FI89910B - FOERFARANDE FOER FRAMSTAELLNING AV THERAPEUTISKT AKTIVA BENSIMIDAZOLDERIVAT - Google Patents

Description

1 89910

Process for the preparation of therapeutically active benzimidazole derivatives

Analgesic benzimidazole derivatives are known from DE-A-2 246 429, benzimidazole derivatives which inhibit gastric acid secretion are known from e.g. DE-A-2 548 340, EP-A-5129, DE-A-313 a3 disclosed in 10 DE patent applications 3,509,333.1 (HOE 85 / F 046).

DE-A-3,531,487 (published March 13, 1986) and EP-Publication 174,717 (published March 19, 1986) also relate to benzimidazole derivatives.

It has now surprisingly been found that certain benzimidate-15 sol derivatives, substituted toluidines, are high potency antacids.

The present invention relates to a process for the preparation of benzimidazole derivatives of the formula 20: - R 4 is T - R 6 H R 14 R 5 wherein A is -S- or -SO-, R 1 is C 1-4 alkyl, preferably methyl or ethyl, R 3, R 4, R 5 and R 6 are the same or different and represent hydrogen, C 1-4 alkyl or methoxy and R 13 and R 14 are the same or different and represent C 1-4 alkoxy, and for the preparation of their physiologically acceptable salts, the process being characterized by that a compound of formula 2 89910 'bor' "" R 1 wherein R 13 and R 14 are as defined above and Q 1 is i) a leaving group or ii) a group -SH or -S is reacted with a compound of formula HK '

H \ / H

15 / n2 (III) 20 wherein R1, R3, R4, R5 and R6 are as defined above, Q2 is in the above case i) -SH- or -S and in the above case ii) a leaving group, and the resulting compound of formula I the compound in which A is -S- is optionally oxidized to the corresponding compound in which A is -SO-, and the compound of formula I obtained is optionally converted into a physiologically acceptable salt. Preferred compounds of formula I are those in which R1 is ethyl, one of R 3, R 4, R 5 and R 6, preferably all, represents hydrogen, or 1 or 2 of these groups represent C 1-4 alkyl and R 13 and R 14 are methoxy or ethoxy groups, preferably methoxy groups.

Preferred are compounds of formula I wherein A is sulfinyl.

3,89910

Any chiral C or S atoms present may be in both the R and S configuration. In such cases, the compounds of formula I are in the form of pure enantiomers or as a mixture of stereoisomers (such as a mixture of enantiomers or a mixture of diastereomers).

Suitable salts are, in particular, alkali and alkaline earth metal salts and salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, aminosulfonic acid, p-toluene-10 sulfonic acid.

Alkyl and alkoxy groups can be straight or branched chain.

When a compound of formula II is reacted with a compound of formula III in process a), Q1 or Q2 is a leaving group which can be removed nucleophilically, such as Cl, Br, J, -OSO2CH3, -O-SO2CF3 or -O- S02C6H4-p CH 3.

The reaction of a compound of formula II with a compound of formula III or a salt thereof is carried out in an inert solvent, examples of which are water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methylene chloride, acetone, ethyl acetate. , dimethylformamide, acetonitrile, dimethylacetamide, dimethylsulfoxide or mixtures of these solvents. The reaction can be carried out in the presence or absence of an inorganic or organic base; suitable bases are, for example, sodium or potassium hydroxide, carbonate, alkoxide, hydride, amide, ammonia, triethylamine, tributylamine, pyridine. The reaction temperature is -20 to + 150 ° C, preferably 0 to 80 ° C.

The compounds of the formula II are known from the literature or can be prepared analogously to known methods, e.g. by cyclization of the correspondingly substituted o-phenylenediamine with carbon disulfide (cf. 35 e.g. DE-A-3 132 167).

* 89910 The o-phenylenediamines required in this reaction are likewise known from the literature and can be prepared e.g. by catalytic reduction from correspondingly substituted o-nitroanilines.

The compounds of the formula III are likewise known from the literature or can be prepared analogously to the preparation of known compounds.

A further reaction in which the compounds of formula I in which A is -S- can be converted into compounds in which A is -SO- with suitable oxidants is carried out in a suitable solvent such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, ethyl acetate, ethyl acetate, acetic acid, trifluoroacetic acid, water, methanol, ethanol or mixtures thereof; the reaction temperature is -20 to + 150 ° C, preferably -10 to + 40 ° C.

Examples of suitable anoxides are hydrogen peroxide, peracids and peresters such as peracetic acid, trifluoroperacetic acid, monoperphthalic acid, m-chloroper-20-benzoic acid and their esters, ozone, nitrous oxide, iodosobenzene, n-chlorosuccinimide, 1-chlorosuccinimide, 1-chloro. tert-butyl hypochlorite, tetrabutylammonium periodate or permanganate, sodium metaperiodate, selenium or manganese dioxide, cerium ammonium nitrate, chromic acid, chlorine, bromine, diazabicyclo [2.2.2] octane bromide dibromide, dioxane bromide dibromide, dioxone

Isolated, possibly immobilized, oxidizing enzymes or microorganisms can also be used as oxygen-free.

Oxygen-free is used in an equimolar amount or also in a slight excess (5-10 mol%) when oxidizing to A -SO-.

The new compounds of the formula I and their salts have valuable pharmacological properties.

5,89910

They clearly prevent the secretion of gastric acid and, in addition, have an excellent protective effect on the stomach and intestines.

In this context, the term "gastric and intestinal protective" refers to the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal diseases and ulcers (such as gastric ulcer, duodenal ulcer, gastritis, hyperacid or medically inflamed stomach). diseases caused by ai-10, for example, microorganisms, bactericides, drugs (e.g., anti-inflammatory and antirheumatic drugs), chemicals (e.g., ethanol), gastric acid, or stress. Due to their excellent properties, the compounds of the formula I and their pharmacologically acceptable salts are suitable for use in human and veterinary medicine, in particular for the treatment and prevention of gastrointestinal diseases caused by excessive gastric acid secretion.

The three compounds prepared according to the present invention (the compounds of Examples 3, 6 and 10) were compared with the known benzimidazole derivative, omeprazole (5-methoxy-2-{- (4-methoxy-3,5-dimethyl-2), which effectively inhibits gastric acid isolation. -pyridyl) methyl] sulfinyl} -1H-benzimidazole, which is structurally similar to the compounds of formula I.

A control experiment was performed on female Wistar rats weighing 150-170 g. Rats were not fed for 16 hours prior to the experiment, but water was freely available. After the gastric port was closed (procedure 30 was performed under anesthesia), the test compound was administered intraperitoneally (i.p.). The compounds were suspended

Tylose solution (1%) and administered at a dose of 5 mg / kg in a volume of 2 ml / kg. Gastric acid secretion was stimulated by intradermal (s.c.) injection of Desglugastrin 35 at a dose of 400 pg / kg. This injection was repeated one hour after 6,09910. Three hours after the start of the experiment, the animals were sacrificed, the stomach was dissected open, and gastric fluid was collected and its volume was measured. The acid concentration was measured by electrical titration against 100 mmol / l NaOH to end point pH 7. The total acid yield (mmol H * / 3 h) was calculated. The percentage inhibition of the group of treated rats compared to the control group was calculated.

The results are shown in the table below.

10 Table

Inhibition of gastric acid secretion

Compound Inhibition of gastric acid secretion in vivo _ (dose 5 mg / kg i.p.) _

Compound 92 of Example 3 Compound 90 of Example 6

Compound 80 of Example 10

Omeprazole 90 20

In a comparative experiment, the compounds prepared according to the present invention had the same gastric acid inhibitory effect as omeprazole. This is very surprising based on what Brändström, A. et al., 25 Scand. J. Gastroenterol. 20 (suppl 108) (1985) 15-22. That article has examined the relationship between the structure and activity of substituted benzimidazoles. Omeprazole consists of three important structural elements: a substituted pyridine ring, a substituted benzimidazole ring, and a chain connecting them, all of which are found to be essential for the biological activity of the compound. The authors note that any attempt to replace any of these structural elements with a similar group resulted in 35 compounds with significantly 7 <9910 inferior biological activity. Thus, one skilled in the art would have expected that, for example, replacing the substituted pyridine ring of omeprazole with a substituted phenyl ring would have produced compounds that substantially inhibit gastric acid secretion substantially, for example, based on the effects of replacing the pyridine ring substituents of omeprazole with other substituents. Surprisingly, as already mentioned, the biological activity of the novel compounds of the present invention is proportional to the activity of omeprazole.

The compounds of the formula I can be used in pharmaceutical preparations containing one or more compounds of the general formula I and / or a pharmacologically acceptable salt thereof.

Medicinal products are prepared by methods known per se and commonly used in the art. The pharmacologically active compounds (active ingredients) of the formula I are used in pharmaceutical preparations either as such or, preferably, in combination with suitable pharmaceutical excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions, the active ingredient content being preferably from 0.1 to 96%.

It will be apparent to those skilled in the art which excipients should be used in the desired pharmaceutical composition. In addition to solvents, gelling agents, suppository bases, tableting aids and other active ingredient carriers and excipients, for example, antioxidants, dispersants, emulsifiers, antifoams, flavoring agents, preservatives and coloring agents can be used.

The active ingredients can be administered orally or parenterally, making oral medication more advantageous.

Human medicine has the desired • results. 35 sex has generally proven to be a beneficial active ingredient or

8 6 9 91 O

an oral daily dose of the active ingredients of about 0.01 to 20 mg / kg of body weight, optionally administered in several doses, preferably 1 to 4 sub-doses. For parenteral treatment, similar or (especially when the active ingredients are administered intravenously) lower doses may be used. The optimum dosage and method of administration required in each case can be determined by any person skilled in the art on the basis of their professional skills.

When the compounds of the formula I and / or their salts are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active ingredients belonging to other classes of drugs, such as antacids, for example aluminum hydroxide, magnesium aluminate; Sedatives such as benzodiazepines, for example diazepam; spasmolytes such as, for example, bietamylin, camylofin; anticholinergic drugs such as oxyphenylimine, fennel urea; local anesthetics such as tetracaine, procaine; possibly also enzymes, vitamins or amino acids.

For the preparation of an oral dosage form, the active compounds and the usual excipients used with them, such as carriers, stabilizers or other inert diluents, are mixed and formed by conventional means into suitable preparations such as tablets, dragees, capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch, can be used. In this case, the preparation can take place either by dry or wet granulation. Suitable carriers or solvents are, for example, vegetable and animal oils, such as sunflower oil or cod-liver oil.

35 9 89910

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable salts and, if desired, other customary substances, such as solubilizers, emulsifiers or other excipients, are formed into a solution, suspension or emulsion. Suitable solvents for the new active compounds and the corresponding physiologically acceptable salts are, for example, water, physiological saline solutions or alcohols, e.g. ethanol, propanol or glycerol, in addition to sugar solutions, such as glucose or mannitol solutions, or also mixtures of the various solvents mentioned.

The following examples illustrate the methods of the invention without limiting the invention to the substances mentioned therein.

Example 1 2- (2-Ethylaminobenzylsulfinyl) -5,6-dimethoxybenzimidazole a) 2- (2-Ethylaminobenzylthio) -5,6-dimethoxybenzimidazole 10.5 g of 5,6-dimethoxy-2-mercaptobenzimidazole were suspended in 250 ml. tetrahydrofuran, and 15 g of 2-ethylaminobenzyl bromide hydrobromide was added portionwise to the suspension. The mixture was stirred for six hours at room temperature, the precipitate was filtered off with suction, washed with THF and petroleum ether and dried under reduced pressure at about 80 ° C.

The obtained hydrobromide was added to 400 ml of 1% aqueous NaOH solution and stirred at room temperature for two hours. The free base was filtered off with suction, washed with water and dried. Sp. 162 ° C (decomposes).

b) 2- (2-Ethylaminobenzylsulfinyl) -5,6-dimethoxybenzimidazole • To 3.4 g of 2- (2-ethylaminobenzylthio) -5,6-dimethoxybenzimidazole in 100 ml of methylene chloride was added dropwise. with stirring for 10 minutes at room temperature at 10 m 9 910, 2.0 g of 85% m-chloroperbenzoic acid dissolved in 70 ml of methylene chloride. Stirring was continued for 20 minutes, then excess 2-M NH 4 OH aqueous solution was added, the organic phase was separated, dried over sodium sulfate and evaporated on a rotary evaporator. The residue was stirred with a small amount of acetone, filtered and recrystallized from acetone and dried. Sp. 168 ° C (decomposes).

Example 2 10 General procedure for the preparation of free benzimidazole derivatives from benzimidazole sodium salts

A mixture of equal parts of tetrahydrofuran and saturated NaHCO 3 solution is suitable for the conversion of the sodium salts into the free sulfinylbenzimidazoles of the general formula I. The organic phase is evaporated and the crystalline product is washed with diisopropyl ether.

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Claims (2)

A process for the preparation of therapeutically active benzimidazole derivatives of the formula 5 "V4 R5 which A is -S- or -SO-, R 1 is C 1-4 alkyl, preferably methyl or ethyl, R 3, R 4, R 5 and R 6 are the same or various and means hydrogen, C1-4 alkyl or methoxy and R13 and R14 are the same or different and mean C1-4 alkoxy, and to prepare their physiologically acceptable salts, characterized therein. . a compound of the formula '' R13 'YVe1 (II): V: 30' in which R13 and R14 mean the same as above and Q1 is i) a leaving group or ii) a group -SH or -S ~ react with a compound of formula 16 (iii) r4 I5 in which R1, R3, R4, R5 and R6, mean the same as. above, Q2 in the above-mentioned case i) is -SH- or -S- and in the above-mentioned case ii) a leaving group, and the monovalent compound of formula I, in which A is -S-, is optionally oxidized to a corresponding compound, in which A is -SO-, and the monovalent compound of formula I is optionally transformed into a physiologically acceptable site. A process according to claim 1, characterized in that 2- (2-ethylaminobenzylsulfinyl) - 5,6-dimethoxybenzimidazole or its physiologically acceptable site is prepared. l!