CA1268462A - Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical preparations containing them and their use as inhibitors of gastric acid secretion - Google Patents

Abstract

Abstract of the disclosure:

Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical preparations contain-ing them and their use as inhibitors of gastric acid secretion.

The invention relates to substituted thienoimidazole derivatives of the formula (I) in which A stands for a) , b) oder c)

Description

126~346;~:

HOECHST AKTIENGESELLSCHAFT HOE 87/F 336K Dr.WS/bs Description:

Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical preparations containing them and their use as inhibitors of gastric acid secretion Thienoimidazole derivatives having gastric acid secre-tion-inhibiting action have been disclosed in EP-A1-234,485, EP-A2-201,094 and EP-A-237,248.

The present invention relates to novel thienoimidazole derivatives of the formula I

R4 ~
T Cl ~ N~ (I) ~ R5 in which A stands for ~ ' ~ ( or T denotes -S-, -S0- or -SOz-, R1 and R2 are identical or different and denote hydro-gen, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl~ (C1-C6)-alkoxy~
-O-[CH2 ~XcfH(2f+1-9)F9r -OCF2Cl, -O-CF2-CHFCl, I(C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-Cg)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methyl-anilino, phenylmercapto, phenylsulfonyl, phenylsulf;nyl,sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-.

:
.

- - , , ' ~,.... . .
, ::

~X6~34~

(C1-C4)-alkylsulfamoyl, or, if A is as defined above under (a) or (c), can also together denote -[CH2]n- or -CH=CH-CH=CH-, in which a CH2 group is optionally replaced by 0, S, S0 or S02, or R3 denotes hydrogen, (C1-C6)-alkanoyl, (C1-C6)-alkyl-carbamoyl, (C1-C6)-alkoxycarbonyl, benzyloxycarbonyl or another physiologically tolerable Nim protecting group which can preferably be cleaved in acidic medium and/or under physiological conditions such as, for example, (C1-C10)-acyloxy-(C1-C6)-alkyl, preferably (C1-C10)-alkanoyloxy-(C1-C6)-alkyl, benzoyloxy-(C1-C6)-alkyl, benzyloxycarbonyloxy-(C1-C6)-alkyl or (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkyl, R4 and R5 are identical or different and denote hydrogen or (C1-C3)-alkyl, R6 and R8 are identical or different and denote hydrogen, halogen, tr;fluoromethYl~ (C1-C12)~alkYl~ (C1-C12)-alkoxy, -o-lcH2-]xcfH(2f+1-g)Fs~ NR R ~
(C1~C12)-alkxY-(c1-c12)-alkyl~ (C1-C12)-alkoxy-(C1-C12)-alkXY~ (C7-C11)-aralkoxy, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl or (C1-C12)-alkylsulfonyl, R7 denotes a substituted (C6-C12)-aryloxy radical or (C7-C11)-aralkoxy radical ~hich carries 1, 2, 3, 4 or 5 identicaL or different substituents selected from the group comprising halogen, cyano, nitro, trifluoro-methyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (c1-c~)-a~koxy~ --~CH2-]XCfH(2f+1-g)F9~
-OCF2Cl, -0-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-d;-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-Cg)-cycloalkyl, phenyl, benzyl, phenoxy~ benzyloxy, NR'R", . ::; .. ~ ;:., . : ~, 126846~

phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-tC1-C4)-alkylsulfamoyl, or which optionally carries up to 3 of the previously mentioned identical or different substituents and two adjacent carbon atoms of the aralkoxy radical together carry a -[CH2-]n or -CH=CH-CH=CH- chain, in which one CH2 group of the chain is optionally replaced by 0, S, S0, S02 or NR', R5 and R6 together stand for -[CH2]j- and R4, R7 and R8 are as defined above, R' and R" are identical or different and denote hydrogen, tC6-C12)-arYl or (C1-Cg)-alkyl, or R' and R" together stand for -CCH2]h-, ;n which a CH2 group can be replaced by 0, S, N-(C1-C4)-alkanoylimino or N-(C1-C4)-alkoxycarbonylimino, f is 1, 2, 3, 4, 5, 6, 7 or 8, preferably 1 to 5, g is 0, 1 to (2f+1), h is 3, 4, 5 or 6, i is 1, 2, 3 or 4, n is 3 or 4, x is 0, 1, 2 or 3, preferably 0 or 1, and their physiologically tolerable salts.

1H-Thieno[3,4-d]imidazole derivatives of the formula I, in which A is as defined above under (b), are preferred.
T is preferably an -S0- group.

R7 preferably stands for a substituted phenylalkoxy ; . :. , ' radicaL of the formula -O{CH2~U ~ Rl1 R~R12 i hi h R9 R10 R11 R12 and R13 are ident;cal or different and denote hydrogen, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, ~C~lZ-]xcfH(2f+1-9)F9~ -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxy-carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyL, phenyl, benzyl, phenoxy, benzyloxy, NR'R", such as amino, anilino, N-methylanilino, phenyl-mercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N
(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or two adjacent subs.ituents together denote a -CCH2-]n or -CH=CH-CH=CH- chain, in ~hich one CH2 group of the chain is optionally replaced by 0, S, S0, S02 or NR', y denotes 0, 1, 2, 3 or 4, preferably 0 and 1, and the remaining substituents R9, R10 R11 R12 and R13 as defined previously, where unsubstituted benzyloxy and unsubstituted phenoxy are excluded, and R', R", f, 9, n and x are as defined above.

Particularly preferred compounds of the formula I are those in which A is preferably as defined above under b), T preferably denotes an -S0- group, R1 and R2 are identical or different and denste hydrogen, :
(C1-C3)-alkyl, halogen, (C1-C4)-alkoxy, --CCH2-]xCfH(2f+1-g)Fg or (c1-c4)-alko~ycarbonyl~

:
.

~2~8462 R3 is as defined above, R4 and R5 each denote hydrogen, R6 and R8 are identical or different and denote hydrogen, halogen, (C1-C3)-alkyl, (C1-C6)-al.koxy and a fluoroalkoxy radical of the formula -O-CCH2-]xCfH(2f+1-g)Fg~

R7 denotes a monosubstituted or poLysubstituted benzyl-oxy or phenoxy radical, R9, R10, R11, R12 and R13 are identical or different and denote hydrogen, fluorine, chlorine, bromine, tri-fluoromethyl, cyano, nitro, (C1-C6)-alkoxycarbonyl and the remaining radicals and variables are as defined above, in particular, ho~ever, compounds of the formula I, in ~hich A is preferably as defined above under (b), T preferably denotes an -S0- group, R1 and R2 are ~entical or different and denote hydrogen or (C1-C3)-alkyl, R3 is as defined above, R4 and R5 each denote hydrogen, R6 and R8 are identical or different and denote hydrogen, (C1-C3)-alkYl or (c1-c3)-alkoxy~

R7 denotes a monosubstituted or poLysubstituted benzyl-oxy or phenoxy radical, R9, R10, R11, R12 and R13 are identical or different ,,;
:~

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

- : : .: , 1;~684~2 and denote hydrogen, fluorine, chlorine, trifluoro-methyl and the remaining radicals and variables are as defined above.

The following are of particular significance:

Z-~4-(4-trifluoromethylbenzyloxy)-2-picolyl-sulfinyl]-1H-thieno[3,4-d]imidazole

2-[3-methoxy-4-(4-trifluoromethylbenzyloxy)-2-picolyl-sulfinyl]-1H-thieno[3,4-d]imidazole 2-[3-methoxy-4-(4-fluorobenzyloxy)-2-picolylsulfinyl1-1H-thieno[3,4-d]imidazole 2-[4-(3,5-bistrifluoromethylbenzyloxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]imidazole 2-[4-(2,4-difluorophenoxy)-2-picolylsulfinyl]-1H-thieno-[3,4-d]imidazole 2-[4-(3-trifluoromethylphenoxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]imidazole 2-[4-(4-fluorophenoxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]-imidazole 2-[4-(4-chlorophenoxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]-imidazole Alkyl and radicals derived therefrom such as, for example, alkoxy, alkylmercapto, alkylsulfinyl~ alkylsulfonyl, aralkyl or alkanoyl can be straight-chain or branched.

(C6-C12)-Aryl is, for example, phenyl, naphthyl or biphenylyl, phenyl being preferred.

(C7-C11)-Aralkyl is, for example, benzyl or phenethyl, - . . ~ ~ ,. . ,. :,:: - - . . : , , . ; . . ~

6~346~

preferably benzyl. The same appl;es to radicals derived therefrom, such as aralkoxy.

Halogen stands for fluorine, chlorine, bromine or iodine.

Suitable N1m protective groups R are described, for example, in connection with substituted picolylsulfinyl-benzimidazoles in EP-A-176,308 and EP-A2-221,041, and for thienoimidazole compounds in EP-A-234,485.

Preferred Nim protective groups are those which can be cleaved in the presence of acids, preferably in a pH range from about 1 - 6 and/or under physiological conditions.

OptionaLly, chiral carbon and sulfur atoms which are present can exist both ;n the R and the S configuration.
In such cases, the compounds of the formula I exist in the form of the pure enant;omers or as a mixture of stereoisomers (such as a mixture of enantiomers and a mixture of diastereomers).

Suitable salts are, in particular, alkali metal and alkaline earth metal salts, and salts with physiologi-cally tolerable amines.

The invention furthermore relates to a process for the preparation of compounds of the formula I, which com-prises a) reacting compounds of the formula II

~ ~ X1 (II) in which Ar R1, R2 and R3 are as defined above and x1 denotes i. a leaving group or ii. -SH, -S M or -SO2-M , with compounds of the formula III

. .

` ~.. :-.
:: ' ~ .'' . :" ~ , . :. . -: ,:: ~: :
, ~ : :

126~3462 ~, (III) in which R4, R5, R6, R7 and R8 are as defined above and x2 in the abovementioned case denotes i. -SH, -S M or -S02-M~ and in the abovementioned case ii. preferably denotes a leaving group or OH, or b) reacting compounds of the formula LV

,~NH2 (IV) ~ NH-R3 in which A, R1, R2 and R3 are as defined above, with compounds of the formula V

~C S~ ( V ) R- o R5 in which R4, R5, R6, R7 and R8 are as defined above and R stands for an esterified group, ~ :' 5 i. in compounds of the formula I, oxidizing tan) optionally present -S- group(s), if desired, to give (an) -SO- or -S02- group(s), ii. in compounds of the formula I, oxidizing (an) optionally present -SO- group(s), if desired, to 20 give (an) -S02- group(s), iii. if desired acylating, alkylating or aralkylating compounds of the formula I, in ~hich R3 stands for hydrogen, :: :: : :: :

~ 26~4~

iv. if desired hydrolyzing compounds of the formula I, - wherein R3 does not denote hydrogen, and v. converting compounds of the formuLa I, if desired, into their physiologically tolerable salts, where two or more of the measures i.-iv. can also be carried out in a sequence other than that indicated.

M stands for cations such as, for example, ions of alkali metals or alkaline earth metals, or ammonium or alkylammonium ions, in particular sodium ions or potas-sium ions.

If, according to the process variant (a) preferred here,compounds of the formula II are reacted with compounds of the formula III, then X1 or x2 stands for a leaving group which can be removed nucleophilically, such as Cl, Br, I, -0-S02-CH3, -0-S02-CF3 or -0-S02-(C6H4-pCH3).

The reaction of a compound of the formula Il with a com-pound of the formula III or its salts takes place ;n an inert solvent such as, for example, water, methylene chloride, methanol, ethanol, acetone, ethyl acetate, toluene, tetrahydrofuran, acetonitrile, dimethylform-amide, dimethyl sulfoxide or mixtures of these solvents, expediently in the presence of an inorganic or organic base, such as, for example, hydrox;des, carbonates, alkoxides, hydrides or amides of sodium or potassium, ammonia, triethylamine~ tributylamine or pyridine at -20 to +150C, preferably at 0 - 80C.
.

The compounds of the formula II are known compounds (see, for example, Gronowitz, "The Chemistry of Heterocyclic Compounds", ~and 44, i'Thiophene and its Derivatives", Parts 1 - 3, New York 1985-6) or can be prepared in analogy to known processes, for example by ring closure of suitably substituted 2,3-, 3,4- or 4,5-diam;nothio-.: . . .

-: :.. : .: , :

~268462 phenes of the formula IV defined above with suitable sulfur compounds such as carbon disulfide (for example DE-A-3,132,167).

The 2,3-, 3,4- or 4,5-diaminothiophenes necessary for this are either known from the literature or can be pre-pared in analogy to known processes. They are, for example, obtained by reduction of suitably substituted aminonitrothiophenes.

In the esters of the formula V employed in process variant (b), R stands for an esterified group, preferably (C1-C6)-alkyl or benzyl.

The reaction of a compound of the formula IV with a com-pound of the formula V according to process variant (b) takes place analogously to the procedures described in Preston et al., ~enzimidazoles and Congeneric Tricyclic Compounds, Part 1, New York, pages 10-13.

The compounds of the formula I thus obtained can, if R3 denotes hydrogen, be converted into physiologically tolerable salts.

Compounds of the formula I having T = -S- can furthermore be converted into those having T = -SO- or -S02- using suitable oxidants. In the same ~ay, -S- groups in the substituents R1, R2 and R7 can be oxidized.

This reaction takes place in a suitable, ;nert solvent such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, toiuene, ethyl acetate, acetic acid, trifluoroacetic acid, water, methanol, ethanol or mixtures thereof at -20C to ~150C, preferably at -1nC to +40C.

Suitable oxidants are, for example: hydrogen peroxide, peracids and peresters such as peracetic acid, trifluoro--- .. ,., . : ..~ ,, , - ... .

: . - :

~2~84~

peracetic acid, monoperphthalic acid, m-chloroperbenzoic acid and its ester, ozone, dinitrogen tetroxide, iodo-benzene, N-chlorosuccinimide, 1-chlorobenzotriazole, sodium hypochlorite, potassium peroxodisulfate, t-butyl hypochlorite, tetrabutylammonium periodate or permangan-ate, sodium metaperiodate, selenium dioxide or manganese dioxide, ceric ammonium nitrate, chromic acid, chlorine, bromine, diazabicyclo-~2.2.2]octane-bromine complex, dioxane dibromide, pyridinium perbromide, sulfuryl chloride, 2-arylsulfonyl-3-aryloxaziridines, titanium tetraisopropoxide/tert.-butyl hydroperoxide (optionally with the addition of dialkyl esters of (D)- or (L)-tartaric acid and a defined amount of water).

Likewise, isolated, optionally immobilized oxidizing enzymes or microorganisms can be used as oxidants.

The oxidants are employed in equimolar amounts, if appropriate even in a slight excess of 5 - 10 mole % in the oxidation to T = -S0- or even in a large excess and/
or at a higher reaction temperature when oxidation to T - -S02- is desired.

The invention furthermore relates to new intermediates of the formula III. They can be prepared by methods known to the person skilled in the art, such as, for example, are described in "The Chemistry of Heterocyclic Compounds - Pyridine and its Derivatives", Pts. 2 and 3, E. Klingsberg Ed. Interscience Publishers, 1962.

In addition to the synthesis of the compounds of the formula III, where x2 denotes a leaving group, from compounds of the formula III, in which x2 denotes a ~0 hydroxyl group, the compounds of the formula III, in which x2 denotes chlorine or bromine, can be prepared, for example, by halogenation of the corresponding 2-picolines with N-bromosuccinimide, trichloroisocyanuric acid (Chem. aer. 120" 649-651 (1987)) or other N-haloamides .
:.. .. : -- :
. . , ~ . .

~6~46~

such as N-chlorophthalimide.

Without limiting the invention to the following examples, several preparation processes for compounds of the formula III, in which x2 denotes hydroxyl, are des-cribed below. Their conversion into compounds of theformula III, in ~hich XZ denotes a leaving group, takes place by standard methods.

Compounds of the formula III, in which x2 denotes a hydroxyl group, R6 and R8 denote identical or different hydrogen or methyl, and R7 denotes a monosubstituted or polysubstituted (C6-C12)-aryloxy or (C7-C11)-aralkoxy radical, are obtained from nitro compounds of the formula VI or chlorine compounds of the formula VII.

R~ RB

~I H3C ~
N02Vl I R7 O O
Vl R7 Vl I I
R~ R8 V~ > ,~ ) 111 ~:

I X R =COCH3 :

A compound of the formula VI or VII iS brought to reac-tion in an ;nert solvent such as, for example, tetra-hydrofuran, dioxane, acetonitrile, acetone, methyl ethyl ketone, dimethyl sulfoxide, dimethylformamide, dimethyl-acetamide, hexamethylphosPhoric triamide or 1,3-dimethyl-

3,4,5,6-tetrahydro-2-(1H)-pyrimidinone, in the presence . . ~

.; . . , : .

' ~

i2~ ,2 of an organic or inorganic base such as, for example, the hydroxide, hydrogen carbonate, carbonate, hydride or propoxide of sodium, lithium carbonate, the hydroxide, carbonate, hydride, hydrogen carbonate or tert.-butoxide of potassium, with an alcohol of the formula R7H between 0C and the boiling point of the solvent~

The preparation of the compounds of the formula III from compounds of the formula VII, which are prepared by the action of chlorinating agents such as, for example, acetyl chLoride, thionyl chloride and phosphorus oxy-chloride on compounds of the formula VI, can be advan-tageous compared to the reaction with compounds of the formula Vl.

4-Fluoro-2-picoline (J. Prakt. Chem. 9, 164-172 (1959)) and 4-fluoro-2-picoline-N-oxide, which is analogous to VII, can also be used.

~ithout limiting the invention to the examples mentioned below, 4-fluoro-, 4-chloro-, 4-trifluoromethyl-, 2,4-di-fluoro-, 3,5-difluoro-, 3,5-dichloro-, 3,5-bistrifluoro-methyl- and pentafluoroben~yl alcohol, 4-fluoro-, 4-chloro-, 3-trifluoromethyl-, 2,4-difluorophenol and penta-fluorophenol are employed, for example, as alcohols.

The compounds of the formula VIII thus obtained are reacted with trifluoroacetic anhydride at 0C or ~ith acetic anhydride, if necessary in the presence of an acid, such as, for example, glacial acetic acid, at 80 -120C to give the acetates of the formula IX.

Their alkaline hydrolysis using hydroxides or carbonates of alkali metals in methanol, ethanol, water or similar solvents Leads to the compounds of the formula III, in which x2 denotes hydroxyl.

Compounds of the formula III, in which X denotes a ,. ~:' ' .
. . -. ~ . , ' ' ~ :
. .
... ..

~268~2 hydroxyl group, R6 denotes an alkoxy radical and R8 denotes hydrogen, can be prepared by the following pro-cess~
O
Ho ~ 1- R920/R x R o ~ 1. POC
H3C ~J Z . NH3oq . H3C ~Nll 2 ~ CPE35 H3C ~N
X ) H ~I
(Xl) (O) 1 .: (X] ] ), X=O
1 .+2.: (X] ] ] ), X=1 H3C~ 2 N~OH HOHzC~

(XIV) ( ~
Maltol X reacts, for example, with a halide RaX ;n the presence of silver oxide or with fluoroalkyl tri-flates to give 3-alkoxypyran-4-ones which are reacted with aqueous ammonia to give 2-methyl-3-alkoxy-4-pyridones of the formula XI (J. Org. Chem. 29, 776 (1964)).

Using a halogenating agent, for example POCl3, the com-pounds of the formula XI are converted into 2-methyl-3-alkoxy-4-chloropyridines, from which 4-alkoxy derivatives are obtained using an alcohol R7H in the presence of a base.

The reaction of the analogous N-oxides XIII with alcohol-ates to give compounds of the formula XIV is advantageous.

The substituted benzyl alcohols and phenols utilized have been mentioned previously.

Compounds of the formula XI can also be reacted directly to compounds of the formula XV in the presence of silver oxide.

- . .

~L26~46~

O ~?7 RO~ R"O~, Il ~ '11,1 H3C--~ H3C ~1 Xl XV

The invention furthermore relates to compounds of the formula III which can be obtained in an analogous manner by employing the isomeric 5-hydroxy-2-methyl-4-pyranone of the formula XVII, which~ for example, is prepared from kojic acid XVI as descr;bed in J. Chem~ Soc. 1956, 2558, instead of maltol X.

O O
~OH ~OH
~ 11 ' J~ IJ ~ ~
HOHzC 0~ H3CO~
XVI XVI l Cl R7 ,¢~ O R ~¢~ O R

XVI I I ~ XIX
: ::
Processes for the preparation of 3~4-dialkoxy~2-p;colines and 4,5-dialkoxy-2-picolines have also been described in EP-A-166,287 and EP-A-208,452.

The novel compounds of the formula I and their salts possess valuable pharmacological properties.

They clearly inhibit gastric acid secretion and, more-over, exhibit an excellent gastric and intestinal pro-tective action.

"Gastric and intestinal protection" is taken in this connection to mean the prevention and treatment of , :

:- 'f .

126~

gastrointestinal disorders, in particular inflammatory gastrointestinal disorders and lesions (such as, for example, gastric ulcer, duodenal ulcer, gastritis, or gastric irritation caused by hyperacidity or medicaments), which, for example, can be caused by microorganisms, bacterial toxins, medicaments (for example antiphlogistics and antirheumatics), chemicals (for example ethanol), gastric acid or stress situations.

On the basis of their excellent properties, the substi-1n tuted thienoimidazoles of the formula I and their pharma-cologically eolerable salts are outstandingly suitable for employment in human and veterinary medicine, where they can be used in particular for the treatment and prophylaxis of disorders of the stomach and intestine and those disorders which are based on excessive gastric acid secretion.

It has been found that the colon H /K ATPase (compare Gustin and Goodman, J~ Piol. Chem. 256 t1981] 10651-10656) is strongly inhibited in vitro by compounds which are formed by treating the compounds of the formula I
according to the invention with acid (for example with sodium acetate/HCl buffer having a pH of about 4-5.5).
Such conversion products can also be formed in vivo by the passage of the compounds of the formula I through the gastrointestinal tract. To whae extent they are formed depends on the substitution pattern and the pH.

A decisive influence on the electrolyte balance in the intestinal mucosa is attributed to the colon H+/K+
ATPase. Colon H+/K+ ATPase inhibitors, such as those mentioned above, can therefore intervene in this balance and be used for the treatment of disorders having a disturbed electrolyte balance.

The invention therefore also relates to the use of com-pounds of the formula I or their acid conversion products . ., ;: . .., . .; . .: .

:. . :., . :., ~ ::
~ , , ; ~ . , ~26~462 in the treatment of diarrheal illnesses. Examples of such disorders are inflammatory gastric iLlnesses, such as cholera, paratyphoid, travel diarrhea or other forms of secretory diarrhea, but also ulcerative colitis, Crohn's disease and regional enteritis.

The invention furthermore relates to conversion products which are formed by treating compounds of the formula I
with acid.

The invention therefore further relates to the compounds of the formula I according to the invention for use in the treatment and prophylaxis of the previously mentioned disorders.

Likewise, the invention embraces the use of the com-pounds according to the invention in the preparation of medicaments which are employed for the treatment and prophylaxis of the previously mentioned disorders.

The invention further relates to medicaments which con-tain one or more compounds of the general formula I and/
or their pharmacologically tolerable salts and also inclusion compounds of compounds of the formula I and cyclodextrin, preferably ~-cyclodextrin.

The medicaments are prepared by processes which are known per se and which are familiar to the person skilled in the art. The pharmacologically active compounds accord-ing to the invention (= active compounds) are eitheremployed as medicaments as such, or preferably in com-bination with suitable pharmaceutical auxiliaries in the form of tablets, dragees, capsules, suppositories, emul-sions, suspensions or solutions, where the active com-pQund content is advantageously between 0.1 and 96%.

Which auxiliaries are suitable for the desired medicamentformulations are familiar to the person skilled in the , .

126846~

art on the basis of his knowledge. In addition to sol-vents, gel-forming agents, suppository bases, tableting auxiliaries and other active compound excipients, anti-oxidants, dispersing agents, emulsifiers, defoaming agents, flavor-correcting agents, preservatives, solubi-lizing agents or colorants can, for example, be used.

The active compounds can be administered orally or paren-terally, oral administration being preferred.

In general, it has proved advantageous in human medicine to administer the active compound(s) in oral doses in a daily dose of about 0.01 to about 20 mg/kg of body weight, if appropriate in the form of several, preferably 1 to 4, individual doses, to obtain the desired results. With parenteral administration, similar or (in particular in intravenous administration of the active compound), as a rule, lower dosages, can be used. The determination of the optimum dosage in each case and the type of adminis-tration of the active compound can easily take place by anyone skilled in the art on the basis of his expert knowledge.

If the compounds according to the invention and/or their salts are to be employed for the treatment of the above-mentioned disorders, then the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other med;cament groups~ such as anti-biotics, for example ofloxazine, antacids, for example aluminum hydroxide, magnesium aluminate, sucralfate, Bi salts, tranquillizers, such as benzodiazepines, for example diazepam; spasmolytics, such as, for example, bietamiverine, camylofine; anticholinergics, such as, for example, pirenzlepine, telezepine, oxyphencyclimine, phen-carbamide; local anesthetics, such as, for example, tetracaine, procaine; and optionally also gastrin antagonists, enzymes, vi~amins or aminoacids.

~L23~4~i ~

To give a form for oral use, the active compounds are mixed with the additives customary for this purpose, such as excipients, stabilizers or inert diluents, and brought into a suitable form for administration, such as tablets, dragees, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions, by customary methods. Gum arabic, magnesium oxide, magnes-ium carbonate, lactose, glucose or starch, in particular maize starch, can, for example, be used as inert excipients. In this case, the preparation can take place both as dry or moist granules. Possible oily excipients or solvents are, for example, vegetable and animal oils, such as sunflower oil or codliver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable salts are brought into solution, suspension or emulsion, if desired with the substances customary for this purpose, such as solubilizing agents, emulsifiers or further auxiliaries. Suitable solvents for the novel active com-pounds and the corresponding physiologically tolerablesalts are, for example: water, physiological saline solutions or alcohols, for example ethanol, propanol or glycerol, in addition to sugar solutions such as glucose or mannitol solutions, and also a mixture of the differ-ent solvents mentioned.

The following examples serve to illustrate the proceduresaccording to the invention, without limiting the inven-tion to the representative substances mentioned here.

The melting and decomposition points indicated are not corrected or standardized.

, , A

Example 1 4-Chloro-2-picoline-N-oxide 15.4 g (0.1 mol) of 4-nitro-2-picoline-N-oxide are added in portions at 0C to 75 ml of acetyl chlorideu On S warming to room temperature, a clear solution results which is added dropwise to ice with stirring. After adding KzC03, the mixture is extracted several times using dichloromethane and ethyl acetate. After evaporat-ing, the product is purified chromatographically on silica gel. The oil obtained crystallizes on standing, m.p. 37C.

xample Z

4-(4-Trifluoromethylben~yloxy)-2-picoline-N-oxide 11.2 9 (100 mmol) of potassium tert.-butoxide are added under an N2 atmosphere at 25C to 25 ml (183 mmol) of 4-trifluoromethylbenzyl alcohol. 7~2 9 (50 mmol) of 4-chloro-2-picoline-N-oxide are subsequently added drop-~ise, then 10 ml of tert.-butanol are added, and the mixture is stirred for 1 hour at 25C and for 30 minutes at 75 - 80C. Water is then added and the mixture is extracted three times using dichloromethane, the extracts are dried and concentrated, and the residue is chromato-graphed on silica gel using dichloromethane/methanol.
The product is obtained from the corresponding fractions, m.p. 113 -115C.

Example 3 4-(4-Trifluoromethylbenzyloxy)-2-hydroxymethylpyridine 3.4 g (12 mmol) of the title compound from Example 2 are warmed to 80C in 5 ml of glacial acetic acid and 10 ml of acetic anhydride are added dropwise at this tempera-,, : , ~, ' - ', : :

: , ,,' ~ : . :, ~L2~346'~

ture with stirring. The mixture is then warmed to 110 -120C for 2 hours, allowed to cool to 80C, 10 ml of meth-anol are added, the mixture is heated to reflux for a further 15 minutes and subsequently concentrated. The residue is taken up in 10 ml of methanol and rapidly added dropwise at 10C to 50 ml of 2N methanolic NaOH. The solution is then clarified over charcoal, concentrated, the residue treated with 50 ml, extracted three times using 50 ml of dichloromethane, and the organic phase dried and concentrated. The crystallized residue is triturated with a petroleum ether/diisopropyl ether mixture (1:1), and the product is filtered of-f with suction, washed with a little diisopropyl ether and dried in vacuo, m.p. 96 - 98C.

Example 4 4-(4-Trifluoromethylbenzyloxy)-2-chloromethylpyridine 2.2 9 (7.8 mmol) of the title compound from Example 3 are d;ssolved in 50 ml of anhydrous dichloromethane and a solution of 2 ml of thionyl chloride in 6 ml of dichloro-methane is added dropwise at -10C. The mixture is warmed to room temperature, stirred for 30 minutes more, and concentrated. The crystalline residue is brought to crystallization using diisopropyl ether and dried using an oilpump, m.p. 133 - 135C.

ExampLe 5 2-C4-(4-Trifluoromethylbenzyloxy)-2-picolylmercapto~-1H-thienoC3,4-d]imidazole dihydrochloride 0.625 9 (4 mmol) of 2-mercaptothieno[3,4-d]imidazole are added at 25C to 1.35 9 (4 mmol) of the title compound from Example 4 in 50 ml of ethanol, and the mixture is stirred at 60C for 1.5 hours. The reaction mixture is concentrated in vacuo, and the residue is treated with acetone, filtered off with suction, washed with acetone ~, ": ' '' . ~
. ~ ~ ' : - , . ' 1~6~462 and dried in vacuo, m.p. 180 - 182C.

Example 6 2-[4-(4-Trifluoromethylbenzyloxy)-2-picolylmercapto]-lH-thienoC3,4-d]imidazole 1.5 9 (3.0 mmol) of the dihydrochloride from Example 5 are suspended in 25 ml of methanol with ice-cooling and under a nitrogen atmosphere and 1.7 ml (about 12 mmol) of triethylamine are added dropwise, by means of which a clear solution is formed which is subsequently clarified over activated charcoal and concentrated. On treating with water, the residue crystallizes and is washed with water and dried in vacuo, m.p. 141 - 143C with decom-position.

ExampLe 7 2-~4-(4-Trifluoromethylbenzyloxy)-2-picolylsulfinyl]-1H-thienoC3,4-d]imidazole A solution of O.S 9 (2.5 mmol, 85~) of m-chloroperbenzoic acid in 10 ml of dichloromethane is added dropwise with stirring at O to 5C to 1.0 9 (2.37 mmol) of the title compound from Example 6 in a two-phase mixture of 200 ml of dichloromethane and 100 ml of aqueous KH2P04/
Na2HP04 buffer solution (pH = 7.5). The organic phase is separated off, shaken with saturated aqueous NaHC03 solution, dried over MgS04, clarified over activated charcoal and concentrated. The crystalline evaporation residue is treated with ethyl acetate, filtered off with suction and washed twice with a little ethyl acetate.
The colorless crystalline product is dried in vacuo, m.p. 149C with decomposition.

~26B46~

Example 8 4-(2,4-Difluorophenoxy)-2-picoline-N-oxide 4.3 9 (30 mmol) of 4-chloro-2-picoline-N-oxide are added to a mixture of 4.6 g (35 mmol) of 2,4-difluorophenol in 25 ml of N,N-dimethylacetamide and 4.9 9 (35 mmol) of finely powdered potassium carbonate and the mixture is warmed to 140C for 3 hours with stirring. After cool-ing, the reaction mixture ;s poured into 250 ml of water, extracted three times using dichloromethane, and the organic phases are dried over MgS04 and concentrated.
The residue is taken up in dichloromethane and extracted by shaking with saturated aqueous NaCl solution. After drying and freeing from solvent, the extract is brought to crystallization using diisopropyl ether and washed with ethyl acetate. Colorless crystals, m.p. 112 - 124C.

The following Examples 9 to 72 were prepared analogously to Examples 1 to 8 and to the synthesis schemes shown:

-,~:
'' , '~, , .' ' ' 34~,~

R6 1 [CH2]U-~R1 1 ~ R~ R12 H3C~

Ex-ample No. Y R6 R9 R10 Rll R12 R13m.D.
. _ A .

12 1 H H F H F H *

14 1 H H H C:l H H 153-lSS
1 H H Cl H Cl H 163-165 16 :LOCH3 H H F H H 78- 80 18 1OCH3 H CF3 H CF3 H 164-167 :
19 1OCX3 H F F H H * ~ :
0 H H CF3 H H H oil*
~ithout purifying, re~ctea further :
:

; : ~:. ., , . - , .
- :- . . :~: ~.
.: : :

~L2~4~i2 6 - [CH2] U-~2R 1 1 E x -a m p l e No. YR6-- R9 R10 Rll R12 R13 m p ~ C

23 l H F H F H H56- 60 24 1 H H F H F Hoi l *
l H H F F H Hoil *
26 1 H H H Cl H H79- 82 27 l H H Cl H Cl H114-115 31 l OCH3 H F F H H93- 95 32 0 H H CF3 H H Hoi l *

reacted further , . . .

- . :,-: '~'' .,'..... .
: - - .. ~ ~: -~L26~ 2 6 --[CH2] y~~ R 1 1 R~ R1 Rl 2 HCI
Cl H2C ~ .

Ex-ample No. Y R6 R9 R10 Rll R12 R13m.p.~Cl 37 1 H H F H F ~ hygroscopi c r 38 l H H F F H H136-138 39 1 H H H Cl H H154-156 1 H H Cl H Cl H159-160 42 l OCH3 H H CF3 H H155-156 43 1 OCH3 H CF3 H CF3H 151-152 :
44 1 OCH3 H F F H Hhrgroscop;c *
0 H H CF3 H H ~ resin *

* reacted further . -.. . -34~

- [CH2] --~ R

~S-CH2 H

E x -amp l e No . Y R6 R9 R10 Rll R12 R13m ~ p .~ Cl 48 1 H H CF3 H CF3 H lB7 52 1 H H H Cl H H 155- 158 53 1 H H Cl H Cl H 178- 179 : .
. ~
. ~ , , : .;

R9 RlO
6 O-~CH2]y~

~-CH2 ~ R1 R12 H

ample m.p-[c]
No. Y R6 R9 R10 Rll R12 R13 and dec.
... _ . .. .

64 l H H F F H H 151 1 H H H Cl H H 144-145 66 1 H H rl H Cl H 102-104 67 1OCH3 H H F ~ H 119-121 71 0 ~ H CF3 H H H 119-121 . .
If not described expl;citly, the~following Examples are obtained analogously to Examples 2-8:

Example 73 4-(4-Fluorophenoxy)-2-picoline-N-oxide 6.2 9 (5S mmol) of 4-fluorophenol are dissolved ;n 75 ml of N,N-dimethylacetamide and Z0.7 9 (150 mmol) of finely powdered potassium carbonate are added. 7.7 9 (50 mmol) of 4-nitro-2-picoline-N-oxide are added to this suspen-1Q sion and the mixture is warmed at 80C for 3 hours. Afurther 7 9 (50 mmol) of potassium carbonate are subse-quently added and the mixture is stirred for one hour at ~' , :,, ,.: -., ~ : : ~ .. : :
. , . - , . . .
-: . , ., ~

~fz~

10QC. After cooling, ;t is freed from N,N-d;methyl-acetamide in vacuo, and the residue is taken up in water, extracted a number of times using dichloromethane, dried over MgS04 and concentrated, and the residue is brought S to crystallization using diisopropyl ether, m.p. 122-124C.

Example 74 4-(4-Fluorophenoxy)-2-hydroxy-methylpyridine, m.p. 75-77C
(from diisopropyl ether) Example 75 4-(4-Fluorophenoxy)-2-chloromethylpyridine hydrochloride, oily crude product, reacted further in Example 76.

Example 76 2-C4-(4-Fluorophenoxy)-2-picolylmercapto]-14-thieno[3,4-d]imidazole 1.60g (10 mmol) of 2-mercaptothieno[3,4-d]imidazole are suspended in 100 ml of methanol and 7 ml of 5.5 M sodium methoxide solution are added. A solution of 3.0 9 (10 mmol) of the title compound from Example 75 in 20 ml of methanol is added dropwise to the resulting clear solu-tion at room temperature and the mixture is heated underreflux for 1 hour. ~ he solution is concentrated, water is added to the residue and the mixture is extracted with dichloromethane. The organic phase is dried over MgS04 and concentrated, and the residue is brought to crystallization using diethyl ether. The pale brown crude product is recrys-tallized from ethyl acetate/active carbon, m.p. 157-159C.

xample 77 2-~4-(4-Fluorophenoxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]imidazole, m.p. 146C ldec.] tfrom ethyl acetate).

. ~ , :. ~

Example 78 4-(4-Chlorophenoxy)-2-picoline-N-oxide, m.p. 81-83C (from diisopropyl ether), preparation anaLogous to Example 73.

Exarnple 79 4-(4-Chlorophenoxy)-2-hydroxymethyl-pyridine, m~p. 64-65C
(from diisopropyl ether) Example 80 4-(4-Chlorophenoxy3-2-chloromethyl-pyridine hydrochloride, m.p. 156-157C (from ethyl acetate) Exa~ple 81 2-[4-(4-Chlorophenoxy)-2-picolyl-mercapto]-1H-thienoC3,4-d]imidazole, m.p. 150-151C ~dec.] (from ethyl acetate/
diethyl ether) Example 82 2-C4-(4-Chlorophenoxy)-2-picolyl-sulfinyl]-1H-thieno[3,4-d]imidazole, m.p. 140-141C Cdec.] (from ethyl acetate) Example 83 4-(3,5-Bistrifluoromethylphenoxy)-2-picoline-N-oxide :
a) 1.84 9 (16.5 mmol) of potassium tert. butoxide are introduced in portions a~ 20C with vigorous stirring and under a nitrogen atmosphere into 3.45 9 (15 mmol) of 3,5-bistrifluoromethylphenol, dissolved in 10 ml of tert.
butanol. Tert. butanol is subsequently distilled off, the residue is taken up in 10 ml of N,N-dimethylacetamide and 1.66 9 (15 mmol) of 4-fluoro-2-picoline in 2 ml of N,N-dimethylacetamide are added dropwise at 20C. The re-action mixture is then heated at 135-140C for 4 hours, 6~2 ~ater is added and the mixture is extracted using d;chloro-- methane. The oily crude product is chromatographed using ethyl acetate/toluene (5:1) on silica gel. (Rf = 0.4).

b) 4.3 9 (13.3 mmol) of the product from Ex. 83 a) are oxidized in dichloromethane at 20C ~ith stirring using 2.7 9 (13.3 mmol) of 85~ strength m-chloroperbenzoic acid.
The organic phase is extracted by shaking with saturated aqueous NaHC03 solution after 2 hours, dried and concen-trated, oily product, Rf (ethyl acetate/methanol = 8:1) = 0.08.

Example 84 4-(3,4-Dichlorophenoxy)-2-picoline-N-oxide, m.p. 125-127C
tfrom petroleum ether), p,eparation analogous to Example 73 Example 85 4-(3,4-Dichlorophenoxy)-2-hydroxymethyl-pyridine, m.p.
103-105C (from diisopropyl ether) Example 86 4-(3,4-Dichlorophenoxy)-2-chloromethylpyridine hydro-chloride, m.p. 173-175C (from diisopropyl ether) Example 87 2-C4-(3,4-Dichlorophenoxy)-2-picolylmercapto]-1H-thieno-C3,4-d]imidazole, m.p. 161-163C (from ethyl acetate) Example 88 2-C4-(3,4-Dichlorophenoxy)-2-picolylsulfinyl~-1H-thieno-C3,4-d]imidazole, m.p. 116C (dec.; from toluene) The following compounds of the formula ., ~ . .
', ~

R~ R10 O - E C HZ] Y--~ R 1 1 R1 R ~ R R1 ~ R12 ~sO-C~2~

can be prepared in an analogous manner:

: :

:. :.. . :. .

34~2 y = 1:

Rl R2 R3R6 R8 R9 R10 Rll R12 R13 H H H H H F F F F F

H H H H H Cl H CF3 H H
H H H H H H H CN H H
H H H H H H Cl Cl H H

H H H CH3 H H H Cl H H
H H H CH3 H H Cl H Cl H

H H H CH3 H H Cl Cl H H

H H H H CH3 H Cl H Cl H

H H H H CH3 H H Cl H H

CH3 CH3 H H H H H Cl H H
CH3 CH3 H H H H Cl H Cl H
CH3 CH3 H H H H Cl Cl H H

CH3 CH3 HCH3 H H Cl Cl H H

H H CH20Ac H H H H CF3 H H
H H (CH3)CHOAc H H H H CF3 H H
H H CH20Ac H H H H F H H
H H CH20Ac CH3 H H H F H H
_, _ _.......... . . . .

' ;, : `~

.
. , :
. .

Y = l;

Rl R2R3 R6 RJ3 R9 R10 Rll R12 R13 . _ _ H HCH20Ac H H H H Cl H H
H H CH20COOEt H H H Cl Cl H H
H H CH20COOEt H H H H CF3 H H
H H CH20COOEt H H H H F H H

OCH2CF3 H H H H H H Cl H H
OCH2CF3 H H H H H Cl Cl H H

OCH2CF3 H H CH3 H H H Cl H H

OCH2CF3 OCH2CF3 H H H H H Cl H H

4CH2CF2CF3 H H CH3 H H H Cl H H

OcH2cF2cF3OCH2CF2CF3 H H H H H CF3 H H

OCH2CF2CF3OCH3 H H H H Cl Cl H H

OCH2CF3 OCH3 H H H H Cl Cl H H
OCH2CF3 OCH3 H ~H H H H CF3 H H

~,.~ r~e 11 Ll u L- Ll Ll Ll ~ u Ll U~r2~r2n n n n rl n n ~1 -- 3s --Y = 1 ;

Rl R2 R3 R6 R8 R9 R10 R _ R R13 OCFzCF2F U H CH3 H H H Cl H H

H H CH20COPh H H H H CF3 H H
H H CH20COOBz H H H H CF3 H H
H H CH20COOBz H H H H F H H
H H CH20Ac CH3 H H H CF3 H H

.
.. . . .
- . - " : . . "
. . ` `' ` .'`' ~ ` :

. :::.,`, , :

~2~;84 Y = o:

Rl R2 R3 R6 R8 R9 R10 Rll Rl~ R13 H H H H H F F F F F

CH3 CH3 H H H H ~F3 H CF3 H

H H H H H Cl H Cl Cl H
H H H CH3 H Cl H Cl Cl H i H H H :H CH3 Cl H Cl Cl H
H H H OCH3 H Cl H Cl Cl H
CH3 CH3 H H H Cl H Cl Cl H :
H H H H H F H F F H
H H H H H H Cl H Cl H
H H H OCH3 H H Cl H Cl H
CH3 CH3 H H H H Cl H Cl H

,, . " ,, - . .. , ... ,.;: ,~ : . :

~ X6~346'~

Y = 0:

Rl R2 R3 R6 R8 R9 R10 Rll R12 R1 CH3 CH3 H H H H Cl Cl H H
H H H CH3 H H Cl Cl H H
CH3 ~H3 H H H H H Cl H H
H H H CH3 H H H Cl H H

Claims (14)

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

1. A compound of the formula I
(I) in which A stands for a) , b) or c) T denotes -S-, -SO- or -SO2-, R1 and R2 are identical or different and denote hydro-gen, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoy.l, (C1-C6)-alkylcarbonyloxy, (C3-Cg)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methyl-anilino, phenylmercapto, phenylsulfonyl, phenylsulfin-yl, sulfamoyl, N-(C1-C4)-alkylsulfanoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or, it A is as defined above under (a) or (c), can also together denote -[CH2]n- or -CH=CH-CH=CH-, in which a CH2 group is optionally replaced by O, S, SO or SO2, or R3 denotes hydrogen, (C1-C6)-alkanoyl, (C1-C6)-alkyl-carbamoyl, (C1-C6)-alkoxycarbonyl, benzyloxycarbonyl or another physiologically tolerable Nim protecting group which can preferably be cleaved in acidic medium and/or under physiological conditions such as, for example, (C1-10)-acyloxy-(C1-C6)-alkyl, preferably (C1-C10)-alkanoyloxy-(C1-C6)-alkyl, benzoyloxy-(C1-C6)-alkyl, benzyloxycarbonyloxy-(C1-C6)-alkyl or (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkyl, R4 and R5 are identical or different and denote hydrogen or (C1-C3)-alkyl, R6 and R8 are identical or different and denote hydrogen, halogen, trifluoromethyl, (C1-C12)-alkyl, (C1-C12)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -NR'R", (C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12) alkoxy (C1-C12)-alkoxy, (C7-C11)-aralkoxy, (C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl or (C1-C12)-alkylsulfonyl, R7 denotes a substituted (C6-C12)-aryloxy radical or (C7-C11)-aralkoxy radical which carries 1, 2, 3, 4 or 5 identical or different substituents selected from the group comprising halogen, cyano, nitro, trifluoro-methyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'R", phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or which optionally carries up to 3 of the previously mentioned identical or different substituents and two adjacent carbon atoms of the aralkoxy radical together carry a -[CH2-]n or -CH=CH-CH=CH- chain, in which one CH2 group of the chain is optionally replaced by O, S, SO, SO2 or NR', R5 and R6 together stand for -[CH2]i- and R4, R7 and R8 are as defined above, R' and R" are identical or different and denote hydrogen, (C6-C12)-aryl or (C1-C8)-alkyl, or R' and R" together stand for -[CH2]h-, in which a CH2 group can be replaced by O, S, N-(C1-C4)-alkanoylimino or N-(C1-C4)-alkoxycarbonylimino, f is 1, 2, 3, 4, 5, 6, 7 or 8, g is 0, 1 to (2f+1), h is 3, 4, 5 or 6, i is 1, 2, 3 or 4, n is 3 or 4, x is 0, 1, 2 or 3, and their physiologically tolerable salts.

2. A compound of the formula I as claimed in claim 1, in which A stands for in which R1 and R2 are identical or different and denote hydro-gen, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (Cl-C6)-alkylcarbonyl, (C1-C6)-2lkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methyl-anilino, phenylmercapto, phenylsulfonyl, phenylsulfin-yl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, and its physiologically tolerable salts.

3. A compound of the formula I as claimed in claim 1, in which T stands for an -SO- group, and its physio-logically tolerable salts.

4. A compound of the formula I as claimed in any one of of claims 1 to 3, in which R7 stands for a substituted phenylalkoxy radical of the formula in which R9, R10, R11, R12 and R13 are identical or different and denote hydrogen, halogen, cyano, nitro, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxy-carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, NR'R", such as amino, anilino, N-methylanilino, phenyl-mercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkylsulfamoyl, or two adjacent substituents together denote a -[CH2-]n or -CH=CH-CH-CH- chain, in which one CH2 group of the chain is optionally replaced by O, S, SO, SO2 or NR', y denotes 0, 1, 2, 3 or 4, preferably 0 and 1, and the remaining substituents R9, R10, R11, R12 and R13 as defined previously, where unsubstituted benzyloxy and unsubstituted phenoxy are excluded, and R', R", f, g, n and x are as defined above, and its physiologically tolerable salts.

5. A compound of the formula I as claimed in any one of claims 1 to 3, in, which R1 and R2 are identical or different and denote hydrogen, (C1-C3)-alkyl, halogen, (C1-C4)-alkoxy, -O-[CH2-]xCfH(2f+1-g)Fg or (C1-C4)-alkoxycarbonyl, R3 is as defined in claim 1, R4 and R5 each denote hydrogen, R6 and R8 are identical or different and denote hydrogen, halogen, (C1-C3)-alkyl, (C1-C6)-alkoxy and a fluoroalkoxy radical of the formula -O-[CH2-]xCfH(2f+1-g)Fg, R7 denotes a monosubstituted or polysubstituted benzyl-oxy or phenoxy radical, R9, R10, R11, R12 and R13 are identical or different and denote hydrogen, fluorine, chlorine, bromine, tri-fluoromethyl, cyano, nitro, (C1-C6)-alkoxycarbonyl and the remaining radicals and variables are as defined in claim 1, and its physiologically tolerable salts.

6. A compound of the formula 1 as claimed in any one of claims 1 to 3, in which R1 and R2 are identical or different and denote hydrogen or (C1-C3)-alkyl, R3 is as defined in claim 1, R4 and R5 each denote hydrogen, R6 and R8 are identical or different and denote hydrogen, (C1-C3)-alkyl or (C1-C3)-alkoxy, R7 denotes a monosubstituted or polysubstituted benzyl-oxy or phenoxy radical, R9, R10, R11, R12 and R13 are identical or different and denote hydrogen, fluorine, chlorine, trifluoro-methyl and the remaining radicals and variables are as defined in claim 1, and its physiologically tolerable salts.

7.2-[4-(4-trifluoromethylbenzyloxy)-2-picolyl-sulfinnyl]-1H-thieno[3,4-d]imidazole, 2-[3-methoxy-4-(4-trifluoromethylbenzyloxy)-2-picolyl-sulfinyl]-1H-thieno[3,4-d]imidazole, 2-[3-methoxy-4-(4-fluorobenzyloxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]imidazole, 2-[4-(3,5-bistrifluoromethylbenzyloxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]imidazole, 2-[4-(2,4-difluorophenoxy)-2-picolylsulfinyl]-1H-thieno-[3,4-d]imidazole, 2-[4-(3-trifluoromethylphenoxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]imidazole, 2-[4-(4-fluorophenoxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]-imidazole or 2-[4-(4-chlorophenoxy)-2-picolylsulfinyl]-1H-thieno[3,4-d]-imidazole and their physiologicallr tolerable salts.

8. A process for the preparation of a compound of the formula I as claimed in any one of claims 1 to 3, which comprises a) reacting compounds of the formula II
(II) in which A, R1, R2 and R3 are as defined above and x1 denotes i. a leaving group or ii. -SH, -S-M+ or -SO2-M+, with compounds of the formula III
(III) in which R4, R5, R5, R7 and R8 are as defined above and x2 in the abovementioned case denotes i. -SH, -S-M+ or -SO2-M+ and in the abovementioned case preferably denotes ii. a leaving group or OH, or b) reacting co-pounds of the formula IV
(IV) in which A, R1, R2 and R3 are as defined above, with compounds of the formula V
(V) in which R4, R5, R6, R7 and R8 are as defined above and R stands for an esterified group, i. in compounds of the formula 1, oxidizing (an) optionally present -S- group(s), if desired, to give (an) -SO- or -SO2- group(s), ii. in compounds of the formula 1, oxidizing (an) optionally present -SO- group(s), if desired, to give (an) -SO2- group(s), iii. if desired acylating, alkylating or aralkylating compounds of the formula 1, in which R3 stands for hydrogen, iv. if desired hydrolyzing compounds of the formula I, wherein R3 does not denote hydrogen, and v. converting compounds of the formula I, if desired, into their physiologically tolerable salts, where two or more of the measures i.-iv. can also be carried out in a sequence other than that indicated.

9. A compound as claimed in any one of claims 1, 2, 3 and 7 for use as a medicament.

10. A compound as claimed in any one of claims 1, 2, 3 and 7 for use as an inhibitor of gastric acid secretion.

11. A pharmaceutical preparation containing a compound as claimed in any one of claims 1, 2, 3 and 7.

12. A process for the production of a pharmaceutical preparation which comprises bringing a compound of the formula I as claimed in any one of claims 1, 2, 3 and 7 together with a physiologically tolerable excipient and, if appropriate, further additives or auxiliaries into a suitable form for administration.

13. Use of a compound as claimed in any one of claims 1, 2, 3 and 7 as a medicament.

14. Use of a compound as claimed in any one of claims 1, 2, 3 and 7 as an inhibitor of gastric acid secretion.