IL88739A - 2-(4-Fluoroalkoxy-2-picolinylsulfinyl)-1h-thieno [3,4-d] imidazole derivatives a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

88739/2 - ( 4-FLUOROALKOXY-2-PICOLINYLSULFINYL 1H- THIENO[ 3, -d] IMIDAZOLE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM UNO- Hi- ^ j-,3i7loi7-,:,^1p',D-2->oi7ip^K,iii >D-4)-2 nni n οηικ o> nn nmpn i eijm om^nt? ΐϊί»ηη ,ίηΤΝΤκ Ν d -4,3] Benz imidazole derivatives having an action inhibiting gastric acid secretion are disclosed in, for example, German Patent A-25 48 340 , European Patent A-5 129 and German Patent A-32 40 248 . European Patent A- 1 76 308 (laid open on April 2 , 1 986 ) relates to N-subst ituted benz m i da z o I e derivatives.

The present Patent Application is for a Patent of addition to Patent No. 81,609 published 21 October, 1994 and which relates to compounds of the formula n which represents (a) (b) (c) T denotes -S, -SO- or -S02_, R1 and R2 are identical or different and denote hydrogen, halogen, cyano, nitro, trifluoromethyl, ( C^-Cg ) -alkyl , (Οχ-06) -hydroxyalkyl , (Ci-CJ -alkoxy, (Cx-C4) -fluoroalkoxy, -0CF2C1-, -0- CF2- CHFCl. , (Ci-Ce) -alkylmercapto, -alkylsulfinyl, alkylcarbonyl (Ci-C -alkylsulfonyl, alkoxycarbonyl , carbamoyl, N- (C1-C4) -alkylcarbamoyl , N,N- di- (C1-C -alkylcarbamoyl , (C^-Ce) -alkyl-carbonyloxy, (C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino , phenylmercapto , pheylsulfonyl , phenylsulfinyl , sulfamoyl, N- ( C1-C4) -alkylsulfamoyl or Ν,Ν-di- (C1-C4) -alkylsulfamoyl or, if A is as defined above together under (a) or (c), can also togchcr denote -[CH2]n_ or - C§=CH-CH=CH- , one CH2 group optionally being replaced by 0,S0 Or S02, R3 denotes hydrogen, alkanoyl, (C^-C8)- alkylcarbamoyl or another physiologically tolerated conventional protecti/e group which can be eliminated, preferably in an acid medium and/or under physiological conditions, 4 and R5 are identical or different and denote hydrogen or (C1-C3) -alkyl, R6, R7, R8 and R9 are identical or different and denote hydrogen, halogen, * ~NR' R" (C^-C^) -alkoxy- ( C C12 ) -alkyl , ( C^C^ ) -alkoxy- ( C^C^ ) - alkoxy, (Cy-C^; ) -aralkyloxy, ( -Cj 2 ) -alkyl-mercapto, (ci_ci2) -alkylsulfinyl or (Ci-C^) -alkylsulfonyl or R5 and R6 together represent -[CH2]1-( R' and R" are identical or different and denote hydrogen or (C^-C^) -alkyl , or R' and R'' together represent -[CH2]h. in which one CH2 group can .1 be replace by 0,N- (C1-C4) -alkanoylimino or N- (C^Ci) - alkoxycarbonylimino, f is 1, 2, 3 or 4, g is 1 to (2f+l), h is 4, 5 or 6, i is 1, 2 or 3, and n is 3 or 4 , and their physiologically tolerated salts.

The present invention' relates to thienoimidazole derivatives of the formula I -3- 88739/3 in which A represents T denotes -SO- R1 and denote hydrogen, R3 denotes hydrogen, R 4 and R5 denote hydrogen, R7 denotes -0/"-CH2 ¾Cf H {2f + 1 _g) Fg , R6, R8 and R9 are identical or different and denote hydrogen, or (Ci-C^*-3^/!., f i s an integer from 1 to 10 , g is 1 to (2f+1), x is 0 or one, with the stipulation that: -when X is zero, f is 1 to 10, and when x is 1, f is 5 to 10, and its physiologically tolerated salts. - 4 - 88739/2 The following are of particular importance: 2-/4- (2,2,3,3,4,4,5,5-octafluoropentylaxy) -2-pioolylsulfinyl7-1H-thieno 3, -d7imidazole; 2-/4-(2,2,3,3,4,4, -heptafluorobutyloxy) -2-pioolylsulfinyl) -4 ,6-dimethyl-1H-thiexio_3,4-d7imidazole; 2- 3-methyl-4-(2,2,2-trifluoroethyloxy) -2-pioolylsulfinyl7-1H-thieno 3,4-d7imidazole; 2- 5-methyl-4-(2,2,2-trifluoroethyloxy)-2-picolylsulfinyl7-1H-thieno/3,4-d/imidazole; 4-/3-nethyl-/(2,2,3,3,3-pentafluoropropyloxy) -2-picolylsulfinyl7-1H-thieno 3, -d7inulazole; 2- 3-methyl-4-(2,2,3,3,4,4,4-heptafluorobutyloxy)-2-picolylsulfnyl-1H-thieno 3,4-d7imidazole? 2-/4- (2 ,2,2-trmuoroettyloxy) -2-pioolylsulfinyl?-1H-thieno 3,4-d?-imidazole; 2-/4-(2,2,3,3-tetrafluoropropyloxy) -2-picolylsulfinyl7-1H-thieno--/3,4-d7imidazole; 2-/4- (2,2,3,3,3-pentafluDrOpropylaxy) -2-pioolylsulfinyl7-1Hr thieno/3,4-d7imida20le; Alkyl can be straight-chain or branched.

Cf H(2f+1-g)Fg is a s^aight'Chain or branched fluorinated alkyJ adical.

Chiral carbon and suLfur atoms which are present where appropriate can exist both in the R and in the S configuration. In such cases, compounds of the formula I are in the form of the pure enantiomers or a mixture of stereoisomers (such as a mixture of enantiomers and a eixture of diastereomers).

Suitable salts are, in particular, alkali eetal and alkaline earth metal salts and salts with physiologically tolerated amines.

The invention also relates to a process for the preparation of compounds of the formula I, which comprises a) reaction of compounds of the formula II in which A, R1, ^ and R^ are as defined above, and denotes i. a leaving group or ii. -SH, -S" or -SO2 ~, with compounds of the formula III in which R4, R5, R6, R7, R8 and R9 are as defined above and X^ in the abovement oned case i. denotes -S H , -S or -SO2 and in the abovement oned case ii. denotes a Leaving group or reaction of compounds of the formula in which A, R , R and R are as defined above, with compounds of the formula V in which R , R , R , R , R and R are as defined above and R^ represents an esterifying group, and i. if desired, oxidation of -S grou which a is present, wheree aapppprropriate, in compound of the ormula I , to -SO- or -SOg- group ii are he ii'-.'. if desired, hydrolysis of compound of the formula - 3 " I in which does not denote hydrogen, and iii if desired, conversion of compounds of the formula I into their physiologically tolerated salts, it also being possible for two or more of measures i.-iii . to be carried out in a sequence different from that indicated.

If, in accordance with process variant (a), which is preferred in this connection, compounds of the formula II are reacted with compounds of the formula III, then or represents a leaving group which can be removed nucleo-philically, such as CI, Br, I, -O-SO2-CH3, -O-SO2-CF3 or -0-S02-CC6H4-pCH3) .

The reaction of a compound of the formula II with a compound of the formula III or its salts is carried out in an inert solvent such as, for example, water, methylene chloride, methanol, ethanol, acetone, ethyl acetate, toluene, tetrahydrof uran, aceton i t r le, dimethylformamide, dimethyl sulfoxide or mixtures of these solvents, advantageously in the presence of an inorganic or organic base such as, for example, sodium or potassium hydroxide, car-bonate, alkoxide, hydride or amide, ammonia, triethyl-amine, tr buty lamine or pyridine, at -20 to +150°C, preferably at 0-80°C.

The compounds of the formula II can be prepared in analogy to known processes, for example by ring closure of appropriately substituted 2,3-, 3,4- or 4,5-diaminothiophenes of the formula IV defined above with appropriate sulfur compounds such as carbon disulfide (for example German Patent A-31 32 167).

The 2,3-, 3,4- or 4,5-diaminoth ophenes required for this purpose are either known from the literature or can be prepared in analogy to known processes. They are obtained by, for example, reduction of appropriately substituted am non i troth iophenes.

R in the esters of the formula V used in process variant (b) represents an esterifying group, preferably (Ci-C0)-al ky I or benzyl .

The reaction of a compound of the formula IV with a compound of the formula V in accordance with process variant (b) is carried out in analogy to the procedures described in Preston et al., Benz imidazoles and Congeneric Tricyclic Compounds, Part 1, New York, pages 10-13.

The compounds of the formula I thus obtained can, if denotes hydrogen, be converted into physiologically toler-ated salts.

Compounds of the formula I with T = -S- can, furthermore, be converted into those with T = -SO- or -SO2- using suitable oxidizing agents. It is also possible in the same manner to oxidize -S- groups in the substituents R^, R^ and R6 to R9.

This reaction is carried out in a suitable inert solvent such as, for example, methylene chloride, chloroform, carbon tetrachlor de, 1,2-dichloroethane, toluene, ethyl acetate, acetic acid, tr if luoroacet c acid, water, methanol, ethanol or mixtures thereof, at -20°C to +150°C, preferably at -10°C to +40°C.

Examples of suitable oxidizing agents are: hydrogen peroxide, peracids and peresters, such as peracetic acid, tr if luoroperacet ic acid, monoperphthal i c acid, m-chloro-perbenzoic acid and their esters, ozone, dinitrogen tetroxide, iodosobenzene, N-chlorosucc nimide, 1-chloro-benzotr azole, sodium hypochlorite, potassium peroxodi-sulfate, t-butyl hypochlorite, tetrabutylammonium perio-date or permanganate, sodium metaper iodate, selenium dioxide or manganese dioxide, eerie ammonium nitrate, chronic acid, chlorine, bromine, diazabicycloC2.2.23octane- bromine complex, dioxane dibromide, pyridinium perbromide, sulfuryl chloride, 2-arylsulf ony l-3-ar loxaz ridines, titanium tetra sopropylate/tert. -butyl hydroperoxide (where appropriate with the addition of dialkyl esters of (D)- or (L)-tartaric acid and a defined amount of water) .

It is likewise possible to use isolated, where appropriate immobilized, oxidizing enzymes or croorganisms as oxi-dizing agents.

The oxidizing agents are used in equimolar amounts, and optionally in a small excess of 5 - 10 mol Z in the oxidation to T * -SO-, or in larger excess and/or at a higher reaction temperature when oxidation to T * -SOj-is desired.

Compounds of the formula I with ≠ H can be prepared starting from compounds of the formula IV with = H and compounds of the formula V, or by acylation, alkylation or aralkylation of compounds of the formula I with = H. The second route will be dealt with in some detail hereinafter .

The acylation, alkylation or aralkylation of compounds of the formula I is carried out in a manner known per se using the appropriate acylating agents, alkylating agents or aralkylating agents in a suitable organic solvent, as a rule at a temperature between -78°C and the boiling point of the reaction mixture, where appropriate in the presence of a base.

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

They markedly inhibit gastric acid secretion and, furthermore, have an excellent protective action on the stomach and intest ines .

In this context, "protection of the stomach and intestines" is defined as the prevention and treatment of gastrointestinal disorders, in particular inflammatory gastrointestinal disorders and lesions (such as, for example, gastric ulcer, duodenal ulcer, gastritis, or irritable stomach related to hyperacidity or drugs) which may be caused by, for example, m croorganisms, bacterial toxins, drugs (for example anti nflammatory and ant rheumatic agents), chemicals (for example ethanol), gastric acid or stress situations.

By reason of their excellent properties, the substituted thienoimidazoles of the formula I and their pharmacologically tolerated salts are outstandingly suitable for use in human and veterinary eedicine, being particularly used for the treatment and prophylaxis of disorders of the stomach and intestines and of those disorders based on excessive gastric acid secretion.

It has been found that also the colonic K+-ATPase enzyme (cf. Gustin, Goodman, J. Biol. Chem. 10651-10656) inhibited in vitro by compounds, which are obtained on treatment of the compounds of the formula I with acid (for example with NaOAc/HCl buffer with pH 4-5.5). Such conversion products can also be formed during the in vivo passage of the gastro-intestinal tract. The amount of their formation depends on the substitution pattern and the pH value.

The colon-K+-ATPase is believed to be of great influence on the electrolyte balance across the mucosal barrier in the colon. Colon-K+-ATPase inhibitors as those mentioned above, can therefore influence said equilibrium, and they are therefore useful for treating diseases involving a disturbed electrolyte balance.

Therefore, the invention relates also to the use of compounds of the formula I, and their acid conversion products for treating diarrhoea diseases. Examples of such diseases are inflammatory intestinal diseases such as cholera, paratyphoid, tourist diarrhoea and other forms of secretory diarrhoea but also other intestinal diseases such as ulcerous colitis and regional enteritis.

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

Hence the invention furthermore relates to the compounds of the formula I according to the invention for use for the treatment and prophylaxis of the abovement ioned disorders.

Likewise, the invention comprises the use of the compounds according to the invention for the preparation of pharmaceuticals which can be used for the treatment and prophylaxis of the abovement oned disorders.

The invention furthermore relates to pharmaceuticals which contain one or more compounds of the general formula I and/or their pharmacologically tolerated salts.

The pha rma ceu t i c a L s are prepared by processes which are known per se and are familiar to the expert. The pharmacologically effective compounds (= active compounds) according to the invention are used as pharmaceuticals either as such or, preferably, in combination with suitable pharmaceutical auxiliaries, in the form of tablets, coated tablets, capsules, suppositor es, emulsions, suspensions or solutions, the content of active compound advantageously being between 0.1 and 96%.

The auxiliaries which are suitable for the desired pharmaceutical formulations are familiar to the expert on the basis of his knowledge. In addition to solvents, gel-forming agents, suppository bases, tableting auxiliaries and other active compound excipients it is possible to use, for example, antioxidants, dispersing agents, emul-sif iers, antifoam agents, flavors, preservatives, solubi-lizers or colorants.

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

In general, it has proven advantageous on oral administration in human medicine to give a daily dose of the ac-tive compound or compounds of about 0.01 to about 20 mg/kg of body weight, where appropriate in the form of several, preferably 1 to 4, individual adm nistrat ons, to achieve the desired result. On parenteral administration, it is possible to use similar or (especially on intravenous administration of the active compounds) as a rule lower doses. Every expert can easily establish, on the basis of his expert knowledge, the optimal dose and mode of administration of the active compounds required in each case.

If the compounds according to the invention and/or their salts are to be used for the treatment of the abovemen-tioned disorders, then the pharmaceut cal compositions can also contain one or more pharmacologically active ingredients of other pharmaceuticals groups, such as antacids, for example aluminum hydroxide, magnesium alu i-nate; tranquilizers such as benzodiazepines, for example diazepam; spasmolytics, such as, "for example, bietami-verine and camylof in; anticholinergics such as, for example, oxyphencyl imine and phenc a rbam i de ; local anesthetics such as, for example, tetracaine and procaine; and, where appropriate, gastrin antagonists, enzymes, vitamins or amino acids.

For an oral presentation, the active compounds are mixed with the additives customary for this purpose, such as vehicles, stabilizers or inert diluents, and converted, by customary methods, into suitable forms for administra-tion, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Examples of inert excipients which can be used are gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, in particular corn starch. This can entail preparation as either dry or moist granules. Examples of suitable oily vehicles or solvents are vegetable and animal oils, such as sunflower oil or f ish l ver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted, if desired with the substances customary for this purpose, such as solubil izers, emulsif iers or further auxiliaries, into a solution, suspension or emulsion.

Examples of suitable solvents for the new active compounds and the corresponding physiologically tolerated salts are: water, physiological saline solutions or alcohols, for example ethanol, propanol or glycerol, as well as sugar solutions, such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

The examples which follow are intended to illustra te the procedures according to the invention without limi t i ng the invention to the substances mentioned here as repre-sentat e.

The stated melting and decomposit on points have not been corrected or standardized.

Examples 1 to 13: Not part of invention Exampl e 1 : 2- 4- (2 , 2,3,3 4,4 , 4-heptafluorobutyloxy) -2-picolyl- sulfinyl?- 1 H-thieno 3 , 4-d7imidazole a) 4-Nitro-2-picoline N-oxide While cooling with ice, 163.5 g (1.5 mol) of 2-picoline N-oxide were introduced to 250 ml of 98 % sulfuric acid. At room temperature, 250 ml of 100 % nitric acid were added dropwise, and subsequently, the reaction mixture was carefully warmed up to 80 °C, with stirring, and was stirred for 3 hours at this temperature.

The reaction mixture was allowed to cool down to room temperature was poured in 1 1 of ice and neutralized with concentrated sodium hydroxide solution, with cooling and stirring. A yellow slush of crystals precipitated, which was filtered with suction, washed with a small portion of ice water and was dried.

Yield: 186 g (80 % of the theory), mp.: 156°C b) M- ( 2 , 2 , 3, 3 , ^ , M , M-heptafluorobutyloxy)-2-plcollne N-oxide . ¾ g (0.1 mol) of the compound of Example 1 .a) were dissolved in 150 ml of dimethylformamide, Ml.4 g (0.3 mol) of pulverised anhydrous potassium carbonate and 23 g (0.11 mol) of 9 % 2,2,3,3,4,4,4-heptafluorobutanol were added, and the reaction mixture was warmed to 70°C, with stirring. After H hours, additional 13·9 g of pottasium carbonate were added, and the mixture was stirred for further 6 hours. The mixture was allowed to cool down to room temperature, the salts were filtered off, and were washed with a small portion of dimethyl- formamide .

The filtrate was concentrated in vacuo, and the residue was extracted with water/ethylacetate. The organic layer was dried with Na^SO^, concentrated, and filtered over silica gel with ethyl acetate/methanol 3:1· After concentrating the filtrate, 22.7 g (74 % of the theory) of the title compound, mp. : 65°C, were isolated. c) 2-Chloromethyl-ll-(2,2,3,3,M,M,¾)-heptafluorobutyloxy- pyridlne 1*9-1 g of the compound of Example 1 .b) in M50 ml of acetic anhydride were stirred at 90°C for 1 hour. A control with TLC showed the complete conversion into 2-acetyloxymethyl-il- ( 2 , 2 , 3 ,3 , 4 , 4 , H )-heptafluorobutyloxy- pyridine .

The solvent was evaporated off In vacuo, the oily residue was dissolved in 500 ml of methanol, and a solution of 12 g of sodium hydroxide in 50 ml of water was added. After stirring at room temperature for 2 hours, TLC control showed the complete saponification of the acetate.

The solvent was removed in vacuo, the residue was dissolved in methylene chloride and washed with water. After drying with Na^O^ the organic layer was concentrated in vacuo. The residue was dissolved in 500 ml of chloroform and 50 ml of thionyl chloride were added dropwise, with stirring. The reaction mixture was heated to reflux for 1 hour, and then allowed to cool down. The solvent was removed in vacuo, the residue was dissolved in methylene chloride, the solvent was again evaporated off, the residue was taken up in diisopropyl ether, and the title compound crystalized.

Yield: 39 g (67 % of the theory); mp.: 98-101°C 2-f -( 2 , 2 , 3 ,3 , ¾ ¾ ,4-heptafluorobutyloxy)-2-picolylmer-capto~l-lH-thlenof 3 » —d"] imidazole 18.7 g of thieno[ 3 ,4-d] imidazole-2-thiol were added to a sodium methylate solution (prepared from 8.2 g of sodium and 300 ml methanol), and, during stirring, a solution of 43· 8 g of the compound of Example 1 .c) in 100 ml of methanol was added. After heating to reflux for 1 hour, a TLC control showed that the reaction was completed. The solvent was evaporated off in vacuo, the residue was dissolved in methylene chloride, and washed with water. The organic layer was dried with Na2S04 and concentrated in vacuo. The residue was triturated with diisopropyl ether, filtered withsuction and dried.

Yield: 43 g (80 % of the theory), mp.: 117°C e) 2-f 4-(2,2,3,3,4,4,4-heptafluorobutyloxy)-2-plcolylsul- finyll-lH-thlenof 3.¾-d1 imidazole 40.0 g of the mercapto compound of Example i.d) were dissolved in 800 ml of methylene chloride, and 500 ml of an aqueous phosphate buffer (pH « 7) were added. The suspension was stirred vigorously, and a solution of 20 g of 77 % meta-chloroperbenzoic acid in 150 ml methylene chloride were added dropwise at 0°C. The reaction mixture was stirred at this temperature for additional 10 minutes, and, after starch-iodine paper no longer showed the presence of the peracid, the organic layer was separated from the aqueous layer.

The aqueous layer was extracted with 100 ml of methylene chloride, the organic layers were combined, dried with a^SO^ and concentrated in vacuo until the volume was approximately 100 ml. After addition of 800 ml of diisopropyl ether, the crystallization (which had already been started) was completed. The crystals were filtered off with suction and were dried.

Yield: 32 g (76 % of the theory); mp. : 140°C (decomp.) The following compounds were prepared in analogous manner.

Example 2 ; 2-[4-(2,2,3,3, , ,5,5-octafluoropentyloxy)-2-picolylsul-finyl]-lH-thieno[ 3 >4-d] imidazole mp.: 116-119°C (decomp.) Example 3 : 2-[4-(2,2,3,3,4,4,4-heptafluorobutyloxy)-2-picolylsul-finyl]-4 , 6-dimethyl-lH-thieno[ 3 , 4-d] imidazole mp.: 147°C (decomp.) Example ; 2-[ 4- ( 2 , 2 , 2-trifluoroethyloxy)-2-picolylsulfinyl]-4 ,6-dimethyl-lH-thieno[ 3 , 4-d] imidazole mp. : 163-165°C (decomp.) Example 5 : 2-[ 4-(2,2,3,3-tetrafluoropropyloxy)-2-picolylsulfinyl]-4,6-dimethyl-lH-thieno[ 3, 4-d] imidazole mp.: il|H_iH7° c (decomp.) Example 6 : 2-[ 1— (2,2,3 ,3,3-pentafluoropropyloxy)-2-picolylsulfinyl]- ,6-dimethyl-lH-thieno[ 3 , 4-d] Imidazole mp.: 1 7-151°C (decomp.) Example 7 : 2-[ 3-methyl-i|-( 2,2, 2-trifluoroethyloxy)-2-picolylsulfinyl]-lH-thieno[ 3, 4-d] imidazole mp.: 121°C (decomp.) Example 8 : 2-[5-methyl-4-(2,2,2-trifluoroethyloxy)-2-picolylsulfinyl]-lH-thieno[ 3, 4-d] imidazole mp. : 163°C (decomp.) Example 9 : ^_ 4-[3- ethyl-(2,2,3,3,3-pentafluoropropyloxy)-2-picolyl-sulfinyl]-lH-thieno[ 3 , 4-d] imidazole mp.: 145°C (decomp.) Example 10 : 2-[ 3-Methyl-H- (2,2,3,3,4,4, 4-heptafluorobutyloxy)-2-picolylsulfinyl-l-thieno[ 3 , 4-d] imidazole mp.: 115°C (decomp.) Example 11: 2-[4-(2,2,2-trifluoroethyloxy)-2-picolylsulfinyl]-lH-thieno[ 3 , 4-d] imidazole mp.: 132-136°C (decomp.) Example i 2 : 2_[ 4-(2,2,3,3-tetrafluoropropyloxy)-2-picolylsulfinyl]-lH-thieno[ 3, 4-d] imidazole mp.: 152 °C (decomp.) Example 13 : 2-[ 4- (2,2,3 ,3 ,3-pentafluoropropyloxy)-2-picolylsulfInyl]-1H-thieno[ 3 , -d] imidazole mp.: 148-152°C (decomp.) Example 14 : 2-[ 4-( 1 , 1 ,1 ,3 ,3 ,3-hexafluoroisopropyloxy)-2-plcolyl-sulflnyll-lH-thlenof 3, 4- l imidazole a) ¾-(! ,1 ,1 ,3,3,3-Hexafluoroisopropyloxy)-2-plc01ine N-oxide The title compound was obtained in analogy to Example 1 .b) using potassium tert .butylate as a base. b) 4-(l ,1,1 ,3,3,3-Hexafluorolsopropyloxy)-2-picollne 4.5 g (l6 mmol) of the compound of Example 14. a) were dissolved in 100 ml of methanol and hydrogenated , using Raney nickel as a catalyst.

MS: m/e= 259 (M+, 100 %) , 2^0 (30 %) , 220 (8 %) 80 (77 %) c) 2-Chloromethyl-H-(l ,1 ,1 ,3 ,3 ,3-hexa luoroisopropyloxy)- pyridlne hydrochloride 2.2 g (8.6 mmol) of the compound of Example 14.b) were dissolved in 50 ml tetrachloromethane, 0.56 g of dimethylformamide and 1.4 g (5.6mmol of trichloro- isocyanuric acid were added, and the reaction mixture was heated to reflux for 1 hour. A precipitate was filtered off, 30 ml of IN hydrochloric acid in methanol were added to the filtrate and the solvent was evaporated off in vacuo. The crude product was used without further purification for the following step. d ) 2-f ¾- ( 1 , 1 , 1 , 3 3 ,3-Hexafluoroisopropyloxy)-2-picolyl- mercaptol-lH-thienof 3 ,it-d"l imidazole The title compound was obtained from the compound of Example 14.c) and thieno[ 3,4-d]lmidazole-2-thiol in analogy to Example 1.d) e) 2-f 4-(l ,1 ,1 , 3,3,3-Hexafluoroisopropyloxy)-2-picolyl- sulfInyll-lH-thienof 3 , ¾-d1 Imidazole The title compound was obtained* from the compound of Example I4.d); mp. : l68-l69°C [from diethyl ether]. *in analogy to Example 1.e)

Claims (5)

1. PATENT CLAIMS HOE 86/F 0¾5 BK compound of the formula in which represents b) denotes -SO- R1 and denote hydrogen, R denotes hydrogen, R 4 and RD denote hydrogen, R7 denotes -o/--CH27-Cf H (2f + 1 _g) Fg, R6, R8 and R9 are ident ical or different and denote hydrogen, or C c1_c12)-aL kyL' f is an integer from 1 to 10, g is 1 to (2f+1), x is 0 or one, with the stipulation that: when X is zero, f is 1 to 10, and when x is 1 , f is 5 to 10, and its physiologically tolerated salts. - 23 - 88739/ 4 2i A process for the preparation of a compound of the ■formula I as claimed in claim 1 which compr ises reaction of a compound of the formula in which A, R1 , R2 and R3 are as defined in claim 1, and x 1 denotes i . a leaving group or ii. -SH or - S,~ with a compound of the formula.

2. Ill in which R , R , R , R7, R8 and R are as defined in claim 1 and x2 in the abovementioned case i. denotes -SH or ~S~ and in the abovementioned case ii. denotes a leaving group or - 24 - 88739/.3 b) reaction of a compound of the formula IV in which A, R , R and R are as defined in cLaim 1, with a compound of the formula V in which R , R , R , R , R and R are as defined in claim 1 and R^ represents an esterifying group, and -if dcoircd, oxidation of -S- group which is present a compound of the formula I7to a -SO- group. if desired, hydrolysis of a compound of the formula I in which R¾ does not denote hydrogen, and if desired, conversion of a compound of the formula I into its physiologically tolerated salt, for it also being possible measures I and II, to be carried out in a sequence different from that indicated. 88739 /^ -25-

3. A pharmaceutical composition as active ingredient an effective quantity of a compound claimed in claim 1. gastric

4. A pharmaceutical composition inhibiting gastic acid secretion which contains as active ingredient an effective quantity of a compound claimed in claim 1.

5. A process for the preparation of a pharmaceutical composition as claimed in claims 3 or 4 which comprises converting a compound as claimed in claim 1 to a suitable form for administration. Attorneys for Applicants.