CS196283B2 - 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-Alkoxycarbonylaminobenzimidazolyl derivatives with alkyl, acyl, phenoxy 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, DUS 2,363,348].

The present invention provides anthelmintically active phenyl esters of 2-alkoxycarbonylaminobenzimidazolyl-5 (6) -sulfonic acid of the formula I '

o- ^s % YqTr-NH-coOR4

H (1) wherein. '' ’

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, alkoxycarbonyl. C 1 -C 4 alkoxy or cyano.

Suitable alkyl radicals in the substituents R1, R2 and R3 are: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl. Suitable 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. Suitable alkoxycarbonyl groups in the 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 3 is hydrogen, chloro, bromo, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, with R 3 being particularly preferred at the 3-position of the phenyl ring.

The present invention provides a process for the preparation of phenyl 2-alkoxycarbonylaminobenzimidazole-5; (6-Jylsulfonic acids of formula 1) wherein R 1, R 2 and R 5 are as defined above, characterized in that the o-phenylenediamine derivative of

condensates with a cyanamide carboxylate of formula 4

NC — N — COORi, '· ’. I. H (4) wherein

R 2 and R ¹ are as defined above, wherein:

R 1 has the same meaning as in Formula 1, in the range of pH from 1 to 6, preferably from 2 to 5.

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

NH.

^W 2.

NC-NCa + CICOOR ^ -> NC-N-COOfy, ^H , 4J (2Μ4λ

OSO:

N _v

-NH-COOR

In order to carry out the reaction according to the invention, chloroformic acid ester of formula 10 is first added to an aqueous suspension of cyanamide in the form of a salt, preferably in the form of the calcium salt of formula 11, maintaining the reaction temperature by cooling between 40 and 60 ° C.

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

The cyanamide carboxylate (4) thus obtained is mixed with the o-phenylenediamine of formula (2) and the mixture is brought to pH by addition of a mineral acid such as concentrated hydrochloric acid. The pH * is between 1 and 6, preferably between 2 and 4. For the purpose of the reaction, the reaction mixture is conveniently kept between 30 and 100 ° C, depending on the reactivity of the o-phenylenediamine derivative between 30 minutes and 10 hours. ^! After cooling the reaction mixture, the precipitated reaction product of formula 1 is isolated by filtration and washing. ,. -,,.

The o-phenylenediamine derivative of Formula 2 can be used either in the form of the free amine or. in the form of its addition salt with a suitable inorganic or organic acid, such as hydrochloric acid, sulfuric acid, acetic acid, oxalic acid or the like.

Suitable chloroformic acid esters of formula (10) are, for example:

fe methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl ester, chloroformate, butyl chloroformate, isobutyl chloroformate and tert-butyl chloroformate.

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

3,4-aminobenzenesulfonic acid phenyl ester; 3,4-diamhiobenzenesulfo- 4-chlorophenyl ester. new acids,

3,4-diaminobenzenesulfonic acid 3-chlorophenyl ester,. . . , ··· «··

3,4-diaminobenzenesulfonic acid 2-chlorophenyl ester;

2,5-diaminobenzenesulfonic acid 2,5-dichlorophenyl ester,

3,5-dichlorophenyl ether. 3,4 - diaminobenzene sulphonic acid,.

4- břomfenylester ^{3,4-diamlnobenzensulfo-:} ester;

3,4-diamine-benzenesulfonic acid 3-bromoethyl ester, .....

3,4-diamine-benzenesulfonic acid 2-bromophenyl ester;

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

3- meťhylfehytester ^{3,4-diaminobenzensulfo-:} new acid.

3,4-Diamino-benzenesulfo 2-methyl-phenyl ester. new acids,

3,4-diaminobenzenesulfonic acid 4- tert -butyl phenyl ester,

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

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

3,4-diamino-benzenesulfonic acid 2-chloro-6-methylphenyl ester;

3,4-Diamino-3-chloro-4-methyl-phenyl ester benzenesulfonic acid,

3,4-diamino-benzenesulfonic acid 3- 'chloro-6-methyl-phenyl ester,

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

4-chloro-2-methylphenyl ester of 3,4-diamino-benzenesulphoric acid,

4-chloro-3-methylphenyl: 3,4-diamino-benzenesulfonic acid ester,

3,4-diamino-benzenesulfonic acid 4-chloro-3,5-dimethyl-phenyl ester,

3,4-diaminobenzenesulfonic acid 3,5-bistrifluoromethylphenyl ester;

3,4-diaminobenzene- ^1- sulfonic acid 4-methoxyphenyl ester, '' ··· ···· '

3,4-diamino-benzene sulfonic acid 3-methoxyphenyl ester,

3,4-Diaminobenzene-2-methoxyphenyl ester? sulfonic acids,

4'for, poxyferi]., 3,4-diaminobenzene · sulfonic acid ester ·· · · ·;

3,4-diaminobenzenesulfonic acid 4-isopropylphenyl ester,

3,4-diaminobenzenesulfonic acid 4-butoxyphenyl ester; and

3,4-diaminobenzenesulfonic acid 4-isobutoxyphenyl ester.

The following compounds are thus obtained:

2-methoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester,

2-Methoxycarbonylamino-5-benzimidazol-4-yl-phonic acid 4-chloro-phenyl ester ^;

3-chloro-phenyl-2-methoxycarbonylamino-5-benzimidazolesulfonic acid,

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

2,5-dichlorophenylether of 2-methoxycarbonylamino-5-benzimidazolesulfonic acid,

IdichIorfenylesteir 3.5- ^and 2-methoxycarbonylamino-5 benzimidazolsulf sulfonic acid

4- bromfenylester methoxykarbonylamino- ^2-one 5-benzimidazolsulfonové acid

3-Bromophenyl 2-methoxycarbonylamino-5-benzimidazole sulfonic acid ester,

2-Methoxycarbonylamino-5-benzimidazole sulfonic acid 2-bromophenyl ester,

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

3-Methylphenyl ester of 2-methoxycarbonylamino-5-benzimidazolesulfonic acid;

2-Methoxycarbonylamino-5-behzimidazole sulfonic acid 2-methylphenyl ester,

4-tert-butylphenyl ester of 2-methoxycarbonylamino-5-benzimidazolesulfonic acid,

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

2-Chloro-4-methylphenyl 2-methoxycarbonylamino-5-benzimidazolesulfonic acid ester,

2-Chloro-6-methylphenyl 2-methoxycarbonylamino-5-benzimidazolesulfonic acid, 2-chloro-6-methylphenyl ester, · ... ···· · ····· · ·.

3-chloro-4-methylphenyl 2-ihethoxycarbonylamino-5-benzimidazole sulfonic acid ester,

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

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 3-chloro-4-carbethoxyphenyl ester;

4-Chloro-2-methylphenyl-phenyl-2-methoxycarbonylamino-5-benzimidazolesulfonic acid,

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid 4-chloro-3-methylphenyl ester, m.p.

2-Methoxy-carbonylamino-5-benzimidazolesulfonic acid 4-chloro-3,5-dimethyl-phenyl ester; ¹ '

2-Methoxycarbonylamino-5-benzimidazolesulfonic acid, 3,5-histrifluoromethylphenyl ester;

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

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

2-Methoxycarbonylamino-5-benzimidazole sulfonic 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-Methoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester, 2-propoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester, 2-isopropoxycarbonylamino-5-benzoimidazolylsulfonyl-phenyl-benzoimidazole sulfonic acid phenyl ester, acids, 2-butoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester, and 2-tert-butoxycarbonylamino-5-benzimidazolesulfonic acid phenyl 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. such as methanol or dimethylformamide 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 reacting the corresponding chloro nitro derivatives of formula 13 wherein R 2 and R 5 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 chloronitroderivatives of formula 13 are obtained by reacting 3-nitro-4-chlorobenzenesulfonic acid chloride of formula 15 with a phenol of formula 14, wherein 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.

2-Alkoxycarbonylaminobenzimidazol-5 (6) -ylsulfonic acid phenyl esters. According to the invention, they are valuable chemotherapeutics and are suitable for 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, for example, Haemonchus, Trichostrongylus, Ostertagia, Strongyloldesj, Cooperia, Chabertia, Oesophagostomumj, Hyostrongylusj, Ancylostoma, Askarls and Heterakis The activity of the compounds of the present invention against the gastric and intestinal tract, especially ruminants, is particularly pronounced. the compounds according to 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 the usual excipients and carriers such as starch, powdered cellulose, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely dispersed silicic acid, carboxymethylcellulose or the like.

For parenteral administration, suitable solutions are, for example, oily yellow solutions which are prepared using sesame oil, castor oil or synthetic triglycerides, optionally with the addition of tocopherol as an antloxidant. and / or surfactants such as sorbitan fatty acid esters. Other suitable suspensions are aqueous suspensions which are prepared using ethoxylated sorbitan fatty acid esters, optionally with the addition of thickeners, such as epoxyethylene 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 the purposes of veterinary medicines. 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, cherotherapeutic experiments were carried out on lambs weighing about 30 kg, to which the larvae of Haemonchus contortus and Trichostrongylus colubriformis, respectively, 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 Modified by McKaster's Wetzel method [Tier & Immediately thereafter it was performed. treatment of sheep (generally 4 to 8 per active substance 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 1g 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 effective when administered orally, but are also effective when administered parenterally at doses up to 2 mg / kg. This far exceeds comparable benzimidazole derivatives, in particular 196228 to all known 5 (6) -substituted 2-benzimidazole carbamates.

The preparation of the compounds of the invention is illustrated in more detail in the following examples. Temperatures are given in degrees Celsius. Example 1

To a solution of 42 g of cyanide in 210 ml of water was added 90 g of methyl chloroformate and 218 g of 33% sodium hydroxide. Reaction mixture. se. was stirred at 30-35 ° C for 1.5 hours. Then a solution of 213 g of 3,4-diaminobenzenesulfonic acid phenyl ester in 1 liter of isopropyl alcohol is added, and then 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 allowed to cool and then left in the refrigerator overnight. The precipitated 2-methoxycarbonylamino-5-benzimidazolesulfonic acid phenyl ester was filtered off and washed with isopropyl alcohol and water. From the purification account, the crude product was dissolved in dioxane, the solution was filtered using charcoal, and water was added to the filtrate. Yield 80 g of the product with a decomposition temperature of 242 ° C.

The 3,4-diaminobenzenesulfonic acid phenyl ester is prepared by hydrogenating 27 g of 3-nitro-4-aminohenzenesulfonic 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-diamino-benzenesulfonic 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 the 3-nitro-4-amino-benzenesulfonic acid phenyl ester, 54 g of 3-nitro-4-chlorobenzenesulfonic acid phenyl ester is held in 500 ml of dioxane under a pressure of 0.5 MPa of ammonia gas for 5 hours at 50 ° C and then the solvent removed under vacuum. 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 water was added to leave an oil which was treated with ether.

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

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

2.

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

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

3,4-diamino-benzenesulfonic acid 3-chloro-phenyl ester (m.p. 84 ° C) · 2-methoxycarbonylamino-5-benziimidazolesulfonic acid 3-chlorophenyl ester (m.p. 234 ° C) (dec.);

3.

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

3-Bromophenyl ester of 3-nitro-4-aminobenzofuranosulfonic acid (m.p. 141 ° C) and 3,4-diaminobenzenesulfonic acid 3-bromophenyl ester (m.p. 94 ° C) gave 3-bromophenyl ester 2-methoxycarbonylamino-5-benzimidazole sulfonic acid (m.p. 242 ° C) (dec.);

4.

via S-nitro-4-chloro-3-methylphenyl ester; zensulfonic acid (m.p. 60 ° C); and

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

3,4-diaminobenzenesulfonic acid 3-methylphenyl ester (m.p. 84 ° C) affords 2-methoxycarbonylamino-5-benzimidazole sulfonic acid 3-methylphenyl ester (m.p. 234 ° C (dec.));

5.

Via 3-nitro-4-chlorobenzenesulfonic acid 3-methoxyphenyl ester (oil) a

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-ethoxyphenyl ester (oil) and

3-Nitro-4-amino-benzenesulfonic acid 3-ethoxy-phenyl ester (m.p. 86 ° C); and

3,4-diaminobenzenesulfonic acid 3-ethoxyphenyl ester (oil) to give 2-methoxycarbonylamino-5-benzimidazolesulfonic acid 3-ethoxyphenyl ester (m.p. 212 ° C) (dec.);

7.

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

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

198283

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

Claims (1)

A process for the preparation of 2-alkoxycarbonylaminobenzimidazol-5 (6) -ylsulphonic acid phenyl esters of general formula (I).