NZ202386A - Substituted 2-pyridylmethyl(thio/sulphinyl)-benzimidazole derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £02386 202386 Priority Dato(&}: — ^ j §£ Complete Cpsc^cation Filed: coi3?wi • m»8A \ fJc: . ■ ■ ■ \**5 ^ p^i Ifll fjfr i/j yi&aa^i N . Z .No.

NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION " SUBSTITUTED BENZIMIDAZOLES, A PROCESS FOR THEIR PREPARATION, THEIRJJSE, _AND MEDICAMENTS CONTAINING_THEM_1^ We, BYK GULDEN LOMBERG CHEMISCHE FABRIK GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, incorporated under the laws of the Federal Republic of Germany of Byk-Gulden- Strabe 2, D-77 50 Konstanz, Federal Republic of Germany do hereby declare the invention, for which We pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement : - - 1 - (Followed by 1A.) Substituted benzimidazoles, a process for their preparation, their use, and medicaments containing them Field of the invention The invention relates to substituted benzimidazoles, a process for their preparation, their use, and medicaments containing them.

The compounds according to the invention are used 10 in the pharmaceutical industry as intermediates and for the preparation of medicaments.

Prior art German Offenlegungsschrift DE-OS 1,804,450 (= British Patent 1,234,058; the equivalent English-15 language patents were located with the aid of the "Patent Mo. Family Index" from Inpadoc) describes benzazole derivatives which are said to have a tuberculostatic, insecti-cidal, fungicidal, antiv-iral, anthelmintic and antiinflammatory action. DE-OS 2,504,252 (= U.S. Patent USP 20 4,045,564) claims 2-benzimidazolyl 2-pyridyl sulfides, -some of which are said to have an inhibiting effect on secretion of hydrochloric acid in the stomach, and some of which are said to have a stimulating effect on secretion of hydrochloric acid in the stomach. DE-OS 2,548,340 25 (= USP 4,045,563) describes 2-benzimidazolyl 2-pyridyl sulfoxides, which are said to inhibit exogenically or endogenically stimulated secretion of hydrochloric acid in the stomach. European Patent Specification EP-B1 0,005,129 (=USP 4,255,431 and USP 4,337,257) also describes 30 2-benzimidazolyl 2-pyridyl sulfoxides, which are said to be used in pharmaceutical products for inhibiting secretion of hydrochloric acid in the stomach. The corresponding substituted sulfides which can be used for the preparation of the 202336 - 2 - I*** abovementioned sulfoxides are described in DE-OS 2,548,340 , l-c U$P ) /and in EP-B1 0,005,129 exclusively as intermediates, without indication of pharmacological activity. - European Patent Application EP-A1 0,045,200 describes substituted 5 heterocvclylalkylsulfinylbenzimidazoles, which are said to be used in the treatment or prevention of special gastrointestinal inflammatory diseases.

It has now been found, surprisingly, that the 2-benzimidazolyl 2-pyridvlmethyl sulfides and sulfoxides 10 according to the invention which are described below in more detail have interesting and unexpected properties whicj advantageously distinguish them from known compounds. Summary of the invention The invention relates to new substituted benzimidazoles 15 of the aeneral formula I ' 0 T: |i (I), wherein 1 R denotes hydrogen or methyl and 2 R cenotes hydrogen cr methyl and n denotes the numbers 0 or 1, and the salts of these compounds.

Possible salts of compounds of the general formula I, 30 wherein n denotes 0 (sulfides), are all the acid addition salts. The pharmacologically acceptable salts of the inorganic and organic acids usually employed galenically may be mentioned in particular. Pharmacologically unacceptable salts, which may initially be obtained as process products, 20238 6 for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes which are known to the expert. Examples of such suitable 5 pharmacologically acceptable salts are water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodid, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate l2-(4-hydroxybenzoyl)-benzoate], fendizoate (o-I(2'-hydroxy-10 4-biphenylyl)-carbonyl]-benzoate), butyrate, sulfosalicyl-ate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate (4,4'—diaminostilbene-2,2'-disulfonate), embonate 14,A1-methylene-bis-(3-hydroxy-2-naphthoate)], metembonate 14,41-methylene-bis-(3-methoxy-15 2-naphthoate)], stearate, tosylate (p-toluenesulfonate), 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate and mesylate (methanesulfonate).

Compounds of the. general formula I, wherein n denotes 1 (sulfoxides) can also be converted into the acid 20 addition salts mentioned above. These salts however have in aqueous solution not the same stability as the salts of the sulfides. On the other hand, the sulfoxides can be converted into their basic salts by reaction with appropriate deprotonization agents, such as inorganic 25 and organic bases. These basic salts are also subject of the invention.

Substituted benzimidazoles of the general formula I 1 (r*>' -yi ii 1.1c 023 8 & wherein R^a has the meaning of r\ 2a 2 R has the meaning of R and denotes 0, and the salts of these compounds, form an embodiment of the invention.

Substituted benzimidazoles of the general formula I* (Ib), CF, wherein 1b 1 R has the meaning of R , 2k 2 R has the meaning of R and n^ denotes 1, and the salts of these compounds, form another embodiment of the invention.

Compounds according to • the invention which may be mentioned are: 4-trifluoromethyl-2-[(4-methoxy-2-pyridyl-methyl)thio]-(lH)-benzimidazole, 4-trifluoromethyl-2-[ (4-methoxy-3-methyl-2-pyridylmethyl)thio]-(1H)-benzimidazole, 25 4-trifluoromethyl-2-[(4-methoxy-5-methyl-2-pyridylmethyl)-thio]-(1H)-benzimidazole, 4-trifluoromethyl-2-[(4-methoxy-3,5-dimethyl-2-pyridylmethyl)thio 3 -(1H)-benzimidazole, 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimidazole, 5-trifluoromethyl-2-[(4-methoxy-3-rnethyl-30 2-pyridylmethyl)thio]-(1H)-benzimidazole, 5-trifluoro- methyl-2-I(4-methoxy-5-methyl-2-pyridylmethyl)thio]-(1H)-benzimidazole and 5-triflucromethyl-2-[(4-methoxy-3,5-dimethyl-2-pyridylmethyl)thio]-(lH)-benzimidazole, M023fi f- 4-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)sulfinyl]-(1H)-benzimidazole, 4-trifluoromethyl-2-[(4-methoxy- 3-methyl-2-pyridylmethyl)sulfinyl]-(1H)-benzimidazole , 4-trifluoromethyl-2-[(4-methoxy-5-methyl-2-pyridylmethyl)-5 sulfinyl]-(1H)-benzimidazole, 4-trifluoromethyl-2-[ (4- methoxy-3,5-dimethyl-2-pyridylmethyl)sulfinyl]-(1H)— benzimidazole, 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)sulfinyl]-(1H)-benzimidazole, 5-trifluoro-methyl-2-[(4-methoxy-3-methyl-2-pyridylmethyl)sulfinyl]-10 (lH)-benzimidazole, 5-trifluoromethyl-2-[(4-methoxy-5-methyl-2-pyridylmethyl)sulfinyl]-(1H)-benzimidazole and -trifluoromethyl-2-[(4-methoxy-3,5-dimethyl-2-pyridyl-methyl)sulfinyl]-(1H)-benzimidazole, and their salts.

Particularly preferred compounds are 5-trifluoromethyl-2-[(4-methoxy-3-methyl-2-pyridylmethyl)- thio]-(1H)-benzimidazole and 5-trifluoromethyl-2-[(4- methoxy-2-pyridylmethyl)sulfinyl]-(1H)-benzimidazole and their pharmacologically acceptable salts.

Because of tautomerism in the imidazole ring, 4- and 5-substitution in the benzimidazole is identical to 7- and, respectively, 6-substitution.

The invention furthermore relates to a process for the preparation of the substituted benzimidazoles of the 1 2 formula I, wherein R , R and n have the abovementioned 25 meanings, and their salts.

The process is characterized in that a) mercaptobenzimidazoles of the formula II or their salts are reacted with picoline derivatives III or their salts II) (III) or ?fff Q.— , J // ^ b) benzimidazoles of the formula IV are reacted with mercaptopicolines V Z" cf3 (IV) och HS-CH (V) or c) o-phenylenediamines of the formula VI are reacted with formic acid derivatives VII and, if appropriate, the 2-benzimidazolyl 2-pyridyl sulfides of the formula VIII s~ch- och3 (VIII) obtained according to a), b) or c) are then oxidized 30 and/or the obtained free base is then converted into a salt, or the obtained salt is then converted into the free base, or that d) benzimidazoles of the formula ix are reacted with pyridine derivatives X 2023 8#** II ^s— CH2—M (ix) ch3 (x) or that e) sulfinyl compounds of the formula XI are reacted with 2-picoline derivatives of the formula XII (xi) M'-CH (xii) and, if appropriate, the products are then converted into the salts, Y, Z, Z' and Z1' being suitable leaving, groups, m representing an alkali metal atom (Li, Na or K), M1 re- 1 2 presenting the equivalent of a metal atom and R , R and n having the abovementioned meanings.

The processes a), b) and c) lead to the sulfides according to the invention, the oxidation of compounds VIII and the processes d) and e) lead to the sulfoxides according to the invention.

The expert, on the basis of his expert knowledge, is familiar with which leaving, groups Y, Z, Z1 and Z'1 are suitable. A suitable leaving group Y is, for example, a. group which, together with the sulfinyl. group to which it is bonded, forms a reactive sulfinic acid derivative. A suitable leaving, group Y is, for example, an alkoxy group, a dialkylamino group or an alkylmercapto. group. Examples of suitable leaving, groups Z, Z' and Z'' which may be mentioned are halogen atoms, in particular chlorine -8 - 202386 w atoms, or hydroxy1. groups activated by esterification (for example with p-toluenesulfonic acid)• The equivalent of a metal atom M' is an alkali metal atom (Li, Na or K), or an alkaline earth metal atom (e.g. Mg) which is substituted 5 by a halogen atom (e.g. Br, Grignard reagent), or any other optionally substituted metal atom which is known to react in substitution reactions of organometallic compounds in the same manner as the abovementioned metal atoms.

The reaction of II with III is carried out in a manner "which is known per se in suitable, preferably polar, solvents (such as methanol, dimethylsulfoxide, acetone, dimethylformamide or acetonitrile) with the addition or exclusion of water. It is carried out for example in 15 the presence of a proton acceptor. Examples of suitable proton acceptors are alkali metal hydroxides, such as sodium hydroxide, alkali metal carbonates, such as potassium carbonate, and tertiary amines, such as pyridine, triethylamine or ethyl diisopropylamine. Alternatively, 20 the reaction is carried out without a proton acceptor, whereby - depending on the starting compounds - an , acid addition salt is optionally obtained,in the first place. The reaction temperature can be between 0° and 150°C, temperatures between 50°c and 100°C, and especially 25 the boiling point of the solvent used, being preferred.

Similar reaction conditions to those in the reaction of II with III are used in the reaction of IV with V, which is carried out in a manner which is known per se. : The reaction of VI with VII is preferably carried out in polar, optionally water-containing solvents in the presence of a strong acid, for example hydrochloric acid, in particular at the boiling point of the solvent used. 2°23g6 The oxidation of the sulfides VIII is carried out in a manner which is known per se and under conditions with which the expert is familiar for the oxidation of sulfides to give sulfoxides [cf. J.Drabowicz and M. Mi-5 kolajczyk, Organic preparations and procedures int. jl_4(1-2), 45-89 (1982)]. Possible oxidizing agents are all the reagents usually employed for oxidation of sulfides, in particular peroxyacids, such as, for example, peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-di-10 nitroperoxybenzoic acid, peroxymaleic acid or, preferably, m-chloroperoxybenzoic acid. The reaction is expediently carried out in inert solvents, for example aromatic or chlorinated hydrocarbons, such as benzene, toluene, methylene chloride or chloroform. The reaction tempera-15 ture is between -70°C and the boiling'point of the solvent used, but preferably between -30°C and +20°C (depending on the reactivity of the oxidizing agent and the degree of dilution) . The oxidation with halogens or hypohalogenites (e.g. with aqueous sodium hypochlorite solution), which 20 is carried out expediently at temperatures between 0° and 30°C, has also prooved to be very advantageous.

The reaction of IX with X is preferably carried out in inert solvents, such as those which are also usually employed for the reaction of enolate ions with 25 alkylating agents. Examples which may be mentioned are aromatic solvents, such as benzene or toluene. The reac- -tion temperature is as a rule between 0° and 120°C (depending on the nature of the alkali metal atom M and the leaving, group Z), preferably at the boiling point of the 30 solvent. For example [if M represents Li (lithium) and Z represents CI (chlorine) and the reaction is carried out in benzene], the boiling point of benzene (80°C) is preferred. 2023 The compounds XI are reacted with compounds XII in a manner which is known per se and under conditions with which the expert is familiar for the reaction of organometallic compounds.

The compounds according to the invention are initially obtained either as such or as their salts, depending on the nature of the starting compounds and depending on the reaction conditions." Moreover, salts are obtained by dissolving the 10 free compounds in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular aliphatic alcohol (ethanol or isopropanol), which contains the desired acid or base or to which the desired acid or base is subse-15 quently added, if necessary in the precisely calculated stoichiometric amount.

The salts are isolated by filtration, reprecipi-tation or precipitation or by evaporation of the solvent.

Resulting salts can be converted into the free 20 compounds by treatment with bases or acids, for example with aqueous sodium bicarbonate or with dilute hydrochloric acid, and the compounds can in turn be converted into their salts. By this means, the compounds can be purified, or pharmacologically unacceptable salts can be converted into 25 pharmacologically acceptable salts.

The sulfoxides according to the invention are optically active compounds. The invention thus includes both the enantiomers and their mixtures and racemates. The enantiomers can be separated in a manner which is 30 known to the expert, e.g. by preparation and separation of corresponding diastereoisomers. The enantiomers can also be prepared bv asymmetric synthesis, e.g. by reaction of pure optically active or diastereoisomerically pure compounds XI with compounds XII [cf. K.K. Andersen, Tetra-35 hedron Lett., 93 (1962)]. c -11- ^2386 •*« The compounds according to the invention are preferably synthesized by reaction of compounds II with III and optionally subsequent oxidation of the resulting sulfides VIII.

The compounds of the formulae II - VII and IX - XII are either known, or they can be prepared by processes analogous to known instructions. Thus, for example, the compounds II are obtained by reacting compounds VI [E. Pouterman and A. Girardet, Helvet. Chim. Acta 3£, 107 10 (1947)3 with carbon disulfide. The compounds III can be prepared according to O.E. Schulz and S. Fedders, Arch. Pharm. (Weinheim) 310, 128-136 (1977).

The compounds IX can be prepared, for example, from the compounds II by methylation, oxidation and subsequent 15 deprotonization with ^alkali metal alkylates or alkanolates. The compounds X are prepared according to Z. Talik, Roczniki Chem. .35, 475 (1 961 ).

?^ CJ Examples for carrying out the invention The examples which follow illustrate the invention in more detail, without restricting it. m.p. denotes melting point, b.p. denotes boiling point. By "ether" there 5 is understood diethyl ether. 1. 4-Trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)-sulf inyl}- (1H) -benzimidazole 2.3 g of commercially available 85% strength m-chloroperoxybenzoic acid, dissolved in 30 ml of methylene 10 chloride, are added dropwise to a solution, cooled to -30°C, of 3.0 g (0.0088 mole) of 4-trifluoromethyl-2-[(4-methoxy-2-pyridylmethy1)thio]-(lH)-benzimidazole in 50 ml of methylene chloride in the course of 45 minutes. The mixture is then stirred for a further 60 minutes and the 15 temperature is subsequently allowed to rise to 0°C. After the mixture has been washed with saturated aqueous sodium carbonate solution (30 ml), it is dried over sodium sulfate, and the solvent is stripped off in vacuo. The solid residue which remains is recrystallized successively from 20 isopropanol and acetonitrile. Yield: 1.6 g of m.p. 150-151°C. 2. 5-Trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl) sulfinyl]-(1H)-benzimidazole 0.1 g of the title compound of m.p. 166°C (with 25 decomposition, recrystallized twice from isopropanol) are obtained by a method analogous to that in Example 1, starting from 0.3 g (0.92 mmole) of 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)-thio]-(1H)-benzimidazole and 0.3 g of 85% strength m-chloroperoxybenzoic acid. 30 3. 5-Tri fluoromethyl-2-[(4-methoxy-3-methy1-2-pyridyl-methyl)sulfinyl]-(1H)-benzimidazole 2.9 g of the title compound of m.p. 225-227°C (with decomposition, from toluene/ether) are obtained by a method analogous to that in Example 1, from 3.7 g (0.01 35 mole) of 5-trifluoromethyl-2-[(4-methoxy-3-m'ethyl-2-pyrid- " / >\ . . v ylmethyl)thio]-(lH)-benzimidazole and 3.3 g of 85% strength m-chloroperoxybenzoic acid. 4. 5-Trifluoromethyl-2-[(4-methoxy-3,5-dimethyl-2-pyrid-ylmethyl)sulfinyl]-(1H)-benzimidazole 3.1, g of the title compound of m.p. 16 3°C (from acetonitrile) are obtained by a method analogous to that in Example 1, startingfrom 3.8 g (0.001 mole) of 5-tri-fluoromethyl-2-[(4-methoxy-3,5-dimethyl-2-pyridylmethyl)-thio]-(1H)-benzimidazole and 3.5 g of 85% strength 10 m-chloroperoxybenzoic acid. . 4-Trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio1-(1H)-benzimidazole 4.5 g (0.023 mole) of 2-chloromethyl-4-methoxyT pyridine hydrochloride are added to 5.0 g (0.023 mole) of 15 4-trifluoromethyl-2-mercapto-benzimidazole, dissolved in 100 ml of ethanol and 23 ml of 2N sodium hydroxide solution, and the mixture is stirred at room temperature for 6 hours. After most of the solvent has been stripped off, the residue is extracted with three 50 ml portions of 20 ethyl acetate, the extract is washed with distilled water and dried over sodium sulfate and the solvent is stripped off in vacuo. The solid residue is recrystallized from acetonitrile. Yield: 5.9 g (76%) of m.p. 146°C. 6. 5-Trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio1-25 (lH)-benzimidazole 2.7 g (59%) of the title compound of m.p. 180-182°C (from acetonitrile) are obtained by a method analogous to that in Example 5 from 3.0 g (0.014 mole) of 5-trifluoromethyl-2-mercaptobenzimidazole and 2.7 g of 2-30 chloromethyl-4-methoxypyridine hydrochloride, after boiling under reflux for three hours. 7. 5-Trifluoromethyl-2-[(4-methoxy-3-methyl-2-pyridyl-methyl)thio]-(lH)-benzimidazole 2.9 g of the title compound of m.p. 148°C (from 35 acetonitrile) are obtained by a method analogous to that in Example 5, from 2.2. g (0.01 mole) of 5-trifluoromethyl- • 102 2-mercaptobenzimidazole and 2.1 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride. 8. 5-Trifluoromethyl-2-[(4-methoxy-3,5-dimethyl-2-pyrid-ylmethyl)thio]-(lH)-benzimidazole 3.5 g of the title compound of m.p. 16 3°C (from 5 acetonitrile) are obtained by a method analogous to that in Example 5, from 2.2 g of 5-trifluoromethyl-2-mercapto-benzimidazole and 2.2 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. 9. 4-Trifluoromethyl-2-[(4-methoxy-3-methyl-2-pyridyl-1 0 methyl)thio]-(1H)-benzimidazole 3.1 g of the title compound of m.p. 175°C (from isopropanol/ether) are obtained by a method analogous to that in Example 5, from 2.2 g (0.01 mole) of 4-tri-fluoromethyl-2-mercaptobenzimidazole and 2.1 g of 15 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride. . 4-Trifluoromethyl-2-mereaptobenzimidazole 4.4 g of solid potassium hydroxide, dissolved in 14 ml of water, and 6 g (0.08 mole) of carbon disulfide are added successively to a solution of 11.0 g (0.062 20 mole) of 3-trifluoromethyl-o-phenylenediamine in 100 ml of ethanol. The mixture is heated under reflux (bath temperature of 60°C) for 4 hours, while stirring. After the mixture has been cooled to 10°C, the precipitate which has separated out is filtered off with suction and recrystal-25 lized from isopropanol: 13.0 g (96%) of the title compound of m.p. 315-320°C.

-Trifluoromethyl-2-mercaptobenzimidazole is obtained in an analogous manner from 4-trifluoromethyl-o-phenylenediamine and carbon disulfide (m.p. 308-310°C). 30 11. 2-Chloromethyl-4-methoxypyridine hydrochloride ml of thionyl chloride are added dropwise to a solution, cooled to -10°C, of 10 g (0.072 mole) of 2-hydroxymethyl-4-methoxypyridine in 30 ml of dry chloroform in the course of 15 minutes. The solution is allowed to 35 come to room temperature and is stirred for another one ' '66 and a half hours. After the solvent and the excess thionyl chloride have been stripped off, colorless crystals are obtained, and are recrystallized from isopropanol (12.1 g (87%), m.p. 140-141°C, decomposition). 2-Chloromethyl-4-methoxy-3-methylpyridine hydro chloride (m.p. 151-153°C, from isopropanol/ether) and 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride (m.p. 128°C, from isopropanol/ether) are obtained in an analogous manner by reacting 2-hydroxymethyl-4-methoxy-3-10 methylpyridine or, respectively, 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine with thionyl chloride.

The compounds 2-hydroxymethyl-4-methoxypyridine and 2-hydroxymethyl-4-methoxy-3-methylpyridine are prepared according to O.E. Schulz and S. Fedders, Arch.Pharm. (Wein-15 heim) 310, 128 (1977). The starting compound 2,3-dimethy]T- 4-nitropyridine-N-oxide is prepared according to H.C.Brown, S. Johnson and H. Podall, J. Am. Chem. Soc . 76_, 5556 (1954). 12. 2-Hydroxymethyl-4-methoxy-3,5-dimethylpyridine hydrochloride 18. g of 2,3,5-trimethylpyridine [F.Bohlmann, A.Englisch, J.Politt, H.Sander and W.Weise, Chem.Ber. 8j3, 1831 (1955)] and 17 ml of 30% strength hydrogen peroxide are heated in 80 ml of. glacial acetic acid for 2.5 hours at 100°C. After this time additional 10 ml of 30% strength hydrogen per-2 5 oxide are added and the mixture is kept at 100°C for a further 8 hours. The mixture is then concentrated to half of its volume in vacuo. If the solution is free of peroxide, the remaining solvent is stripped off in vacuo. The residue is distilled under a high vacuo. 19.2 g (95%) 30 of 2,3,5-trimethylpyridine-N-oxide of b.p. 95-98°C (1.3 Pa) are obtained. .0 g of this compound are dissolved at room temperature in 7 ml of fuming nitric acid and 7 ml of concentrated sulphuric acid. This mixture is heated for 35 18 hours at 40°C and is then poured onto ice water. It is made alkaline by addition of concentrated sodium hydroxide solution with cooling. The mixture is extracted with ethyl acetate 'and the organic phase is concentrated in vacuo. The resulting crude 2,3,5-trimethyl-4-nitropyridine-5 N-oxide is dissolved without further purification in 20 ml of dry methanol. 4.7 ml of 30% strength sodium methoxide solution are added, and the mixture is heated for 12 hours at 50°C. The solvent is then removed. The residue is dissolved in water and extracted with ethyl acetate. The 10 organic phase is concentrated and the resulting oil (crude 4-methoxy-2,3,5-trimethylpyridine-N-oxide) is poured into 20 ml of hot (100°C) acetic anhydride. The mixture is kept for one hour at this temperature. It is then concentrated in vacuo and dissolved without further purification 15 in 20 ml of 10% strength aqueous hydrochloric acid. The solution is stirred for 2.5 hours at 50°C and is then concentrated to half of its volume in vacuo. The remaining solution is made alkaline with potassium carbonate and is extracted with ethyl acetate. The organic phase is dried 2 0 with sodium sulphate and concentrated in vacuo. The oily residue is dissolved in 50 ml of ethyl methyl ketone. An etheral solution of hydrogen chloride is added to precipitate the title compound quantitatively. The precipitate is recrystallized from dioxan/isopropanol. 3.1 g 25 of the title compound of m.p. 126°C are obtained. 13. 5-Trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benz imidazole A hot solution of 2.06. g (10.6 mmole) of 2-chloromethy1-4-methoxypyridine hydrochloride in 20 ml of isopropanol 30 is added to a solution of 2.25 g (10.3 mmole) of 5-tri-fluoromethyl-2-mercaptobenzimidazole in 19 ml of isopropanol, and the mixture is stirred at 100°C for 4 hours.

After cooling in an ice-bath 4.21 g (99%) of 5-trifluoro-methyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimi-35 dazole dihydrochloride of m.p. 195-197°C (decomposition) • 202386 Q - 17 - are obtained.

A solution of 4.66 g (11.3 mmole) of the dihydro-chloride in 13 ml of water is purified with active charcoal. 3.7 g (96%) of the free base are precipitated by 5 slow addition of 17 ml of a 2 N. potassium bicarbonate solution, which contains a littel isopropanol. M.p. 182-184°C. 14. 5-Trifluoromethyl-2-C(4-methoxy-2-pyridylmethyl)-sulfinyl]-(1H)-benzimidazole 10 600 ml of a 1.5 % strength aqueous sodium hypochlorite solution are added within 3 minutes at 10°C with vigorous stirring to a solution of 16.2. g (0.048 mole) of 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimidazole in 960 ml of ethyl acetate. The mixture 15 is then stirred for a further 2 minutes. The organic phase is separated off and is washed with 100 ml of distilled water. The aqueous phase is adjusted to pH 7-8 by addition of glacial acetic acid and is then extracted three times with ethyl acetate. The extracts are washed 20 with water and the combined organic phases are then concentrated to a volume of 100 ml and cooled in an ice bath. The precipitate which has separated out is filtered off with suction and washed with cold ethyl acetate.

Yield: 13.2 g of m.p. 166°C (decomposition). 25 15. 5-Trifluoromethvl-2-[(4-methoxy-2-pyridylmethyl)-sulfinyl]-(1H)-benzimidazole A suspension of 20.0 g (0.092 mole) of 5-triflucromethyl-2-mercaptobenzimidazole and 13.1. g (0.092 mole) of methyl iodide in 200 ml of ethanol is heated to the boil for 30 three hours. The solvent is stripped off in vacuo and the residue is recrystallized from acetonitrile. 17.5 g (82%) of 5-trifluoromethyl-2-methylthio-benzimidazole of m.p. 145-146°C are obtained.

•SE&m - 18 - l*piW 2.6 g (0.013 mole) of commercially available 85% strength m-chloroperoxybenzoic acid are added dropwise to a suspension, cooled to -20°C, of 3.0. g (0.013 mole) of 5-trifluoromethyl-2-methylthio-benzimidazole in 50 ml of methylene chloride 5 in the course of 30 minutes. The mixture is then stirred for a further 6 0 minutes and is then extracted twice with, each time, 20 ml of an aqueous potassium carbonate solution. The solvent is stripped off in vacuo and the solid residue which remains is recrystallized from acetonitrile. 1.8 g 10 of 5-trifluoromethyl-2-methylsulfinyl-benzimidazole of m.p. 135°C are obtained. Deprotonation of this compound with n-butyllithium and reaction with 2-chloro-4-methoxy-pyridine in dry benzene yields the title compound of m.p. 166°C (decomposition). 15 16. 5-Trifluoromethyl-2-[(4-methoxy-3,5-dimethy1-2-pyridylmethyl) thi<3~ (1H) -benzimidazole 2.27 g of 2 — C2 —(4-methoxy-3,5-dimethyl-2-pyridylmethyl)-thio] formic acid and 1.76. g of 5-trifluoromethyl-o-phenyl-enediamine are heated under reflux for two hours in 20 ml 20 of 4 N. hydrochloric acid. The mixture is cooled and neutralized with ammonia solution. The neutral solution is then extracted with ethyl acetate. The solvent is stripped off in vacuo and the solid residue which remains is recrystallized from acetonitrile. M.p. 163°C. 25 17'. 5-Trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimidazole 22.1 g (0.1 mole) of 5-trifluoromethyl-2-chlorobenzimidazole and 15.7 g (0.11 mole) of 4-methoxy-2-thiomethylpyridine in 250 ml of isopropanol are heated under reflux for 10 30 hours. The solvent is stripped off in vacuo, and 500 ml of ice water are added to the residue. The title compound is filtered off with suction and recrystallized from acetonitrile. M.p. 180-182°C. 18. 5-Trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)-sulfinyl]-(1H)-benzimidazole calcium salt 0.09 g (0.003 mole) of 80% sodium hydride (in paraffin) are added to a solution of 1.1 g of 5-trifluoromethyl-2-5 [ (4-methoxy-2-pyridylmethyl) -sulf inyl]- (1H) -benzimidazole in 20 ml of dry dioxan under an inert gas atmosphere.

After the evolution of gas has subsided, the solvent is stripped off in vacuo. The residue (5-Trifluoromethy1-2-[(4-methoxy-2-pyridylmethyl)-sulfinyl]-(1H)-benzimidazole 10 sodium salt•is dissolved in a few water, and a 1 % strength aqueous calcium chloride solution is added. The precipitate which has separated out is filtered off with suction and dried in a high-vacuum for several hours. M.p. 176°C (decomposition). 2023§£ Commercial usefulness The substituted benzimidazoles of the. general formula I and their pharmacologically-acceptable salts have valuable pharmacological properties which render them commercially 5 useful. In particular, they significantly inhibit the gastric acid secretion. In addition, they are characterized by an excellent protection action on the stomach and intestines of warm-blooded animals. This protection action can even be observed on administering doses which are 10 lower than those needed to inhibit gastric acid secretion. Another advantage of the compounds according to the invention is their comparatively great chemical stability.

The excellent activity of the substituted benzimida- zoles and of their pharmacologically acceptable salts, their * low toxicity and the absence of significant side effects enables the compounds to be used in human medicine and veterinary medicine, where they are employed, in particular, for the treatment and prophylaxis of illnesses which 20 are based on diseases of the stomach and intestine and on excessive secretion of gastric acid. For example, acute and chronic ulcus ventriculi and ulcus duodeni,. gastritis, hyperacid gastric irritation and stomach complaints caused by medicaments are treated in humans and animals 25 with these compounds or with medicament compositions containing these compounds.

The invention thus also relates to a method of treating mammals suffering from one of the abovementioned illnesses. The method is characterized in that a thera-30 ;peutically active and pharmacologically acceptable amount of one or more of the abovementioned substituted benzimidazoles is administered to the sick mammal.

The invention furthermore relates to the compounds t according to the invention which are mentioned therein, for use in this method. The invention also relates to the use of compounds according to the invention in the produc-5 tion of medicaments which can be used for combating the illnesses mentioned.

The invention moreover relates to medicaments which contain one or more substituted benzimidazoles of the general formula I and/or their pharmacologically 10 acceptable salts.

The medicaments are produced by processes which are known per se and with which the expert is familiar. As medicaments, the pharmacologically active compounds (= active ingredients) according to the invention are used 15 either as such or, preferably, in combination with suitable pharmaceutical auxiliaries, in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions.

'The expert is familiar, on the basis of his expert 20 knowledge, with the auxiliaries which are suitable for the desired medicament formulations. Besides solvents, gelling agents, suppository bases, tableting auxiliaries and other excipients for active ingredients, it is also possible to use, for example, antioxidants, dispersing f agents, emulsifiers, anti-foaming agents, flavor correct-jants, preservatives, solubilizing agents and colorants. ' The active compounds can be administered orally or parenterally, oral and intravenous administration being preferred.

In general, it has proved advantageous in human medicine to administer the active compound or compounds, when these are given orally, in a daily dose of about 0.01 to about 20 mg/kg of body weight, preferably O.05 to 7 and in particular 0.1 to 2 mg/kg of body weight, if 35 appropriate in the form of several, preferably 1 to 4, individual administrations to achieve the desired result. In the case of parenteral treatment, similar or,(especially with intravenous administration of the active compounds) as a rule lower dosages can be used. The optimum 5 dosage and method of administration of the active compounds required in each particular case can easily be determined by any expert, in accordance with his expert knowledge.

If the compounds according to the invention and/or 10 their salts are to be used for treatment of the above-mentioned illnesses, the pharmaceutical formulations can also contain one or more pharmacologically active members of other groups of medicaments, such as antacids, for example aluminum hydroxide or magnesium 15 aluminate; tranquillizers, such as benzodiazepines, for example diazepam; spasmolytic agents, such as, for example, bietamiverine and camylofin; anticholinergic agents, such as, for example, oxyphencyclimine and phen-carbamide; local anesthetics, such as, for example, 20 tetracaine and procaine; and in some cases also enzymes, vitamins or aminoacids.

The active compounds can be formulated, for example, in the following manner: a) Tablets containing 40 mg of active compound 25 20 kg of 4-trifluoromethyl-2-[(4-methoxy-2- pyridylmethyl)thio]-(1H)-benzimidazole, 40 kg of lactose, 26 kg of corn starch and 3 kg of polyvinylpyrrolidone are moistened with about 20 liters of water and the mixture is granulated through a sieve of 1.25 mm mesh width. 30 The granules are dried to a relative moisture content of 50-60% in a fluidized bed drier, and 8 kg of sodium car-boxymethylcellulose, 2 kg of talc and 1 kg of magnesium stearate are then added. The finished granules are pressed to 200 mg tablets 8 mm in diameter. - 23 - ^023 8 6^ b) Capsules with an active compound content of 30 mg 300 g of 5-trifluoromethyl-2-[(4-methoxy-3-methyl-2-pyridylmethyl)thio]-(lH)-benzimidazole, 695 g of micro-crystalline cellulose and 5 g of amorphous silicic acid are finely powdered and mixed thoroughly and the mixture is filled into hard gelatin capsules, size 4. c) Capsules with an active compound content of 30 mg "■ 300 g of 5-trifluoromethyl-2-[(4-methoxy-~ 2-pyridylmethyl)sulfinyl]-(lH)-benzimidazole, 695 g of microcrystalline cellulose and 5 g of amorphous silicic acid are finely powdered and mixed thoroughly and the mixture is filled into hard gelatin capsules, size 4. 202 Pharmacology The excellent protection action on the stomach, and 5 the gastric secretion inhibition shown by the substituted benzimidazoles is demonstrated by a test using the Shay rat model. The compounds according to the invention prove to have a protective action on the stomach and a. gastric secretion inhibition which are clearly superior to the state of the art.

The substances investigated in the tests are characterized in the table which follows by means of serial numbers which are allocated as follows: Serial No. Name of Compound 1 Omeprazole*(INN, USP 4,255,431 and USP 4,337,257) 2 5-Trifluoromethyl-2-[(4-methoxy-2-pyridyl-methyl)sulfinyl]-(1H)-benzimidazole 3 5-Trifluoromethyl-2-[(4-methoxy-3-methyl-2- pyridylmethyl)sulfinyl]-(1H)-benzimidazole 4 5-Trifluoromethyl-2-[(4-methoxy-3,5-dimethy1-2-pyridylmethyl)sulfinyl]-(1H)-benzimidazole 4-Methyl-2-[(2-pyridylmethyl)thio]-(1H)- benzimidazole (USP 4,045,564) 6 5-Trifluoromethyl-2-[(4-methoxy-2-pyridyl-methyl)thio]-(1H)-benzimidazole 7 5-Trifluoromethyl-2-[(4-methoxy-3-methyl-2-pyridylmethyl)thio]-(1H)-benzimidazole 8 4-Trifluoromethyl-2-[(4-methoxy-3-methyl-2- pyridylmethyl)thio]-(1H)-benzimidazole * Omeprazole= 5-Methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridylmethyl)-sulfinyl]-(1H)-benzimidazole The effect of the compounds according to the invention on the formation of. gastric ulcers provoked by a pylorus ligature (4 hours, so-called Shay rat) and oral administration of 100 mg/kg acetylsalicylic acid and on the 5 inhibition of gastric secretion in rats during 4 hours is shown in the following table: Serial No.

Dose [mg/kg] p.o.

Protec on th ( reduction in the ulcer index (%) tive action e stonach rat) .

ED25+) ED50+) mg/kg, p.o.] Gastric Sec (rat) inhibition in % of HCl-secreti retion m25+) ^SO*' on [mg/kg/ p.o.] 1 0.1 0.3 1.0 3.0 +1 12 27 58 0.9 2.3 9 22 > 3.0 - 2 0.1 0.3 1.0 3.0 6 29 88 100 0.24 0.45 0 18 60 84 0.35 0.75 | 3 0.3 1.0 10.0 98 100 0.3 0.45 40 88 92 < 0.3 0.4 : 4 0.1 0.3 1.0 3.0 1 69 89 0.24 0.55 +5 10 50 75 0.48 1.0 .0 30.0 100.0 51 61 16.0 .0 0 0 - > 100 6 1.0 3.0 27 97 «"*» 1.0 1.4 70 1.2 2.0 7 0.3 1.0 94 <0.3 0.5 26 85 0.3 0.5 8 1.0 3.0 50 63 «1.0 1.0 12 50 1.5 3.0 +'see next page 20238$ + ^ED2j- and ED^q (logarithmic interpolation) = dose which reduces the ulcer index and the HCl-secretion (£ 4 hours) of the rat stomach by 25% and 50% in the treated, group compared with the control, group.

The antiulcerogenic action was tested in accordance with the method using the so-called Shay rat: Rats (female, 180 to 200 g, 4 animals per cage on a high, grid) which had been fasted for 24 hours were subjected to ulcer provocation by 10 pylorus ligature (under diethyl ether anaesthesia) and oral administration of 100 mg/10 ml/kg of acetylsalicyclic acid. The substances to be tested are administered orally (10 ml/ kg) 1 hour before the pylorus ligature. The wound is closed by means of Michel clamps. 4 hours thereafter, the 15 animals are killed under ether anaesthesia by atlas dislocation, and the stomach is removed. The stomach is opened longitudinally and fixed to a cork tile after the amount of: gastric juice secreted [volume/ and its hydro-ichloric acid content (titration with sodium hydroxide 20 solution] has been determined, the number and size j (=diameter) of ulcers present are determined with a ,stereomicroscope with 10-fold magnification.' The product of the degree of severity (according to the following |rating scale) and the number of ulcers serves as the individual ulcer index.

Scale of points: no ulcers 0 ulcer diameters 0.1 - 1.4 mm 1 1.5 - 2.4 mm 2 30 2.5-3.4 mm 3 3.5 - 4.4 mm 4 4.5 - 5.4 mm 5 ■_ 5 .5 mm 6

Claims (27)

1. The reduction in the average ulcer index of each treated group compared with that of the control, group (=100%) serves as a measure of the antiulcerogenic effect. The ED25 and the ED^q designate the doses which reduce the 5 average ulcer index and the gastric secretion by 25 and 50%. Toxicity:
2. The dosis tolerata of all tested compounds is >1000 mg/kg 10 [p.o.] . 15 20 25 30 35 - 28 -
3. 3 ,c ■#S" .,at^WE clam m tii a .to Q..n.i ti I C I 3 ii in <c Substituted benzimidazoles of the formula I (I) , 1o wherein R*' denotes hydrogen or methyl and 2;R denotes hydrogen or methyl and n denotes the numbers 0 or 1,;and the salts of these compounds. 15 2. Substituted benzimidazoles of the formula Ic;20;:ia),;25;30;35;wherein r''3' denotes hydrogen or methyl and;2 3;r denotes hydrogen or methyl and n denotes 0,;and the salts of these compounds.;3 .;Substituted benzimidazoles of the formula I;och,;<ib.,;cf-;wherein;^ o23 8;- 29 - W2;1 K;R denotes hydrogen or methyl and;0 V* R denotes hydrogen or methyl and n denotes 1, and the salts of these compounds.
4. 4. A compound according to Claim 2, selected from the group comprising 4-trifluoromethyl-2-[(4-methoxy-2-pyrid-ylmethyl)thio]-(lH)-benzimidazole, 4-trifluoromethyl-2- {(4-methoxy-3-methy1-2-pyridylmethyl)thio]-(1H)-benzimidazole , 4-trifluoromethyl-2-I(4-methoxy-5-methyl-2-pyricyI-methyl)thio]-(lH)-benzimidazole, 4-trifluoromethyl-2-I (4-methoxy-3,5-dimethyl-2-pyridylmethyl)thic]-(1H)-benzimidazole , 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)-thio]-(1H)-benzimidazole, 5-trifluoromethy1-2-[ (4-methoxy-5-methvl-2-pyridylmethyl)tnio]-(1H)-benzimidazole and 5-trifluoromethvl-2-[ (4-metnoxy-3,5-dimethyl-2-pyridyl-methyl)thio]-(1H)-benzimidazole and tautomers thereof, as well as the salts of these compounds.
5. 5. A compound according to claim 2 which is 5-tri- fluoromethyl-2-[(4-methoxy-3-methy1-2-pyridylmethyl)thio]-(1H)-benzimidazole , its tautomer, and the salts of these compounds.
6. 6. A compound according to claim 3, selected from the group comprising 4-trifluoromethyl-2-l(4-methoxy-2-pyrid- ylmethyl)sulfinyl]-(1H)-benzimidazole, 4-trifluoromethyl- 2-1(4-methoxy-3-methy1-2-pyridylmethyl)sulfinyl]—(1H)— benzimidazole, 4-trifluoromethyl-2-((4-methoxy-5-methy 1-2-pyridylme thy1)sulfinyl]-(1H)-benzimidazole, 4-trifluoro-methyl-2-l(4-methoxy-3,5-dimethy1-2-pyridylmethyl)sulfin-yi]-( 1H)-benzimidazole , 5-trifluoromethyl-2-[(4-methoxy- 3-methyl-2-pyridylmethyl)sulfinyl]-(1H)-benzimidazole, 3-trifluoromethyl-2-[ (4-methoxy-5-methy 1—2-pyridylmethyl) -sulfinyl]-(1H)-benzimidazole and 5-trifluoromethyl-2-[(4-methoxy-3,5-dimethyl.-2-pyridy lmethyl) -sulfinyl]- (1H) -benzimidazole and tautomers thereof, and the salts of thes compounds. - 30 - 202386
7. 7. A compound according to claim 3 which is 5-trifluoro-methyl-2-[(4-methoxy—2-pyridylmethyl)sulfinyl]-(1H)-benzimidazole, its tautomer, and the salts of these compounds.
8. 8. Medicaments containing one or more compounds as claimed in claim 1.
9. 9. Medicaments containing one or more compounds as claimed in claim 2.
10. 10. Medicaments containing one or more compounds as claimed in claim 3.
11. 11. Medicaments containing one or more compounds as claimed in claim 4.
12. 12. Medicaments containing one or more compounds as claimed in claim 5.
13. 13. Medicaments containing one or more compounds as claimed in claim 6.
14. 14. Medicaments containing one or more compounds as claimed in claim 7.
15. 15. Process for the preparation of substituted benzimidazoles of the general formula I according to claim 1, characterized in that a) mercaptobenzimidazoles of the formula II or their salts are reacted with picoline derivatives III or their salts och3 (II) (III) cf3 h or b) benzimidazoles of the formula IV are reacted with mercaptopicolines V och3 (IV) hs-ch2 (v) /.'' / - 31 - 202336 or c) o-phenylenediamines of the formula VI are reacted with formic acid derivatives VII och- (VI) hooc-s-ch (VII) and, if appropriate, the 2-benzimidazolyl 2-pyridyl sulfides of the formula VIII cf. (VIII) obtained according to a) , b) or c) are then oxidized and/or the obtained free base is then converted into a salt, or the obtained salt is then converted into the free base, or that d) benzimidazoles of the formula IX are reacted with pyridine derivatives X och- N 1? cf- CH^—M (x) 3 H (IX) or that e) sulfinyl compounds of the formula XI are reacted with 2-picoline derivatives of the formula XII och- 0 (xi) (XII) CF- m'-ch2 >n 202336 32 and, if appropriate, the products are then converted into the salts, Y, Z, Z1 and Z'' being suitable leaving groups, M representing an alkali metal atom (Li, Na or K), M1 n having the meanings given in claim 1.
16. 16. A process according to claim 15 in which the product obtained is a compound as claimed in claim 2.
17. 17. A process according to claim 15 in which the product obtained is a compound as claimed in claim 3.
18. 18. A process according to claim 15 in which the product obtained is a compound as claimed in any one of claims 4 to 7.
19. 19. Compounds according to claim 1 for use in the treatment and prophylaxis of illnesses which are based on excessive secretion of gastric acid in the stomach.
20. 20. Compounds according to claim 1 for use in the protection of the stomach and intestine.
21. 21. Compounds according to claim 2 for use in the treatment and prophylaxis of illnesses which are based on excessive secretion of gastric acid in the stomach.
22. 22. Compounds according to claim 3 for use in the treatment and prophylaxis of illnesses which are based on excessive secretion of gastric acid in the stomach.
23. 23. Compounds according to any one of claims 4 to 7 for use in the treatment and prophylaxis of illnesses which are based on excessive secretion of gastric acid in the stomach.
24. 24. Compounds according to claim 2 for use in the protection of the stomach and intestine.
25. 25. Compounds according to claim 3 for use in the protection of the stomach and intestine.
26. 26. Compounds according to any one of claims 4 to 7 for use in the protection of the stomach and intestine.
27. 27. A process for producing a compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples. representing the equivalent of a metal atom and R^, and r patent OFFICE BALDWIN, SON & CAREY