, the following compounds:

Benzenesulfonic acid 3,4-diaminophenyl ester, δ 27 9 9

4-chlorobenzenesulfonic acid 3,4-diamino-phenyl ester

3-chlorobenzenesulphonic acid diaminophenyl ester, ‘

3.4- diaminofehylester ^{2-chlorobenzene:} sulphonic acids; ''

3,4-Dichlorophenyl ester of 2,5-dichlorobenzenesulfonic acid, 4-palladiumphenyl ether of 3,5-dichlorophenesulfonic acid;

3.4-diaminophenyl 4-bromo-benesulfonic acid ester,

3,4-diaminophenyl ether of 3-bromo-enene-sulfonic acid; '-'

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

3,4-diaminophenyl ester of 3-methylbenz-: zenesulfonic acid,

3,4-diaminophenylester of 2-methylbenzenesulfonic acid, and the .beta.-diamino-phosphoryl ether-tert-butyl. benzenesultonic acids, Ή '.

2,4-dimethyl-benzenesulfonic acid 3,4-diaminophenyl ester; : '‘‘

3,4-diaminophenyl 2-chloro-4-methylbenzenesulfonic acid ester;

3,4-diaminesphenyl ester of 2-chloro-6-methyl-benzenesulfonic acid, n.

3,4-diamphenophenyl ester 3-chloro-4-methyl-:

thylbenzenesulonic acid; : 'or ·'

3-Chloro-8-methyl-benzenesulfonic acid 3,4-aminophenyl ester, r; *, ,, ·· ϋ ..,.,,. ,, ... ... .. ,,,.

3 ^f, 4-dlaminofenyléšter 4-chloro-2-me- 'thylbenžensulfbnúvé: ^acid! . . · ' ¹ n ·'!

3,4- diamino 4-; ^l Chloe ^-3; -me-- - O 'thylbenzénsulfónoVé acid ^-1

4-Chloro-3,5-dimethylbenzenesulfonic acid, 3,4-diaminophenyl ester, ^1:

3,4-diaminopheyl ester ^; 3-Trifluoromethylbenzenesulfonic acid, *

3,4-diaminophenyl ester of 4-methoxybenzenesulfonic acid;

3-Methoxybenzenesulfonic acid 3,4-diaminophenyl ester; 2-methoxybenzenesulfonic acid 3,4-diaminophenyl ester; 4-propoxybenzenesulfonic acid 3,4-diaminophenyl ester; ^of <'

3.4-4-isopropoxy-benzenesulfonic acid diaminophenyl ester,

3,4-diaminophenyl 4-butoxybenzenesulfonic acid ester; and ¹

3,4- diamino-išobUtoxybett- ¹¹ .4 sulphonic acids. The following compounds are preferably obtained according to the process of the invention: - ^; '' ^r '·

2-methoxycarbonyl-5 (6) -phenylsulfonyloxybenzimidazol,

^2-J methoxykarb'ó riyli5 f E) - (4-chloro phenyl lsulfonylóxyjbénzimidazól,

2-methoxycarbonyl-5 (6) - (3-chloro- ^{'fenylsulfonyloxyjbenzimídazol,}

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

2-methoxycarbonyl-5 (6) - (2,5-dičhlórfenylsulfonyloxy) benzimidazůl, ¹ '2-methoxykar'boiíýl-5 (®T- (3, S- dichlbrA' -r · 'fenylsulfonyloxyjbenzimidazol · .:'

2-ιηβΐΐιοχνΚθίΐ3'ΰΰγί-5 (0) - (4-ΰΐΟΐηί · ^{^? Nylsulfonyloxyjbbnzirnidazol,;?}

2-methoxycarbonyl-5 (6) - (3-bromophenyl) nonylsulfonyloxy] benzimidazole,

2-měthoxykárhbnyI-5 (6 ') - i [2-broňife ^·'. ' -nylsulfonyloxyjehehititidazole, '''

2-methoxykarbóhyl-5 (6) - (4-methylphenyl ^· 'nýlsulf onyloxy) benzitnidazol, Z:

2-methoxycarbonyl-5 (6) - (3-methylphenylsulfonyloxy) benzitnidazole;

2-methoxycarbonyl-5 (6) - (- 2-methylphenyl ^; nonylsulfonyloxy) benzimidazole;

2-methoxycarbonyl-5 (6) - (4-tert-butylphenylsulphonyloxy) benzyl-1-dazole,

2-Methoxycarbonyl-5 (6) - (2-chloro-4-methylphenylsulfonyloxy) benzimidazole.

2-methoxycarbones 1-5 (6) - (2-chloro-67)

methylphenylsulfonyloxy-imidazole;

2-methoxycarbonyl-SfBJ-O-chloro; , -methylphenylsulfonyloxy] benzimidazole

2-Methoxycarbonyl-5 (6) - (3-chloro-6-methylphenylsulfonyloxy) benzimidazole

2-Methoxycarbonyl-5 (6) - (4-chloro-2-methylphenylsulfonyloxy) benzimidazole 2-methoxycarbonyl 1-5 (6) - (4-chloro-3-methylphenylsulfonyloxy) benzimidazole

2-Methoxycarbonyl-5 (6) - (4-chloro-3,5-dimethylphenylsulfonyloxy) benzimidazole.

2-methoxycarbonyl-5 (8) - (3-trifluoromethylphenylsulfonyloxy) benzyl- ¹ 'imidazole

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

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

2-methoxycarbonyl-5 (6) - (2-methoxyphenylsulfonyloxy) benzimidazole,

2-methoxycarbonyl-5- (6) - (4-propoxyphenylsulfonyloxy) benzimidazole; . ·. ,: · I

2-methoxycarbonyl-5 (6) -f4'is-propoxyphe-. · Nylsulfonyloxybenzimidazole,

2-methoxycarbonyl-5 (6) - (4-butoxyphenyl _; p-phenylsulfonyloxy) benzimidazole;

2-ethoxycarbonylamino-5 (6'-phenyl).

sulfonyloxybenzimidazole,

2-propoxycarbonylamino-5 (6) -phenylsulfonyloxybenzimidazole,

2-isopropoxycarbonylamino-5 (6) -phenylsulfonyloxybenzimidazole,

2-butoxycarbonylamino-5 (6) -phenyl-1 ...; sulfonyloxybenzimidazole,

2-isobutoxycarbonylamino-5 (6'-phenylsulfonylbenzimidazole),

2-tert-butoxycarbonylamino-5 (6) -phenyl. sulfonyloxybenzimidazole.

The o-phenylenediamine derivative of formula (2) may be used either in the form of a warrant amine or in the form of its addition salt with a suitable inorganic or organic acid, such as hydrochloric, sulfuric, acetic, oxalic and the like.

The o-phenylenediamine derivative of formula (2), which serves as the starting material, is obtained by reduction of the corresponding amino nitro derivative of formula (12) in which R 2 and R 1 have the same meaning as in formula (1). the presence of Raney nickel and a solvent such as methanol or dimethylforminamide at temperatures between 20 and 60 ° C or with reducing agents such as sodium dithionite.

The amino nitro derivatives of formula (12) are obtained by the use of benzenesulfonic acid chloride of formula (13) wherein R a and R 3 are as defined above. in formula 1, is reacted with 3-nitro-4-aminophenol of formula 14, in an inert solvent and in the presence of a base such as triethylamine. J r

The 2-alkoxycarbonylamino-5 (6) -phenylsulfonyloxybenzimidazoles of the present 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 helipinties. such as Trichostrongylus (Trichostrongylus), Ostertagia, Strongyloides, Cooperiaj (Chabertia), Oesophagostonum, Hyostrongylus, Ancylos. In particular, the efficacy of the compounds according to the invention against the gastric and intestinal tract, especially ruminants, has been shown to be of great concern. as a result, the active substances have particular use in veterinary medicine.

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

Oral administration occurs in; consider tablets, dragees, capsules, powders, granules or pastes which contain the active substances together with the usual excipients and carriers such as starch, powdered cellulose, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely divided silicic acid , carboxymethylcellulose or the like.

Suitable solutions for parenteral administration 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 esters with sorbitan. fatty acids. Other suitable suspensions are aqueous suspensions which are prepared using ethoxylated sorbitan fatty acid esters, optionally with the addition of thickeners;

100270 such as polyethylene glycol or carboxymethylcellulose.

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

In order to determine the effect of the compounds according to the invention, chemotherapeutic experiments were carried out on lambs weighing about 30 kg, to which the larvae of Haemonchus contortus and goat trumpet (Trlchostrongylus 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 g of faeces 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 1 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 7th, 14th and 28th 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 for oral administration, but also effective for 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 illustrated by the following examples. Temperatures are given in degrees Celsius.

Example 1

To a solution of 42 g of cyanamide in 210 ml of water is added 90 g of methyl chloroformate and 218 g of 33% sodium hydroxide solution. The reaction mixture was then stirred at 30-35 ° C for 1 1/2 hours. A solution of 213 g of benzenesulfonic acid 3,4-dlaminophenyl ester in 1 liter of isopropyl alcohol is then added and the temperature is raised to 80 ° C. After addition of 200 ml of glacial acetic acid, the reaction mixture is maintained at 90 ° C for 3 to 4 hours. The reaction mixture was then allowed to cool and left in the refrigerator overnight. The precipitated 2-methoxycarbonylamino-5- (6'-phenylsulfonyloxy benzimidazole) was filtered off, washed with isopropanol and water, and the crude product was recrystallized from glacial acetic acid / methanol (80 g), mp 242 ° C.

Benzenesulfonic acid 3,4-diamino-tertiary 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 pressure. 5 MPa. The catalyst was then filtered off and the solvent was removed in vacuo. The rest 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-amlnophenol in 100 ml of acetone in 100 ml of acetone with 14 ml of triethylamine and 17.6 g of benzenesulfonic acid chloride dissolved in 30 ml of water are added dropwise with stirring at an internal temperature not exceeding 20 °. ml of acetone. 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. Washing with methanol and drying gave 18.2 grams of benzenesulfonic acid 3-nitro-4-aminophenyl ester, m.p. 140 ° C.

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

2) via 3-nitro-4-aminophenyl ester

3-Trifluoromethylbenzenesulfonic acid (m.p. 131 ° C) a

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

3) via 3-nitro-4-aminophenyl ester

3-Trifluoromethylbenzenesulfonic acid (m.p. 131 ° C) a

3-Trifluoromethylbenzenesulfonic acid 3,4-diaminophenyl ester gives 2-isopropoxycarbonylamino-5 (6) - (3-trifluoromethylphenylsulfonyloxy) benzimidazole, m.p. 205 ° C (dec.);

4) via 3-nitro-4-aminophenyl ester

3-Trifluoromethylbenzenesulfonic acid (m.p. 131 ° C) a

3-Trifluoromethylbenzenesulfonic acid 3,4-diaminophenyl ester gave 2-isobutoxycarbonylamino-5 (6) - (3-trifluoromethylphenylsulfonyloxy) benzimidazole, m.p. 243 DEG C. (dec.).

22 ί? Π! Ίί '. · ‘

GCi OBJECT

Claims (1)

Preparation of 2-alkoxycarbonylamino-5 (6) -fenylsulfonylOxybenzimidazoiů of formula 1 wherein R s is an alkyl radical, having 1 to 4 carbon atoms, ⁵ R 2 and R 1 are independently from each other ^; C 1 -C 4 -alkoxy, halogen, trifluoromethyl, C 1 -C 4 -alkyl or cyano, characterized in that the O-phenylenediamine derivative of general formula (2) is: · '···· itú- í'i ·· · · · · -' ·· '' · '' · '? * Rz and R3 are -stejný meaning as in formula 1, is condensed · 's kyanamidkarboxylátem formula ^4! NC — N — COORi ‘<'<' -? ··· (3) H-. · -. - in which it has *; P. . Ri, the same meaning as in Formula 1, 'within the range of pH 1 to 6.