CH634059A5 - Process for preparing benzimidazole derivatives - Google Patents

Abstract

The invention relates to a process for preparing benzimidazole derivatives of the formula <IMAGE> in which R is a hydroxymethyl group, R1 represents an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, R2 represents hydrogen, or an aliphatic radical, and Ph represents a 1,2-phenylene group containing the radical R1-C(=O)- and optionally having further substituents, characterised in that, in a compound of the formula <IMAGE> in which X represents a formyl group, or a carboxyl group which may optionally be present in the salt form or the halide form, reduction is effected to give hydroxymethyl. The compounds of the formula I have antiallergic properties and may be used as active compounds in antiallergics.

Description

The invention relates to a process for the preparation of benzimidazole derivatives of the formula

0 ii r -c-p

\: - r

(i)

r "

20th

wherein R is an optionally etherified or esterified hydroxymethyl group, Ri is an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, r2 is hydrogen or an aliphatic radical, and Ph one is the radical Ri-C (= 0) - Containing and optionally having further substituents 1,2-phenylene group, with the proviso that Ri has at least 2 carbon atoms if Ph is otherwise unsubstituted, r2 is ethyl and 30 R is acetoxymethyl.

In the context of this description, groups and compounds labeled "lower" contain in particular up to and with 7, preferably up to and with 4 carbon atoms.

35 In esterified carboxy and etherified hydroxymethyl R, the etherified hydroxy group means, for example, a hydroxy-40 group etherified by an aliphatic or araliphatic radical, such as an optionally substituted aliphatic or araliphatic hydrocarbon radical, e.g. corresponding lower alkoxy or phenyl-lower alkoxy. Substituents of lower alkoxy include Hydroxy, lower alkoxy and / or di-lower alkylamino, and those of phenyl-lower alkoxy, e.g. Lower alkyl, lower alkoxy and / or halogen, where one or more substituents may be present.

In esterified hydroxymethyl R, the esterified hydroxy group means, for example, hydroxy esterified with a carboxylic acid, such as an aliphatic or aromatic carboxylic acid, e.g. corresponding lower alkanoyloxy so or optionally substituted by lower alkyl, lower alkoxy and / or halogen benzyloxy. Lower alkanoyloxy is e.g. Acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeroyloxy, caproyloxy or pivaloyloxy.

Aliphatic, cycloaliphatic, aromatic and araliphatic radicals R 1 and r 2 are primarily optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as corresponding lower alkyl, lower alkenyl, cycloalkyl, phenyl, naphthyl or phenyl-lower alkyl. Substituents are e.g. 60 hydroxy, lower alkoxy, lower alkyl or phenylthio, lower alkyl or phenylsulfinyl, or lower alkyl or phenylsulfonyl, in particular lower alkyl R 1 and lower alkyl, r 2, further lower alkyl, lower alkoxy and / or halogen, in particular phenyl or phenyl lower alkyl 65 RI. Heterocyclyl in one heterocyclic or heterocyclic-aliphatic radical Ri is primarily monocyclic heterocyclyl aromatic in character with a heteroatom, such as oxygen, sulfur or nitrogen, as a ring

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member such as furyl, thienyl or pyridyl. In a heterocyclic aliphatic radical Ri, the aliphatic part is e.g. a corresponding aliphatic hydrocarbon radical, in particular lower alkyl.

In addition to the rest of the formula Ri-C (= 0), 1,2 phenylene can also be substituted one or more times by lower alkyl, lower alkoxy, hydroxy and / or halogen.

Lower alkoxy means e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy or n-hexyloxy.

Phenyl lower alkoxy is e.g. Benzyloxy or 1- or 2-phenylethoxy.

Hydroxy, lower alkoxy or di-lower alkylamino lower alkoxy is in particular 2- and / or 3-hydroxy-lower alkoxy, e.g. 2-hydroxyethoxy, 3-hydroxypropyloxy or 2,3-dihydroxy-propyloxy, as well as 2- or 3-lower alkoxy-lower alkoxy, e.g. 2-methoxyethoxy, 2-ethoxyethoxy or 3-methoxypropyloxy or di-lower alkylamino lower alkoxy, e.g. The methylamino or diethylamino ethoxy.

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl.

Halogen is especially halogen with atomic numbers up to and including 35, i.e. Fluorine, chlorine or bromine.

Lower alkylene is e.g. 1,4-butylene, 1,5-pentylene or 1,6-hexylene.

Lower alkenyl is e.g. Vinyl, 1-methyl-vinyl, 1-ethyl-vinyl, allyl, 2- or 3-methyl-allyl or 3,3-dimethyl-allyl.

Cycloalkyl preferably contains 3 to 8 ring atoms and is e.g. Cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Lower alkylthio is e.g. Methylthio or ethylthio, while lower alkylsulfinyl and lower alkylsulfonyl e.g. Met-methylsulfinyl, ethylsulfinyl, methylsulfonyl or ethylsulfonyl mean.

Lower alkyl substituted by lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl is e.g. Methylthio- or ethylthiomethyl, 1- or 2-methylthio- or 1- or

2-ethylthioethyl, or 2- or 3-methylthio- or 2- or

3-ethylthiopropyl, methylsulfinyl- or ethylsulfinyl-methyl, 1- or 2-methylsulfinyl- or 1- or 2-ethylsulfonyl-ethyl, or 2- or 3-methylisulfinyI- or 2- or 3-ethylsulfinylpropyl, or methylsulfonyl- or Ethylsulfonylmethyl, 1- or 2-methylsulfonyl or 1 or 2-ethylsulfonyl-ethyl, or 2- or 3-methylsulfonyl or 2- or

3-ethylsulfonylpropyl. Lower alkyl substituted by phenylthio, phenylsulfinyl or phenylsulfonyl is e.g. Phenylthio *, phenylsulfinyl- or phenylsulfonylmethyl, or 1- or 2-phenylthio-, 1- or 2-phenylsulfinyl, or 1- or 2-phenylsulfonylethyl.

Phenyl lower alkyl is e.g. Benzyl, 1- or 2-phenylethyl or 1-, 2- or 3-phenylpropyl.

Furyl is e.g. 2-furyl, and thienyl e.g. 2-thienyl, while pydridyl can be 2-, 3- or 4-pyridyl.

Furyl-lower alkyl, thienyl-lower alkyl and pyridyl-lower alkyl are in particular appropriately substituted methyl radicals, such as furfuryl, 2-thienyl or picolyl, e.g. 2- or

4-pyridylmethyl.

Salts are those of compounds of formula I, wherein R is carboxy, with bases; such salts are particularly pharmaceutically acceptable, non-toxic salts with bases such as alkali metal or alkaline earth metal e.g.

Sodium, potassium, magnesium or calcium salts, also ammonium salts with ammonia or amines such as lower alkyl or hydroxy lower alkyl amines, e.g. Trimethylamine, triethylamine or di- or tri- (2-hydroxyethyl) amine.

The new compounds show valuable pharmacological properties. In particular, they have anti-allergic effects, e.g. on the rat in doses of about 0.03 to about 10 mg / kg for intravenous and in doses of about 1 to about 100 mg / kg for oral administration in the passive cutaneous anaphylaxis test (PCA reaction), which is analogous to that of Goose and Blair , Immunology, vol. 16, p. 749 (1969), can be detected, the passive cutaneous anaphylaxis being produced according to the method described by Ovary, Progr. Allergy, vol. 5, p. 459 (1958) becomes. The antiallergic, in particular the degranulation-inhibiting effect can also be used in an in vitro experiment on the basis of the histamine release from peritoneal cells of the rat in the dose range from about 0.1 to about 100ug / ml in the case of immunologically induced release (whereby rats infected with Nippostrongylus brasiliensis, for example, are used ) and from about 1.0 to about 100 µg / ml in the case of chemically induced release (which is effected, for example, with a polymer of N-4-methoxy-phenylethyl-N-methylamine). The compounds of the present invention are therefore useful as inhibitors of allergic reactions, e.g. in the treatment and prophylaxis of allergic diseases such as asthma, both extrinsic and intrinsic asthma, or other allergic diseases such as allergic rhinitis, e.g. Hay fever, conjunctivitis, or allergic dermatitis, e.g. Urticaria or eczema can be used.

The invention relates in particular to a process for the preparation of compounds of the formula I in which R represents free hydroxymethyl or lower alkanoyloxy- or benzoyloxymethyl which is optionally substituted by lower alkyl, lower alkoxy and / or halogen, Ri optionally by lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, phenylthio, phenylsulfinyl or phenylsulfonyl-substituted lower alkyl, lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl optionally substituted in the phenyl part by lower alkyl, lower alkoxy or halogen, furyl, thienyl or pyridyl or furyl-lower alkyl, thienyl-lower alkyl or pyridyl-lower alkyl, R2 represents hydrogen or lower alkyl, and Ph for the rest of the formula Ri -C (= 0) - containing and optionally substituted by lower alkyl, lower alkoxy, hydroxy and / or halogen-substituted 1,2-phenylene, with the proviso that Ri has at least 2 carbon atoms if Ph is otherwise unsubstituted, r2 Ethyl means and R represents acetoxymethyl.

The invention relates primarily to a process for the preparation of compounds of the formula

, «-> VV

r'-c - + - y Vr '(Ia),

wherein R 'is hydroxymethyl or further with a lower alkanol having up to 4 carbon atoms, e.g. Methanol or ethanol, or di-lower alkylamino lower alkanol with up to 7 carbon atoms, e.g. Dimethylaminoethanol, etherified hydroxymethyl or lower alkanoyloxy with up to 7 carbon atoms, e.g. Is acetoxy, having esterified hydroxymethyl, and wherein R [in particular lower alkyl having up to and with 7 carbon atoms, e.g. Methyl, ethyl, n-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl, furthermore lower alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, phenylthione lower alkyl or phenylsulfinyl

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lower alkyl, in which the lower alkyl radicals contain up to and with 4 carbon atoms, e.g. Methoxy-, methylthio-, met-hylsulfinyl- phenylthio- or phenylsulfinylmethyl, 2-met-hoxy-, 2-methylthio-, 2-methylsulfinyl-, 2-phenylthio- or

2-phenylsulfinylethyl, or 3-methoxy- 3-methylthio-,

3-methylsulfinyl, 3-phenylthio or 3-phenylsulfinyl-propyl, cycloalkyl with up to and with 6 ring carbon atoms, e.g. Cyclopropyl or cyclohexyl, phenyl, furyl or pyridyl, e.g. 3- or 4-pyridyl, Rj is in particular hydrogen, furthermore lower alkyl having up to 4 carbon atoms, e.g. Methyl, and R3 is hydrogen, lower alkyl of up to 4 carbon atoms, e.g. Methyl, lower alkoxy of up to 4 carbon atoms, e.g. Methoxy, hydroxy or halogen with atomic numbers up to and including 35, e.g. Chlorine means, where the rest of the formula R2-C (= 0) - and the group R3, if this is different from hydrogen, can take any of those suitable for substitution, preferably the 5- and 6-positions of the benzimidazole ring with the proviso that R (has at least 2 carbon atoms when r3 is hydrogen, R, ethyl and R 'is acetoxymethyl.

The invention relates primarily to a process for the preparation of compounds of formula Ia, in which R 'is hydroxymethyl or furthermore with a lower alkanol having up to and with 4 carbon atoms, e.g. Methanol or ethanol, etherified hydroxymethyl, and wherein Rf is lower alkyl with up to and with 7, preferably with up to and with 4 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, cycloalkyl with up to and with 6 ring carbon atoms, e.g. Cyclopropyl or cyclohexyl or phenyl means R, in particular for hydrogen, furthermore for lower alkyl with up to and with 4 carbon atoms, e.g. Methyl, and R3 is hydrogen, lower alkyl of up to 4 carbon atoms, e.g. Methyl, lower alkoxy of up to 4 carbon atoms, e.g. Methoxy, or halogen with atomic numbers up to and including 35, e.g. Chlorine means, the radicals R [-C (= 0) - and R3, if this is different from hydrogen, preferably occupying the 5- or 6-position of the benzimidazole ring.

The invention relates primarily to a process for the preparation of compounds of formula Ia, in which R 'is hydroxymethyl, and in which R [lower alkyl with up to and with 7, e.g. with up to and with 4 carbon atoms, e.g. Represents methyl, ethyl, n-propyl, isopropyl or n-butyl, R {stands for hydrogen and R3 is hydrogen or lower alkyl having up to and with 4 carbon atoms, e.g. Represents methyl, the radical Rf —C (= 0) - the 5- and a lower alkyl radical R3 taking the 6-position of the benzimidazole ring.

The invention relates in particular to a process for the preparation of the compounds of the formula I mentioned in the examples.

The process according to the invention for the preparation of the new compounds is characterized in that in a compound of the formula

0

R1-C-P

A-x di)

R "

wherein X represents a formyl or optionally in salt or halogenide carboxy group, reduces this to hydroxymethyl and, if desired, converts a compound of the formula I thus obtainable into another compound of the formula I.

A formyl group can e.g. by reaction with a selective reducing agent such as a suitable borohydride or sodium borohydride, e.g. with sodium borohydride or with sodium cyanoborohydride, preferably in a lower alkanol or in hexamethylphosphoric triamide, or diisoamylborane in tetrahydrofuran, if necessary with cooling or gentle heating, e.g. at about 0 ° C to about 100 ° C, and / or under an inert gas, such as nitrogen, can be reduced to hydroxymethyl.

A carboxy group, optionally in halide or salt form, can be reduced to hydroxymethyl by reaction with a borohydride or with hydrogen in the presence of a hydrogenation catalyst. To reduce any salt, e.g. as the alkali metal, such as sodium salt, carboxy group present, a borane, e.g. Diboran or the borantetrahydrofuran complex. Halocarbonyl groups, such as chlorocarbonyl, are preferably reduced with hydrogen in the presence of palladium, preferably on a support such as barium sulfate, and if necessary a sulfur-containing cocatalyst, e.g. of thiourea.

The starting materials can be prepared in a manner known per se.

Starting materials of the formula II in which X is formyl 25 can be prepared, for example, by using a corresponding compound of the formula

A

30 Y-Phf NC-X

(III)

I.

R "

35

wherein acetalized formyl, such as lower alkylenedioxy or diniederalkoxymethyl, and Y is a group -M-Hal or -M / 2, M is a metal atom of group II of the periodic table and Hai chlorine, bromine or iodine 40, with an acid of Formula Ri-COOH or a reactive functional derivative, such as the chloride or especially nitrii, thereof, and the acetalized formyl group and, if appropriate, a primarily formed group of the formula -C (= NH) -Ri, for example under acid catalysis, 45 hydrolyzed. The compounds of formula III used as starting materials for this purpose are advantageously prepared in situ by working in a compound of formula

50

Hai-P

A

: c ~ y.

(IV)

R "

wherein shark is chlorine, bromine or iodine, shark by reaction with the corresponding metal, e.g. with magnesium, in group Y, e.g. of the formula -MgHal. Connecting

60 fertilize the formula III, in which Y is different from magnesium and e.g. a group is -Cd / 2, can further be obtained by reacting the corresponding halogen magnesium compounds with a salt of the formula MHah, e.g. with cadmium chloride.

65 Other starting materials of the formula II, starting from the corresponding 1,2-phenylenediamines, which are substituted by the acyl radical of the formula —C (= 0) —Ri and may optionally contain further substituents and

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6

derived from the corresponding nitroanilino compounds by reduction of the nitro group, e.g. with hydrogen in the presence of Raney nickel, can be prepared in a manner analogous to that known for their treatment with glycolic acid or a suitable reactive derivative thereof, e.g. by reaction with a di-lower alkoxyacetic acid or a reactive derivative such as a lower alkyl ester thereof and subsequent hydrolysis.

Furthermore, starting materials of the formula II in which X is formyl can also be obtained by using a benzimidazole which is unsubstituted in the 1 - and 2-position and contains the acyl group of the formula Ri-C (= 0) in the carbocyclic ring and is optionally further substituted reacted with 2-chloro-1,1,2-trifluoro-ethene, and the thus obtainable 1 - (2-chloro-1,1,2-trifluoro-ethyl) -benzimi-dazol, which is unsubstituted in the 2-position, that contains in the carbocyclic part the group of the formula Ri-C (= 0) - and optionally other substituents, with an alcohol, such as a lower alkanol, for example Ethanol, in the presence of a base such as an alkali metal hydroxide, e.g. Sodium hydroxide, or with a hydroxy-laminic acid addition salt, e.g. the hydrochloride, in the presence of a base, e.g. Pyridine. A compound of formula II is thus obtained, in which X represents an acetalized formyl group such as diniederalkoxymethyl, e.g. Diethoxymethyl, or the hydroximinomethyl group, which is known in a manner known per se, e.g. by hydrolysis, can convert into the formyl group X.

A compound of the formula I obtainable according to the invention can be converted into another compound of the formula I in a manner known per se.

Thus, in a compound of formula I in which R2 is hydrogen, this, e.g. by treatment with a reactive ester of a corresponding alcohol, such as a halide, in the presence of a base, e.g. of an allcali metal alkali, with an aliphatic residue.

Furthermore, in a compound of formula I in which R is hydroxymethyl, this can be carried out in a conventional manner, e.g. converted into an etherified hydroxymethyl group by reaction with an etherifying agent, etherifying agents are, for example, reactive esters of corresponding alcohols, for example their esters with inorganic acid, such as hydrochloric, bromic or hydroiodic acid or sulfuric acid, or with organic sulfonic acids, e.g. with methane, benzene, p-bromobenzene or p-toluenesulfonic acid, and epoxides derived from corresponding 1,2-diols. The reaction with the etherifying agents mentioned can be carried out in a customary manner, for example in the presence of an alkali metal hydride or alcoholate, e.g. of sodium hydride or sodium methoxide, or by treating the compound to be etherified as a salt, e.g. Sodium salt. Furthermore, in a compound of formula I in which R is hydroxymethyl, it can be esterified in a conventional manner, e.g. by direct esterification with an appropriate carboxylic acid in the presence of a mineral acid, e.g. of hydrochloric acid or sulfuric acid, or by reaction with a reactive derivative, e.g. an anhydride, such as the anhydride or chloride, or an ester, such as lower alkyl or p-nitrophenyl, 2,4-dinitrophenyl ester, the carboxylic acid, if necessary in the presence of an acidic or especially basic condensing agent, when reacting with an acid anhydride, e.g. of pyridine, and when reacted with an ester, e.g. convert an alkali metal such as sodium or potassium alcoholate into an esterified hydroxymethyl group R. The etherification or esterification of a hydroxymethyl group can, however, also be carried out in such a way that this is initially carried out in a customary manner, e.g. with phosphorus tribromide or thionyl chloride, converted into a halomethyl group and then with an alkali metal, e.g. the sodium alcoholate of the corresponding alcohol, or an alkali metal, e.g. the sodium salt of the corresponding carboxylic acid.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable.

The pharmaceutical preparations which contain compounds of the formula I or pharmaceutically usable salts thereof are those for enteral, such as oral, nasal or rectal, and also parenteral or topical administration to warm-blooded animals which contain the pharmacological active ingredient alone or together with contain a pharmaceutically usable carrier material. The dosage of the active ingredient depends on the warm-blooded species, the age and the individual condition, as well as on the mode of administration.

The pharmaceutical preparations contain e.g. to about 95%, preferably from about 5% to about 90% of the active ingredient. Pharmaceutical preparations according to the invention are e.g. those in unit dosage forms, such as coated tablets, tablets, capsules or suppositories, and ampoules, furthermore inhalation preparations, furthermore topical and locally usable pharmaceutical preparations (e.g. for insufflation).

The pharmaceutical preparations are made in a manner known per se, e.g. produced by conventional mixing, granulating, coating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, into tablets or dragée core after addition of suitable auxiliaries .

Suitable carriers are in particular fillers such as sugar, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch paste using e.g. of corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and / or polyvinylpyrrolidone, and / or,

if desired, disintegrants, such as the starches mentioned above, also caxboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow regulators and lubricants, e.g. Silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragée kernels are provided with suitable, possibly gastric juice-resistant coatings, whereby one of the things Concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments, e.g. for identification or for labeling different doses of active ingredient.

Other orally applicable pharmaceutical preparations are plug-in capsules made of gelatin, and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active ingredient in the form of granules, e.g. in a mixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers.

In soft capsules, the active ingredient is preferably in ge5

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suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols dissolved or suspended, stabilizers may also be added.

As rectally applicable pharmaceutical preparations, e.g. Suppositories into consideration, which consist of a combination of the active ingredient with a suppository base mass. Suitable suppository bases are e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material; as basic materials come e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration, primarily aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. Contain sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers.

Inhalation preparations for the treatment of the respiratory tract by nasal or buccal administration are e.g. Aerosols or sprays, which can distribute the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension. In addition to the active ingredient, preparations with powder-distributing properties usually contain a liquid propellant with a boiling point below room temperature and, if desired, carriers such as liquid or solid nonionic or anionic surface-active agents and / or solid diluents. Preparations in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant and, if necessary, an additional solvent and / or a stabilizer. Instead of the propellant gas, compressed air can also be used, which can be generated as required by means of a suitable compression and expansion device.

Pharmaceutical preparations for topical and local use are e.g. for the treatment of the skin lotions and creams containing a liquid or semi-solid oil-in-water or water-in-oil emulsion and ointments (which preferably contain a preservative), for the treatment of the eyes eye drops which are the contain active compound in aqueous or oily solution and eye ointments, which are preferably produced in sterile form, for the treatment of nose powders, aerosols and sprays (similar to those described above for the treatment of the respiratory tract), as well as coarse powder, which can be inhaled quickly the nostrils are administered, and nasal drops which contain the active compound in aqueous or oily solution, or for local treatment of the mouth, lozenges which contain the active compound in a mass generally formed from sugar and gum arabic or tragacanth, to which flavorings have been added can, as well as pastilles, the active substance in an inert mass, for made of gelatin and glycerin or sugar and gum arabic.

The daily dose which is administered to a warm-blooded animal of approximately 70 kg is, depending on the form of application, from approximately 2 mg to approximately 700 mg.

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees Celsius.

example 1

5 g of crude 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxaldehyde are dissolved in 30 ml of ethanol and 20 ml of hexamethylphosphoric acid triamide and converted into a suspension of 1 g of sodium borohydride, which has been cooled from 10 °, and 50 ° C. under nitrogen ml of ethanol was added dropwise. The mixture is stirred for one hour at room temperature and one hour under reflux. 10 ml of water are then added, the mixture is evaporated under reduced pressure and recrystallized from ethyl acetate. The 5-butyryl-1,6-dimethylbenzimidazole-2-methanol of mp 142 ° is obtained.

The starting material can be prepared as follows: 2.06 g of 3-butyryl-4-methyl-6-methylamino-aniline are dissolved in 40 ml of 6N hydrochloric acid, mixed with 2.6 g of dichloroacetic acid and heated under reflux for 5 hours. The mixture is allowed to cool, diluted with water, neutralized with sodium hydrogen carbonate and extracted with methylene chloride. It is evaporated and crude 5-butyryl-2-dichloromethyl-1,6-dimethyl-benzimidazole is obtained. 2 g of the same are dissolved in 100 ml of ethanol and a sodium ethylate solution (obtained by dissolving 0.5 g of sodium in 50 ml of ethanol) is added. The mixture is heated to reflux for 2 hours, the alcohol is distilled off, taken up in ethyl acetate and washed with water. After evaporation, crude 2-diethoxymethyl-5-butyryl-l, 6-demethylbenzimi-dazol remains. 1.6 g of the same are dissolved in 30 ml of dioxane, 20 ml of n-hydrochloric acid are added and the mixture is heated at 90 ° C. for 3 hours. It is evaporated and recrystallized from petroether. The 5-butyryl-l, 6-dimethyl-benzimidazole-2-carboxaldehyde of mp 117-118 ° is obtained.

The following connections can be made in an analogous manner:

5-butyryl-1-ethyl-6-methyl-benzimidazole-2-methanol,

Mp 152-154 °;

5-acetyl-1-butyl-benzimidazole-2-methanol, mp 121-124 °;

5-butyryl-1-butyl-6-methylbenzimidazole-2-methanol,

F. 78-81 °;

5 (6) -benzoyl-benzimidazole-2-methyl, mp 226-227 °;

5-benzoyl-1-methyl-benzimidazole-2-methanol mp 168-172 °;

5-butyryl-1-methyl-6-methoxy-benzimidazole-2-methanol, mp 179-184 °;

5-cyclopropylcarbonyl-1,6-dimethyl-benzimidazole-2-met-ethanol, mp 143-144 °;

5-oenanthyl-1,6-dimethyl-benzimidazole-2-methanol, mp 93-93.5 °;

5 (6) -valeryl-benzimidazole-2-methanol, mp 134-136 °;

5-valeryl-6-methyl-benzimidazole-2-methanol, mp 169-171 °;

5 (6) -butyryl-benzimidazole-2-methanol, mp 141-143 °;

5-acetyl-l-methyl-benzimidazole-2-methanol, mp 176-177 °;

5-butyryl-1-methyl-benzimidazole-2-methanol,

Mp 153-154 °;

5-butyryl-1-methyl-6-chloro-benzimidazole-2-methanol, mp 183-185 °;

5-valeryl-l, 6-dimethyl-benzimidazole-2-methanol, mp 125 °;

5-isobutyryl-1,6-dimethyl-benzimidazole-2-methanol, mp 158-160 ° and

5-isovaleryl-1,6-dimethyl-benzimidazole-2-methanol, mp 142-152.5 ° C.

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Claims (14)

634059 2. The method according to claim 1, characterized in that in a compound of formula II, wherein X is formyl, this is reduced to hydroxymethyl. 2nd PATENT CLAIMS 1. Process for the preparation of benzimidazo derivatives of the formula 0 II R-C-F A C-R (I) wherein R is a hydroxymethyl group, Ri is an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, Rz is hydrogen or an aliphatic radical, and Ph is a radical containing the radical Ri-C (= 0) - and optionally further Representing 1,2-phenylene group, characterized in that in a compound of formula ° A C-Plk 'C-X (Ii) A-A. , - II ^ -R * > / V (Ia), I. R ' wherein R 'is hydroxymethyl, R (lower alkyl having up to 7 carbon atoms, lower alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, phenylthione lower alkyl or phenylsulfinyl lower alkyl, in which the lower alkyl radicals contain up to and with 4 carbon atoms, cycloalkyl with up to and with 6 ring carbon atoms, Represents phenyl, furyl or pyridyl, Rî for hydrogen or lower alkyl having up to and with 4 carbon atoms, Niederal- koxy with up to 4 carbon atoms, hydroxy or halogen with atomic number up to 35 means. 3rd 634 059 is, R.2 is ethyl and R is acetoxymethyl, characterized in that in a compound of the formula 0 ii Rj-C-P A ; c-x (Ii) 15. The compounds obtained by the process of claim 1. 16. Compounds according to claim 15, obtained by the method of claim 2. 17. The compounds obtained by the method of claim 14. R " wherein X represents a formyl or optionally present in salt or halide carboxy group, reduces this to hydroxymethyl and esterifies the compound obtained. 3. The method according to claim 1 or 2, characterized in that compounds of formula 1, wherein R is hydroxymethyl, Ri optionally by lower alkoxy, lower alkylthio. Lower alkylsulfinyl, lower alkylsulfonyl, phenylthio, phenylsulfinyl or phenylsulfonyl-substituted lower alkyl, lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl, optionally substituted in the phenyl radical by lower alkyl, lower alkoxy or halogen, or furyl-lower alkyl, thienyl-lower alkyl or pyridyln-alkyl or pyridyl-R-alkyl or pyridylnyl Represents lower alkyl, and Ph represents the rest of the formula Ri-C (= 0) - containing and optionally substituted by lower alkyl, lower alkoxy, hydroxy and / or halogen 1,2-phenylene. 4. The method according to any one of claims 1 and 2, characterized in that compounds of the formula • R® (Ia), is wherein R 'is hydroxymethyl, R is [lower alkyl having up to and with 7 carbon atoms, cycloalkyl having up to and having 6 ring carbon atoms or phenyl, R | represents hydrogen or lower alkyl having up to and with 4 carbon atoms, and R3 is hydrogen or lower alkyl having up to 20 and having 4 carbon atoms, and R3 is hydrogen, lower alkyl having up to and with 4 carbon atoms, lower alkoxy having up to and with 4 carbon atoms or halogen with atom number up to and with 35 means produces. 5. The method according to any one of claims 1 and 2, characterized in that compounds of; formula I. R " wherein X represents a formyl or optionally present in salt or halide carboxy group, this reduced to hydroxymethyl. 6. The method according to any one of claims 1 and 2, 25, characterized in that compounds of the formula r: S / v \ -C — H— II '& / / © V k C-R ' (Ia) 35 wherein R 'is hydroxymethyl, R; Represents lower alkyl with up to and with 7 carbon atoms, Rî stands for hydrogen, and R3 represents hydrogen or lower alkyl with up to and with 4 carbon atoms, the remainder being R [-C (= 0) - the 40 5- and a lower alkyl group R3 occupies the 6-position of the benzimidazole ring. 7. The method according to any one of claims 1 and 2, characterized in that the 5-butyryl-l, 6-dimethyl-benzimidazole-2-methanol is produced. 45 8. The method according to any one of claims 1 and 2, characterized in that the 1,6-dimethyl-5-valeryl-benzimidazole-2-methanol is produced. 9. The method according to any one of claims 1 and 2, characterized in that the l-ethyl-5-butyryl-6- 50 methyl-benzimidazole-2-methanol produces. 10. Process for the preparation of benzimidazole derivatives of the formula 0 II R -C-Ph ' V C-R (I) R " 60 wherein R is an esterified hydroxymethyl group, Ri is an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, R2 is hydrogen or an aliphatic radical, and Ph is a radical containing Ri-C (= 0) - and optionally represents further substituted-1,2-phenylene group, with the proviso that Ri has at least 2 carbon atoms if Ph is otherwise unsubstituted 11 x < ; c-R ' (Ia) I. wherein R 'as an esterified hydroxyl group means lower alkanoyloxy having up to 7 carbon atoms, esterified hydroxymethyl, R [lower alkyl having up to 7 carbon atoms, lower alkoxy lower alkyl, lower alkylthio-lower alkyl, lower alkylsulfinyl-lower alkyl, phenylthio-lower alkyl or phenylsulfinyl-lower alkyl, in which the lower alkyl radicals contain up to and with 4 carbon atoms Cycloalkyl with up to 6 ring carbon atoms, Phenyl, furyl or pyridyl represents, R £ stands for hydrogen or lower alkyl with up to and with 4 carbon atoms, and R3 hydrogen, lower alkyl with up to and with 4 carbon atoms, lower alkoxy with up to and with 4 carbon atoms, hydroxy or halogen with atom number up to and 35 means that R {has at least 2 carbon atoms when R3 is hydrogen, R-! Ethyl and R 'is acetoxymethyl. 11. The method according to claim 10, characterized in that compounds of formula I, wherein R is lower alkanoyloxy or optionally substituted by lower alkyl, lower alkoxy and / or halogen substituted benzoyloxy-methyl, Ri optionally by lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl , Phenylthio, phenylsulfinyl or phenylsulfonyl-substituted lower alkyl, lower alkenyl, cycloalkyl, optionally substituted in the phenyl radical by lower alkyl, lower alkoxy or halogen-substituted phenyl or phenyl-lower alkyl, furyl, thienyl or pyridyl or furyl-lower alkyl, thienyl-lower alkyl or pyridyl-lower alkyl, and R2 represents hydrogen or lower alkyl, and R2 represents hydrogen or lower alkyl, and R2 represents hydrogen or lower alkyl, and R2 represents hydrogen or lower alkyl, stands for the rest of the formula Ri-C (= 0) -containing and optionally substituted by lower alkyl, lower alkoxy, hydroxy and / or halogen 1,2-phenylene. 12. The method according to claim 10, characterized in that compounds of the formula 0 II Rj-C- A 13. The method according to claim 10, characterized in that the 2-acetoxymethyl-5-butyryl-l, 6-dimethyl-benzimidazole is produced. 14. Use of compounds of formula I obtained according to claim 1, wherein R is hydroxymethyl, for the preparation of corresponding compounds of formula I, wherein R is etherified hydroxymethyl, characterized by reaction with an etherifying agent.