BE834973A - AGENTS AFFECTING GASTRIC ACID SECRETION - Google Patents

Description

       

  The present invention relates to novel compounds having properties useful in affecting the secretion of gastric acid in mammals, including humans. The invention also covers a method for the preparation of these compounds, the method of affecting gastric secretion, and pharmaceutical preparations relating to said novel compounds.

  
Agents affecting the secretion of gastric acid.

  
The object of the present invention is to obtain

  
compounds which affect gastric secretion, and which inhibit exogenously or endogenously stimulated gastric acid secretion. These compounds can be used for the treatment of peptic ulcer disease.

  
It has now been found that the processes of the above formula have such properties:

  
A. Compounds according to the invention are those of the general formula

  

 <EMI ID = 1.1>


  
 <EMI ID = 2.1>

  
selected from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, carboxy-alkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoyloxy, hydroxy, alkoxy, hydroxy alkyl,

  
 <EMI ID = 3.1>

  
from the group consisting of a straight or branched alkyl chain having 1 to 4 carbon atoms, a single methylene group being present between S and Het, and Het is selected from the group consisting of imidazolyl, imidazolinyl, benzimidazolyl,

  
thiazolyl, thiazolinyl, ouinolyl, piperidyl and pyridyl, these compounds possibly being further substituted, preferably

  
in position 3 to 5, with lower alkyl groups such as ethyl and propyl and / or with halo substituents such as chlorine and bromine, or the therapeutically acceptable salts of these compounds.

  
The alkyl R and R <3> of formula I are advantageously an alkyl having up to 7 carbon atoms, preferably up to 4 carbon atoms. Thus, the alkyl R can be methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

  
The halogen R and R <3> are fluoro, iodo, bromo and chloro, preferably bromo and chloro.

  
 <EMI ID = 4.1>

  
where the alkyl group has up to 4 carbon atoms, preferably up to 2 carbon atoms. Carboxyalkyl R and R <3>

  
are for example carboxymethyl, carboxyethyl.

  
Carboalkoxy R and R <3> are alkyl-O-OC- groups, where

  
the alkyl group has up to 4 carbon atoms, preferably up to 2 carbon atoms. Carboalkoxy R and R <3> are for example

  
 <EMI ID = 5.1>

  
The carboalkoxy alkyl R and R <3> are the alkyl-OOC-alkyll groups, in which the alkyl group has up to 4 carbon atoms, preferably up to 2 carbon atoms, and the alkyl group has up to 4 carbon atoms, from preferably up to 2 carbon atoms, such as:

  
 <EMI ID = 6.1>

  
where the alkyl group has up to 4 carbon atoms, preferably up to 2 carbon atoms such as carbamoylmethyl

  
 <EMI ID = 7.1>

  
 <EMI ID = 8.1>

  
alkoxy having up to 5 carbon atoms, preferably up to 3 carbon atoms, such methoxy, ethoxy, n-propoxy, or isopropoxy.

  
Hydroxyalkyl R and R <3> advantageously have up to 7 carbon atoms, preferably up to 4 carbon atoms, and are straight or branched and are for example hydroxy methyl, 1-hydroxy-propyl-2, 1-hydroxy-ethyl-2 ,

  
or 1-hydroxy-2-methyl-propyl-2.

  
 <EMI ID = 9.1>

  
carbon atoms and are for example: formyl, acetyl, or propionyl.

  
 <EMI ID = 10.1>

  
having up to 5 carbon atoms, preferably up to 3 carbon atoms, and is for example methyl, ethyl, or n-propyl.

  
 <EMI ID = 11.1>

  
carbon, and is for example formyl, acetyl or propionyl.

  
 <EMI ID = 12.1>

  
the alkyl group has up to 4 carbon atoms, preferably up to 2 carbon atoms, and is for example carbomethoxy

  
 <EMI ID = 13.1>

  
alkyr

  
in which the straight or branched alkyl group has up to

  
 <EMI ID = 14.1> ethylcarbamoyl, isopropylcarbamoyl.

  
 <EMI ID = 15.1>

  
wherein the alkyl groups each represent an alkyl group having up to 4 carbon atoms and is for example dimethylcarbamoyl, diethylcarbamoyl, N-methylN-ethylcarbamoyl.

  
 <EMI ID = 16.1>

  
wherein the alkyl group has up to 4 carbon atoms and is for example acetyl-methyl, propionylmethyl.

  
 <EMI ID = 17.1>

  
wherein the alkyl group has up to 4 carbon atoms and is for example methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxyoarbonylmethyl.

  
Alkylsulfonyl is the alkyl-SO2 group in which the alkyl group has up to 4 carbon atoms and is for example methylsulfonyl, ethylsulfonyl, isopropylsulfonyl.

  
 <EMI ID = 18.1>

  
more with alkyl or halogen, preferably at position 3-5. Such alkyl groups are preferably lower alkyl groups such as methyl, ethyl or propyl. Such halogen substituents are preferably chlorine or bromine.

  
The heterooyol group Het is preferably linked in position-2 but may also be linked in position 4 with the rest of the formula.

  
 <EMI ID = 19.1>

  
prepared by the following methods: a) by oxidizing a compound of formula II
 <EMI ID = 20.1>
 <EMI ID = 21.1>

  
fications than those given for the format:! .on of a compound of formula I.

  
b) by reacting the compound of formula III
 <EMI ID = 22.1>
 <EMI ID = 23.1>

  
tions than those given above, and M is a chosen metal

  
 <EMI ID = 24.1>

  
of the formula

  
Z-Het

  
 <EMI ID = 25.1>

  
above, and Z is a reactive esterified hydroxy group

  
 <EMI ID = 26.1> <EMI ID = 27.1>

  

 <EMI ID = 28.1>
 

  
 <EMI ID = 29.1>

  
esterified reactive with a compound of the formula VI

  

 <EMI ID = 30.1>


  
 <EMI ID = 31.1>

  
reactive, or SH, for the formation of an intermediate of formula II above, which is then oxidized to

  
 <EMI ID = 32.1> d) by reacting a compound of formula VII
 <EMI ID = 33.1>
 <EMI ID = 34.1>

  
than those given above for a compound of formula VIII

  
HOOC - S - R6 - Het (VIII)

  
 <EMI ID = 35.1>

  
given above for the formation of an intermediate of formula II above, which compound is then oxidized

  
 <EMI ID = 36.1>

  
converted to its therapeutically acceptable salts, if desired.

  
e) by reacting a compound of the formula
 <EMI ID = 37.1>
  <EMI ID = 38.1>

  
compound of formula I.

  
f) by reacting a compound of the formula
 <EMI ID = 39.1>
 <EMI ID = 40.1>

  
than those given above with an alkylisocyanate for

  
 <EMI ID = 41.1>

  
alkylcarbamoyl, which compound is further oxidized to give a compound of formula I.

  
Reactions e) and f) proceed normally in

  
 <EMI ID = 42.1>

  
* hearth a reactive esterified hydroxy group which is a hydroxy group esterified with a strong inorganic or organic acid, preferably with a hydrohalogenic acid, such as hydrochloric acid, hydrobromic acid or hydriodic acid, also sulfuric acid or a strong organic sulfonic acid, such as a strong aromatic acid, for example the acid

  
 <EMI ID = 43.1>

  
oxidant selected from the group consisting of nitric acid, <EMI ID = 44.1>

  
dinitrogenetetraoxide, iodoso-benzene, N-halosuooinimide,

  
 <EMI ID = 45.1>

  
bromodiazobicyclo- (2,2,2) octane, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid,

  
 <EMI ID = 46.1>

  
is generally done in a solvent in which the oxidizing agent is present in excess with respect to the product which is to be oxidized.

  
According to the operating conditions and according to the starting materials, the final product is obtained either as a free base or in the acid addition salt, these two products being included within the scope of the invention. Thus, basic, neutral or mixed salts can be obtained, as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds can in a manner known per se be converted into the free base by employing basic agents such as alkalis, or by ion exchange.

  
On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the preparation of acid addition salts, the acids forming therapeutically acceptable salts are preferably employed.

  
Such acids include hydrogen halide, sulfonic, phosphoric, nitric and perchloric acids;

  
 <EMI ID = 47.1>

  
carboxy or sulfonic, such as formic, acetic, propionic, inic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, <EMI ID = 48.1>

  
sulfonic, halogenbenzenesulfonic. toluenesulfonic, naphthysulfonic or sulfanilic; methionine, tryptophan, lysine or arginine. These salts or other salts of the new compounds, for example picrates, can serve as agents for purifying the free bases obtained. The salts of the bases can be formed, separated from the solution, and then the free base can be recovered from a new, purer saline solution. Because of the relationship between the new compounds in the free base form and

  
their salts, it will be understood that the corresponding salts are within the scope of the invention.

  
Some of the new compounds may, depending on the choice of materials provided and depending on the operating conditions, be present as optical isomers or racemates, or else if they contain at least two asymmetric carbon atoms, they may be present in the form of an isomeric mixture
(racemate mixture).

  
The isomer mixtures (racemate mixtures) obtained

  
 <EMI ID = 49.1>

  
(diastereomeric) by means of chromatography or fractional crystallization.

  
The racemates obtained can be separated according to known methods, for example by recrystallization from an optically active solvent, by the use of microorganisms, by reaction with optically active salt-forming acids which can be separated, this separation being based on solubilities different from diasteromers. Suitable optically active acids are the L and D forms

  
 <EMI ID = 50.1>

  
malic, mandelic acid, camphrosulfonic acid, or quinic acid. Preferably, it is the more active part of the two antipodes which is isolated.

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

  
In clinical use, the compounds according to the invention are administered orally, rectally or by injection in the form of a pharmaceutical preparation containing an active component either as a free base or as an acid addition salt, non-toxic. , pharmaceutically acceptable, such as the following: hydrochloride, lactate, acetate, sulfamate, in combination with a pharmaceutically acceptable carrier. The support may be in the form of a solid, semi-solid, or liquid diluent, or of a capsule. These pharmaceutical preparations constitute a further object of the present invention. In general, the amount of active compound is between 0.1 and 95% by weight of the preparation,

  
between 0.5 and 20% by weight in the preparations intended to be injected, and between 2 and 50% by weight in the preparations intended to be administered orally.

  
In the preparation of pharmaceutical preparations containing a compound according to the present invention in the form of dosage units for oral administration, the compound chosen:, may be mixed with a powdery, solid carrier, such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin, as well as with an anti-friction agent such as magnesium stearate, calcium stearate and polyethylene glyool waxes. The mixture is then formed into tablets.

  
If it is desired to have coated tablets, the core prepared as above can be coated with a concentrated solution.

  
sugar which may contain gum arabic, gelatin, talc, titanium dioxide, or with a lacquer dissolved in a volatile organic solvent or in a mixture of solvents.

  
Various coloring materials can be added to this coating in order to be able to distinguish between them the tablets having

  
different active compounds or containing different amounts of the active compound present.

  
Soft gelatin capsules can be prepared containing a mixture of the active compound or compounds, active according to the invention and a vegetable oil. Capsules in

  
hard gelatin may contain granules of the active compound

  
in combination with a powdered, solid carrier, such as lactose, sucrose, sorbitol, mannitol, starch

  
potatoes, corn starch, amylopectin,

  
cellulose derivatives and gelatin.

  
Dosage units for rectal administration can be prepared in the form of suppositories containing

  
 <EMI ID = 51.1>

  
neutral fat or they can be prepared under the

  
in the form of total gelatin capsules containing the active substance mixed with vegetable oil or with oil / paraffin.

  
Liquid preparations for oral administration can be prepared in the form of syrups or this

  
 <EMI ID = 52.1>

  
into sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain coloring agents,

  
flavor, saccharin, and carboxymethylcellulose as a thickening agent.

  
Solutions for parenteral administration by injection can be prepared as aqueous solutions of the active compound of a water-soluble pharmaceutically acceptable salt, preferably in concentrations

  
 <EMI ID = 53.1>

  
also contain stabilizers and / or buffering agents and can be made in ampoules which differ in dosage unit.

  
Pharmaceutical tablets for oral use are prepared as follows: the solids are crushed or sieved to a certain particle size and the binding agent is homogenized and suspended in a suitable solvent. Therapeutically active compounds and auxiliary agents are mixed with a solution of binding agent, the resulting mixture is moistened so as to form a uniform suspension having the consistency of wet snow, the moistening produces

  
slight aggregation of the particles and the resulting mass is squeezed through a stainless steel sieve having a mesh size of about 1 mm. The layers of the mixture are dried in carefully controlled drying cabinets for 10 hours to achieve the required particle size and consistency. The granules of the dried mixture are sieved to remove any dust.

  
To this mixture are added disintegrating, anti-friction and anti-adhesive agents. Finally * the mixture is compressed into tablets using a machine having the appropriate mandrels and dies to achieve the desired dimensions for the tablets. The pressure that

  
has been applied affects the dimensions of the tablet, its strength and its ability to dissolve in water. The compression pressure used should be included

  
between 0.5 and 5 tonnes. The tablets are manufactured at a rate of 20,000 to 200,000 per hour. The tablets, especially those which are coarse or bitter in taste, may be coated with a coating of sugar or

  
other pleasant tasting substance. They are then packed by machines with electronic devices.

  
count. The different types of packaging consist

  
in glass or in small plastic jars, in boxes, tubes and in various specific packaging suitable for

  
specific dosages.

  
The typical daily dose of the active substance varies according to individual needs and according to the method of administration. In general, dosages for administration

  
oral are between 100 and 400 mg / per day of active substance and dosages for intravenous administration are between 5 and 20 mg per day.

  
A preferred embodiment of the invention is described below, without however being limited thereto.

  
The temperature is given in degrees Centigrade.

  
The starting materials in the examples below were prepared by the following methods:

  
1) a 1,2-diamino compound, such as o-phenylenediamine, was reacted with potassium ethylxanthate
(according to Org. Synth. Vol. 30 p. 56) to form a 2-mercaptobenzimidazole.

  
2) The 2-chloromethylpyridine compound was prepared by reacting 2-hydroxymethylpyridine

  
with thionyl chloride (according to Arch. Pharm. Vol. 26,

  
pp. 448-451 (1956);

  
 <EMI ID = 54.1>

  
prepared by condensing o-phenylenediamine with chloroaaetic acid.

Example 1.

  
28.9 g of 2- (2-pyridylmethylthio) -benzimidazole have

  
 <EMI ID = 55.1>

  
m-Chloroperbenzoic was added in portions, with stirring, and cooled to 5 [deg.] C. After 10 minutes, the acid

  
 <EMI ID = 56.1>

  
Examples 2 to 30.

  
 <EMI ID = 57.1>

  
 <EMI ID = 58.1>

  
identifies the substituents for these compounds.

  
 <EMI ID = 59.1>

  
were dissolved in 20 ml. of water and 200 ml. of ethanol containing 0.2 mole of sodium hydroxide. Ona added

  
 <EMI ID = 60.1>

  
the mixture was refluxed for two hours.

  
The sodium chloride formed was filtered off and the solution was evaporated in vacuo. The residue was dissolved in acetone and was treated with activated carbon. An equivalent amount of concentrated hydrochloric acid was added, and the mono-.

  
 <EMI ID = 61.1>

  
benzimidazole. Yield: 0.05 moles; Fusion point
137 [deg.] C.

  
This compound was then oxidized according to Example 1 above.

  
Example 32 (method b)

  
 <EMI ID = 62.1>

  
and 0.1 mole 2-ehloropyridine was added and the mixture was refluxed for two hours. The lithium chloride formed was separated by filtration and the solution was evaporated in vacuo. The residue was crystallized from OISON and was recrystallized from the same solvent. The yield was

  
 <EMI ID = 63.1>

  
which melted between 151-154 [deg.] C.

  
Example 33 (method d).

  
18.3 gr of 2 - ((2-pyridine) methylthio) formic acid

  
 <EMI ID = 64.1>

  
for 40 minutes in 100 ml. of 4N HCl. The mixture was cooled and made neutral with ammonia. The neutral solution was then extracted with ethyl acetate. The organic phase was treated with activated carbon and evaporated in vacuo. The residue was dissolved in acetone and then one equivalent of concentrated HCl was added. The precipitated hydrochloride was filtered off after cooling and the salt <EMI ID = 65.1>

  
This compound was then oxidized according to Example 1 above.

  
Example 34 (method e).

  
 <EMI ID = 66.1>

  
were dissolved in 100 ml. acetonitrile. The mixture was heated to 40 [deg.] 0 'in a water bath for 30 minutes. After cooling, the crystals formed were separated by filtration and were suspended in water in order to dissolve the triethylamine hydrochloride. The residue

  
 <EMI ID = 67.1>

  
119-124 [deg.] CI as the basis.

  
This compound was then oxidized according to Example 1 above.

Example 35.

  
 <EMI ID = 68.1> <EMI ID = 69.1>

  
 <EMI ID = 70.1>

  
16.2 gr of 2-mercaptobenzimidazole and 16.4 gr

  
of chloromethylpyridine hydrochloride were dissolved in
200 ml. 95% ethanol. 8 g were added. of sodium hydroxide in 20 ml. of water and the solution was then refluxed for two hours. The sodium chloride formed was filtered off and the solution was evaporated under

  
 <EMI ID = 71.1>

  
This compound was then oxidized according to the example above.

Example 37

  
2- (2-pyridylmethylsulfinyl) - (N-carbamoyl) -benzimidazole was prepared starting from 2- (2-pyrldylmethylthlo) -benzimidazole and carbamoyl-ehloride, and the obtained thio compound was oxidized according to Example 1 to the sulfonyl compound corresponding. Point

  
 <EMI ID = 72.1>

  
 <EMI ID = 73.1>

  
4.82 gr (0.02 moles) of 2- (2-pyridylmethylthio) benzimidazole and 1.5 gr of methyl isocyanate were refluxed in 150 mls of toluene for 2 hours. The mixture

  
was cooled, the precipitate formed was separated by filtration

  
and recrystallized from toluene. The yield of 2- (2pyridylmethylthio) - (N-methylcarbamoyl) -benzimidazole was

  
of 4.5 gr. Melting point: 135 [deg.] C. The thiocompound was oxidized

  
into the corresponding sulfinyl compound according to Example 1 above. The melting point of 2- (2-pyridylmethylsulfinyl) - (N-methylcarbamoyl) -benzimidazole was 140 [deg.] C.

Example 39.

  
12.0 gr (0.05 moles) of 2- (2-pyridylmethylthi.o) -

  
 <EMI ID = 74.1>

  
(0.059 moles) of 1-ehloro-2-propane were refluxed in 200 ml. of acetonitrile for two hours. The solution

  
was then filtered and evaporated. The residue 2- (2-pyridylmethylthio) -

  
 <EMI ID = 75.1>

  
carbon tetrachloride. The yield was 8 gr. The melting point was 113 [deg.] C.

  
The thiocompound was oxidized to the corresponding sulfinyl compound according to Example 1 above.

Example 40.

  
 <EMI ID = 76.1>

  
ester of chloroacetic acid.

  
thio

  
The / compound was then oxidized to the corresponding sulfinyl compound.

  
 <EMI ID = 77.1>

  
4.82 gr (0.02 moles) of 2- (2-pyridylmethylthio) benzimidazole and 4.05 gr. (0.05 moles) of triethylamine have

  
was dissolved in 200 ml of acetonitrile. 2.52 gr (0.022 moles) of methylsulfonic chloride in 20 parts of acetonitrile

  
were added dropwise and the solution was then left to stand overnight. The mixture was poured onto

  
ice and the product crystallized. Recrystallization

  
 <EMI ID = 78.1>

  
 <EMI ID = 79.1>

  
TABLE 1.

  
Compounds of formula 1 prepared.

  

 <EMI ID = 80.1>
 

  

 <EMI ID = 81.1>
 

  

 <EMI ID = 82.1>
 

  
Biological effects.

  
The compounds according to the present invention possess important therapeutic properties as agents affecting gastric acid secretion, as proved by the following tests. To check the gastric acid secretory activity a modified perfusion technique was used, using dogs as test animals.

  
An anesthetized dog was given a tube passing through the esophagus to the stomach for fluid installation, and a second tube passing through the duodenum through the ligated pylorus for fluid drainage. Every 15 minutes 5 ml were introduced. per kilogram of body weight of saline solution in the test animal and samples collected and quantified at pH 7.0 were drained with 0.04 N NaOH, and using a radiometer machine automatic titration to calculate the acid outputs.

  
Gastric acid secretion was induced by pentagastrin by administering 1-2 Mu.g / k per hour giving a submaximal secretory response. Test compounds

  
 <EMI ID = 83.1>

  
were introduced into the duodenum near the ligature at least two hours after the start of stimulation; when the secretion had reached a constant level for three consecutive periods of 15 minutes each. The gastric secretion response was noted and it was found that

  
 <EMI ID = 84.1>

  
The following data on the inhibitory effect of gastric aid were obtained for a number of compounds.

  
 <EMI ID = 85.1> TABLE 1.

  

 <EMI ID = 86.1>

Example 57.

  
A syrup containing 2% (weight by volume) of act substance:
ve has been prepared using the following ingredients:

  

 <EMI ID = 87.1>


  
Sufficient distilled water to obtain a final volume of 100 ml Sugar, saccharin, and soil were dissolved

  
addition acid in 60 gr. hot water. After cooling, glycerin and a solution of agent were added.

  
giving flavor dissolved in ethanol. To the mixture we

  
added water to obtain a final volume of 100 ml.

  
The active substance given above may be replaced by other acid addition salts which are pharmaceutically acceptable.

Example 58.

  
 <EMI ID = 88.1>

  
was mixed with lactose (175.8 gr.), potato starch
(169.7 gr.) And colloidal silicic acid (32 gr.). The mixture was moistened with a 10% gelatin solution and was ground through a 12 mesh screen. After drying was added

  
 <EMI ID = 89.1>

  
magnesium stearate (5 gr.) and the mixture thus obtained was made into tablets (10,000), each tablet containing

  
25 mg of active substance. Tablets can be prepared

  
so as to contain any required amount of the active ingredient.

Example 59.

  
Pellets were prepared starting from

  
 <EMI ID = 90.1>

  
hydroxybenzoate (250 gr.), lactose (175.9 gr) and an alcoholic solution of polyvinylpyrrolidone (25 gr). After drying, the granules were mixed with talc (27 gr.), potato starch (40 gr. ) and magnesium stearate
(2.50 gr.) And was made into 10,000 tablets. These tablets are first coated with an alcoholic solution of <EMI ID = 91.1>

  
coloring matters (0.2%). Talc and powdered sugar were used for dusting after the first 5

  
coatings. The coating was then covered with a syrup

  
66% sugar and was polished with a wax solution

  
 <EMI ID = 92.1>

Example 60.

  
2- (4- (5-methyl) -imidazolylmethylsulfinyl) benzimidazole hydrochloride (1 g), sodium chloride (0.8 g) and ascorbic acid (0.1 g) were dissolved in a sufficient quantity of distilled water to get 100 ml. of solution. This solution which contained 10 mg. of active substance for each

  
ml. was used to fill ampoules, which were sterilized by heating at 120 [deg.] C for 20 minutes.


    

Claims (1)

<EMI ID = 93.1> CLAIMS. 1. A method for inhibiting the secretion of gastric acid by administering to mammals, including humans, suffering from disorders due to secretion of gastric acid, a compound of the formula <EMI ID = 94.1> <EMI ID = 95.1> in this formula being the same or different and being chosen from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, <EMI ID = 96.1> from the group consisting of hydrogen, alkyl, acyl, carboalkoxy, darbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl and alkylsulfonyl, R6 being a straight or branched alkyl group having 1 to 4 carbon atoms and all-, at most a single group of methylene being present between S and Het, and Het being chosen from the group <EMI ID = 97.1> thiazolinyl, quinolyl, piperidyl, and pyridyl, which may be more preferably substituted in the 3 to 5 position with lower alkyl groups, such as methyl, ethyl, and propyl, or with halo substituents, such as chlorine and bromine, or their therapeutically acceptable salts. 2. The method of claim 1, wherein <EMI ID = 98.1> only acceptable of this compound, and in this formula R is hydrogen, hydroxy, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, tert-butyl, trifluoromethyl, acetyl, oarboxy or carboethoxy, R <3> is hydrogen, methyl or chloro, <EMI ID = 99.1> can be further substituted with methyl, ethyl or chlorine. <EMI ID = 100.1> <EMI ID = 101.1> <EMI ID = 102.1> which can be further substituted with methyl, ethyl or chlorine. 4. The method of claim 1, wherein <EMI ID = 103.1> <EMI ID = 104.1> . 5. The method of claim 1, wherein <EMI ID = 105.1> is acceptable of this compound, and in this formula R and <EMI ID = 106.1> which can be further substituted with methyl, ethyl or chloro. 6. The method of claim 1, wherein to inhibit gastric acid secretion is administered a <EMI ID = 107.1> <EMI ID = 108.1> <EMI ID = 109.1> or a therapeutically acceptable salt thereof. <EMI ID = 110.1> <EMI ID = 111.1> or a therapeutically acceptable salt thereof, in <EMI ID = 112.1> from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, <EMI ID = 113.1> R6 is a straight or branched alkyl group having 1 to 4 carbon atoms, and at most a single ethylene group is present between 3 and Het, and Het is selected from the group consisting of imidazolyl, imidazolinyl, benzimidazolyl, thiazolyl, thiazolinyl, quinolyl, piperidyl and pyridyl, which may be further substituted, preferably in position 3 to 5, with lower alkyl groups, such as methyl, ethyl, or propyl, or with halogen substituents such as chlorine and bromine. 8. A compound according to claim 7 or a therapeutically acceptable salt thereof, wherein R is hydrogen, hydroxy, cyano, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, methoxy, acetyl, <EMI ID = 114.1> methylcarbonylmethyl, ethoxycarbonylmethyl or methylsulfonyl, <EMI ID = 115.1> <EMI ID = 116.1> are hydrogen, methyl, ethyl, trifluoromethyl, cyano or chloro, <EMI ID = 117.1> can be further substituted with methyl, ethyl or chlorine. <EMI ID = 118.1> can be further substituted with methyl, ethyl or chlorine. 11. A compound according to claim 7, or a therapeutic salt. <EMI ID = 119.1> which can be further substituted with methyl, ethyl or chlorine. 12. Compound selected from the group consisting of: <EMI ID = 120.1> <EMI ID = 121.1> <EMI ID = 122.1> or a therapeutically acceptable salt of these compounds. 13. Process for preparing compounds of formula I <EMI ID = 123.1> <EMI ID = 124.1> from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl and acyl, in any position, R 4 is selected from the group consisting of <EMI ID = 125.1> alkylcarbamoyl, dialkylcarbamoyl, alkyloarbonylmethyl, alkoxycarbonylmethyl, and alkylsulfonyl, R is selected from ;, the group consisting of alkyl groups, straight or branched, having 1 to 4 carbon atoms, and at most a single ethylene group is present between S and Het , and Het is selected from the group consisting of imidazolyl, imidazolinyl, benzimidazolyl, thiazolyl, thiazolinyl, quinolyl, piperidyl and pyridyl, which may be further substituted, preferably in position 3 to 5 with lower alkyl or halogen, this process being characterized in that: a) the oxidation of a compound of formula II is carried out <EMI ID = 126.1> <EMI ID = 127.1> than those given above for the formation of a compound of formula I, or b) reacting a compound of the formula <EMI ID = 128.1> <EMI ID = 129.1> those given above and M is a metal selected from the group consisting of K, Na and Li, with a compound of the formula Z-Het in which Het has the same meaning as given above, Z is a hydroxy group, esterified, reactive for forming a compound of formula I, or c) reacting a compound of formula <EMI ID = 130.1> <EMI ID = 131.1> esterified reactive, respectively, with a compound of the formula <EMI ID = 132.1> where Het and R6 have the same meanings as those <EMI ID = 133.1> or Sh, respectively, to give an intermediate of formula II, and this intermediate is oxidized to give a compound of formula I, or d) reacting a compound of the formula <EMI ID = 134.1> <EMI ID = 135.1> '\ data above with a compound of the formula <EMI ID = 136.1> data above for the formation of an intermediate product of formula II, which is then oxidized to give a compound of formula I. e) reacting a compound of the formula <EMI ID = 137.1> <EMI ID = 138.1> <EMI ID = 139.1> <EMI ID = 140.1> as a base, can be converted into an acid addition salt or if it is present as a salt can be converted to its base. 14. Pharmaceutical preparation for inhibiting the secretion of gastric acid, characterized in that it contains as active agent a compound of formula I <EMI ID = 141.1> or an acid addition salt, non-toxic, pharmaceutically acceptable, in a therapeutically effective amount, in <EMI ID = 142.1> from the group consisting of hydrogen, alkyl., halogen, eyano, carboxy, carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, <EMI ID = 143.1> straight or branched having 1 to 4 carbon atoms, and at most <EMI ID = 144.1> <EMI ID = 145.1> and pyridyl, which may be further substituted, preferably in position 3 to 5 with substituents selected from the group consisting of methyl, ethyl, propyl, chlorine or bromine. 15. Pharmaceutical preparation according to claim <EMI ID = 146.1> weight of the preparation. 16. Pharmaceutical preparation according to claim 14, in a form suitable for administration by injection, <EMI ID = 147.1> <EMI ID = 148.1> for parenteral application, comprising an aqueous solution of a water soluble salt of the active ingredient in amounts of about 0.5 to 10% by weight of the preparation. <EMI ID = 149.1> about 50% by weight of the preparation. 19. Pharmaceutical preparation according to claim 14, in a form suitable for oral administration, in which the dosage of the active ingredient is between 100 and 400 milligrams per day. 20. Pharmaceutical preparation according to claim 14, in a form suitable for intravenous administration, wherein the dosage of the active ingredient is between 5 and 20 milligrams per day. 21. A pharmaceutical preparation according to claim 14, wherein the active ingredient is selected from the group consisting of: <EMI ID = 150.1> <EMI ID = 151.1> 2- (2-pyridyl- (ethyl) methylsulfinyl) - (5-ethyl) benzimidazole, <EMI ID = 152.1> <EMI ID = 153.1> or a non-toxic, pharmaceutically acceptable addition salt of these compounds. 22. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) benzimidazole or a pharmaceutically acceptable non-toxic addition salt thereof. <EMI ID = 154.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 24. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) - (5-ethyl) benzimidazole or a non-toxic, pharmaceutically acceptable addition salt thereof. <EMI ID = 155.1> wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) - (4-methyl, 6-chloro) benzimidazole or an addition salt, non-toxic, pharmaceutically acceptable <EMI ID = 156.1> 26. Pharmaceutical preparation according to claim 14, <EMI ID = 157.1> (5-methoxy) benzimidazole or a pharmaceutically acceptable, non-toxic, addicton salt thereof. 27. Pharmaceutical preparation according to claim 14, <EMI ID = 158.1> (5-hydroxy) -benzimidazole or a non-toxic, pharmaceutically acceptable addition salt thereof. 28. Pharmaceutical preparation according to claim 14, <EMI ID = 159.1> (5-acetyl) -benzimidazole or a non-toxic, pharmaceutically acceptable addition salt thereof. 29. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) - (5-carboxy) -benzimidazole, or a non-toxic, pharmaceutically acceptable addition salt thereof. 30. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) - <EMI ID = 160.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 31. A pharmaceutical preparation according to claim 14, wherein the active ingredient is <EMI ID = 161.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 32. A pharmaceutical preparation according to claim 14, wherein the active ingredient is <EMI ID = 162.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 33. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2- (4-chloro) <EMI ID = 163.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 34. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2- (5-methyl) pyridylmethylsulfinyl) -benzimidazole <EMI ID = 164.1> of these products. 35. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-piperidylmethylsulfinyl) benzimidazole. or a pharmaceutically acceptable, non-toxic, addicton salt thereof. 36. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-quinolylmethylsulfinyl) benzimidazole. or a non-toxic, pharmaceutically acceptable addition salt thereof. 37. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) - (N-acetyl-methyl) benzimidazole or a non-toxic, pharmaceutically acceptable addition salt thereof. <EMI ID = 165.1> where the active ingredient is 2- (2-pyridylmethylsulfinyl) -N-methyl-benzimidazole or a non-toxic, pharmaceutically acceptable addition salt thereof. 39. Pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) <EMI ID = 166.1> of these products. 40. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (4- (5-methyl). <EMI ID = 167.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 41. Pharmaceutical preparation according to claim 14, <EMI ID = 168.1> or a pharmaceutically acceptable, non-toxic, addition salt thereof. 42. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2- (4-methyl) <EMI ID = 169.1> or an additon, non-toxic, pharmaceutically acceptable salt thereof. 43. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2- (5-methyl) <EMI ID = 170.1> or an additon, non-toxic, pharmaceutically acceptable salt thereof. 44. Pharmaceutical preparation according to claim 14, <EMI ID = 171.1> or a non-toxic, pharmaceutically acceptable addition salt of these products. 45. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl- (ethyl). <EMI ID = 172.1> or a non-toxic, pharmaceutically acceptable addition salt of these products. 46. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyrldyl- (methyl) <EMI ID = 173.1> or a non-toxic, pharmaceutically acceptable addition salt of these products. <EMI ID = 174.1> wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) - (4-methyl) -benzimidazole or a non-toxic, pharmaceutically acceptable addition salt of these products. 48. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl- (ethyl) methylsulfinyl) - (5-chloro) benzimidazole or a non-toxic, pharmaceutically acceptable addition salt thereof. 49. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl- (methyl). <EMI ID = 175.1> or an addition salt, non-toxic, pharmaceutically acceptable of these products. 50. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2- (3-methyl) <EMI ID = 176.1> or a non-toxic, pharmaceutically acceptable addition salt of these products. 51. Pharmaceutical preparation according to claim 14, <EMI ID = 177.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. <EMI ID = 178.1> <EMI ID = 179.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 53. Pharmaceutical preparation according to claim 14, <EMI ID = 180.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 54. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2- (5-ethyl). <EMI ID = 181.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 55. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl (ethyl). <EMI ID = 182.1> or a non-toxic, pharmaceutically acceptable addition salt of these products. 56. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl- (methyl). <EMI ID = 183.1> or a non-toxic, pharmaceutically acceptable addition salt of these products. 57. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl- <EMI ID = 184.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. <EMI ID = 185.1> wherein the active ingredient is 2- (2-pyridyl- <EMI ID = 186.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 59. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl- (ethyl). <EMI ID = 187.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. <EMI ID = 188.1> wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) (5-chloro) benzimidazol e or an addition salt, non-toxic, pharmaceutically acceptable of these products. 61. Pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) - (5-isopropyl) -benzimidazole <EMI ID = 189.1> of these products. <EMI ID = 190.1> <EMI ID = 191.1> <EMI ID = 192.1> <EMI ID = 193.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 64. Preparation. pharmaceutical according to claim 14, <EMI ID = 194.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 65. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl- (ethyl). <EMI ID = 195.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 66. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridylmethylsulfinyl) - <EMI ID = 196.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. <EMI ID = 197.1> wherein the active ingredient is 2- (2-pyridyl- (isopropyl) <EMI ID = 198.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 68. A pharmaceutical preparation according to claim 14, wherein the active ingredient is 2- (2-pyridyl- (methyl) <EMI ID = 199.1> or a non-toxic, pharmaceutically acceptable addition salt thereof. 69. Pharmaceutical preparation according to claim 14, <EMI ID = 200.1> or a non-toxic, pharmaceutically acceptable addition salt of these products. 70. Pharmaceutical preparation according to claim 14, <EMI ID = 201.1> of these products. 71. Intermediate products of the formula <EMI ID = 202.1> <EMI ID = 203.1> are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, carboalkoxy, carboalkoxyalkyl, c: arbamoyl, carbamoyalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl <EMI ID = 204.1> <EMI ID = 205.1> methyl and alkylsulfonyl, R6 is selected from the group consisting of alkyl groups, straight or branched having 1 to 4 atoms of carbon and at most a single methylene group is present between S and Het, and Het is selected from the group consisting of in imidazolyl, imidazolinyl, benzimidazolyl, thiazolyl, thiazolinyl ,, quinolyl, piperidyl and pyridyl, which can be further substituted, preferably in position 3 to 5, with lower alkyl or halogen, or one of their acid addition salts.