NO169169B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE SUBSTITUTED BENZIMIDAZOLES - Google Patents

Description

The present invention relates to the production of new therapeutically active substituted benzimidazoles.

Benzimidazole derivatives with analgesic effect are known from DE-A 22 46 429, those with gastric acid secretion-inhibiting effect are e.g. known from DE-A 25 48 340, EP-A 5129, DE A 32 40 248 and DE-A 33 33 314. Further benzimidazole derivatives are proposed in DE-B 35 09 333.1. DE-A 3531 487 and EP-A 174 717 likewise relate to benzimidazole derivatives.

It has surprisingly been found that certain substituted benzimidazoles are highly potent gastric acid secretion inhibitors.

According to the present invention, new therapeutically active substituted benzimidazoles with the general formula have thus been provided:

where

A means -S- or -SO-,

R 1 means C.-C. alkyl, preferably methyl or ethyl,

2 7 8 15

R , R , R and R mean hydrogen,

3 4 5 6

R , R , R and R are the same or different and mean hydrogen, (C 1 -C 4 ) alkyl or methoxy, or R 4 and R < 5 > together mean -CH=CH-CH=CH,

13 14

R and R are the same or different, and mean hydrogen and/or (C^-C^) alkoxy,

as well as their physiologically acceptable salts.

Any chiral C- or S-amines present can occur in R- as well as in S-configuration. In such cases, the compounds of formula I are available in the form of the pure enantiomers or as a mixture of stereoisomers (eg

enantiomeric mixture or diastereomer mixture).

As salts, alkali and alkaline earth metal salts, and salts of inorganic or organic acids such as e.g. HCl, HBr, f^SO^, methanesulfonic acid, amido-sulfonic acid, p-toluenesulfonic acid.

The alkyl and alkoxy groups can be straight or branched.

According to the present invention, the compounds of formula (I) are prepared by:

a) reacts a compound with the formula:

13 14 15

where R , R and R have the meanings given above, and

Q 1 i. means a cleavable group or

ii. means -SH, -S or _S02~ ,

with a compound of the formula:

where R1, R2, R3, R4, R5, R6, R7 and R8 have the above

given meanings, and

2

Q in the above case (i) means -SH, -s or -SO2~,

in the above case (ii) means a leaving group,

b) reacts a compound with the formula:

13 14 where R and R have the meanings given above, with a compound of the formula:

where R1, R<2>, R3, R4, R5, R6, R7, R8 and A have the meanings given above, and

1 6

R means a (C 1 -C 8 ) alkyl or benzyl group, or

c) for the preparation of a compound of formula (I) where R 1 and R 2 respectively mean hydrogen, reduces

a compound with the formula:

where R<3>, R<4>, R<5>, R<6>, R<7>, R8, R13, R14 and R1<5> have the meanings given above, and A means a sulfur atom,

the compounds of formula obtained according to a), b) or c).

3 fi

(I) where A means -S- or SO- and/or R to R and/or

13 14

R , R means -S- or -SO2-containing residues are oxidized

to corresponding -SO groups,

a compound of formula (I) where R 1 and/or R 2 means hydrogen, is alkylated or acylated,

1 2

a compound of formula (I) where R and R are acyl is subjected to a deacylating hydrolysis or hydrogenolysis, a thus obtained compound of formula (I) is optionally transferred to its physiologically acceptable salt.

1 2

Cl, Br, J, -OS02CH3, -0-SO2CF3 or -0-SO2C6 ~ H4-pCH3 can be mentioned as cleavable groups Q or Q in method a).

The reaction of a compound of formula II with a compound of formula III or their salts takes place in an inert solvent, such as e.g. water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methylene chloride, acetone, acetic acid ethyl ester, dimethylformamide, acetonitrile, dimethylacetamine, dimethylsulfoxide or mixtures of these solvents. The reaction is carried out in the presence or absence of an inorganic or organic base, as sodium or potassium hydroxide, -carbonate, -alkoxide, -hydride, -amide, ammonia, triethylamine, tributylamine, pyridine can be used. The reaction temperature is between -20 and +150°C, preferably at 0-80°C.

The compounds of formula II are known from the literature or can be prepared analogously to the known methods, e.g. by ring closure of correspondingly substituted o-phenylenediamines with sulfur carbon (e.g. DE-A-31 32 167).

The o-phenylenediamines required for this are also known from the literature, and can be obtained, e.g. by catalytic reduction and correspondingly substituted o-nitroanilines.

Compounds of formula III are likewise known from the literature, or can be prepared analogously with the known methods.

The transesterifications of the compounds of formula IV with the compounds of formula V in method b) take place analogously to the methods described in Preston et al., Benz-imidazoles and Congenetic Tricyclic Compounds, Part 1,

New York, pages 10-13.

Particularly suitable reducing agents in method c) for compounds of formula VI are tin(II) salts such as SnC₂. The reduction is particularly advantageously carried out in an aqueous medium or in mixtures of an aqueous phase with polar organic solvents under strongly acidic conditions, for example in a concentrated hydrochloric acid between G" and 100°C, preferably between 20 and 80°C.

separation and isolation of the substance preferably takes place under alkaline conditions in a manner known per se from the literature.

The 2-(2-nitrobenzylthio)benzimidazole derivatives used as starting products are obtained corresponding to method a) ii. in a manner known per se by reaction with 2-mercaptobenzimidazole of formula II with a 2-nitrobenzyl halide, preferably with a 2-nitrobenzyl chloride or bromide derivative of formula VII (Hal = Cl or Br).

The thus formed compounds of formula I in which A

may mean -S-, if R 3 means hydrogen, is converted with bases into physiologically acceptable salts.

The compounds of formula I where A = -S- can further be converted with suitable oxidizing agents to those where A = -S0-.

This reaction takes place in a suitable inert solvent such as e.g. methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, acetic acid ethyl ester, acetic acid, trifluoroacetic acid, water, methanol, ethanol or mixtures thereof at from -20°C to +150°C, preferably from

-10°C to +40°C.

As oxidizing agents, e.g. hydrogen peroxide, peracids and peresters such as peracetic acid, trifluoroperacetic acid, monoperphthalic acid, m-chloroperbenzoic acid, and their esters, ozone, dinitrogen teroxide, iodosobenzene, N-chlorosuccinimide, 1-chlorobenzotriazole, sodium hypochlorite, potassium peroxydisulfate, p-butyl hypochlorite, tetrabutylammonium periodate or - permanganate, sodium meta-periodate, selenium or manganese dioxide, cerammine nitrate, chromic acid, chlorine, bromine, diazabicyclo /2,2,27octane-bromine complex, dioxane dibromide, pyridinium perbromide.

Likewise, isolated, possibly immobilized oxidized enzymes or microorganisms can be used as oxidizing agents.

Oxidizing agents are used in equimolar amounts, possibly also in a small excess of 5-10 mol-% in the oxidation of

A = -SO-.

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

They clearly inhibit gastric acid secretion and also have

an excellent stomach and intestinal protection effect.

In this context, "stomach and intestinal protection" is understood to mean the change and treatment of gastrointestinal diseases, especially gastrointestinal inflammatory diseases and lesions (e.g. ulcus ventriculi, ulcus duodeni, gastritis, hyperazides or drug-induced stomach irritation), which can for example are caused by microorganisms, bacterial toxins, drugs (e.g. antiphlogistics and antirheumatics), chemicals (e.g. ethanol), stomach acid or stressful situations.

Because of. their excellent properties make the compounds of formula I and their pharmacologically acceptable salts well suited for use in human and veterinary medicine,

they are especially used for the treatment and prophylaxis of diseases of the stomach and intestines, and such diseases which are due to increased gastric acid secretion.

Pharmaceutical preparations contain one or more compounds of the general formula I and/or their pharmacologically acceptable salts.

The preparations are produced according to usual procedures known per se to those skilled in the art. As pharmaceuticals, the pharmacologically active compounds (= active substances) according to the invention are used, 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 substance content preferably constitutes

between 0.1 and 96%.

Such auxiliaries which are suitable for the desired drug formulations are often known to the person skilled in the art due to his professional knowledge. Alongside solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, antioxidants, dispersants, emulsifiers, antifoams, taste correctors, preservatives, solubilizers or dyes can be used, for example.

The active substance can be applied orally or parenterally, the oral application being preferred.

In general, in human medicine it has proven advantageous to administer the active substance(s) by oral administration in a daily dose of 0.01-20 mg/kg body weight, possibly in the form of several, preferably 1 to 4 single administrations.

is for achieving the desired result. In the case of parenteral treatment, it can be used correspondingly or

(especially with intravenous administration of the active substance), usually lower dosages. Determination of the resp. the necessary optimal dosage of the application type of the active substance can be carried out by any expert due to his professional knowledge.

Shall the compound produced according to the invention and/or

their salts are used to treat the above diseases, then the pharmaceutical preparations may also contain one or more pharmacologically active ingredients from other drug groups, such as antacids, resp. aluminum hydroxide, magnesium aluminate, tranquilizers, such as benzodiazepines, for example dia-

zepam, spasmolytics, such as bietamiverine, camylofin, anticholenergica, such as e.g. oxyphenyllimine, fencarbamide, local anaesthetics, such as e.g. tetracaine, procaine, possibly also ferments, vitamins or amino acids.

For an oral application form, the active compounds are formed with the usual additives such as carriers, stabilizers or inert diluents, and are brought by means of usual methods into a suitable administration form such as tablets, dragees, injectable capsules, aqueous alcohols or oily suspensions, or aqueous alcoholic or oil solutions. As inert carriers, it can e.g. gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, are used. Thereby, the preparation can take place as well as dry or wet granules. For example, vegetable or animal oils such as sunflower oil or cod liver oil come into consideration as oily carriers or solvents.

For subcutaneous or intravenous use, active compounds or their physiologically tolerable salts are brought, if desired, with the usual substances such as solubilizers, emulsifiers or further auxiliaries in solution, suspension or emulsion. As a solvent for the new active compounds and the corresponding physiologically tolerable salts, e.g. in question: Water, physiological saline solutions or alcohols, e.g. ethanol, propanol or glycerol, to this also sugar solutions such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.

The invention will be explained in more detail with the help of some examples.

Example 1

2-(2-ethylaminobenzylsulfinyl)-5,6-dimethoxy- benzimidazole. a) 2-(2-ethylaminobenzylthio)-5,6-dimethoxybenzimidazole.

10.5 g of 5,6-dimethoxy-2-m.ercaptobenzimidazole are suspended

in 250 ml of THF and mixed in portions with 15 g of 2-ethylamino-benzylbromide-hydrobromide. It is stirred for 6 hours at room temperature, then the precipitate is filtered off with suction, washed with THF and petroleum ether and dried under reduced pressure at approx. 80OC.

The hydrobromide formed is introduced into 400 ml of 1% aqueous sodium hydroxide solution, and stirred for 2 hours at room temperature. The free base is suctioned off, washed with water and dried.

Sm.p. 162°C during decomposition.

2-(2-ethylaminobenzylsulfinyl)-5,6-dimethoxybenzimidazole.

To 3.4 g of 2-(2-ethylaminobenzylthio)-b,6-dimethoxy-benzimidazole in 100 ml of methylene chloride, 2.0 g of 85% m-chloroperbenzoic acid dissolved in 70 ml of methylene chloride at room temperature are added dropwise with stirring over the course of 10 minutes .

Stir for 20 minutes, mix with excess

2-n aqueous ammonia solution and separate the organic phase for drying over sodium sulphate and invert, stir with a little acetone, suction off, recrystallize from acetone and dry.

Sm.p. 16 8°C during cleavage.

Claims (2)

1. Analogy method for the preparation of therapeutically active compounds of the formula: when A means -S- or -SO-, R is methyl C 1 -C 4 alkyl, preferably methyl or ethyl, 2 7 8 15 R , R , R and R mean hydrogen, R<3>, R<4>, R5 and R<6> are the same or different and mean hydrogen, (Cj-C^) alkyl or methoxy, or R 4 and R<5> together mean -CH=CH-CH =CH-, 13 14 R and R are the same or different, and mean hydrogen and/or (C₁-C₁) alkoxy, as well as their physiologically acceptable salts, characterized by: a) reacting a compound with the formula: 13 14 15 where R , R and R have the meanings given above, and Q 1 i. means a removable group or ii. means -SH, -S~ or -S02~, with a compound of the formula: where R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings given above, and Q in the above case (i) means -SH, -S or -SC>2 , in the above case (ii) means a leaving group, b) reacts a compound with the formula: 13 14 where R and R have the meanings given above, with a compound of the formula: where R1, R2, R3, R4, R5, R6, R7, R8 and A have the meanings given above, and R 1 fi means a (Cj-Cg) alkyl or benzyl group, or c) for the preparation of a compound of formula (I) 1 2 where R and R respectively mean hydrogen, reduces a compound of the formula: where R<3>, R<4>, R<5>, R<6>, R<7>, R8, R13, R14 and R<15> have the meanings given above, and A means a sulfur atom, the compounds of formula 3 6 (I) obtained according to a), b) or c) where A means -S- or SO- and/or R to R and/or 13 14 R , R means -S- or -SO2-containing residues are oxidized to corresponding -SO- groups; a compound of formula (I) where Ri and/or R 2 means hydrogen, is alkylated or acylated, 1 2 a compound of formula (I) where R and R_denote acyl is subjected to a deacylating hydrolysis or hydrogenolysis, a thus obtained compound of formula (I) is optionally transferred to its physiologically acceptable salt. 2. Analogous method according to claim 1, for the production of 2-(2-ethylaminobenzylsulfinyl)-5,6-dimethoxybenzimidazole or its physiologically acceptable salt, characterized in that correspondingly substituted starting materials are used.