CS226749B2 - Method of preparing 5(6)-phenylsulphonyloxybenzimidazol derivatives - Google Patents

Description

The present invention relates to novel 5 (6) -phenylsulfonyloxybenzimidazole derivatives with anthelmintic properties. Further, the invention relates to a process for the production of such novel compounds and their use as effective "anti-liver drugs". The 2-alkylthiobenzimxdazole derivatives with phenoxy- and phenylthio groups at the 5-position (6) are known as the anthelmintics as well as the corresponding 2-alkylsulfinyl- and 2-alkylsulfonyl derivatives (cf. DE-OS 28 15 621) The present invention relates to the antimony-effective 2-alkylthio-, 2-alkylsulfinyl- and 2-alkylsulfonylbenzimidazole derivatives which are substituted by substituted phenylsulfonyloxy in the 5-position (6) and which are represented by Formula 1

(1) 226 749 and salts thereof with physiologically tolerated acids, wherein R 1 represents an alkyl group having 1 to 4 carbon atoms,

E 1 and are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl, B 4 is hydrogen or halo and n is 0, 1 or 2. a compound of formula I wherein R 1 is C 1 -C 4 alkyl means halo, such as fluoro, chloro, bromo, iodo, or trifluoromethyl; E 2 is hydrogen, halo, such as fluoro, chloro, bromo, iodo or trifluoromethyl R1 is hydrogen or chloro and n is 0 or 1.

Compounds of formula Ia 228 749 are particularly preferred

(1a) wherein the alkyl group is 1 to 4 carbon atoms, in particular methyl, and n is 0 or 1. The present invention is directed to a process for the preparation of compounds of Formula 1 wherein the compound of Formula 2 is reacted.

wherein R 2, R 3, and R 4 are as defined in formula 1, 226,749 with an alkylating agent of formula 3 (3) wherein R 1 is as defined above and X is halogen, preferably iodo or bromo, a moalkylsulfate group, preferably a monomethyl sulfate group or a p-toluenesulfonyl group, and optionally the compound of formula 1 thus obtained wherein n is zero is oxidized. the gelling is carried out at temperatures between 0 and 100 ° C, preferably between 20 and 80 ° C, in water, in an organic solvent or in mixtures thereof, preferably in the presence of a base. If the organic base is used in excess, the additional solvent may be omitted.

Suitable organic solvents are alcohols, esters, ethers or ketones. Examples of bases include alkali, carbonate alkali metal, alkali metal bicarbonate, and the corresponding alkaline earth metal compounds, such as pyridine, collidine, lutidine, or picoline or tertiary amines.

The isolation of the free alkylmercaptobenzimidazole derivatives of formula 1 is conveniently effected by removing the reaction mixture after alkylation with an inert solvent which is immiscible with water, for example an ester such as ethyl acetate, or a chlorinated hydrocarbon such as methylene chloride, washing out the inorganic ions with water, delaying the aqueous solution and stirring the residue obtained by evaporation. organic phases, in ether, such as diisopropylether. If the base is rooted with an alkyl iodide, then alkylmercaptide 1 hydroiodides are directly obtained. In other cases, if desired, salts of compounds of formula 1 can be obtained by adding a physiologically acceptable acid, a preferred mineral acid, such as hydrochloric acid, sulfuric acid or phosphoric acid.

The oxidation of compounds of formula 1, wherein n is 0, may be carried out at temperatures between -20 and + 50 ° C, preferably at temperatures between 0 and 30 ° C. Suitable oxidizing agents are preferably equivalent equivalents of hydrogen peroxide in organic acid, preferably glacial acetic acid, percsadine such as 226,749 peracetic acid, pertrifluoroacetic acid or metachloroperbenzoic acid, as well as nitric acid or chromic acid in glacial acetic acid or salts thereof. acids, as well as permanganates, hypochlorites, chlorates, iodates and nitrogen oxides. If only one oxygen atom is to be introduced into the molecule, m-chloroperbenzoic acid is preferably used for this purpose. If two oxygen atoms are to be introduced into the molecule, preferably peracetic acid or hydrogen peroxide is used.

The procedures outlined above are known as analogous procedures to J. Chem. 1949, 3311-3315. The starting materials of formula (2) used for the preparation of compounds of formula (1) can be obtained from the derivatives of o-phenylenediamine known from DE-OS24 41 201 by reaction with carbon disulphide (DE-OS) 2815 621).

The compounds of formula (1) which are produced according to the invention are suitable as chemotherapeutic agents for combating diseases caused by worms in humans and animals. These diseases are caused by helmites, ie, Testo (Cestoidea), nematode (Nematoda) and Trematoda. The compounds of formula (1) are, for example, effective against Pascioli-dea. Liver fluke (Fasciola hepatica) is particularly effective. Administration is carried out from one to five 226,749 consecutive days, orally or parenterally, in an amount of 1-50 mg / kg, preferably 2.5-15 mg / kg body weight.

In order to detect the action of the compounds of the invention against the flute (Pasciolidae), therapeutical tests are carried out with rats? about 250 g, in rabbits weighing about 2 to 3.5 with sheep lamb weighing about 25 to 30 kg. The experimental animals are orally infected with 15, 50 or 350 motculoskeletal tumors (Pasciola hepatica). After the prepatient periode (the time between infection and the parasite sexual maturity with the incipient excretion of the reproductive products), the parasite is monitored by faecal or shit analyzes. The qualitative-quantitative evidence of eggs is performed according to Telemann (Deutsche Medizinische Vochenschrift 341 1510,1908).

Immediately after the number of eggs per 1 g of faeces or shit is determined, treatment of the test animals is carried out (generally using 3 to 4 animals per active substance, but at least 2). The animals are orally dosed with suspensory amounts of the active ingredients, each at the detected volume (rat: 0.5 ml / animal, rabbit: 2 µl / animal, sheep: 10 ml / animal) in a tyloid suspension. On the 7th, 14th and 28th day after the treatment, the number of eggs in 1g of faeces or shit, and the percentage decrease compared to the pre-treatment baseline and in comparison with the untreated control animals, was re-determined according to the above method. In some compounds according to the invention, in addition to testing the effect of infestation by the liver fluke, it performs an additional investigation: after the pre-patency period, sheep with a positive liver tract are found to have a bile duct that contains a sieve in the gallbladder outlet so as to kill the liver fluke specimen. capture in the gallbladder.

After 4-7 days xs after treatment, the thus treated and then treated sheep are sacrificed, the number of killed hepatic fluke in the gallbladder as well as the number of motolicejateral specimens present in the liver being counted and the percentage of killed parasites calculated from the total number of worms. In the case of selected substances, in addition to the analysis of faeces and resp. The treated animals are still necropsied to examine the liver for possible residual infestation of the motoring liver (Pasciola hepatica).

The single administration of the active compounds according to the invention at the indicated doses leads to the complete disappearance of the excretion of the eggs and to almost 100% of the depletion of the liver fat (Fasciola hepatica). All doses - 10,226,749 were tolerated by the animals without side effects. This fact underscores the safety factor, which is substantially more favorable than comparative means:

Clioxanide: 2-acetoxy-4-chloro-3,5-diiodobenzanilideNicofolan: 5,5-dichloro-2,2-dihydroxy-3,3-dinitro-phenyl.

The safety factor is expressed by the quotient of the maximum tolerated dose and the dose used. The results of these experiments are summarized in the following table: 9-226,749 the percentage decrease compared to baseline before treatment and compared to untreated control animals is calculated. In some compounds of the invention, testing of the liver will result in an additional test of liver fluke: after a period of pre-patency, sheep with a positive liver tract will form an artificial bile duct that contains a sieve in the gallbladder outlet so that the liver is killed by the liver fluke specimen. capture in the gallbladder.

After 4 to 7 days xk after treatment, the thus treated and then treated sheep are sacrificed, the number of killed hepatic flukes in the gall bladder as well as the number of motolicejateric specimens present in the liver being counted and the percentage of killed parasites calculated from the total number of worms. In the case of selected substances, in addition to the analysis of faeces and resp. The treated animals are still necropsied to examine the liver for possible residual infestation of the motoring liver (Pasciola hepatica).

The single administration of the active compounds according to the invention at the indicated doses results in the complete disappearance of the egg excretion and almost 100% of the depletion of the liver fat (Pasciola hepatica). All doses - 10,226,749 were tolerated by the animals without side effects. This fact underscores the safety factor, which is substantially more favorable than comparative means:

Clioxanide: 2-acetoxy-4-chloro-3,5-diiodobenzanilide-Wicolofolane: 5,5-dichloro-2,2-dihydroxy-3,3-dinitrophenyl.

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The compounds of the invention can be applied in the form of powders, tablets, capsules in concentrations of 2 to 20 active substances. For this purpose, said compounds are admixed with excipients such as, for example, pharmaceutically customary liquid or solid fillers, solvents and emulsifiers.

tastes and / or buffers. In addition, the thio compounds can also be applied in admixture with suitable liquid or solid feeds in the corresponding lower concentrations. The following examples further illustrate the process of the invention, but do not limit the scope of the invention in any way. EXAMPLE 1 60 g of 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-mercaptobenzimidazole are dissolved in a mixture of 500 ml of ethyl acetate and 500 ml of methanol at reflux and then 11 ml of methyl iodide in 160 ml of ethyl is added slowly. The reaction mixture was then refluxed for 2 hours and then the solvent was evaporated. The residue is then stirred with ethyl acetate and the remaining portion is filtered off. After washing with ethyl acetate and drying, 72 g of 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-methylmercaptobenzimidazole hydroiodide of m.p. 226 749

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The compounds of the invention may be administered in the form of liquids, powders, tablets, capsules at concentrations of 2 to 20% of the active ingredient. For this purpose, said compounds are admixed with auxiliaries, such as, for example, pharmaceutically customary, liquid or solid fillers, solvents, emulsifiers, lubricants, flavoring agents, coloring agents and / or buffers. In addition, the thio compounds can also be applied in admixture with suitable liquid or solid feeds in the corresponding lower concentrations. The following examples further illustrate the process of the invention, but do not limit the scope thereof in any way. EXAMPLE 1 60 g of 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-mercaptobenzimidazole are dissolved in a mixture of 500 ml of ethyl acetate and 500 ml of methanol at reflux and 11 ml of methyl iodide in 160 ml of ethyl alcohol are slowly added. The reaction mixture was then refluxed for 2 hours and then the solvent was evaporated. The residue is then stirred with ethyl acetate and the remaining portion is filtered off. After washing with ethyl acetate and drying, 72 g of 5- (6) - (3-Trifluoromethylphenylsulfonyloxy) -2-methylmercaptobenziraidazole hydroiodide, m.p. Instead of mixing in ethyl acetate, it can be redundantly dissolved in 500 ml of hot ethanol and added to this solution of 1000 ml of 2N hydrochloric acid. After cooling and after being left in the refrigerator for one day, filtering off with washing with hydrochloric acid and acetone gives 62 g 5 (6) - (3-Trifluoromethylphenylsulfonyloxy) -2-methylmercaptobenzimidazole hydrochloride, mp 226 ° C (dec.).

To produce 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-mercaptobenzimidazole, which is needed as a starting material, 3-nitro-4-amino-phenyl-3-trifluoromethyl-benzenesulfonic acid (90.5 g, cf. DOS 24) is dissolved. 41 201, Example 22) in 1000 ml of methanol, and after addition of Raney nickel, the solution is hydrogenated at atmospheric pressure and at room temperature, whereby the resulting 3,4-diaminophenyl 3-trifluoromethylbenzenesulfonic acid ester precipitates as a crude product upon evaporation of the catalyst. the further purification is directly further processed by dissolving in 400 ml of methanol, 105 ml of carbon disulfide are added and the solution obtained from 44.3 g of 85% potassium hydroxide and 190 ml of absolute ethanol is added dropwise over 1 hour at room temperature. The reaction mixture is then stirred at reflux for 1 hour - 14,226,749

cooler. One day thereafter, 1000 ml of acetic acid was added, the mixture was stirred for half an hour and the residue was filtered off. After washing with water and after drying, 79 g of 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-mercaptobenzimidazole remain at melting point 222 DEG C. EXAMPLE 2 18.5 g of 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-mercaptobenzimidazole The slurry was suspended in 50 mL of 1N sodium hydroxide solution and 150 mL of methanol was added to give a solution. 8.5 g of methyl iodide are added dropwise to the solution at room temperature and the temperature is 10 ° C. After stirring for 2 hours at room temperature, the reaction mixture is taken up in ethyl acetate and shaken with water until the presence of iodide is no longer detectable. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue is taken up in 250 ml of hot 97% ethanol, then 500 ml of 2 N hydrochloric acid are added, after cooling the product is filtered off and washed with hydrochloric acid and acetone. After drying, 17 g of 5 (6) - (3-trifluoroethylphenylsulfonyloxy) -2-methylmercaptobenzimidazole hydrochloride with a melting point of 226 DEG C. (decomposition) is obtained which is identical to that obtained in Example 1. 15,226,74!

In an analogous manner to that described in Example 1, 5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) -2-mercaptobenzimidazole with the following alkyl iodide is prepared as follows: Example 3

Reaction with ethyl iodide affords 5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) -2-ethyl-mercaptobenzimidazole-iodide, m.p. 186 ° C. Example 4

Reaction with propyl iodide gave 5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) -2-propylmercaptobenzimidazole iodide, m.p. 199 ° C. Example 5

Reaction with butyl iodide affords 5 (6) - (3-trifluoromethyl-phenylsulfonyloxy) -2-butyl mercaptobenzimidazole iodide, m.p. 138 ° C.

In an analogous manner to that described in Example 2, an appropriate mixture of the free base was prepared by adding diisopropyl ether to the residue of the reaction mixture of ethyl acetate, which was washed with water, the following compounds: - 16 6 226 749 Z 5 (6) -phenylsulfonyloxy- 247 DEG C. to give 5 (6) -phenylsulfonyloxy-2-methyl-mercaptobenzimidazole, m.p. 116 DEG. Example 7 From 5 (6) - (4-methylphenylsulfonyloxy) -2-mercaptobenzimidazole, mp 228 ° C, 5 (6) - (4-methylphenylsulfonyloxy) -2-methylmercaptobenziraidazole is obtained, m.p. ° C. Example 8

From 5 (6) - (4-chlorophenylsulfonyloxy) -2-mercaptobenzimidazole, m.p. 243 DEG C., 5 (6) - (4-chlorophenylsulfonyloxy) -2-methylmercaptobenziridazole is obtained, m.p. 130 DEG C. EXAMPLE 9 Z 5 ( 6) - (3-Methylphenylsulfonyloxy) -2-mercaptobenzimidazole, mp 236 ° C, to give 5 (6) - (3-methylphenylsulphonyloxy) -2-methylmercaptobenzimidazole, m.p. 118 ° C. EXAMPLE 10 226,749 From 5 (6) - (3-chlorophenylsulfonyloxy) -2-mercaptobenzimidazole, m.p. 270 ° C, 5 (6) - (3-chlorophenylsulfonyloxy) -2-methylmercaptobenzimidazole is obtained, m.p. C. EXAMPLE 11 5 (6) - (3-Methoxyphenylsulfonyloxy) -2-mercaptobiazziimidazole, m.p. 230 ° C, gives 5 (6) - (3-methoxyphenylsulfonyloxy) -2-methylmercaptobenzimidazole at 104 ° C. Example 12 From 5 (6) - (4-isopropylphenylsulfonyloxy) -2-mercaptobenzimidazole, m.p. 248 ° C, 5 (6) - (4-isopropylphenylsulfonyloxy) -2-methylmercaptobenzimidazole of 190 ° C is obtained. (decomposition). Annexes 13 and 13

20 g of 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-methylmercaptobenzimidazole are dissolved in 750 ml of chloroform and a solution of 10 g of 20% o-m-chloroperbenzoic acid is added dropwise at 0-5 ° C to this solution. acid in 250 ml of chloroform with stirring for 30 minutes. The reaction mixture was then stirred at 0-5 ° C for 3 hours and then at room temperature overnight. The filtrate is shaken with a bisulfite solution to remove excess m-chloroperbenzoic acid; it is then washed with water and dried with calcium chloride. It is then evaporated under reduced pressure and the residue, consisting of dry 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-methylsulfinylbenzimidazole, is recrystallized from ethyl acetate. Example 14 20 g of 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-methylmercaptobenzimidazole are dissolved in 150 ml of acetic acid and a solution of 25 ml of 407 peracetic acid is added dropwise to this solution over 30 minutes at room temperature. The reaction mixture was stirred overnight at room temperature and then 5 (6) - (3-trifluoromethylphenylsulfonyloyl) -2-methylsulfonylbenzimidazole was precipitated by the addition of water.

Claims (2)

- 19 228 749 OBJECT OF THE INVENTION A process for the preparation of 5 (6) -phenylsulfonyloxybenzimidazole derivatives of formula (1) wherein R 1 is C 1 -C 4 alkyl, &amp; 2 and R 3 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or trifluoromethyl, R 4 is hydrogen or halogen and n is 0, 1 or 2, as well as salts thereof with physiologically acceptable acids, characterized in that the compound of formula 2 - 20 (2) 226 749 wherein R R, R ^ and R ^ are as defined above, are treated with an alkylating agent of the formula 3 R X - X (3) wherein R ^ is as defined above and X is halogen, a monoalkyl sulphate moiety or a p-toluenesulphonyl moiety; optionally the compound of formula 1 thus obtained, wherein n is 0, is oxidized. 2. A process according to claim 1, wherein the corresponding compounds of formulas 2 and 3j are used as starting materials to give 5 (6) - (3-trifluoromethylphenylsulfonyloxy) -2-methylmercaptobenzimidazole. Printed by Moravské tiskařské závody, provoz 12, Leninova 21, Olomouc Price: 2,40 Kčs