FI59590B - FOERFARANDE FOER FRAMSTAELLNING AV THERAPEUTIC ACTIVE SUBSTITUTES BENSIMIDAZOLER ELLER SYRAADDITIONSSALTER DAERAV - Google Patents

Description

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c (45) Patent ayinr-rity 10 39 1901 Vs ^ '(51) Kv.ik? /int.ci.3 C 07 D 401/12, 235/28 ENGLISH —EN N LAN D (21) PiMnttlh * k * mu «—Ρμ · λ * μΛΙ« * Ιο * 750I + 21 (22) Hkkamltpllvt - Antttknlnpdtg lU .02.75 ^ ^ (13) Alkuptlvt — Glttighatadag lL.02.75 (41) Tullut lulktouksl - MMt offantlig 19 · 08.75

National Board of Patents and Registration (44) Nihtlvikslptnon ft kuLLililiu pvm. -

Patent- och registerstyrelsen 'AnattkM utlagd odi utl ^ kriftwi puMkerad 29.05.81 (32) (33) (31) Pyydetty «Tuoikuut — Begird prlorltet 18.02. lk

Sweden-Sweden (SE) 7 ^ 02101-5 (71) AB Hässle, Fack, S-l + 31 20 Mölndal 1, Sweden-Sweden (SE) (72) Peder Bernhard Berntsson, Mölndal, Stig Äke Ingemar Carlsson, Mölnlycke, Lars Erik Garberg, Mölnlycke, Ulf Krister Junggren,

Pixbo, Sven Erik Sjöstrand, Kungsbacka, Gunhild Vika von Wittken Sundell, Askim, Sweden-Sweden (SE) (7l) Berggren Oy Ab (5 * 0 Analogue method for the preparation of therapeutically active substituted benzimidazoles or their acid addition salts eller syraadditionssaJLter därav

This invention relates to an analogous process for the preparation of new therapeutically active substituted benzimidazoles or their acid addition salts of general formula I.

R I

R 4 3 4 wherein the substituents R, R, R, A and Het have the meanings defined in claim 1.

The compounds of the formula I and their acid addition salts have valuable pharmaceutical properties because they affect the gastric acid secretion of mammals, i.e. also humans. A particularly advantageous property of these compounds is that they inhibit externally or internally stimulated gastric acid secretion and the new compounds are therefore suitable for the treatment of peptic gastric ulcers.

The alkyl R and R 1 of the general formula I can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

59590

Halogen R and may be fluorine, iodine, bromine or chlorine, preferably bromine or chlorine.

Carboxy R and R 2 are the group HOOC-.

3

Carboalkoxy R and R are a group alkyl -O-OC-, wherein the alkyl group contains 1 to 4 carbon atoms, preferably up to 2 to 3 carbon atoms. Carboalkoxy R and R are, for example, carbomethoxy (CH 2 OOC-) or carboethoxy (C 2 H 1 -OOC-).

3

Alkoxy R and R can be, for example, methoxy, ethoxy, n-propoxy or isopropoxy.

3

Hydroxyalkyl R and R having up to 4 carbon atoms may be straight or branched and are e.g. hydroxymethyl, 1-hydroxypropyl-2,1-hydroxyethyl-2 or 1-hydroxy-2-methylpropyl-2.

Alkanoyl R and R 2 may, for example, be formyl, acetyl or propionyl, i.e. O, O or O.

11 11 n HC-CH, C-CH3CH, C-4

Alkanoyl R may be one of the groups mentioned above, i.e. e.g. formyl, acetyl or propionyl.

4

Carboalkoxy R is an alkyl-O-OC- group in which the alkyl group has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, and is e.g.

carbomethoxy (CH, OOC-) or carboethoxy (C-HcOOC-).

J 2d

The heterocyclic group Het is a 2-pyridyl group which may be substituted by alkyl or halogen. Such alkyl groups are preferably lower alkyl groups such as methyl, ethyl or propyl. Such halogen substituents are preferably chlorine or bromine.

The method according to the invention is characterized by what is apparent from the appended claims.

3,59590

The reactive esterified hydroxy group Z or Z1 in reaction variant a) is a hydroxy group esterified with a strong inorganic or organic acid, preferably a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, in addition to a sulfuric acid or a strong organic sulfonic acid such as sulfuric acid. , 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid. Thus, Z and Z * are preferably chlorine, bromine or iodine.

Depending on the process conditions and the starting material, the final product is obtained either as the free base or in the form of its acid addition salt, which are within the scope of the invention. Thus, for example, basic, neutral or mixed salts can be obtained as well as hemiamino, sesquis or polyhydrates. The acid addition salts of the novel compounds can be converted into the free base in a manner known per se using, for example, basic substances such as alkali or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the preparation of acid addition salts, those acids which form suitable therapeutically acceptable salts are preferably used. Such acids include, for example, hydrohalic acids, sulfonic acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulfonic acids such as formic acid, acetic acid, lactic acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or palic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, ethanesulfonic acid, salicylic acid, p-aminosalicone, p-aminosalicyl halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acid; methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, such as picrates, can act as a scavenger for the resulting free bases when the 59590 free bases are converted to salts, these are separated and the bases are then re-released from the salts. Due to the close structure between the new compounds in free form and their salts, it is to be understood from above and below that the reference to free compounds and their effects in many cases also applies to the corresponding salts, unless otherwise stated.

Some of the novel compounds, depending on the choice of starting materials and process, may be present as optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, may be present as an isomeric mixture (racemic mixture).

The resulting mixtures of isomers (racemic mixtures) can, depending on the physicochemical differences between the components, be separated into both stereoisomeric (diastereoisomeric) pure racemates, e.g. by chromatography and / or fractional crystallization.

The racemate obtained can be separated by known methods, e.g. by recrystallization from an optically active solvent, by microorganisms or by reaction with optically active acids which form salts of the compound and separating the salts thus obtained, e.g. by diastereomers substance. Suitable useful optically active acids are, for example, the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, maleic acid, mandelic acid, camphorsulfonic acid or quinic acid. The more active portion of both antipodes is preferably separated.

The starting materials are known or can be prepared by methods known per se if they are new.

The principle and application of the invention are described below. Temperatures are given in ° C.

The starting materials in the examples below were prepared as follows: A 5,59590 1,2-diamino compound such as o-phenylenediamine was reacted with potassium methylxanthate (Org. Synth, Vol. 30, page 56) to form 2-mercaptobenzimidazole.

2-Chloromethylpyridine was prepared by reacting 2-hydroxymethylpyridine with thionyl chloride (Arch. Pharm. Vol. 26, pages 448-451 (1956)).

2-Chloromethylbenzimidazole was prepared by condensing o-phenylenediamine with chloroacetic acid.

Example 1 0.1 mol of 4-methyl-2-mercaptobenzimidazole was dissolved in 20 ml of water and 200 ml of ethanol containing 0.2 mol of sodium hydroxide, 0.1 mol of 2-chloromethylpyridine hydrochloride were added and the mixture was refluxed for 2 hours. The sodium chloride formed was removed by filtration and the solvent was evaporated in vacuo. The residue was dissolved in acetone and treated with activated carbon. An equivalent amount of concentrated hydrochloric acid was added, after which (2-pyridylmethylthio) -4-methyl-2-benzimidazole monohydrochloride was separated. Yield 0.05 mol, melting point 137 ° C.

Examples 2-27

The preparation was performed according to Example 1. The compounds prepared are listed in Table 1 below.

Example 28 13.5 g (0.05 mol) of 2- (2-pyridylmethylthio) -benzimidazole hydrochloride, 3.9 g (0.05 mol) of acetyl chloride and 10.1 g (0.1 mol) of triethylamine were dissolved in 100 ml of acetonitrile. The mixture was heated at 40 ° C in a water bath for 30 min. The crystals formed after cooling were collected by filtration and suspended in water to dissolve triethylamine hydrochloride. The residue, 2- (2-pyridylmethylthio) -N-acetylbenzimidazole, was removed by filtration. Yield 7.2 g (51 S). Sp. 119-124 ° C as a base.

6 59590

Example 29 2- (2-Pyridylmethylthio) -N-methoxycarbonylbenzimidazole was prepared according to Example 28 above.

Example 30 17.2 g of 2-pyridinemethylthiocarboxylic acid and 12.2 g of 4-methyl-o-phenylenediamine were boiled for 40 minutes in 100 ml of 4N hydrochloric acid. The mixture was cooled and neutralized with ammonia. The neutral solution was extracted with ethyl acetate. The organic phase was purified on activated carbon and evaporated in vacuo. The residue was dissolved in acetone, followed by the addition of an equivalent amount of concentrated hydrochloric acid. After cooling, the precipitated hydrochloride was filtered off and the salt was recrystallized from absolute ethanol and an ether. There was obtained 2- (2-pyridylmethylthio) -4-methylbenzimidazole (5.3 g), m.p. 137 ° C (HCl).

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9 59590

Biological effect

The compounds of the invention have valuable therapeutic properties as compounds acting on gastric acid.

Thus, a testing technique for compounds with secretory activity was used in dogs. The test was performed in accurate dog experiments with a modified perfusion technique.

Anesthetized dog's stomach was supplied with one tube for supplying the liquid through the esophagus and the other tube was fitted to the stomach via the duodenum tied down directions through a fluid removal. The saline solution was instilled in at 5 ml / kg body weight and the instilled liquid was changed every 15 min.

The collected samples were titrated to pH 7.0 with 0.04 N sodium hydroxide using a Radiometer automatic titrator and the acid production every 15 min was counted (collection periods).

Gastric acid secretion was induced by pentagastrin at 1-2 ug / kg for one hour, giving an almost maximal secretory effect.

Test compounds were administered in 0.5% Methocel suspension in the duodenum near the dressing for at least 2 hours after the start of stimulation after secretion had reached a steady state for three consecutive 15 min periods.

The effect on gastric acid secretion was taken into account, in which case it was found that all the compounds of the above-mentioned examples were inhibitors of gastric acid secretion.

Norwegian Patent Publication 133,196 discloses N-methyl-N '- [2 - ((5-methyl-4-imidazolyl) -methyl) -ethyl] -thiourea, which resembles some of the compounds prepared by the process of this invention, and has an antacid activity.

10 59590

Table 2 compares said compound (labeled A: 11a in the table) with the compounds prepared according to Examples 1, 3 and 9. A comparison test was performed on anesthetized dogs with a vertical hoop. Gastric acid secretion in dogs was stimulated with pentagastrin. The amount of gastric acid secretion was determined titrimetrically before and after administration of the blocked compound. Table 2 shows the percent inhibitory effect in relation to initial excretion, as well as the dose of test compound mg / kg administered to dogs.

Table 2

Compound Time Inhibitory effect%

Dose 123 hours A 2 mg / kg 50 30 20

Eg 1 "50 60 65

Ex. 3 "50 60 65

Eg 9 "50 60 65 A 1 mg / kg 15 0 0

Eg 1 "20 25 25

Eg 3 "20 25 25

Eg 9 "20 25 25

As can be seen from Table 2, the preliminary inhibitory effect on gastric acid secretion is of the same order of magnitude for the known compounds prepared by the method of the invention. However, the compounds prepared by the method of the invention have a significantly better duration of the inhibitory effect, i.e. the inhibitory effect is better after 2 and 3 hours after administration of the compound.

Table 3 shows the inhibitory effect values obtained according to the screening test described above for some of the compounds prepared according to the invention.

11 59590

Table 3

Eg 1 3 5 9 15 27 28

Inhibitory effect% 10 mg / kg 89 86 40 70 50 80 76

Table 3 shows that the compounds have a strong inhibitory effect on gastric acid secretion.

The present invention provides for the use of a therapeutically active substituent benzimidazoler or a compound of formulation which is suitable for the formulation.

R3 yy \

|! V A -Het I

W 1 N / R 1 «3 4 are substituents R, R, R, A and Het har de i patentkravet 1 givna betydelserna.

For example, the first and the following formulations are used in the form of a pharmaceutical form of the invertebrate head of the magnesia secretion, which is dvs. In particular, the excipients are present in which the exogenous or endogenous stimulation of the nucleus secretion and in the case of the extracellular warming of the pigs account for the use of the peptide nucleus.

3 I have all the formulas I with alkyl R and R reserve t.ex. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

3

Halogen R and R can be fluorine, iodine, Bromine or chlorine, formate Bromine or chlorine.

Carboxy R and R 3 are HOOC-.

3

Carboalkoxy R and R are alkyl groups -0-00, with alkyl groups having 1-4 colaters, preferably 2 colaters. Carbo- 3,59590 alkoxy R and R är t.ex. carbomethoxy (CH 2 OOC-) or carboethoxy (c2h5ooc-).

3

Alkoxi R och R kan t.ex. copper, methoxy, ethoxy, n-propoxy or isopropoxy.

3

Hydroxyalkyl R and R with up to 4 cholaters can be added or substituted with hydroxymethyl, l-hydroxypropyl-2,1-hydroxyethyl-2 or l-hydroxy-2-methylpropyl-2.

3

Alkanoyl R and R kan t.ex. copper formyl, acetyl or propionyl, dvs 0, 0 or 0

II II II

HC- CH3C- CH3CH2C-

Alkanoyl can be found in the form of a group, dvs. exempted formyl, acetyl or propionyl.

Carboalkoxy groups are alkyl-O-OC-, with alkyl groups having 1-4 cholaters, for example 1-2 cholaters, and then t.ex. carbomethoxy (CH 2 OC-) or carboethoxy (C 1 H 2 OOC-).

The heterocyclic group is a 2-pyridyl group which may be substituted by alkyl or halogen. As an alkyl group, the alkyl group is optionally methyl, ethyl or propyl. Halogenated substituents are chlorinated or brominated.

For the purposes of this Regulation, the provisions of this Regulation do not apply.

In the case of reactive hydroxyl groups Z or Z, the reaction alternatives are a) a hydroxyl group, which is a starch group with a starch or an organic substance, a compound with a halogen content, a salt salt, a bromide content or an iodine content, Stark organic sulfonic acid is added to Stark aromatic syrup, t.ex. benzenesulfonyl, 4-Bromobenzenesulfonyl or 4-toluenesulfonyl. Sälunda är Z och Z ^ · fördelaktigt chloro, Brom eller iod.

Beroende pä processförhällandena och utgängsämnet erhälls slutproductten antingen säsom en fri bas eller et syraadditionssalt därav, t- 13 59590 vilka bägge är inom ramen förfpinningen. Härvid kan exempelvis erhällas basiska, neutrala eller blandsalter sAsom även hemiamino-, seskvi- eller polyhydrater. Syraadditionssalter av de nya föreningar-na kan med i sig kända förfaranden överföras till fria baser genom användning t.ex. basiska ämnen säsom ett alkali eller en jon-bytare. Andra sidan kan de erhAllna fria baserna bilda salter med organic or oorganiska syror. Vid framställning av syraadditionssalter används fördelaktigt sAdana syror, vilka bildarluspliga therapeutiskt acceptable salter. SAdana syror är t.ex. halogenated syrup, sulfone syrup, phosphorus syrup, salpetersyra, perchloric syrup, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulfone syrup, sAsom myrsra, acetic acid, citionyra, byrnstensyra, glycol syrup, glycols, eller pyro-druvsyra, phenylathixer, benzoic acid, p-aminobenzoic acid, anthranilicyr, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonsyran, methanesulfonic acid, sulfonyl sulfate, ethanesulfonyl sulfate, hydroxyethane sulfone sulfane, ethylene sulf methionine, tryptophan, lycin or Arginine.

Dessa nämnda eller andra salter sAsom exempelvis pikrater, av de nya föreningarna kan fungera som reningsämnen av de erhallna fria baserna da de fria baserna överförs account salter, dessa avskiljs och baserna frigörs efter detta pA nytt frAn salterna. Beroende pa att den fria formen and salter därav av de nya föreningarna har en mycket liknande structur bör av ov ovämämnda och det som námns i det újande förstas, att det mom föreningarna och deras verkan i de Fiesta fall även de motsvarande salterna, ifali det motsatta inte speciellt omnämnes.

In this case, the assay is based on the use of an optical material and a process, such as an optical antipoder or a race or an auxiliary memory of an asymmetric color atom, and an isomeric assay.

De erhAllna isomerblandningarna (rasematblandningarna) kan, beroende pa ämnesdelarnas physico-chemical skillnader, avskiljas i de bägge stereoisomer (diastereoisomer) Rena rasematen t.ex. genomic chromatographic and / or fractional crystallization.

14 59590

The results of the application are limited to the following, t.ex. The genomic crystallization of the optically active lysis medium, with the presence of microorganisms or genomics in the form of optically active syrups, is characterized by the presence of optically active syrups and the genome of the present invention t.ex. the base of the mixture is treated with a diastereomer, the antipod of which is protected by an inverted cell. With lamp, användbara optiskt aktiva syror är t.ex. L- and D-formerna av vinsyra, di-o-tolyl-vinsyra, maleinsyra, mandelsyra, camphorsulfonyl or kinasyra. For example, an asset with an antipode is required.

Utgängsmaterialen är kända eller kan framställas med i sig kända metoder, ifali utgängsmaterialen är nya.

I set out the principles of application and development. The temperature does not exceed ° C.

However, the following materials are excluded from this Regulation:

In 1,2-diaminoforming, the o-phenylenediamine is treated with potassium methylxanthate (Org. Synth, Vol. 30, en 56) to give 2-mercaptobenzimidazole.

The genome of 2-chloromethylpyridine contains 2-hydroxymethylpyridine medionyl chloride (Arch. Pharm. Vol. 26, supra 448-451 (1956)).

The genome of 2-chloromethylbenzimidazole is condensed with o-phenylenediamine in chlorate.

Exempel 1 0.1 mol of 4-methyl-2-mercaptobenzimidazole are poured into 20 ml of water and 200 ml of ethanol, containing 0.2 mol of sodium hydroxide, 0.1 mol of 2-chloromethylpyridine concentrate, and the mixture is stirred under 2 times. The sodium chloride in the genome is filtered and treated under vacuum. Ater stops are taken up in acetone and treated with active moths. En ekvi-Valent games concentrate saltsyra tillsattes, varefter (2-pyridyl-methylthio) -4-methyl-2-benzimidazole monovalent chlorides avskildes. 0.05 mol, m.p. 137 ° C.

15 59590

Exemplen 2-27

Framställningen utfördes enligt exempel 1. The framställdingen föreningarna är uppräknade i nedanstäende tabell 1.

Exempel 28 13.5 g (0.05 mol) of 2- (2-pyridylmethylthio) -benzimidazole chloride, 3.9 g (0.05 mol) of acetyl chloride and 10.1 g (0.1 mol) of triethylamine are added in 100 ml. acetonitrll. The mixture was heated to 40 ° C under 30 minutes. After this, upstream crystals are used to filter the genomic filtration and suspension in water up to the triethylamine structure. Ether, 2- (2-pyridylmethylthio) -N-acetylbenzimidazole, genome filtration. Yield 7.2 g (51%). Smp. 119-124 ° C at bas.

Exempel 29 2- (2-pyridylmethylthio) -N-methoxycarbonylbenzimidazole is preferably exempted 28.

Exempel 30 17.2 g of 2-pyridinemethylthiocarboxylic acid and 12.2 g of 4-methyl-o-phenylenediamine cocade for 40 minutes in 100 ml of 4N salt syrup. Blandningen av-kyldes och neutraliserades med ammoniak. The neutral solution is extracted with ethyl acetate. The organic form is reacted with an active mole and induced in a vacuum. The mixture is taken up in acetone, which is then treated with the equivalent of concentrated salts.

The hydrochloride is filtered off after cooling and crystallizing with absolute ethanol and ether. The precipitate was 2- (2-pyridylmethylthio) -4-methylbenzimidazole (5.3 g), m.p. 137 ° C (HCl).

16 59590

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Biological effects Fertilizers are enriched in the form of a therapeutic effect with invertebrate secretions.

In this case, the test technician will be responsible for the secretarial activities of the competent authorities. The use of batteries in the genome can be performed with a modified perfusion engineer.

Tili magsäcken av en nedsövd hund fördes et rör genom matstrupen för inmatning av vätska och et rör anpassades via den hopsnörda nedre olppningen av magsäcken genom tolvfingertarmen för avförning av Vätska. Salting in drops is performed at 5 ml / kg by volume and drop by drop for 15 minutes.

The pH was adjusted to 7.0 with 0.04-n sodium hydroxide and an automatic radiometer titration apparatus and syrup production for up to 15 minutes (up-sampling period).

The secretion from the nucleus stimulation with pentagastrin is obtained at a rate of 1-2 .mu.g / kg and the time, the color is excreted and the maximal secretion effect is observed.

The test administration is carried out at a rate of 0.5%. The method suspension is then used for at least 2 minutes after the stimulation, and the secretion is set at a constant level for a period of 15 minutes.

The effects of the secretory secretion are best, the colors are reduced, and the effect of the magnesia secretion is exemplified.

According to the Norwegian patent, 133,196 in N-methyl-N '- / 2 - ((5-methyl-4-imidazolyl) -methylthio) ethyl] thiourea is used as the main compound for the preparation of the active compounds, and in particular for the preparation of magnesia secretions.

I tabell 2 framställs en jämförelse mellan nämnda förening (i tabellen betecknad som A) and föreningarna som framställts enligt exemplen 1, 3 och 9. Jämförelseförsöket utfördes pä vakna hundar, i9 5 9590 vilka försetts med vert vert. Hundarnas magsyrasekre- tion stimulated with pentagastrin. The playing field shall be titrimetriskt for the administration of the authorities and after that date. Table 2 shows that the inhibitory effects in the percentage of the basal secretions, as well as the mg / kg for each administration, are indicated.

Table 2 Forms of inherent effect%

Dosage 1 2 3 Timmar A 2 mg / kg 50 30 20

Exempel 1 "50 60 65

Exempel 3 "50 60 65

Exempel 9 ”50 60 65 A 1 mg / kg 15 00

Exempel 1 "20 25 25

Exempel 3 ”20 25 25

Exempel 9 "20 25 25 Säsom framgär av tabel 2, harden kända ocur förfarandet enligt uppfinningen framställda föreningarna en primary primary inhibitory effect with magsyrasretionen is not the same as in the case of Stora. inherent in the operation of the service 2 and 3 times after the administration.

I tabell 3 framställs inhiberingsvärden för nägra av föreningarna framställda enligt uppfinningen, vilka erhölls enligt ovannämnda screening test.

Table 3

Exempel 1 3 5 9 15 27 28

Inhibitory effect% 10 mg / kg 89 86 40 70 50 80 76

In Table 3, the effect of the kraftig secretion is limited.

Claims (2)

20 5 9 5 9 0 1. An analogous process for the preparation of therapeutically active substituted benzimidazoles or their acid addition salts of the general formula IRL R 4 in which R and R are the same or different and represent hydrogen, an alkyl group, a halogen atom, hydroxy, carboxy, C 1-4 a carboalkoxy, C 1-4 alkoxy, C 1-4 hydroxyalkyl or C 1-4 alkanoyl group, R 4 is hydrogen or a C 1-4 alkanoyl or C 2-4 carboalkoxy group, A is -SCl · ^ - or -SCH (CH 3) - and Het is an optionally C 1-4 alkyl or halogen-substituted 2-pyridyl group 4, provided that when Het is 2-pyridyl, A -SCH 9 and R 3 Δ is hydrogen, R and R are not 5-CH 3 and 6-CH 3, are not hydrogen and 5-C1 or R and R3 do not both represent hydrogen, characterized in that a) a compound of general formula II L is administered. 3 4 wherein R, R and R have the same meaning as above and Z is -SH or reactive esterified hydroxy group, react with a compound of general formula III Z1-CH2Het III wherein Het has the same meaning as above. and is a reactive esterified hydroxy group or -SH group, respectively, or b) administering a compound of general formula IV R 3 - nh 9 R-- | 2 IV to NH 2 21 59590 wherein R and are as defined above, react with a compound of general formula V HOOC-A-Het V wherein Het and A are as defined above, or c) to prepare a compound of general formula I wherein 3 R is a C 1-4 alkanoyl or C 2-4 carboalkoxy group and R, R, A and Het are as defined above, a compound of general formula I or an acid addition salt thereof is given in which R is a hydrogen atom and R, R, A and Het are as defined above. above, react with an alkanoyl chloride or a chloroformic acid ester of the general formula C1-R4, in which R represents a C1-4alkanoyl or C2-4carboalkoxy group, after which the compound of the general formula I thus obtained, if obtained in the form of a base, can be modified if desired. to an acid addition salt, or if the compound is obtained in the form of a salt, may be converted to the free base, if desired. Process according to Claim 1, characterized in that a compound of general formula I is prepared in which R 4 is hydrogen or methyl, R is carbomethoxy, R is hydrogen, A is a -SCH 2 group and Het is a methyl-substituted 2-pyridyl group. 1. Analogifarfarande för framställning av terapeutiskt aktiva substituer benzimidazoler eller syraadditionssalter därav med den allmänna formuleln I hrv * - * R | R 4 is R 1 and R 2 is an alkyl or a C 1-4 alkyl group, a C 1-4 alkyl group, a halogen atom, a hydroxy, carboxy, C 2-5 carboalkoxy, a C 1-4 alkoxy, a C 1-4 hydroxyalkyl or a C 1-4 alkyl group; C 1-4 alkanoyl, R 4 is C 1-4 alkanoyl or C 2-5 carboalkoxy, A is -SCH 2 - or -SCH (CH 2) -, and Het 1 is optionally C 1-4 alkyl or halogen substituted with 2-pyridyl, Het 2-pyridyl, A and -SCH 2 - group and R 4, is R 5 and R 22 22 59590 or 5-CH, and 6-CH 1 or 5-C 1 or R 2 and R 2 are different, kännetecknat av att a) en förening med den allmänna formuleln II> - l1 3 4 där R, R och R betecknar decamma som ovan oc Z and Z är -SH eller reactiver förestrad hydroxygroup, omsättes med en förening med denemnna Formula III Z1-CH2Het III is a straight-chain solution having a hydroxyl group or an -SH group, or (b) a compound having the formula IV R2 R-NH2 IV -NH2 3 of the R-group C-^ alkanoyl - or a C 1-4 carboalkoxy group and R, R, A and Het at the same time as above, in which case the first of the formulas I, then R is the same as R, R, A and Het at the same time as above. , with alkanoyl chlorides or chlorohydroxy esters having all of the substituents 4 to 4, R 1 to R 4 to C 1-4 alkanoyl or C 2 -C 5 carboalkoxy groups, varying the number of compounds obtained from all of the compounds of formula I, behov omvandlas account ett syraadditionssalt, eller dä föreningen utvinns som ett sait vid behov omvandlas account fri bas. 2 to R and R in the case of the form of an overnight form, in addition to the form of a form of the first form of the form I, or (c) for the purpose of the form of the form of the form I,