CA1060448A

CA1060448A - Gastric acid secretion agents

Info

Publication number: CA1060448A
Application number: CA220,235A
Authority: CA
Inventors: Peder B. Berntsson; Stig A. I. Carlsson; Ul F K. Junggren; Lars E. Garberg; Sven E. Sjostrand; Gunhild W. Von Wittken Sundell
Original assignee: Hassle AB
Current assignee: Hassle AB
Priority date: 1974-02-18
Filing date: 1975-02-17
Publication date: 1979-08-14
Also published as: NO750541L; FI750421A; DK141122C; FI59590C; DE2504252A1; CS194715B2; LU71872A1; GB1500043A; CH616160A5; JPS50116474A; IE40858L; DK141122B; AT343659B; AU499639B2; FR2261007B1; IE40858B1; FI59590B; SU795476A3; MY8100208A; NO142401C

Abstract

ABSTRACT OF THE DISCLOSURE
Compounds, and process for their preparation, of the general formula

Description

Gastric acid secretion agents The present invention relates to a process for the preparation of new compounds having valuable properties in inhibiting gastric acid 5ecretion in mammals, incluting man, as well as compounds prepared accortingly.
The object of the present invention is to obtain compounds which inhibit exogenously or endogenously stimulated gastric acid secretion, thereby obtaining compounds for treating i.a. peptic ulcer disease.
It has now been found that compounds of the formula below possess such properties.
Novel compounds of the invention are these of the general formula I

. ~ S-A-Het (I) N

q~

~Q60448 wherein R and R3 are the same or different, are in any position and are sel-ected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, halogen, and alkoxy containing 1 to 4 carbon atoms; R4 is selected from the group consisting of hydrogen, and acyl containing 1 to 4 carbon atoms; A
represents the group -CH2- or the group -CH(CH3)- and Het represents 2-quinolyl, 2-pyridyl, alkyl or halo-2-quinolyl and alkyl or halo-2-pyridyl, the alkyl groups having 1 to 4 carbon atoms, provided that when Het is 2-pyridyl, A is -CH2-, R is hydrogen, R and R3 are not (i) both hydrogen (ii) not 5-CH3 and 6-CH3, and (iii) not hydrogen and 5-Cl or its therapeut-ically acceptable salts.
Alkyl R and R3 of form~la I are suitable alkyl having up to 4 carbon atoms. Thus alkyl R may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
Halogen R and R3 are fluoro, iodo, brom~ and chloro, preferably bromo and chloro.
Alkoxy R and R3 are suitably alkoxy groups having up to 5 carbon atoms, preferably up to 3 carbon atoms, as methoxy, ethoxy, n-propoxy, isopropoxy.
Acyl R has up to 4 carbon atoms and ls e.g. formyl (HC-), acetyl (CH3C-) or propionyl (CH3CH2C-).
The heterocyclic group Het may be further substituted with alkyl or halogen. Such alkyl groups are lower alkyl groups as methyl, ethyl or propyl. Such halogen substituents are preferably chloro or bromo.

~ ~ ~ --2--~, ' - , :- ; , - ; -The compounds of the Present invention may be prepared according to processes known per se.
m us compounds of formula I above may be prepared by a. r~acting a compound o~ the formula IV

N ~
N ~ (IV) R

wherein R, R3 and R are as defined above and Z represents a thiol (-SH) group or a reactive esterified hydroxy group, in which the esterifying acid ls a strong organic or inorganic acid with a compound of the formula V
zl _ A - Het whereln Het has the same meanlng as glven above, and zl represents a reactive esterified hydroxy group, in which the esterifying acid ls a strong organic or inorgania acid or a thiol (-SH) group provided that Z and zl are not the same, and, if desired, converting a free base thus obtained into a pharm~
aceutically acceptable salt thereof, or converting a salt into either the free base or a pharmaceutically acceptable salt.
In the reactions above, Z and zl may be a reactive ester-ified hydroxy grouP.
A reactive, esterified hvdroxy grouP is particularly a hvdroxy group esterified with a strong, inorganic or organic acid, preferably a hDdrohalogen acid, as hydrochloric acid, hydrobromic acid, or hydroiodic acid, further sulphuric acid or a strong organic sulphonic acid ::~ ,.~.~i as a strong aromatic acid, e.g. benzenesulphonic acid, 4-bromobenzene-sulphonic acid or 4-toluenesulphonic acid. Thus, Z and zl are prefer-ably chloro, bromo or iodo.
Depending on the process conditions and the starting material the end product is obtained either as free base or in the form of its acid addition salt, which is included in the scope of the invention.
Thus, for example, basic, neutral or mixed salts may be obtained as well as hemiamino, sesqui-or polyhydrates. The acid addition salts of the new compounds may in a manner known per se be transformed into free base using e.g. basic agents as alkali or ion exchanger. On the other hand, the free bases obtained may form salts with organic or inorganic acids.
In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts. Such acids are e.g.
hydrohalogen acids, sulphonic acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicylic, aromatic or heterocyclic carboxy or sulphonic acids, as formic, acetic, propionic, succinic, glycolic, lactic, malic, tar-taric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, phenyl-acetic, benzoic, p-aminobenzoic,anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, en~onic acid, methanesulphonic, ethanesulphonic, h ffl roxyethanesulphonic, ethylenesulphonic acids, halogenbenzenesulphonic, toluenesulphonic, naphthylsulphonic acids or sulphanilic acid; methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds as e.g. picrates may serve as purifying agents of the free bases obtained as the free bases are transformed into salts, these are separated and the bases are then set free from the salts again. According to the close relationship between the new compounds in free form and in the form of their salts it will be understood from the above and the below, that, if possible, the corresponding salts are .. ..

;, . , :.: . ~ , . -~ . ' . ` . :

':
.
. . . ..

included in the free compounds.
Some of the new compounds may, depending on the choice of starting materials and process, be present as optical antipodes or racemate, or if they contain at least two asymmetric carbon atoms, be present as an isomer mixture (racemate mixture).
The isomer mixtures ~racemate mixtures) obtained may, depending on physical-chemical differences of the components, be separated into the both stereoisomeric (diastereomeric) pure racemates, e.g. by means of chromatography and/or fractionated crystallization.

The racemate obtained can be separated according to known methods, e.g. by means of recrystallization from an optically active solvent, by means of microorganisms, or by a reaction with optically active acids forming salts of the compound and separating the salts thus obtained, e.g.
by means of their different solubility in the diastereoisomers, from which the antipodes by the influence of a suitable agent may be set free. Suit-ably useable optically active acids are e.g. L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, campheresulphonic acit or china acid. Preferably the more active part of the two antipodes is isolated.
The starting materials are known or may, if they should be new, be obtained according to processes known per se.
In clinical use the compounds o~ the invention are administered normally orally, rectally or by injection in the form of a pharmaceutical preparation, which contains an active component either as free base or as pharmaceutically acceptable, non-toxic acid addition salt, e.g. the hydro-chloride lactate, acetate, sulphamate or the like in combination with a pharmaceutically acceptable carrier. Thereby the mentioning of the new compounds of the invention is here related to either the free amine base .. - , ~. ., . . . : :

- - .. . . . . .. .

~ 1060~48 or the acid addition salts of the free base, even if the compounds are generally or specifically described, provided that the context in which such expressions are used, e.g. in the examples, with this broad meaning should not correspond. The carrier may be a solid, semisolid or liquid diluent or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compound is between 0.1 to 95 % by weight of the preparation, suitably between 0.5 to 20 % by weight in preparations for injection and between 2 to 50 % by weight in preparations for oral administration.
In the preparation of pharmaceutical preparations containing a compound of the present invention in the form of dosage units for oral administration the compound elected may be mixed with a solid, pulveru-lent carrier, as e.g. with lactose, saccharose, sorbitol, mannitol, starch, as potato starch, corn starch, amylopectin, cellulose deriva-tives or gelatine, as well as with an antifriction agent as magnesium stearate, calcium stearate, polyethyleneglycol waxes or the like, and be pressed into tablets. If coated tablets are wanted, the above pre-pared core may be coated with concentrated solution of sugar which solution may contain e.g. gum arabicum, gelatine, talc, titan-dioxide or the like. Furthermore, the tablets may be coated with a lacquer dissolved in an easily volatile organic solvent or mixture of solvents. To this coating a dye may be added in order to easily dis-tinguish between tablets with different active compounds or with dif-ferent amounts of the active compound present.
In the preparation of soft gelatinecapsules ~pearl-shaped, closed capsules), which consist of gelatine and e.g. glycerine or in the preparation of similar closed capsules the active compound is mixed - , : . -. . . .
. .
..

". . ~, '" , ' ~ ~ .

- ~060448 with a vegetable oil. Hard gelatine capsules may contain granules of the active compound in combination with a solid, pulverulent carrier as lactose, saccarose, sorbitol, mannitol, starch ~as e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active substance in a mixture with a neutral fat base, or they may be prepared in the form of gelatin-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil.
Liquid preparations for oral administration may be present in the form of syrups or suspensions, e.g. solutions containing from about 0 2 % by weight to about 20 % by weight of the active substance describ- -ed, whereby the residue consists of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, sacoarine and carboxymethyl-cellulose as a thick0ning agent.
Solutions for parenteral administration by injection may be pre-pared as an aqueous solution of a water soluble pharmaceutically accep-table salts of the active compound, preferably in a concentration from about 0.5 % by weight to about Q.lQ % by weight. These solutions may al-50 contain stabilizing agents and/or buffering agents and may suitably be available in different dosage unit ampoules.
The preparation of pharmaceutical tablets for peroral use is carried out in accordance with the following method:
The solid substances included are ground or sieved to a certain particle size. The binding agent is homogenized and suspended in a certain amount of solvent. The therapeutic compound and necessary auxiliary ~,, , agents are mixed during a continuous and constsntly mixing ~ith the bind.ing agent solution and are moistened so that the solution is uniformly divided in the mass without overmoistening any parts. The amount of solvent is usually so adapted that the mass obtains a consistency reminding of wet snow. The moistening of the pulverulent mixture with the binding agent solution causes the particles to gather together slightly to aggreg-ates and the real granulating process is carried out in such a way that the mass is pressed through a sieve in the form of a net of stainless having a mesh size of about 1 mm. The mass is then placed in thin layers on a tray to be dried in a drying cabinet. This drying takes place during 10 hours and has to be standardized carefully as the damp degree of-the granulate is of outmost importance for the following process and for the feature of the tablets. Drying in a fluid bed may possibly be used. In this case the mass is not put on a tray but is poured into a container having a net bottom.
After drying step the granules are sieved so that the particle size wanted is obtained. Under certain circumstances powder has to be removed.
To the so called final mixture, disintegrating, antifriction agents and antiadhesive agents are added. After this mixture the mass shall have its right composition for the tabletting step.
The cleaned tablet punching machine is provided with a certain set of punches and dies, whereupon the suitable adjustmentfor the weight of the tablets and the degree of compression is tested out. The weight of the tablet is decisive for the size of the dose in each tablet and is calculat-ed starting from the amount of therapeutic agent in the granules. The degree of compression affec~s the size of the tablet, its strength and its ability ~ - 8 -.. . .
. .
.. . . , ~ . , ,. . : , . - .
, . , . ., . . -' ~ ~ . '. ' ' - ', . `

.

-` j 1060448 to disintegrate in water. Especially as regards the two later properties the choice of compression pressure (0.5 to 5 ton) means something of a balance-step. When the right adjustment is set, the preparation of tablets is start-ed, which is carried out with a rate of 20.000 to 200.000 tablets per hour.
The pressing of the tablets requires different times and depends on the size of the batch.
The tablets are freed from adhering pulver in a specific apparatus and are then stored in closed packages until they are delivered.
Many tablets, especially these which are rough or bitter, are coated with a coating. This means that these are coated with a layer of sugar or some other suitable coating.
The tablets are usually packed by machines having an electronic counting device. The different types of packages consist of glass or plastic gallipots, but also boxes, tubes and specific dosage adapted packages.
The daily dose of the active substance varies ant is depending on the type of administration, but as a general rule it is 100 to 400 mg/day of active substance at peroral administration and 5 to 20 mg/day at intra-venous administration.
The following illustrates the principle and the adaption of the invention, however, without being limited thereto. Temperature is given in degree Celsius.
The starting materials in the examples found below were prepared in accordance with the following.
A 1,2-diamino compound, as o-phenylenediamine was reacted with potassiumethylxanthate ~according to Org. Synth, vol. 30 p. 56) to form a

2-mercaptobenzimidazole.
2-Chloromethylpyridine was prepared by reacting 2-hydroxymethyl-k - 8a -pyridine with thionylchloride ~according to Arch. Pharm. vol. 26 pp. 448-451 ~1956)).
2-Chloromethylbenzimidazole was prepared by condensating o-phenylen-diamine with chloroactic acid.
Example 1 0.1 moles of 4-methyl-2-mercaptobenzimidazole were dissolved in 20 ml of water and 200 ml of ethanol containing 0.2 moles of sodiumhydroxide. 0.1 moles of 2-chloromethylpyridine hydrochloride were added and the mixture was refluxed during 2 hours. The sodiumchloride formed was filtered off and the solution was evaporated in vacuo. The residue was dissolved in acetone and was treated with active carbon. An equivalent amount of concentrated hydro-chloric acid was added, whereupon the mon-hydrochloride of L~-pyridylmethyl-thio7-4-methyl-1-benzimidazole was isolated. Yield 0.05 moles melting point Examples 2-18 The preparation was carried out in accordance with Example 1 above.
The compounds prepared are listed in the following table 1.
Example 19 13.5 g ~0.05 moles) of 2-C2-pyridylmethylthio7-benzimidazole hydro-chloride, 3.9 g (0.05 moles) of acetylchloride, and 10.1 g (0.1 moles) of triethylamine were dissolved in 100 ml of acetonitrile. The mixture was heated in a 40C-waterbath for 30 min. After cooling the crystals formed were filtered off which were suspended in water in order to dissolve the tri-ethylamine hydrochloride. The residue, 2-L2-pyridylmethylthiç7-N-acetylbenz-imidazole, was filtered off. Yield 7.2 g (51 %) M.p. 119-124C as base.
Example 20 2-~2-pyridylmethylthio~-N-methoxycarbonylbenzimidazole was prepared in accordance with Example 19 above.

- 8b -,, ` .: ' ', :' , ' ' ` ;' , ` ~ ' ' .

.. ..

Example 21 2-[2 pyridylmethylthio]-3H-quinazoline was prepared according to Example 1.
M.p. 182C as dihydrochloride. (cf Table 1).
Exan~)le 22 2-[2-pyridylmethylthio]-(4.5-benz)-1,3-homopiperazin-1-ene, m.p. > 250C as hydrochloride (cf Table 1) was prepared according to Example 1.
Table 1 Compounds of formula I prepared R ~ ~ S - ~ - Set -Ex R3 R R4 A Het M.P. C

1 H 4-CH3 H -SCH2- 2-pyridyl 137-83 (2.HCl 2 6-CH3 4-CH3 H -SCH2- 2-pyridyl 230 (HCl)

3 H 5-C2H5 H -SCH2- 2-pyridyl 180 (HCl)

4 6-C1 4-CH3 H -SCH2- 2-pyridyl 180 (HCl) H 5-OCH3 H -SCH2- 2-pyridyl 155-95 (2.HCl) 6 H 5-OH H -SCH2- 2-pyridyl 7 H 5-COCH3 H -SCH2- 2-pyridyl 8 H 5-COOH H -SCH2- 2-pyridyl 9 H 5-COOC2H5 H -SCH2 2-pyridyl H H H -SCH2 2-(6-methyl-pyridyl) 121 (HCl) 11 H H H -SCH2- 2-(6-chloro-pyridyl) 145 (base) 12 H H H -SCH2- 2-(4-chloro-pyridyl) _ g _ ' ` : . : - " .
, . ...

~060448 Table I continued Ex R3 R R4 A Het M.P. &
13 H H H -SCH2- 2-(5-methyl-pyridyl) 134 (HCl) 14 H H H -SCH2- 2-quinolyl 144-63 (HCl) H 5-CH20H H -SCH2- 2-pyridyl 16 H H H -S-CH(CH3)- 2-pyridyl 165 (HCl) 17 H H COCH3 -SCH2- 2-pyridyl 119-24 (base~
18 H 3 H2 2-pyridyl 78 (base) - 9a-. .
'~
. - - ; .

., .- , .

Biological effect The compounds of the invention possess worthwhile therapeutical prope~rties as gastric acid affecting compounds.
Thus in a testing technique for compounds having secretory activ-ity were used on dog. The testing was performed in acute dog experiments with a modified perfusion technique.
The stomach of the anaesthetized dog was provided with one tube through oesophagus for instillation of fluid and another tube via the ligated pylorus through duodenum for drainage of fluid. Saline was instil-led in a volume of 5 ml/kg body weight, and the instillation fluid was changed every 15 minutes.
The samples collected were titrated to pH 7.0 with 0.04 N NaOH
using a Radiometer automatic titrator, and the acid output per 15 minutes was calculated (collection periods).
Gastric acid secretion was intuced by pentagastrin in 1-2 g/kg and hour, giving a submaximal secretory response.
Test compounds in 0.5 % Methocel suspension were given into the duodenum close to the ligation at least 2 hours following onset of stimulation, when the secretion had reached a steady level for three con-secutive 15 minutes periods.
The gastric secretion response was noted, whereby it was found that all compounds of the examples above were gastric acid secretion inhibitors.

- lQ _ ,. ~ , . -, - . , ~ . . ~ . . . . . .

:1060448 SUPPLEMENTARY DISCLCSURE
With reference to the details given in Table I above, the melting points of certain co~pounds listed therein are as follows:-Ex. No. M.P. C
6 190-200 (HCl) 7 144 (base) 8 268 (base) 9 180-190 (2.HCl) 190 (HCl) '~ ' .~

,, , -,, ,, . , . ~ . . . .
.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the preparation of formula I

(I) wherein R and R3 are the same or different, are in any position, and are selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy, wherein the alkyl moieties may have 1 to 4 carbon atoms;
R4 is selected from the group consisting of hydrogen, and acyl of 1 to 4 carbon atoms;
A represents either the group -CH2- or the group -CH(CH3)-;
and Het represents a heterocyclic group selected from the group consisting of 2-quinolyl, 2-pyridyl, halo-2-pyridyl, alkyl-2-quinolyl and alkyl-2-pyridyl, the alkyl groups having 1 to 4 carbon atoms;
provided that when Het is 2-pyridyl, A is -CH2- - and R4 is hydrogen then R and R3 are not (i) both hydrogen; (ii) 5-CH3 and 6-CH3; or (111) hydrogen and 5-C1, which process comprises reacting a compound of formula IV

(IV) wherein R, R3 and R are as defined above, and Z represents a thiol (-SH) group or a reactive esterified hydroxy group, in which the esterifying acid is a strong organic or inorganic acid, with a compound of formula V
Z' - A - Het wherein A and Het are as defined above, and Z' represents a reactive ester-ified hydroxy group, in which the esterifying group is a strong organic or inorganic acid, or a thiol (-SH) group, provided that Z and Z' are not the same, and, if desired converting a free base thus obtained into a pharma-ceutically acceptable salt thereof, or converting a salt into either the free base or into a pharmaceutically acceptable salt.

2. A compound of formula I, or a pharmaceutically acceptable salt thereof, (I) wherein: R and R3 are the same or different, are in any position, and are selected from the group consisting of hydrogen, alkyl, and alkoxy, wherein the alkyl moieties may have 1 to 4 carbon atoms;
R4 is selected from the group consisting of hydrogen, and acyl of 1 to 4 carbon atoms;
A represents either the group -CH2- or the group -CH(CH3)-;
and Het represents a heterocyclic group selected from the group consisting of 2-quinolyl, 2-pridyl, halo-2-quinolyl, halo-2-pyridyl, alkyl-2-quinolyl and alkyl-2-pyridyl, the alkyl groups having 1 to 4 carbon atoms;
provided that when Het is 2-pyridyl, A is -CH2- and R4 is hydrogen then R
and R3 are not (i) both hydrogen; (ii) 5-CH3 and 6-CH3; or (iii) hydrogen and 5-C1, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

3. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-4-methyl-2-benzimidazole hydrochloride which comprises reacting 4-methyl-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

4. [2-Pyridylmethylthio]-4-methyl-2-benzimidazole whenever pre-pared by the process of claim 3 or by an obvious chemical equivalent thereof.

5. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-4,6-dimethyl-2-benzimidazole hydrochloride which comprises re-acting 4,6-dimethyl-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

6. [2-Pyridylmethylthio]-4,6-dimethyl-2-benzimidazole hydrochloride whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

7. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-5-ethyl-2-benzimidazole hydrochloride which comprises reacting 5-ethyl-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

8. [2-Pyridylmethylthio]-5-ethyl-2-benzimidazole hydrochloride whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

9. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-6-chloro-4-methyl-2-benzimidazole hydrochloride which comprises reacting 6-chloro-4-methyl-2-mercapto-benzimidazole with 2-chloromethyl-pyridine hydrochloride in the presence of sodium hydroxide.

10. [2-Pyridylmethylthio]-6-chloro-4-methyl-2-benzimidazole hydro-chloride whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

11. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-5-methoxy-2-benzimidazole dihydrochloride which comprises re-acting 5-methoxy-2-mercapto-benzimidazole with 2-chloromethylpyridine hydro-chloride in the presence of sodium hydroxide.

12. [2-Pyridylmethylthio]-5-methoxy-2-benzimidazole dihydrochloride whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

13. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-5-hydroxy-2-benzimidazole hydrochloride which comprises reacting 5-hydroxy-2-mercato-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

14. [2-Pyridylmethylthio]-5-hydroxy-2-benzimidazole hydrochloride whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

15. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-5-acetyl-2-benzimidazole which comprises reacting 5-acetyl-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

16. [2-Pyridylmethylthio]-5-acetyl-2-benzimidazole whenever pre-pared by the process of claim 15 or by an obvious chemical equivalent thereof.

17. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-5-carboxy-2-benzimidazole which comprises reacting 5-carboxy-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

18. [2-Pyridylmethylthio]-5-carboxy-2-benzimidazole whenever pre-pared by the process of claim 17 or by an obvious chemical equivalent thereof.

19. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-5-carboethoxy-2-benzimidazole dihydrochloride which comprises reacting 5-carboethoxy-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

20. [2-Pyridylmethylthio]-5-carboethoxy-2-benzimidazole dihydro-chloride whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

21. Process according to claim 1 for the preparation of [2-(6-methyl-pyridyl)methylthio]-2-benzimidazole hydrochloride which comprises reacting 2-mercapto-benzimidazole with 2-chloromethyl-6-methylpyridine hydrochloride in the presence of sodium hydroxide.

22. [2-(6-Methylpyridyl)methylthio]-2-benzimidazole hydrochloride whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

23. Process according to claim 1 for the preparation of [2-(6-chloro-pyridyl)methylthio]-2-benzimidazole which comprises reacting 2-mercapto-benzimidazole with 2-chloromethyl-6-chloropyridine hydrochloride in the presence of sodium hydroxide.

24. [2-(6-Chloropyridyl)methylthio]-2-benzimidazole whenever pre-pared by the process of claim 23 or by an obvious chemical equivalent thereof.

25. Process according to claim 1 for the preparation of [2-(4-chloropyridyl)methylthio]-2-benzimidazole which comprises reacting 2-mercapto-benzimidazole with 2-chloromethyl-4-chloropyridine hydrochloride in the presence of sodium hydroxide.

26. [2-(4-Chloropyridyl)methylthio]-2-benzimidazole whenever pre-pared by the process of claim 25 or by an obvious chemical equivalent thereof.

27. Process according to claim 1 for the preparation of [2-(5-methyl-pyridyl)methylthio]-2-benzimidazole hydrochloride which comprises reacting together 2-mercapto-benzimidazole with 2-chloromethyl-5-methylpyridine hydro-chloride in the presence of sodium hydroxide.

28, [2-(5-Methylpyridyl)methylthio]-2-benzimidazole hydrochloride whenever prepared by the process of claim 27 or by an obvious chemical equivalent thereof.

29. Process according to claim 1 for the preparation of [2-quinolyl-methylthio]-2-benzimidazole hydrochloride which comprises reacting 2-methyl-thio-benzimidazole with 2-chloromethylquinoline hydrochloride in the presence of sodium hydroxide.

30. [2-Quinolylmethylthio]-2-benzimidazole hydrochloride whenever prepared by the process of claim 29 or by an obvious chemical equivalent thereof.

31. Process according to claim 1 for the preparation of [2-Pyridyl-methylthio]-5-hydroxymethyl-2-benzimidazole hydrochloride which comprises re-acting 5-hydroxymethyl-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

32. [2-Pyridylmethylthio]-5-hydroxymethyl-2-benzimidazole hydro-chloride whenever prepared by the process of claim 31 or by an obvious chemical equivalent thereof.

33, Process according to claim 1 for the preparation of [1-(2-Pyridyl)ethylthio]-2-benzimidazole hydrochloride which comprises reacting 2-mercapto-benzimidazole with 1-(2-pyridyl)-1-chloroethane in the presence of sodium hydroxide.

34. [1-(2-Pyridyl)ethylthio]-2-benzimidazole hydrochloride whenever prepared by the process of claim 33 or by an obvious chemical equivalent thereof.

35, Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-3-acetyl-2-benzimidazole which comprises reacting 3-acetyl-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

36. [2-Pyridylmethylthio]-3-acetyl-2-benzimidazole whenever pre-pared by the process of claim 35 or by an obvious chemical equivalent thereof.

37. Process according to claim 1 for the preparation of [2-pyridyl-methylthio]-3-carbomethoxy-2-benzimidazole which comprises reacting 3-carbo-methoxy-2-mercapto-benzimidazole with 2-chloromethylpyridine hydrochloride in the presence of sodium hydroxide.

38. [2-Pyridylmethylthio]-3-carbomethoxy-2-benzimidazole whenever prepared by the process of claim 37 or by an obvious chemical equivalent thereof.