HU182938B - Process for producing novel benzimidazole-2-derivatives - Google Patents

Abstract

The present invention relates to novel benzimidazole-2 derivatives of formula I wherein R is a carboxyl group optionally esterified with an alkanol of up to 4 carbon atoms, or a hydroxymethyl group optionally etherified with up to 4 carbon atoms, R C 1 -C 6 alkyl, R 1 and R 3 are hydrogen or C 1-4 alkyl and X is methylene and salts thereof. The novel compounds are primarily anti-allergic. (I) -1-

Description

The present invention relates to novel benzimidazole-2 derivatives of formula I wherein R is a carboxyl group optionally esterified with up to 4 carbon atoms or an hydroxymethyl group optionally etherified with up to 4 carbon atoms,

R 1 is C 1-6 alkyl,

R ₂ and R ₃ are hydrogen or C 1-4 alkyl, and

X is a methylene group - and salts thereof.

Examples of etherified hydroxy in the etherified hydroxymethyl group in R include methoxy, ethoxy, η-propoxy, isopropyloxy, η-butyloxy, isobutyloxy, tert-butyloxy, or tert-butyloxy. group.

Examples of alkyl groups having up to 4 or 6 carbon atoms are methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and alkyl having up to 6 carbon atoms. n-pentyl or n-hexyl.

For example, salts with bases are those compounds of formula I wherein R is carboxyl. Such salts are, in particular, pharmaceutically acceptable, non-toxic salts such as alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium, and also with ammonia or amines such as lower alkyl amines such as trimethylamine, or salts with triethylamine. Compounds of formula I containing a basic side chain may also form salts, e.g. with mineral acids such as the corresponding hydrogen halides such as hydrochlorides.

Benzimidazole-2-carboxylic acids and -2-methanol derivatives substituted with one or two alkyl groups are known. For example, U.S. Patent No. 766,749. United Kingdom Patent No. 5,123,125 proposes to incorporate such benzimidazoles, such as 5,6-dimethylbenzimidazole-2-carboxylic acid or 5,6-dimethylbenzimidazole-2-methanol, into cobalamin.

Further, it is known from U.S. Patent No. 243,766. United Kingdom Patent No. 2,900,125, which discloses that 2-ethoxymethylbenzimidazole has antipyretic properties.

The novel compounds of the present invention have valuable therapeutic properties. Thus, they primarily exhibit an antiallergic effect, such as in the rat passive cutaneous hypersensitivity assay (PCA reaction) at oral doses of 10-100 mg / kg in rats, according to the method described by Goose and Blair, Immunology, 16, 749 (1969). the passive cutaneous hypersensitivity reaction Ovary, Progr. Allergy, 5, 459 (1958). The antiallergic, predominantly antiproliferative effect can also be demonstrated by in vitro assays with histamine release of rat peritoneal cells, immuno-induced release (e.g., rats infected with Nippostrongylus brasiliensis), and chemically-induced release of N-methyl (e.g. The compounds of the present invention are therefore useful as inhibitors of allergic reactions such as allergic diseases such as asthma, such as asthma of external and internal origin, or other allergic diseases such as allergic rhinitis such as hay fever, conjunctivitis, or allergic skin diseases such as Utricaria or eczema. and preventive treatment.

The invention relates in particular to the preparation of compounds of formula I wherein R is, on the one hand, an esterified carboxyl group containing up to 4 carbons or an etherified hydroxy group, such as methoxy or ethoxy, or, on the other hand, a hydroxyl group containing 4 or more carboxylates. an ethereal hydroxymethyl group containing an alkoxy group such as methoxy or ethoxy; R1 being an alkyl group having up to 6 carbon atoms such as methyl, ethyl, η-propyl, n-butyl or tert-butyl.

X is methylene, R ₂ is hydrogen, and alkyl having up to 4 carbon atoms, such as methyl, and R _{3 is} hydrogen, or alkyl having up to 4 carbon atoms, such as methyl. AzRj-X- and the group R ₃ in the case when not hydrogen, preferably is a benzimidazole ring of 5- or 6-position. The present invention also relates to a process for the preparation of pharmaceutically acceptable salts of such compounds of formula (I) which contain a carboxyl group as R.

The present invention relates in particular to the preparation of compounds of formula I wherein R is a carboxyl group or an esterified carboxyl group containing up to 4 carbon atoms as etherified hydroxy group, for example methoxy or ethoxy group, R 1 -X- is alkyl group having 2 to 7 carbon atoms, e.g. , n-propyl, isopropyl, η-butyl, n-pentyl or n-hexyl, R ₂ and R _{3 are} hydrogen, and in particular alkyl up to 4 carbon atoms, such as methyl. The present invention also relates to a process for the preparation of pharmaceutically acceptable salts of such compounds of formula (I) which contain a carboxyl group as R.

The present invention relates in particular to the preparation of compounds of formula I wherein R is a carboxylic, hydroxymethyl or alkoxycarbonyl group, or an alkoxymethyl group having up to 5 carbon atoms in total, for example methoxy or ethoxycarbonyl or methyl group, e.g. methyl, ethyl, η-propyl, isopropyl, n-butyl or isobutyl, and R ₂ and R ₃ are each independently alkyl containing up to 4 carbon atoms, such as methyl, and the base salts thereof with compounds containing R; It applies.

The present invention relates, in particular, to the preparation of compounds of formula I wherein R is a carboxyl group or an alkoxycarbonyl group containing up to 5 carbon atoms in total, such as methoxyl or ethoxycarbonyl, and wherein R 1 -X 2 -C 7 alkyl group such as ethyl, η-propyl , isopropyl, n-butyl, n-pentyl or n-hexyl, and R ₂ and R _{3 are} alkyl groups of up to 4 carbon atoms, such as methyl, and R _{3 is at} the 5-position of the benzimidazole ring, and the alkyl group is in the 6-position and refers to the preparation of base salts of compounds having such an R group with a carboxyl group.

The present invention relates, in particular, to the preparation of compounds of formula I wherein R is a carboxyl group, R _{x is an} alkyl group of up to 4 carbon atoms,

-2 182 938 for example, methyl, ethyl, η-propyl, isopropyl or n-butyl, X is methylene, R ₂ is hydrogen and R ₃ is hydrogen or up to 4 carbon atoms such as a methyl group, wherein the group -X-R the benzimidazole ring is in the 5-position and the R ₃ alkyl group is in the 6-position and is intended for the preparation of pharmaceutically acceptable salts of such compounds.

The present invention relates in particular to the preparation of the compounds specifically named in the Examples.

The novel compounds can be prepared by methods known per se. For example, by reacting the compound (II) is a compound of formula wherein Xi and X ₂ substituents are each -C (= 0) -R radical, the other is hydrogen, or gyűrűzáquk a salt of such a compound, and 15 optionally converting the compound thus obtained to another compound of formula (I) and / or converting a resulting free salt-forming compound into one of its salts or converting a resulting salt into the free compound or another salt;

The salts of the compounds of formula II used as starting materials for the ring closure reaction are, for example, the acid addition salts such as the hydrohalides, e.g. the hydrochlorides, and the carboxyl group containing the R, the carboxyl group containing the hydroxymethyl group optionally etherified with up to 4 carbon atoms. ), for example, alkali metal or ammonium salts, such as sodium salts.

The ring closure is carried out at a higher temperature, such as from about 50 ° C to about 160 ° C, preferably at about 50 ° C to about 160 ° C, in a conventional manner, for preparing compounds having a hydroxymethyl group normal or predominantly C 1-4 alkanol etherified.

110-140 ° C, if necessary in the presence of an acidic condensing agent such as a hydrogen halide such as hydrochloric acid and / or a water-binding agent such as dicyclohexylcarbodiimide and preferably under an inert gas such as nitrogen.

Said process is particularly suitable for the preparation of compounds of formula I wherein R is a hydroxymethyl group optionally etherified with an alkanol having up to 4 carbon atoms, which can then be readily converted to other compounds of formula I by conventional means. 45

The starting materials of formula (II) are conveniently prepared in situ, for example, by the preparation of a suitable 1,2-phenylenediamine which may be substituted with R ₁ -X and may optionally contain further substituents, e.g. IIa) or an acid addition salt such as a hydrochloride, an acid of formula R-COOH (IIb) or a reactive derivative of such an acid, preferably an ester such as a lower alkyl ester, an amide or an anhydride thereof, with an acid halide, an iminoether such as an imino (lower) alkyl ester or an imino ester such as an iminochloride such as optionally etherified glycolic acid or ethyl chloro or bromo oxalic acid, optionally as a solvent or diluent, e.g. in the presence of methanol or ethanol and / or during heating at about 50-160 ° C, e.g. 110-140 ° C. The 1,2-phenylenediamines used as starting materials for this reaction are, for example, by reaction with the corresponding 1,2-nitraniline compounds, for example, by reduction, for example by reaction with a chemical reducing agent, such as sodium dithionite, or by a suitably actuated hydrogen such as a noble metal catalyst. Raney nickel is available in methanol or ethanol catalytically activated hydrogen. Alternatively, 1,2-phenylenediamines may be prepared by reacting the intermediate 1,2-nitranilines with the aforementioned acids, such as glycolic or oxalic acid, or a corresponding reactive derivative thereof, such as ethoxyacetic acid or chloroxalic acid (e.g. and then reduce the nitro group with, for example, hydrogen in the presence of Raney nickel.

The 1,2-nitraniline compounds required for the preparation of the starting compounds of formula II, if not known, can be prepared, for example, from the corresponding chlorobenzenes H-PhH-Cl. The chlorobenzenes are substituted in a conventional manner, for example by reaction with a compound of formula Rj-X-Hal or Rj-X-OH or the corresponding alkene or cycloalkene in the presence of aluminum chloride, and the compound of formula IIc obtained is then nitrated with nitric acid-sulfuric acid. reacting the thus obtained chloronitrile compound (IId) with ammonia or an amine of formula R ₂ NH ₂ .

In a preferred embodiment of the process described, a compound of formula (IIa) is reacted with an acid of formula R-COOH (IIb) or a corresponding functional derivative thereof and, if desired, the resulting compound is converted into another compound of formula (I) and / or converting a resulting compound having a free salt-forming group into a salt or a resulting salt into a free compound or another salt.

Suitable functional derivatives of the acids of formula IIb include, for example, esters, such as lower alkyl esters, or anhydrides, such as acid halides. The acids and functional derivatives of formula (IIb) which may be used in the above process variant include, for example, glycolic acid optionally etherified with C 1 -C 4 alkenyl and ethyl chloro or bromo oxalic acid.

The reaction is preferably carried out in the presence of a solvent or diluent, such as a lower alkanol such as methanol or ethanol, if necessary heated at 50-160 ° C, preferably 110-140 ° C.

The novel compounds may also be prepared by reacting a compound of formula III wherein X _{3 is} formyl, a carboxyl group which is functionally rearranged other than R 4 alkoxycarbonyl, or an etherified hydroxymethyl group other than an R 4 -C 4 alkoxymethyl group. , oxidizing the formyl group to a carboxyl group or solubilizing a functionally converted carboxyl group to a carboxyl group or an esterified carboxyl group R or hydrolyzing an esterified or etherified hydroxymethyl group to a hydroxymethyl group and / or optionally converting the resulting salt or , a salt-forming compound is converted to one of its salts.

The formyl group may also be formed in situ during the oxidation reaction, for example, by esterification with an inorganic acid such as a hydrogen halide such as hydrochloric acid or a cyclic 2-hydroxyether such as 2-hydroxytetra3.

-3182 938 of hydroxymethyl etherated with hydropyran, or with a cyclic 2- or 4-hydroxythioether such as 2-hydroxytetrahydrothiopyran, 2-hydroxytetrahydrothiophene or 4-hydroxy-4-methoxytetrahydropyran, or a derivative thereof, e.g. lower alkyl acetate or an imine such as benzylimine, or an iminium salt such as N, N-di (lower) alkyl such as N, N-dimethyliminium salt such as chloride or methosulfate.

The oxidation is carried out according to methods known per se, for example by treatment with an oxidizing heavy metal compound, preferably an oxidation compound containing chromium VI or manganese VII, such as chromium trioxide or, in particular, potassium permanganate, and the starting material of formula III. wherein X ₃ is one of the aforementioned etherified hydroxymethyl groups, may also be carried out with a manganese-IV-containing compound such as manganese dioxide. The oxidation is preferably carried out in a suitable solvent or diluent, such as acetone or pyridine, or preferably in an aqueous mixture thereof, if necessary under cooling or heating, preferably at a temperature from 0 ° C to 80 ° C.

Functionally modified carboxyl groups other than alkoxycarbonyl R include, but are not limited to, cyano, halo, e.g., chlorocarbonyl, reactive esterified carboxyl, such as mono-, di-, or trihalogen, e.g. or 2,4-dinitrophenoxycarbonyl groups, carbamoyl groups or reactive carbamyl groups such as imidazolyl-2-carbonyl, open chain or cyclic iminoether groups such as iminoalkyl groups or 4,4- or 5,5-dimethyl-4,5-dihydrooxazolyl- (2) or 4,4,6-trimethyl-5,6-dihydroxyazazinyl (2) or tri- (lower) alkoxy or trihalomethyl groups such as trichloromethyl. These groups can be solubilized, e.g. can be converted to an alkoxycarbonyl group. The hydrolysis of the cyano group and the trihalomethyl groups is preferably carried out in a basic medium, and the hydrolysis of the iminoether groups is preferably carried out in an acidic medium. If a formula (III) starting material of formula I where X ₃ halogénkarbonil- or one of said reactive esterified carbonyl group is, treated with a C1-4 alkanol in combination with appropriate basic agent such as pyridine in the presence of (I) a compound of formula to give wherein R is an esterified carboxyl group such as a C 1 -C 4 alkoxycarbonyl group. In the case of an (III) starting material of formula in which X ₃ trihalogénmetilcsoportot, especially trichloromethyl, with a C 1-4 alkanol and water, can be obtained directly from compounds of general formula I, wherein R is esterified carboxy. The aforesaid reactions may be carried out according to methods known per se, usually in a solvent or diluent, or a mixture thereof, and, if necessary, under cooling or heating, for example at a temperature from 0 ° C to 120 ° C. 4

Esterified hydroxymethyl groups include, for example, an inorganic acid such as halohydrogen acid, esterified hydroxymethyl groups such as bromomethyl or chloromethyl, and a carboxylic acid esterated hydroxymethyl group such as a C2-C7 alkanoyloxymethyl group or optionally C1-C4 alkyl, benzyloxymethyl substituted with C alk alkoxy and / or halogen. Etherified hydroxymethyl groups as defined above include, for example, cyclic, preferably 5- or 6-ring, 2- or 4-hydroxyethers or thioethers, such as 2-hydroxytetrahydrothiopyran, 2-hydroxytetrahydrothiopyran, 2-hydroxytetrahydrothiophene, or 4-hydroxy-4-methoxy, hydroxymethyl groups etherified with a silanol such as tri- (lower) alkylsilanol such as trimethylsilanol. Said groups may be hydrolyzed by conventional means, for example, by hydrolysis with an acidic or, above all, basic hydrolyzing agent such as an organic sulfonic acid such as p-toluenesulfonic acid or mesitylene sulfonic acid or a mineral acid such as sulfuric or hydrochloric acid or an alkali metal hydroxide such as sodium hydroxide. The hydrolysis of the esterified hydroxymethyl groups is preferably carried out in a basic medium such as sodium hydroxide. Hydrolysis of hydroxymethyl groups etherified with hydroxyethers and hydroxyethioethers is preferably carried out in a slightly acidic medium, for example with p-toluenesulfonic acid in methanol or toluene. The thioether compounds can also be hydrolyzed in the presence of silver salts, such as silver nitrate, in a neutral medium. No additives are required for the hydrolysis of the silanyloxymethyl groups.

The starting materials may be prepared by methods known per se.

The starting materials of formula (III) wherein X _{3 represents} a cyclic iminoether group or a hydroxymethyl group etherified with a cyclic 2- or 4-hydroxyether or 2- or 4-hydroxythioether may be prepared by reacting a corresponding compound of formula (IIIa), wherein Y is -Μ-Hal or M / 2, wherein M is a metal atom in Group II of the Periodic Table and Hal is a halogen atom such as chlorine, bromine or iodine is reacted with a halide of formula R 1 -X-Hal, and optionally hydrolyzing the resulting primary product. Preferably, the starting materials of formula (IIIa) used in this reaction are prepared in situ by reacting a compound of formula (IIIb) wherein Hal represents a chlorine, bromine or iodine atom and Y1 represents a carboxylic, cyano or hydroxymethyl group. , first, the Yi group is converted to an X ₃ group and then the Hal group is reacted with a suitable metal, such as magnesium, for example to form a -MgHal Y group. Compounds of formula IIIa wherein Y is other than magnesium, such as -Cd / 2, can be prepared by reacting the corresponding halogen magnesium compounds with a salt of MHal ₂ , such as cadmium chloride. Conversion of the Yi group to said groups is carried out in the usual manner. For example, the carboxyl group is converted, for example or first, into a halocarbonyl group with thionichloride in methylene chloride. It is then reacted with a suitable aminoalkanol such as aminoisobutanol or a suitable aziridine such as 2,2-dimethylaziridine. Subsequently, acid-catalyzed ring extension-4182 938 is added to one of said iminoether groups, e.g.

It can be converted to a 4,4- or 5,5-dimethyl-4,5-dihydrooxazolyl (2) group. The cyano group may also be converted into an iminoether group, e.g. 4,4,6-trimethyl-5,6-, with an appropriate aminoalkanol or alkanediol such as 4-amino-2-methylpentan-2-ol or 2-methylpentan-2,4-diol, in acidic medium. can be converted to the dihydrooxazinyl (2) group. The hydroxymethyl group may be etherified, for example, with a chlorosilane, such as trimethylchlorosilane, pyridine, or a suitable cyclic unsaturated ether or thioether, e.g. using 4- (4-methoxy) methylhydroxymethyl-4-methoxymethyl ether as the hydroxymethyl group etherified with a cyclic 2- or 4-hydroxyether or thioether in acetone, e.g. over. Similarly, the (III) starting materials of formula I wherein X means ₃ is formyl may be prepared to a (IIIb) wherein Yj acetalized formyl group, such as a lower alkylenedioxy group or a di (lower alkyl) -alkoximetil group means, converting the Hal group into a Y group, then a R 1 -X group, and hydrolyzing the acetalized formyl group, for example, under acidic conditions.

Other starting materials of formula (III) may be prepared from the corresponding 1,2-phenylenediamines of formula (IIa) which are substituted with R 1 -X- and may optionally contain a R ₃ substituent. 1,2-Phenylenediamines can be obtained by reduction of the nitro group of the corresponding nitroaniline compounds with, for example, hydrogen in the presence of Raney nickel. The reaction is carried out in a manner similar to that described for the treatment of the above compounds with glycolic acid or a corresponding reactive derivative thereof, for example, with an acid of the formula X ₃ -COOH, for example mono- or tri-haloacetic acid, di- (lower) alkoxyacetic acid or Reaction with 5-di- (lower) alkoxymethylfuran-2-carboxylic acid or a reactive derivative thereof.

Compounds of formula (III) starting materials of formula in which X ₃ is formyl or cyano, may also be prepared by reacting a substituted 1- and 2-position, the carbocyclic ring is R -X- and optionally one R ₃ of formula benzimidazole containing a substituent is reacted with 2-chloro-1,1,2-trifluoroethane to give the 2-chloro-unsubstituted 1- (2-chloro-1,1,2-trifluoroethyl) benzimidazole in its carbocyclic moiety R1 and optionally additional substituents are reacted with an alcohol such as a lower alkanol such as ethanol in the presence of a base such as an alkali metal hydroxide such as sodium hydroxide or a hydroxylamine acid addition salt such as hydrochloride, e.g. presence. Thus, a compound of formula (III) is obtained wherein X _{3 is an} acetalized formyl group such as a di- (lower) alkoxymethyl group such as diethoxymethyl group or hydroxyiminomethyl group, and by methods known per se by hydrolyzing the formyl group X ₃ or phosphorus pentoxide. -metilfenilszulfonilkloriddal dihidratizálva, X ₃ is converted to the cyano group.

A (III) starting material, wherein X ₃ represents a cyano group may also be prepared by reacting a formula (III) compound, in which X ₃ trihalogénmetilcsoportot such triklórmetilc was swept, is treated with aqueous ammonia.

The novel compounds may also be prepared by reacting a compound of formula V wherein X _{6 is} 1-hydroxy (C 2 -C 7) alkyl or C 2 -C 7 alkanoyl or a salt thereof with X _6. reducing the group to the desired R 1 -X- and optionally converting the thus-obtained compound of general formula (I) into another compound of general formula (I) and / or optionally a salt obtained to the free compound or another and / or converting a free salt-forming compound into a salt.

Examples of X 0 groups which can be reduced to the said Ri-X group are, for example, Ri-C (= O), or Ri-CH (OH) - groups.

Reduction of the X ₆ - wherein X ₆ is a hydroxy group, such as an R-CH (OH) group of the formula in situ, as appropriate, from the group consisting of an oxo substituent, for example R-CO- group of the formula can be formed in the oxidation, or or a derivative thereof, such as a rationale such as a hydrohalic acid or a lower alkanecarboxylic acid ester thereof, by methods known per se. The reducing agent is, for example, catalytically activated hydrogen, for example hydrogen in the presence of a hydrogenation catalyst such as a platinum, palladium or nickel catalyst such as palladium on carbon, preferably in the presence of a suitable solvent or diluent such as ethanol at room temperature or during cooling or heating, for example in the range of 0-80 ° C.

The starting materials of formula (VI) can be prepared according to known methods with a suitable (IIc) chlorobenzene formula for introducing a Xe group compound such as an Rx-COHal compound or (Rico) _2O compound of formula reaction with aluminum trichloride in the presence of acylated, and the compound thus obtained (VIa) is nitrated with nitric acid-sulfuric acid mixture, and the resulting (VIb) wherein klómitrovegyületet wherein _X6 is selected from R, -C (= 0) - group of the formula with ammonia, or with an amine R ₂ NH ₂ and the resulting compound VIc is reacted under mild conditions such as hydrogen in the presence of a palladium on carbon catalyst, preferably in an inert solvent such as ethanol, optionally in the presence of hydrogen chloride and reducing at normal pressure and temperature to give compounds of formula VId, wherein X _{6 is,} for example, R 1 -CH (O H) -, with an acid of formula R-COOH, or a corresponding functional derivative thereof, e.g. condensed with a lower alkyl ester.

The compounds of formula (I) of the present invention can be converted to other compounds of formula (I) by methods known per se.

For example, in a compound of formula (I) wherein R is a carboxyl group, this group may be converted to the esterified carboxyl group by R by known methods. Such esterification processes include, for example, a C 1 -C 4 alkane, a suitable N, N-di (C 1 -C 4 alkyl) formamide acetal such as Ν, Ν-dimethylformamide diethyl acetal or N, N-dimethylformamide methosulfate, or a tri- (1- C 4 -alkyloxonium tetrafluoroborate or hexafluorophosphate, a carbonate or a pyrocarbonate such as diethyl (pyro) -calonate, or an organic sulfite or phosphite such as di (C 1-4) alkylsulfite or tri- C 4 alkyl alkyl phosphite in the presence of a suitable acidic material such as p-toluenesulfonic acid. A further esterification process is, for example, reaction with a C 1-4 alkanol in the presence of a suitable condensing agent such as a dehydrating agent such as dicyclohexylcarbodiimide.

Compounds of formula (I) containing an esterified carboxyl group may be prepared from a compound of formula (I) wherein the carboxyl group R is present in a salt form, such as an alkali metal salt, such as a sodium salt. The esterification reaction is carried out with a reactive ester of a C 1-4 alkanol such as a strong acid such as a suitable C 1-4 alkyl halide, chloride, bromide or iodide, or a di (C 1-4 alkyl) Compounds of formula (I) in which the free carboxyl group R is present in the anhydride form, preferably in the form of a halocarbonyl group such as chlorocarbonyl, a metal (C 1 -C 4) alkanolate or a C 1 -C 4 alkanol are an acid acceptor. in the presence of a base, compounds of formula (I) wherein R is an esterified carboxyl group can be prepared by reacting compounds of formula (I) containing an free carboxyl group in an anhydride with halogenating agents such as thionyl chloride wherein R is a free carboxylic acid. je below.

Compounds of formula (I) wherein R represents an esterified carboxyl group such as p-nitro, or 2,4-dinitrophenoxy or benzyloxycarbonyl by transesterification, for example with a C 1 -C 4 alkanol, optionally with a suitable transesterification catalyst , for example, by reaction with an optionally substituted alkali metal, such as sodium or potassium (C1-C4) alkanolate, to form compounds of formula (I) containing an esterified carboxyl group.

The aforementioned compounds of formula (I) wherein R represents a carboxyl group in the halide form can be prepared from compounds of formula (I) by reaction with a thionyl halide such as thionyl chloride in which R represents a carboxyl group. When R _{2 is} hydrogen, they may dimerize to compounds of formula VII. Such an intermediate can be converted, for example, with a suitable C 1 -C 4 alkanolate, for example an alkali metal such as sodium or potassium alkanolate, or a C 1 -C 4 alkanol in the presence of a mineral acid such as hydrochloric acid, wherein represents an esterified carboxyl group.

In compounds containing a carboxyl group esterified as an R group, these groups can be converted to the free carboxyl group in a conventional manner, for example by hydrolysis, usually in an alkaline medium such as water in the presence of an alkali metal or alkaline earth metal hydroxide such as potassium hydroxide.

In compounds of formula I wherein R _{2 is} hydrogen, it can be replaced with an aliphatic group by reaction with a reactive ester of a suitable C 1 -C 4 alkanol such as a halide in the presence of a base such as an alkali metal alcohol.

A C 1-4 alkoxycarbonyl group or a carboxyl group in the halide or salt form may be reduced to a hydroxymethyl group by treatment with a light metal borohydride or hydrogen in the presence of a hydrogenation catalyst. When the carboxyl group is optionally in the form of an esterified or alkali metal salt such as sodium, the reduction is preferably carried out with a light metal hydride such as borane, e.g. Halogen carbonyl groups such as chlorocarbonyl are preferably reduced with hydrogen in the presence of a palladium catalyst, barium sulfate is preferably used as the catalyst support and a sulfur-containing co-catalyst such as thiourea is added if necessary.

The hydroxymethyl group R can be oxidized to the carboxyl group and the etherified hydroxymethyl group R to the esterified carboxyl group. The oxidation is carried out according to methods known per se, for example by reaction with a heavy metal compound with oxidizing properties. When starting materials are compounds of formula I wherein R is hydroxymethyl, the oxidizing agent preferably contains a chromium-VI or manganese-VII-containing oxidant such as chromium trioxide or, in particular, potassium permanganate. A manganese-IV compound such as manganese dioxide may also be used as the oxidizing agent for the oxidation of etherified hydroxymethyl group R. The oxidation reactions are preferably carried out in the presence of a suitable solvent or diluent, such as acetone or pyridine, or preferably in an aqueous mixture thereof, if necessary under cooling or heating, for example at temperatures from 0 ° C to 80 ° C.

The resulting free salt-forming compounds of formula (I) may be converted into salts according to methods known per se. For example, the acids may be converted to a salt with a base or a suitable salt of a carboxylic acid and the bases reacted with a mineral acid, usually in the presence of a solvent or diluent.

The salts formed may be converted into the free compounds by methods known per se, for example by reaction with an acidic reagent such as a mineral acid.

The novel compounds and their salts may also be obtained in the form of their hydrates or may contain the solvent used for their crystallization.

Due to the close association between the free form and the salt form of the novel compounds, the term "free compounds and their salts" as used hereinbefore and hereinafter is understood to mean, preferably, the corresponding salts or free compounds.

-6182 938

The process of the invention preferably utilizes starting materials that lead to the compounds mentioned as particularly valuable in the introduction.

The present invention also relates to a process for the preparation of a pharmaceutical composition comprising the novel compounds of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the present invention may be administered enterally, for example, orally, nasally or rectally, as well as in the mammal, topically or topically, and contain the active pharmaceutical ingredient alone or in combination with other pharmaceutically acceptable carriers. The dosage of the active ingredient depends on the type, age, individual characteristics of the warm-blooded animal and the mode of administration.

The novel pharmaceutical compositions contain up to about 95%, preferably from about 5% to about 90%, of the active ingredient. The pharmaceutical compositions of the present invention are in the form of a dragee, tablet, capsule or suppository, as well as an ampoule, and for topical and topical (e.g., for insufflation) administration.

The pharmaceutical compositions of the present invention may be prepared by methods known per se, for example, by conventional mixing, granulating, dragee-making, dissolving or lyophilizing processes. For example, pharmaceutical compositions for oral administration may be prepared by combining the active ingredient with a solid carrier, granulating the resulting mixture, and preparing the mixture or granules, if desired or necessary, in the form of tablets or dragee cores.

Suitable carriers are, in particular, fillers such as sugars such as lactose, sucrose, mannitol or sorbitol, cellulose formulations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and binders such as starch, and potato starch, gelatin, tragacanth, methylcellulose and / or, if desired, stretching agents such as the aforementioned starches, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid and salts thereof such as sodium alginate. Excipients are, in particular, flow-regulating and tackifying agents, for example silica, talc, stearic acid and its salts, such as magnesium and calcium stearate and / or polyethylene glycol. The dragees may have a suitable, optionally gastric-resistant coating, which may include, but is not limited to, concentrated sugar solutions, optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, and lacquer solutions containing suitable organic solvents or solvent mixtures. solutions of suitable cellulose formulations such as acetylcellulose phthalate or hydroxypropylmethylcellulose fllatate. Tablets or dragee coatings may be prepared by the addition of coloring agents or pigments to identify or recognize dragees and tablets containing various amounts of the active ingredient.

Further dosage forms suitable for oral administration include a gelatin openable capsule and a closed capsule made of gelatin with a plasticizer such as glycerol or sorbitol. Opening capsules may contain the active ingredient in the form of granules with excipients such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and optionally stabilizers. Soft capsules preferably contain the active ingredient dissolved or suspended in a suitable liquid such as fatty oils, paraffin oil or liquid polyethylene glycols, optionally with the addition of stabilizers.

Suitable formulations for rectal administration are, for example, suppositories consisting of a mixture of the active ingredient and a suppository base. Suitable suppository bases are natural and synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols and longer-chain alkanols. Gelatin suppositories for rectal administration which contain the active ingredient together with a ciliary mass are suitable. As suppository bases liquid triglycerides, polyethylene glycols and paraffin hydrocarbons can be mentioned.

Suitable formulations for parenteral administration include aqueous solutions such as an aqueous solution of an active ingredient, such as a water-soluble salt, and suspensions of the active ingredient, for example, a suitable oily injection, for use in the preparation of lyophilic solvents such as fatty oils, for example, jtiloleate or triglycerides. Aqueous injection suspensions of the active ingredient, which may contain viscosity enhancing agents such as sodium carboxymethylcellulose, sorbitol and / or iextran and optionally stabilizing agents, are also suitable for parenteral administration.

Formulations suitable for nasal or buccal administration of the respiratory tract include, for example, aerosols or sprays, which are capable of delivering the active ingredient in powder form or as droplets in solution or suspension. Formulations for distribution in powder form generally contain, in addition to the active ingredient, a liquid propellant boiling below room temperature. If desired, the compositions may also contain carriers, such as liquid or solid nonionic or anionic surfactants and / or solid diluents. Formulations in which the active ingredient is present as a solution further comprise a suitable propellant and, if desired, an additional solvent and / or stabilizer. Instead of the propellant, pressurized air may be used, which may be produced arbitrarily by a suitable pressure relief device.

Pharmaceutical formulations for topical and topical application include skin elixirs and creams containing a liquid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (preferably containing a preservative), eye drops suitable for treating the eye. the active ingredient in the form of an aqueous or oily solution, and serum ointments, preferably in sterile form, nasal powders for nasal aspiration, and nasal drops containing the active ingredient in aqueous or oily solution for topical administration to the mouth. suitable lozenges "bonbons" containing the active ingredient in a mass generally of sugar and gum arabic or tragacanth, to which flavoring agents may be added, and lozenges which contain the active ingredient 7182 938 in an inert mass such as gelatin and glycerol or of sugar and gum arabic.

The present invention also relates to a process for the preparation of pharmaceutical compositions containing the compounds of the formula I and their salts, in particular anti-allergic formulations. The daily dose is 70 to 7000 mg / kg body weight, depending on the dosage form.

The process of the present invention will now be described in more detail, without, however, being limited to the scope of the invention. Temperatures are given in degrees Celsius.

The process of the present invention achieves a yield of 20-95%, which can be easily increased by optimizing the process parameters.

Example 1 To g of crude 4-butyl-1,2-phenylene diamine is added 20.8 g of getoxyacetic acid and then heated at 130 ° for 90 minutes. After cooling, the reaction mixture was dissolved in ethyl acetate, washed with sodium bicarbonate solution, three times with water, dried over sodium sulfate, filtered and the filtrate was finally evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (600 g), eluting with chloroform. After trituration of a small amount of eluate, 2-ethoxymethyl-5-butylbenzimidazole is obtained in the main fraction.

The starting material can be prepared as follows:

To a solution of 18.3 g of 4-chlorobutyrophenone in 100 ml of sulfuric acid at -20 ° C is added a mixture of 40 ml of sulfuric acid and 21 ml of fuming nitric acid over 5 minutes at -20 ° to -15 ° to obtain a clear solution. After stirring for 45 minutes at -15 ° to -10 °, the reaction mixture is poured onto 1000 g of ice, filtered, washed with water and the filtrate is dissolved in chloroform. The chloroform solution was washed with saturated sodium bicarbonate solution, then twice with water, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was digested with 25 ml of methanol. There is thus obtained 4-chloro-3-nitrobutyrophenone, m.p. 52-54 ° C.

A solution of 22.8 g of 4-chloro-3-nitrobutyrophenone in 300 ml of ethanol is autoclaved with 50 g of ammonia. The reaction mixture was heated at 100 ° C for 10 hours and then, after cooling to room temperature, evaporated to dryness under reduced pressure. The reaction mixture was heated with 80 ml of 2N hydrochloric acid for 1 hour at 80-90 ° C, then cooled to 15 ° with ice, finally filtered and washed with water. The filtrate was dissolved in methylene chloride (1000 mL), dried over sodium sulfate and evaporated. Then petroleum ether (b.p. 60-80 ° C) was added and the methylene chloride was completely evaporated. The 4-amino-3-nitrobutyrophenone, which is crystalline, is filtered off and dried under reduced pressure. The product thus obtained melts at 128-129 °.

19.9 g of 4-amino-3-nitrobutyrophenone are dissolved in a mixture of about 300 ml of ethanol and 15 ml of 12.8% hydrochloric acid ethanol, and after addition of 2 g of 5% palladium on carbon, the mixture is hydrolyzed at 30-35 °. After uptake of hydrogen (11.2 L), the hydrogenation is complete, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue was dissolved in ether and the ether solution was dried over sodium sulfate, filtered and evaporated.

There is thus obtained 4-butyl-1,2-phenylenediamine which can be used without further purification.

Example 2

Dissolve 4.65 g of 2-ethoxymethyl-5-butylbenzimidazole in 100 ml of acetone and 5 ml of water, add 5 g of potassium permanganate and reflux for 6 hours. During the course of refluxing, 1-1 g of potassium permanganate (10 g) was added at intervals of about half an hour, which was filtered hot after 6 hours, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, ice was added and the mixture was extracted with a slightly acidic sodium bicarbonate solution. The aqueous phase was separated and washed twice with ethyl acetate. The organic layers were combined, washed twice with water, dried over sodium sulfate, filtered and evaporated. The ethyl ester of 5-butylbenzimidazole-2-carboxylic acid is thus obtained in the form of a yellowish oily substance which crystallizes on standing, m.p. 129-130 °.

Example 3 To a solution of 5-butyl-6-methyl-2-methylaminoaniline bis hydrochloride (150 g) in 2N hydrochloric acid (150 mL) was added 15.6 g of ethoxyacetic acid and refluxed for 5 hours. After cooling, ice was added, the pH was made alkaline with concentrated sodium hydroxide solution and extracted three times with ethyl acetate. The extract was washed twice with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. Thus, 2-ethoxymethyl-5-butyl-1,6-dimethylbenzimidazole is obtained.

The starting material can be prepared as follows:

To a yellow slurry of 900 ml of 3-chlorotoluene and 367.5 g of finely powdered aluminum chloride was added 266 g of butyric acid chloride per hour. During the instillation, chlorine gas evolves. The reaction is exothermic, allowing the temperature to rise to 70 °. Meanwhile, the aluminum chloride dissolves. After the addition of the butyric acid chloride, the temperature was maintained at 70 ° until gas evolution ceased (about 45 minutes). The reaction mixture was cooled to 50 ° C and poured onto 2500 g of ice.

After extraction with ethyl acetate, the organic extract was washed twice with 2N hydrochloric acid, once with saturated aqueous sodium chloride solution, twice with 2N aqueous sodium carbonate solution and once more with saturated aqueous sodium chloride solution. The resulting brown oily residue is distilled to give a mixture of 4-chloro-2-methylbutyrophenone and 2-chloro-4-methylbutyrophenone. The mixture boils at 160-164 ° C at 14 mm Hg.

1275 ml of concentrated sulfuric acid were cooled to -20 ° to -25 ° C with carbon dioxide-chloroform and, with vigorous stirring, 285.5 g of 4-chloro-2-methylbutyrophenone and 2-chloro-4-methyl butyrophenone-containing mixture is added dropwise. The resulting solution was treated at -20 ° to 25 ° for 30 minutes

After stirring for a further 15 minutes, the temperature was allowed to rise to -15 °. The reaction mixture was poured into ice water (8000 mL) and the oily residue was extracted with chloroform. The organic extract was washed with aqueous sodium bicarbonate 8182 938 and water, dried over sodium sulfate and evaporated. The residue was dissolved in two volumes of spinning methanol and allowed to stand for 16 hours. The crystalline residue was filtered, washed with cold water and dried at room temperature under 100 mmHg for 18 hours. There was thus obtained 4-chloro-2-methyl-5-nitrobutyrophenone, m.p. 71-72 °.

A mixture of 24.1 g of 4-chloro-2-methyl-5-nitrobutyrophenone in 250 ml of 33% ethanol in methylamine is allowed to stand at room temperature while the crystalline starting material is dissolved. The resulting solution is pale yellow. The reaction is mildly exothermic, so the reaction mixture is cooled with a water bath to prevent the methylamine from becoming more volatile. After 20 minutes, a clear solution is obtained, from which precipitation begins. The reaction mixture was allowed to stand at room temperature for 16 hours and then concentrated to dryness under reduced pressure. Diethyl ether, ice and sodium carbonate (about 1000 ml) were added to the residue, shaken and the organic layer was separated. This was washed twice with water and the aqueous phase re-extracted with diethyl ether. The combined organic solutions were dried over sodium sulfate, filtered, and concentrated to a volume of about 300 mL, diluted with 100 mL of petroleum ether, and cooled. The yellow crystalline 2-methyl-4-methylamino-5-nitrobutyrophenone is precipitated, which is filtered off, washed with petroleum ether and dried in the open air. M.p. 107-1080.

Conversion of 4-chloro-2-methyl-5-nitrobutyrophenone to 4-amino-2-methyl-5-methylaminobutyrophenone can be accomplished as follows (starting material may also be a mixture of crude muscle):

241 g of crude chloromethyl nitrobutyrophenone (containing about 75% of 4-chloro-2-methyl-5-nitrobutyrophenone) are suspended in 1200 ml of ethanol and 1200 ml of 33% methylamine solution are added. The reaction is exothermic and therefore dissolution occurs. The reaction mixture was allowed to stand for two days, then evaporated to dryness under reduced pressure, 600 ml of 2N hydrochloric acid was added and the mixture was heated at 80-90 ° C for 1 hour. The reaction mixture was cooled to about 15 ° with ice and the crystalline precipitate formed was filtered off, washed with water and dissolved in methylene chloride. The solution was dried over sodium sulfate, filtered, and the methylene chloride was evaporated under reduced pressure with cyclohexane and petroleum ether (60-80 ° C). The reaction mixture was cooled and the precipitated 2-methyl-4-methylamino-5-nitrobutyrophenone was filtered. Melting point 105-107 °.

Dissolve 23.6 g of 2-methyl-4-methylamino-5-nitrobutyrophenone in 240 ml of ethanol and 57 ml of 12.8% hydrochloric acid in ethanol, add 7.4 g of 5% palladium-on-carbon catalyst, and Hydrogenate at 30-35 °. The hydrogenation was discontinued after taking up 11.6 L of hydrogen, the catalyst was filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was suspended in toluene. The water is removed by azeotropic distillation. The resulting crystalline 4-butyl-6-methyl-2-methylaminoaniline bis hydrochloride was filtered. The product melts above 160 °.

Example 4

Crude 2-ethoxymethyl-5-butyl-1,6-dimethylbenzimidazole (27.0 g) was reacted with 50 g of potassium permanganate in the same manner as in Example 2 to give ethyl 5-butyl-1,6-dimethylbenzimidazole-2-carboxylic acid. The product melts at 56-57 ° C.

EXAMPLE 5 Crude 4-butyl-2-methylaminoaniline bis hydrochloride (g) was dissolved in 2N hydrochloric acid (200 mL), and ethoxyacetic acid (23.4 g) was added to the solution and refluxed for 2 hours. sodium hydroxide was added and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed twice with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from petroleum ether 51. There is thus obtained 2-ethoxymethyl-5-butyl-1-methylbenzimidazole, m.p. 55-58 ° C.

The starting material can be prepared in a similar manner to the procedure described in Example 3, using chlorobenzene, 4-chlorobutyrophenone and 4-chloro-3-nitrobutyrophenone as intermediates.

Example 6

8.9 g of 2-ethoxymethyl-5-butyl-1-methylbenzimidazole were seeded in a mixture of 180 ml of acetone and 9 ml of water, 10 g of potassium permanganate was added and stirred for 2 hours at room temperature. It is then refluxed for 7 hours, with 2 g of potassium permanganate (2 g, 22 g total) being added at intervals of about half an hour. After cooling, it is filtered through diatomaceous earth, the filtrate is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate. The solution was extracted with sodium hydroxide carbonate solution, washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel. The eluent was a mixture of chloroform, petroleum ether and ethyl acetate in the same amount. so it is

The ethyl ester of 5-butyl-1-methylbenzimidazole-2-carboxylic acid is obtained, m.p. 49-50 ° C.

EXAMPLE 7 Ethyl 5-butyryl-6-methylbenzimidazole-2-carboxylic acid ethyl ester (g) was dissolved in ethanol (140 ml) and hydrogenated at 20-50 ° C after addition of 3.5 g of 5% palladium on carbon. The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel, eluting with a 1: 1 mixture of methylene chloride and ethyl acetate. This gives 5-butyl-6-methyl-benzimidazole-2-carboxylic acid ethyl ester, m.p. 123-125 °.

The breeding material can be prepared as follows:

4-Amino-2-methyl-5-nitrobutyrophenone (22.2 g) was dissolved in methanol (230 mL), Raney nickel (2 g) was added and hydrogenated at 15-25 ° C under normal pressure until 4.9 L of hydrogen was taken up. Ethoxyacetic acid (20.8 g) was added under nitrogen, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure and heated at 130 ° for 3 hours. After cooling, it is dissolved in 200 ml of 2N hydrochloric acid, washed twice with hydrochloric acid and then with ethyl acetate, and the solution is alkalinized cold by addition of sodium carbonate, extracted twice with ethyl acetate, and the combined extracts are dried over sodium sulfate and concentrated by chromatography on silica gel. Elution is carried out first with chloroform, collecting about 1200 ml of the pre-eluate and eluting with 1200 ml of 24: 1 chloroform-ethanol to give 2-ethoxymethyl-5-butyryl-6-methyl-benzimidazole.

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To a solution of 18.9 g of 2-ethoxymethyl-5-butyryl-6-methylbenzimidazole in 380 ml of acetone, 9.5 ml of pyridine and 5.7 ml of water was cooled to 10 ° C while stirring was added 15 g of potassium permanganate. The reaction mixture was stirred for 1 hour under ice-cooling, for an additional 40 hours at room temperature, filtered, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed successively with pH 6 buffered sodium bicarbonate solution and twice with water, dried over sodium sulfate and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), allowed to stand overnight, and the crystallized ethyl 5-butyryl-6-methylbenzimidazole-2-carboxylic acid was collected. The product melts at 137-139 °. Further quantities of product can be recovered from the mother liquor. 129-132 °. After recrystallization from methylene chloride / ethyl acetate, the melting point rises to 146-147 °.

Example 8

In a similar manner to that described in Example 1, 25 g of 5-butyl-6-methyl-2-methylaminoaniline bis hydrochloride was prepared by reacting 11.5 g of glycolic acid with 2-hydroxymethyl-5-butyl-1,6-dimethylbenzimidazole. in the form of a flowable oily substance which is converted to a crystalline product melting at 142-145 °.

Example 9

In the same manner as in Example 2, 8.5 g of 2-hydroxymethyl-5-butyl-1,6-dimethylbenzimidazole can be prepared by oxidation of 24 g of potassium permanganate in 200 ml of 95% aqueous acetone to give 5-butyl-1,6-dimethyl benzimidazole-2-carboxylic acid, m.p. 85 ° (dec.).

Example 10

A 2% aqueous solution of 5 (6) -methyl-benzimidazole-2-carboxylic acid sodium salt for inhalation can be prepared as follows:

composition (per 100 ml):

Sodium salt of 5 (6) -methylbenzimidazole-2-carboxylic acid Sodium salt of ethylenediaminetetraacetic acid (2.000 g) 0.010 g (stabilizer) benzalkonium chloride (preservative) 0.01 g of distilled water to make up 100 ml

The sodium salt of 5 (6) -methylbenzimidazole-2-carboxylic acid is dissolved in freshly distilled water and ethylenediaminetetraacetic acid disodium salt and benzalkonium chloride (alkyl dimethylbenzylchloride containing 8-18 carbon atoms in the alkyl group) are added. After complete dissolution of the components, the resulting solution is made up to 100 ml with water, filled and sealed.

By the same method, a 2% aqueous solution of the 5,6-dimethylbenzimidazole-2-carboxylic acid sodium salt or the 5-butyl-1,6-dimethylbenzimidazole-2-carboxylic acid sodium salt for inhalation can be prepared.

example

Inhalable capsules containing 0.025 g of 5-butyl-1,6-dimethylbenzimidazole-2-carboxylic acid ethyl ester can be prepared as follows:

composition (per 1000 capsules):

butyl-1,6-dimethylbenzimidazole-2-carboxylic acid ethyl ester 25.00 g

Lactose (Ground) 25.00 g

The 5-butyl-1,6-dimethylbenzimidazole-2-carboxylic acid ethyl ester and the freshly ground lactose are mixed well. The resulting powder was sieved and filled in 0.05 g portions into gelatin capsules.

In the same way, the following compounds (containing 0.325-0.025 g of the active ingredient) can be made into an insufflation capsule:

2-ethoxymethyl-5-butyl-1-methyl-benzimidazole, 2-oxymethyl-5-butyl-1,6-dimethylbenzimidazole, 2-ethoxymethyl-5-butylbenzimidazole,

5-butyl-benzimidazole-2-carboxylic acid ethyl ester,

5-Butyl-1-methyl-benzimidazole-2-carboxylic acid ethyl ester and

5-Butyl-6-methyl-benzimidazole-2-carboxylic acid ethyl ester.

Example 12

Each tablet containing 100 mg of butyl-1,6-dimethylbenzimidazole-2-carboxylic acid ethyl ester (active ingredient) can be prepared in the following composition:

Composition Per tablet

Ethyl 5-butyl-1,6-dimethylbenzimidazole-2-carboxylic acid 100 mg

Lactose 50 mg

Wheat starch 73 mg

Colloidal silica 13 mg

Talcum 12 mg

Magnesium stearate 2 mg

250 mg

manufacture:

The active ingredient is mixed with the milk sugar, a portion of the wheat starch and colloidal silica and sieved through a sieve. The remainder of the wheat starch is greased with 5 times water in a water bath, and the powder mixture is kneaded with this powder until a slightly plastic mass is obtained. This mass is then broken through a 3 mm mesh sieve, then dried and sieved again through the dried granulate. It is then mixed with the remaining wheat starch, talc and magnesium stearate. The resulting mixture is compressed into 250 mg tablets with a score line.

Similarly, tablets containing from 00 to 100 mg of the following compounds or their pharmaceutically acceptable salts, for example base salts with carboxylic acids, for example sodium salts, may be prepared:

butyl-6-methylbenzimidate ol-2-carboxylic acid ethyl ester, (6) -butylbenzimidazole-2-carboxylic acid ethyl ester, 2-ethoxymethyl-5-butyl-1-methylbenzimidazole 2-ethoxymethyl-5-butyl-1,6-dimethylbenzimidazole, 2-ethoxymethyl-5-butylbenzimidazole and 5-butyl-1-methylbenzimidazole-2-carboxylic acid ethyl ester.

Example 13

Similarly to the procedures described in Examples 11 and 12, the following pharmaceutical compositions can be prepared from the following compounds:

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2-hydroxymethyl-5-butyl-1,6-dimethylbenzimidazole, 5 (6) -methylbenzimidazole-2-carboxylic acid,

5.6-dimethylbenzimidazole-2-carboxylic acid,

5-Butyl-1,6-dimethyl-benzimidazole is ol-2-arbonic acid, 2-hydroxymethyl-5 (6) -methyl-benzimidazole, or

5.6-Dimethyl-2-hydroxymethyl-benzimidazole.

The listed compounds may also be used as active compounds in the form of their salts, for example their sodium salts.

Example 14

In analogy to Example 2, 8.5 g of 2-hydroxymethyl-5-butyl-1,6-dimethylbenzimidazole are oxidized with 24 g of potassium permanganate in 200 ml of 95% aqueous acetone to give 5-butyl-1,6-dimethyl benzimidazole-2-carboxylic acid. The starting material is obtained by reaction of 25 g of 5-butyl-6-methyl-2-methylaminoaniline bis (hydrochloride) with 11.5 g of glycolic acid as a viscous oil.

Example 15

Dissolve 0.1 g of 1,6-dimethyl-5-butyl-2-trichloromethylbenzimidazole in 10 ml of 2N sodium hydroxide solution and 20 ml of dioxane and allow to stand overnight at room temperature. It is then evaporated to dryness under reduced pressure, taken up in water and the insoluble matter is removed by filtration. The filtrate was acidified with acetic acid. 1,6-Dimethyl-5-butyl-benzimidazole-2-carboxylic acid is precipitated, which is filtered off and dried at room temperature. Melting point above 106 ° (dec.).

The starting material was prepared as follows:

A solution of 4.1 g of 3-butyl 4-methyl-6-methylaminoaniline in 25 ml of methanol and 4 ml of ethereal hydrochloric acid (5n) is stirred at room temperature with 3.6 g of trichloroacetiminomethyl ether and allowed to stand for 20 hours. The reaction mixture was cooled to 5 ° and the precipitated ammonium chloride was filtered off. The filtrate was concentrated under reduced pressure. evaporate to dryness and purify the residue by chromatography. The product was pure 1,6-dimethyl-5-butyl-2-trichloromethylbenzimidazole.

Example 16

2-Acetoxymethyl-5-butyl-1,6-dimethylbenzimidazole (2.9 g) is dissolved in ethanol (30 ml), mixed with 10 ml of 2N sodium hydroxide solution and stirred for 1 hour at room temperature. The ethanol was removed under reduced pressure, the precipitated 5-butyl-1,6-dimethylbenzimidazole-2-methanol was filtered off and recrystallized from ethyl acetate. M.p. 142-145 °.

The starting material is e.g. can be prepared as follows:

12.1 g of 2-butyl-5-chloro-4-nitrotoluene are dissolved in 100 ml of ethanol, and the solution is mixed with 5.0 g of N-methylethylamine and refluxed for 3 hours. It is then evaporated to dryness under reduced pressure, taken up in methylene chloride, washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. The resulting 4-butyl-5-methyl-2-nitro-N-ethyl-N-methylaniline has a melting point of 57-58 °. 4-Butyl-5-methyl-2-nitro-N-ethyl-N-methylaniline (2.64 g) was dissolved in acetic anhydride (10 ml), mixed with zinc chloride (1.4 g) and heated to reflux for 3 hours. The reaction mixture was allowed to cool, poured into 50 ml of ice-cold sodium acetate solution, extracted with chloroform, dried over sodium sulfate, evaporated and recrystallized from ethyl acetate / petroleum ether. 2-Acetoxymethyl-5-butyl-1,6-dimethylbenzimidazole is obtained.

Example 17

Dissolve 2.6 g of 5-butyl-2-chloromethyl-1,6-dimethylbenzimidazole in 100 ml of ethanol, add 50 ml of 4N sodium acetate solution and reflux for 8 hours. The reaction mixture was allowed to cool, the ethanol was removed under reduced pressure, extracted with methylene chloride, chromatographed on silica gel and crystallized from ethyl acetate. The received

5-Butyl-1,6-dimethylbenzimidazole-methanol m.p. 142-145.

The starting material can be prepared as follows:

241 g of crude 3-butyl-6-chloro-4-methylnitrobenzene are suspended in 1200 ml of ethanol and the suspension is mixed with 1200 ml of 22% methylamine solution; dissolution occurs during exothermic reaction. After standing for 2 days, evaporate to dryness under reduced pressure, mix with 600 ml of 2N hydrochloric acid solution and heat to 80-90 ° for 1 hour. Adding ice for approx. After cooling to 15 °, the crystalline precipitate is filtered off with suction, washed with water and taken up in methylene chloride. It is then dried over sodium sulfate, the methylene chloride is evaporated under reduced pressure, finally by adding cyclohexane and petroleum ether (boiling range 60-80 ° C), cooled and the 3-butyl-4-methyl-6-methylaminonitrobenzene is filtered off with suction.

A solution of 59.1 g of the product obtained is dissolved in 1000 ml of methanol, mixed with 6 g of Raney nickel and hydrogenated at 20-25 ° under normal pressure. After uptake of hydrogen (16.8 L), the hydrogenation was discontinued, warmed slightly to dissolve the precipitated product, the catalyst was removed by filtration, mixed with 50 ml of concentrated hydrochloric acid, cooled to 3 ° and filtered off with suction. The resulting 3-butyl-6-chloro-2-methylaminoaniline hydrochloride melts above 180 ° (dec.).

A mixture of 2.06 g of the product obtained and 1.9 g of chloroacetic acid was added to 40 ml of 6N hydrochloric acid solution and refluxed for 5 hours. The reaction mixture was allowed to cool, diluted with water (20 mL), neutralized with sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed twice with water, dried, filtered and evaporated. 5-Butyl-2-chloromethyl-1,6-dimethylbenzimidazole is obtained.

Example 18

0.8 g of sodium is dissolved in 150 ml of ethanol. 10.0 g of 2-ethoxymethyl-5-butylbenzimidazole in 500 ml of ethanol are then added, followed by stirring at room temperature for 30 minutes, and a solution of 6.0 g of methyl iodide in 75 ml of ethanol is added. The reaction mixture was stirred at room temperature for 20 hours, evaporated to dryness, taken up in ethyl acetate, washed with a little water, dried over sodium sulfate and evaporated again under reduced pressure. The crystalline residue was recrystallized from ethyl acetate. The resulting 2-ethoxymethyl-5-butyl-1-methylbenzimidazole has a melting point of 55-58 °.

The starting material is e.g. can be prepared as follows:

A solution of 18.3 g of 4-chlorobutyrophenone in 100 ml of sulfuric acid at -20 ° C is stirred for 5 minutes at -20 to 15 ° with a mixture of 40 ml of sulfuric acid and 21 ml of fuming nitric acid to form a solution.

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At -15 ° to -10 ° for 45 minutes,

It is poured onto 1000 g of ice, filtered off with suction, washed with water and taken up in chloroform, washed with saturated sodium bicarbonate solution and washed twice with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was digested with 25 ml of methanol. The resulting 4-chloro-3-nitrobutyrophenone melts at 52-54 ° C.

A solution of 22.8 g of 4-chloro-3-nitrobutyrophenone in 300 ml of ethanol in an autoclave was charged with 300 g of ammonia. The reaction mixture was heated to 100 for 10 hours, evaporated to dryness under reduced pressure after cooling to room temperature, warmed to 80-90 ° with 200 ml of 2N hydrochloric acid for 1 hour, cooled to 15 ° with ice, filtered off with suction and rinsed with water. The aspirated material was taken up in 1000 mL of methylene chloride, dried over sodium sulfate, evaporated, mixed with petroleum ether (boiling range 60-80 ° C) and the methylene chloride was completely evaporated. The crystalline precipitated 4-amino-3-nitrobutyrophenone is filtered off with suction and dried in vacuo. Melting point 128-129 °.

19.9 g of 4-amino-3-nitrobutyrophenone is ca. 300 ml of ethanol and 15 ml of 12.8% hydrochloric acid in ethanol were added and after addition of 5% palladium on carbon (2 g), ca. Hydrogenate at 30-35 ° C up to 11.2 liters of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was taken up in ether, dried over sodium sulfate and evaporated. The resulting 4-butyl-1,2-phenylenediamine was reacted further without further purification.

Crude 4-butyl-1,2-phenylene diamine (g) was mixed with 20.8 g of ethoxyacetic acid and the reaction mixture was heated to 130 ° for 90 minutes. The mixture was allowed to cool, taken up in ethyl acetate, washed three times with sodium bicarbonate solution and water, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed on 600 g of silica gel with chloroform as the eluent. After a few pre-fractions, the main fraction gives 2-ethoxymethyl-5-butylbenzimidazole.

Analogously, 2-ethoxymethyl-5-butyl-1,6-dimethylbenzimidazole, 5-butyl-1,6-dimethylbenzimidazole-2-carboxylic acid ethyl ester, m.p. yl-1-methyl-b-enzimidazole-2-carboxylic acid ethyl ester, m.p. 49-50 °, 2-hydroxymethyl-5-butyl-1,6-dimethylbenzimidazole and 5-butyl-1,6-dimethyl benzimidazole-2-carboxylic acid.

Example 19

A solution of 5 g of crude 5-butyl-1,6-dimethylbenzimidazole-2-carboxaldehyde in a mixture of 30 ml of ethanol and 20 ml of hexamethylphosphoric triamide in 1 g of sodium borohydride in 50 ml of ethanol is cooled to 10 ° C and stirred under nitrogen. After 1 hour at room temperature and 1 hour under reflux. It was then decomposed with 10 ml of water, concentrated under reduced pressure and recrystallized from ethyl acetate. 5-Butyl-1,6-dimethylbenzimidazole-2-methanol is obtained.

The starting material is e.g. can be prepared as follows:

A mixture of 2-chloro-4-methyl-5-butylnitrobenzene (24.1 g) and methylamine in ethanol (250 ml, 33%) was allowed to stand at room temperature; the crystalline starting material slowly dissolves, thereby turning yellowish. The reaction is slightly exothermic, so it is cooled in a water bath to prevent strong methylamine head formation. After 20 minutes it completely dissolves, after which time precipitation begins. Allow to stand for 16 hours at room temperature and then evaporate to dryness under reduced pressure. The residue was stirred with diethyl ether (about 1C00 mL), ice and sodium carbonate, shaken and the organic layer was separated. This layer was washed twice with water and the aqueous solution was backwashed with diethyl ether. The combined organic solutions were dried over sodium sulfate, filtered over ca. It is concentrated to a volume of 300 ml, diluted with 100 ml of petroleum ether and cooled. The yellow crystalline 5-butyl-4-methyl-2-methylaminonitrobenzene precipitates, is filtered off, washed with petroleum ether and air dried.

A solution of the product (4.7 g) in dioxane (40 ml) was diluted with water and refluxed and treated with a solution of sodium dithionite (16 g) in water (70 ml) for 10 minutes, after which the yellow color of the reaction mixture faded. Reflux for a further 15 minutes at about pH approx. It is adjusted to 3 by the addition of 30 ml of 6N hydrochloric acid solution and refluxed for 15 minutes, during which time the sulfur dioxide is removed. The pH of the reaction mixture was adjusted to 2, ca. After refluxing for 15 minutes, the dioxane was evaporated under reduced pressure. The remaining solution precipitates the hydrochloride of 5 amino-2-methyl-4-methylaminobutyrophenone; After cooling, the suspension is made basic with concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic extracts were washed twice with water, dried, filtered and evaporated. 5-Butyl-4-methyl-2-methylanananiline is obtained.

6.6 g of the resulting material are mixed with 2.3 g of g'oxylic acid and heated to 120 ° for 2 hours. It is then taken up in 100 ml of ether, washed with 10 ml of 2N sodium hydroxide solution, dried over sodium sulphate and evaporated to dryness. The resulting 5-butyl-1,6-dimethylbenzimidazole carboxaldehyde can be further reacted in crude form.

Example 20

5-Butyl-1,6-dimethylbenzimidazole-2-carboxylic acid (0.8 g) was dissolved in ethanol (30 mL) at 46 ° C and stirred dropwise with NaOH (3.26 mL) in ethanol. The reaction mixture was concentrated to 15 ml by boiling and then allowed to cool slowly. Does it start at about 40 °? crystals precipitated in the form of luminous plates. Allow to stand overnight at 10-15 ° C, aspirate and dry under reduced pressure. The resulting bright plates of sodium 5-butyl-1,6-dimethylbenzimidazole-2-carboxylate melt at 270-275 ° (with decomposition).

EXAMPLE 21 Ethyl 5- (1-hydroxybutyl) -6-methylbenzimidazole-2-carboxylic acid ethyl ester (g) was dissolved in ethanol (200 ml), stirred with 3 g of carbon containing 5% palladium and hydrogenated at 20-30 ° C for 1 hour. . The catalyst is filtered off and the filtrate is evaporated to dryness and chromatographed on silica gel with methylene chloride / ethyl acetate (1: 1). This gives 5-butyl-6-methylbenzimidazole-2-carboxylic acid ethyl ester, m.p. 24-125 ° C.

For example, the starting material may be prepared as follows.

Ethyl 5-butyryl-6-methylbenzimidazole-2-carboxylic acid ethyl ester was dissolved in ethanol (200 ml) and stirred vigorously for 30 minutes.

-12182 938 is added dropwise with stirring to a suspension of 1.0 g of sodium borohydride in 50 ml of ethanol. After stirring for 1 hour at room temperature, acetone (5 ml) was added, stirred for an additional 30 minutes, evaporated to dryness under reduced pressure, and the residue was chromatographed on silica gel with methylene chloride / ethyl acetate (1: 1) and recrystallized from methylene chloride. This gave ethyl 5- (1-hydroxybutyl) -6-methylbenzimidazole-2-carboxylic acid, m.p. 82 ° C (dec).

Claims (16)

Patent claims A process for the preparation of a new benzimidazole-2 derivative of formula (I): wherein: R is a carboxyl group optionally esterified with up to C4 alkanol or a hydroxymethyl group optionally etherified with up to C4 alkanol, R 1 is C 1-6 alkyl, R ₂ and R ₃ are hydrogen or C 1-4 alkyl and X is a methylene group - and salts thereof, characterized in that a) a compound of formula IIa wherein: R 1, X, R _2, and R ₃ are as defined above, with an acid of formula IIb wherein R is as defined above, or a corresponding functional derivative thereof, or b) cyclizing a compound of formula II wherein one of the substituents X ₁ and X ₂ is a -C (= O) -R group in which R is as defined above and the other is hydrogen; or a salt thereof; or c) in a compound of Formula III wherein R 1, X, R ₂ and R ₃ are as defined above, X _{3 is a} formyl group, a carboxyl group which is functionally modified other than R 4, or an esterified or C 1-4 alkoxy group; etherified hydroxymethyl group other than methyl - the formyl group is oxidized to the carboxyl group or the functionally converted carboxyl group is solvolized to the carboxyl group or the esterified carboxyl group R or the esterified or etherified hydroxymethyl group is hydrolyzed, or d) in a compound of formula V wherein R 1, R ₂ and R ₃ are as defined above and X _{6 is} 1-hydroxy (C 2 -C 7) alkyl or C 2 -C 7 alkanoyl, preferably R 1 -C (= O) - wherein R 1 is as defined above - or a salt thereof, X _{6 is} reduced to the desired R 1 -X- and, if desired, the resulting compound of formula I - wherein R 1, R ₂ , R ₃ and X are as defined above and R is a carboxyl group - the carboxyl group R is esterified and / or, if desired, the resulting compound of formula I wherein R 1, R ₂ , R ₃ and X are as defined above and R is hydroxymethyl The hydroxymethyl group R is oxidized to the carboxyl group and / or, if desired, the alkoxymethyl group R in the resulting compound of formula (I) wherein R 1, R ₂ , R ₃ and X are the hydroxymethyl group as defined above and R is alkanol etherified Rtot oxidized alkoxycarbonyl, and / or, if desired, the compound of formula (I) obtained - wherein R, R, R ₃ and X have the above meanings and R ₂ is hydrogen - R ₂ hydrogen to an alkylation with an alkyl group, and / or if desired a the resulting salt is converted to the free compound or another salt and / or a free salt-forming compound into a salt. (Priority: February 27, 1978) Process for carrying out the process of claim 1, wherein the compound of formula IIa is reacted with an acid of formula IIb or a corresponding functional derivative thereof wherein R 1, X, R ₂ , R ₃ and R is as defined in claim 1. (Priority: July 11, 1978) 3. The process of claim 1, wherein the compound of formula II, wherein R 1, R ₂ , R ₃ , X, X ₁ and X ₂ are as defined in claim 1, is an acidic condensing agent. in the presence and / or at elevated temperatures. (Priority: February 27, 1978) A process for carrying out the process of claim 2, wherein the compound of formula (IIa) and (IIb) wherein R, R 1, R ₂ , R ₃ and X are as defined in claim 1 is an acidic condensing agent. in the presence and / or at elevated temperatures. (Priority: July 11, 1978) 5. The process of claim 1 c) wherein the compound of formula III wherein R 1, R ₂ , R ₃ , X and X ₃ are as defined in claim 1 is formyl or esterified hydroxymethyl to a carboxyl group. oxidized. (Priority: February 27, 1978) 6. A process for the preparation of process c) according to claim 1 wherein in the compound of formula III wherein R ₃ , R ₂ , R ₃ , X and X ₃ are as defined in claim 1, the trihalomethyl group X _{3 is} converted to a carboxyl group. or the halomethyl group or the C2-C7 alkanoyloxymethyl group is hydrolyzed to the hydroxymethyl group. (Priority: February 27, 1978) The process according to claim 1, process a) or b) or c) or d) or the process according to claims 2-6. A process for the preparation of a compound according to any one of claims 1 to 6 wherein: R represents a carboxyl group or an esterified carboxyl group containing up to 4 carbon atoms or a hydroxymethyl group or an ethereal hydroxymethyl group containing up to 4 carbon atoms and R 1 is alkyl having up to 6 carbon atoms, X is methylene, R ₂ is alkyl of up to 4 carbon atoms and R ₃ is alkyl of up to 4 carbon atoms - and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (IIa) and an acid of formula (IIb) or a functional derivative thereof or ), (III) or (V), wherein X is -13 182 938 and X ₂ are as defined in claim 1. The method of b), X ₃ is as in claim 1 c) a method of, as defined hereinbefore defined and X ₆ in Claim 1, of d) and R is as defined above and where R-X- R _{2 is} lower alkyl having up to 7 carbon atoms; R ₂ and R ₃ are lower alkyl having up to 4 carbon atoms. (Priority: February 27, 1978) 8. A process according to claim 2 or 4, wherein the compound of formula IIa and the acid of formula IIb or a functional derivative thereof are provided wherein R is a carboxyl group or at most 4. an esterified carboxyl group containing a lower alkoxy group, R 1 -X-C 2 -C 7 alkyl, and R ₂ and R ₃ are hydrogen or alkyl of up to 4 carbon atoms. (Priority: July 11, 1978) A process according to claim 1, process a) or b) or c) or d) or a process according to claims 2 to 6. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, wherein R is carboxyl, hydroxymethyl or alkoxycarbonyl having up to 5 carbon atoms or alkoxymethyl having up to 5 carbon atoms, R ₁ -X- is alkyl of up to 5 carbon atoms and R ₂ and R ₃ are independently alkyl of up to 4 carbon atoms, characterized in that it is an acid of formula (IIa) and (IIb) or a functional derivative thereof or ), (III) or (V), wherein X is and X ₂ is as defined in claim 1 (b), X ₃ is as defined in claim 1 (c), and X _{6 is as} defined in claim 1 (d), R is as defined above, and R 1 is -X- lower carbon. and R ₂ and R ₃ are lower alkyl having up to 4 carbon atoms. (Priority: February 27, 1978) The process of claim 1, process a) or b) or c) or d) or the process of claims 2-6. A process for the preparation of a compound according to any one of claims 1 to 6, wherein R is a carboxyl group or a alkoxycarbonyl group containing up to 5 carbon atoms in total, R 1 -X 2 -C 7 alkyl group and R ₂ and R _{3 being} up to C 4 alkyl group - and pharmaceutically acceptable salts thereof with bases, starting from a compound of formula IIa and an acid of formula IIb or a functional derivative thereof, or a compound of formula II, III or V, wherein X ₁ and X _{2 are as} defined in claim 1; specified process b) of X ₃ to claim c) a method of, as defined and X ₆ in claim 1 d) by a procedure as defined, R is as defined above and Ri -X- up to 7 carbon atoms, lower alkyl group, and R ₂ and R ₃ is not more than 4 lower alkyl. (Priority: Feb. 27, 1978) 11. A process according to claim 2, wherein the compound of formula IIa and the acid of formula IIb or a functional derivative thereof are provided, wherein R is carboxyl, R 1 is hydrogen. is an alkyl group of up to 6 carbon atoms, X is a methylene group, R ₂ is a hydrogen atom and R ₃ is a hydrogen atom or an alkyl group of up to 4 carbon atoms, and R 1 -X- at the 5-position of the benzimidazole ring; 5 the R ₃ alkyl group is in the 6-position of the benzimidazole ring. (Priority: July 11, 1978) Process for the preparation of 2-ethoxymethyl-5-butyl-1,6-dimethylbenzimidazole according to claim 1, process a) or b) or d) or process according to any one of claims 3 and 4, characterized in that: starting from a suitable compound of formula (IIa) and an acid of formula (IIb) or a functional derivative thereof or a suitable compound of formula (II), (III) or (V) wherein X ₁ and X ₂ are In the process of claim 1 b), R 10 -X- is butyl, X ₆ is butyryl or 1-halo or 1-hydroxybutyl, R ₂ and R ₃ are methyl and R is ethoxymethyl. 20 (Priority: February 27, 1978) The process according to claim 1, process a) or b) or c) or d) or the process according to claims 3 to 6. A process for the preparation of a 5-butyl-1,6-dimethylbenzimidazole-2-carboxylic acid ethyl ester according to any one of claims 1 to 3, wherein Starting from 25 suitable compounds of formula IIa and an acid of formula IIb or a functional derivative thereof, or a suitable compound of formula II, III or V, wherein X ₁ and X ₂ are as defined above. A process according to claim 3 (b), X ₃ 30 represents a functionally modified carboxyl group, X ₆ represents a butyryl group or a 1-halo or 1-hydroxytutyl group, R 1 -X- represents a butyl group, R ₂ and R ₃ represents a methyl group and R represents a carboxyl group, ethoxycarbonyl group or ethoxymethyl group. In the clyan compound, where R is carboxyl, it is esterified to ethoxycarbonyl, and in the resulting compound, where R is ethoxymethyl, it is oxidized to ethoxycarbonyl. (Priority: February 27, 1978) 40 The process according to claim 1, process a) or b) or c) or d) or the process according to claims 3-6. A process according to any one of claims 1 to 6 for the preparation of 5-butyl-1,6-dimethylbenzimidazole-2-carboxylic acid or a pharmaceutically acceptable salt thereof, characterized in that 45 are prepared from the corresponding compound of formula ITa and the acid of formula IIb, or a functional derivative thereof, or of the corresponding compound of formula II, III or V, wherein X ₁ and X ₂ are as defined above. X _{3 in} the process of claim 1 b), X _{3 in} the process of claim 1 c), X ₆ is butyryl, 1-halobutyl or i-hydroxybutyl, R is carboxyl, alkoxycarbonyl or alkoxymethyl, R ₁ -X is butyl and R ₂ and R ₃ are methyl, 55 and the compound R is oxidized to an alkoxymethyl group / alkoxycarbonyl group, the alkoxycarbonyl group is hydrolyzed to a carboxyl group, or the hydroxymethyl group is oxidized to a carboxyl group. (Priority: February 27, 1978) θθ The process according to claim 1, a) or b) or c) or d) or the process according to claims 3 to 5. A process for the preparation of 1,6-dimethyl-5-butyl-2-hydroxymethylbenzimidazole according to any one of claims 1 to 6, characterized in that it is prepared from a suitable compound of formula IIa and 65 of an acid of the formula or a functional one -14182 938 or a corresponding compound of formula (II), (III) or (V), wherein X ₁ and X ₂ are as defined in claim 1 (b), X ₃ is an etherified or esterified hydroxymethyl group, X ₆ represents a butyryl, halogénbutilcsoport 1, 5 or 1-hydroxybutyl, R is hydroxymethyl, R-X- is butyl and R ₂ and R ₃ are methyl. (Priority: February 27, 1978) 16. A process for the preparation of medicaments having an antiallergic effect, characterized in that the compound of the formula I prepared according to any one of claims 1 to 15, wherein R, R 1, R ₂ , R ₃ and X are as defined in claim 1, or a salt thereof, for preparing pharmaceuticals, excipients, binders, lubricants, flavoring agents, tablets, pills, capsules, suppositories, emulsions, suspensions, solutions for injection or other pharmaceutical preparations.