AU622866B2 - Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical formulations containing them and their use as gastric acid secretion inhibitors - Google Patents

Description

1.

1 i. i 622866 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Application Number: Lodged: Form Int. Class Complete Specification Lodged: S tAccepted: a Accepted: *e a Published: P i Priority: S Bt r 'gelated Art: Cr I

II

I I, Name of Applicant: 4 I Address of Applicant: I Wctual Inventor: HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany HANS-JOCHEN LANG, KLAUS WEIDMANN, ROBERT RIPPEL, KARL-HEINZ SCHEUNEMANN and ANDREAS W. HERLING EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Address for Service: Complete Specification for the invention entitled: SUBSTITUTED THIENOIMIDAZOLE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, PHARMACEUTICAL FORMULATIONS CONTAINING THEM AND THEIR USE AS GASTRIC ACID SECRETION INHIBITORS The following statement is a full description of this invention, including the best method of performing it known to us 1.

i :i i r- 1 r la Description Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical formulations containing them and their use as gastric acid secretion inhibitors.

Thienoimidazole derivatives with a gastric acid secretion-inhibiting action are known from EP-A1-234,485, EP-A2-201,094 and EP-A-237,248.

In order that the compounds of the invention may reach the secretory canaliculus of the parietal cell via the blood system, they must be stable at pH7.4, the pH of blood. The 1 0 typical passage of, compounds of the invention through a patient is illustrated in Figure 1.

In dosage form, djing the passage of compounds of the invention through the stomach pn .o (acidic medium.pHf=26), the compounds are encapsulated by micro capsules stable against such an acidic medium. However, so as to be effective, the compounds must pass 1 5 through into the blood system, where, it is essential that they remain effective until they achieve the target site. Surprisingly, it has been found that compounds of the Formula I are unexpectedly stable in solutions of pH7.4 when compared to compounds of ,,the prior art. This increased stability enables the compounds of the invention to reach their target site in an effective condition unlike those compounds of the prior art which 2 0 are likely to have reduced activity due to degradation prior to achievement of the target site.

The present invention relates to novel thienoimidazole derivatives of the formula I 7 6

R

R

N R R A N 13

R

R

in which

R

R

1 1 S1 2 2 2 A stands for a) R b) R or c) R T denotes -SO- or -SO 2 Ri and R2 are identical or different and denote hydrogen, halogen, cyano, nitro, trifluoromethyl, (Ci-Ce)- alkyl, (C -C 6 )-hydroxyalkyl, (C -Cs)-alkoxy, -O-[CH 2 o S1 (0 CpH(2p+l-q)Halq, preferably (C 1

-C

8 )-fluoroalkoxy, (C 1 -Ca)-fluoroalkenyloxy, (C1- I I lb

C

8 )-fluoroalkynyloxy, -OCF 2 -CI or -O-CF 2 -CHFCI, (C 1

-C

6 )-alkylmercapto, (C 1 -06)alkylsulfinyl, (Ci -C 6 )-alkylsulfonyl, (C 1

-C

6 )-alkylcarbonyl, (Cl -06) alkoxycarbonyl, carbamoyl, N-(C 1

-C

4 )-alkylcarbamoyl, N,N-di-(C 1 -04)alkylcarbamoyl, (Ci -C 6 )-alkylcarbonyloxy, (C 3

-C

8 )-cycloalkyl, phenyl, benzyl, phenoxy, -2benzyLoxy, anilino, N-methyLaniLino, phenylniercapto, phenylstuLfonyL, phenylsulfinyL, suLfamoyL, N-(Cl-C 4 alkyLsulfamoyL or N,N-di-(C -C 4 )-aL kyl suLfamoyL, or, if A is as defined above under or can aLso together denote -ECH2)n- or -CH=CH-CH=CH-, wherein one CH 2 group is optionally replaced by NVr, 0, S, SO or S0 2 or denote a substituted CC 6 -Cl 2 )-aryLoxy,

(C

7 -Cll)-araLkyLoxy, (C 6 -Cl 2 )-aryL or CC 7 -Cll)araLkyl radical, which carries in the aryL part 1, 2, 3, 4 or 5 identical or different substituents from the series comprising halogen, cyano, nitro, trifLuoromethyL, (Cl-C 6 )-aLkyL, (Cl-C6)-aLkoxy, -0-CH2o-CPH(2p+..q)HaLq, -OCF 2 C I, -0-CF 2

-CHFCI,

3 (Cl-C 6 )-aLkyLmercapto, (Cl-C 6 )-aLkyLsuLf inyL,

CC-C

6 )-aLkyLsuLfonyL, CC-C 6 )-aLkyLcarbonyL, 1C -CO-aLkoxycarbonyL, carbamoyL, C -C 4 )-aLkyLcarbamoyL, N,N-di-(C C-C 4 )-aL kyLcarbamoyL, (C 1

-C

6 aLkyLcarbonyLoxy, (C 3

-C

8 )-cycLoaLkyL, NR'R", suLfamoyl, N-(C -C 4 )-aLkyLsuLfamoyL or N,N-di-(C-C 4 )-aLkyLsuLfamoyL, R denotes hydrogen, (C -C 6 )-aLkanoyL, (C -C 6 )-aLkyLcarbamoyL, (CC-C 6 )-aLkoxycarbonyL, benzyLoxycarbonyL or another physiologically tolerated N -protective group, which can preferably be split off in an acid tr 25 medium and/oI under physiological conditions, such as, for example, (CC-Cj 0 )-acyLoxy-(C-C 6 )-aLkyL, preferably (CC-Cl 0 )-aLkanoyLoxy-(C-C 6 )-aLkyL, benzoyloxy-(Cl -C 6 )-aLkyL, benzyLoxycarbonyLoxy-

(CC-C

6 )-aLkyL or (CC-C 6 )-aLkoxycarbonyLoxy-(Cl-C 6 aLkyL, Rand R5are identical or different and denote hydrogen or (CC-C 3 )-aLkyL, a) R 6 denotes hydrogen and R 8 denotes fLuorine, chlorine or bromine, or b) R6denotes (Cl-C 3 )-aLkyl and -3- Rdenotes fluorine, or c) R 6 denotes fluorine or bromine and Rdenotes hydrogen, or d) R6denotes fluorine and R 8 denotes (C 1

-C

3 )-aLkyL, or 4 10 4" 4" V V.

e) one of the substituents R6and R8denotes the radical O0ECH2Jo-CPHC2p+1-q)Halq and the other denotes hydrogen, halogen, (Cj-C 3 )-aLkyL or the radical -O-[CH2]o-CpHC2p+1-q)HaL q, or f) one of the substituents R6and R 8 denotes a substituted (C 6

-C

12 )-aryLoxy radical or (C 7 -Cll)-araLkyLoxy radical, which carries in the aryl part 1, 2, 3, 4 or identical or different substituents from the series comprising halogen, cyano, nitro, trifLuoromethyL, (C 1

-C

6 -aLkyt, (C 1

-C

6 -aLkoxy, O(-CH23o-CpH(2p+1-q)HaLq, -OCF 2 Ct, -0-CF 2

-CHFCI,

(C 1

-C

6 )-at kyLmercapto, (C 1

-C

6 )-aLkyLsuLf inyL,

(CC-C

6 )-aLkytsuLfonyt, (C1-C 6 )-aLkyLcarbonyL, (Cl-C 6 )-aLkoxycarbonyL, carbamoyL, N-(C -C 4 )-aLkyLcarbamoyL, N,N-di-(C 1

-C

4 )-aLkyL carbamoyL, (C 1

-C

6 aLkyLcarbonytoxy, (C 3

-C

8 )-cycLoaLkyL, suLfamoyL, N-(Cl-C 4 )-aLkyLsuLfamoyL or N,N-di-(C 1

-C

4 )-aLkytsuLfamoyL, and the other denotes hydrogen, halogen, (Cl-C 3 aLkyL, the radical -0-CCH23o-CPH(2p+..q)HaLq or a substituted (C6-C12)-aryLoxy radical or (C 7

-C

11 araLkyLoxy radical, Hal denotes halogen, for example fluorine, chlorine or bromine, preferably fluorine, R 7 denotes hydrogen, halogen, (C 1

-C

1 2)-atkyt, (C 1

-C

12 at koxy, -O-ECH23o-Cp H2f...l.q)HaLq, -NRR"

CC

1 -C 12 )-aLkoxy-(C i-C 12 )-aLkyL, (C 1 -C 12)-aLkoxy- -4- (CC-C-1 2 )-aLkoxy, (Cj'-Cll1)-araLkyLoxy, (CC-Cl 2 aLkyLmercapto, (Cl-Cl 2 )-aLkyLsuLfinyt or (Cl-Cl 2 aLkylsuLfonyL, or IIif at Least one of the substituents R6and R8denotes a substituted (C 6 -Cl 2 )-aryLoxy radical or (C 7 -Cll)aralkyLoxy radical, R 7 can Likewise denote a (C 6 -Cl 2 aryloxy radical or (C 7 -Cll)-araLkyLoxy radical substituted as defined above under f), Rand Rtogether stand for -CCH2Ji-, R' and R" are identical or different and denote hydrogen,

(C

6 -Cl 2 )-aryL or (Cl-Cl 2 )-aLkyL, or RI and R" together stand for -ICH2)h-, in which one CH 2 group can be replaced by 0, S, N-(Cl-C 4 )-aLkanoyLiniino or N-(Cl-C 4 )-aLkoxyLcarbonyL imino, h is 3, 4, 5 or 6, preferably 4 to 6, i is 1, 2, 3 or 4, preferably 1 to 3, n is 3 or 4, o is 0, 1, 2 or 3, preferably 0 or 1, ji p is 1, 2, 3, 4, 5, 6, 7 or 8, preferably 1 to 5, and q is 0 or 1 to (2p+l), and physiologically tolerated salts thereof, with the proviso that the compounds 5-methyL-2-(2-pyridyLmethyLthio)-3H-thieno[2,3-dlimidazoL e, 5-niethyL-2-( (4-methoxy-2-pyr idyL )methyL th io)-3H-th jeno- 12P3-dJ imidazoLe, 2-(pyridyL)methytthio-3H-thieno(2,3-dJ imidazote, 2-((4-methoxy-2-pyridyL )methyLthio)-3H-thienoE2,3-d)imidazoLe, 5-acetyL-.Z-((4-methoxy-3,5-dimethyL-2-pyridyL )methyLthio)- 3 H-thienio-[2,3-d~jmidazoLe, methyl 2 -((4-uethoxy-3,5-dimethyL-2-pyridyL )methylthio)- 3 H-thieno[2,3-d~imidazoLe-5-carboxyLate, 5-acetyL-2-((4-methoxy-2-pyridyL)methyLthio)-3H-thieno- E2,3-d~imidazoLe, 5-acetyl-2-C2-pyridyL )methyLthio-3H-thienoE2,3-d~imidazoLe, and the corresponding suLfinyl compounds are excluded.

1H-Thienot3,4-dlimjdazoLe derivatives of the formula I in which A is as defined above under are preferred.

T is preferably an -SO- group.

Particularly preferred compounds of the formula I are those in which A is preferably as defined above under T preferably denotes an -SO- group, Rand R 2 are identical or different and denote hydrogen, (Cl-C 3 )-.3LkyL, halogen, (Ci-C 4 )-aLkoxy or (Cl-C 4 aLkoxycarbonyL, Ris as defined above, R nd R5each denote hydiugen, Rand R8are identical or different and are as defined above under a) e) and R 7 denotes hydrogen, (Cl-C 3 )-atkyt or a haLogenated aLkoxy, aLkenyloxy or aLkynyLoxy radical of the formula -O-CH23oCpH(2p+l.q)HaLq, (Cl 1

C

7 aLkoxy, benzyloxy or (Cj-C7)-aLkoxy-(C 1

-C

3 )-aLkyL, and in which halogen preferably denotes fluorine, -6chlorine or bromine, o is 0 or 1, p is 1 to 8 and q is 0 or 1 to and but in particular those compounds of the formula 1 in which A is preferabLy as defined above under T preferably denotes an -SO- group, Rand R 2 are identical or different and denote hydrogen or (Cl-C 3 )-aLkyL, 3 Ris as defined above, o0 ao Rand R 5 each denote hydrogen, 0 10 Rand Rare identical or different and are as defined above under a) e) and R 7 denotes hydrogen, (Cl-C 4 )-aLkoxy, a fluorinated n-aLkoxy radlical of the formula -O(H)-PCp1.)aq 0 or (Cl-C 3 )-aLkyL, in which halogen denotes fluorine,.

o is p is 1 to 5 and q is 0 or 1 to (2p+l).

Compounds which are of particular importance are 2-E3-methoxy-4-(2,2,2-tr ifLuoroethoxy)-2-picoLyLsuLfinyL3- IH-thienot3,4-d~imidazoLe, 2-C3-fethoxy-4-(2,2,3,3-tetrafLuoropropoxy)-2-picoLyLsulf inyL)-IH-thienoE3,4-d) imidazote, 2-[3-methoxy-4-(2,2,3,3,3-pentafLuoropropoxy)-2-picoLyLsuLfinyLJ-IH-thienoE3,4-d~iniidazoLe.

2-[3-methoxy-4-(2,2,3,3,4,4,4-heptafLuorobutoxy)-2picoLyLsutfinyL)-lH-thienoE3,4-d~imidazoLe, 2-(3-bromo-4-methoxy-2-picoLyLsuLf inyL )-IH-th ienot3,4-d)imidazoLe, 2-(4-methoxy-5-browfzn-2-picoLyLsuLfinyL)-lH-thieno[3,4-d3imidazoLe, and 7 2-(4-methoxy-5-chloro-2-picoLylsulfinyl)-1H-thieno[ 3 4 -d3imidazoLe.

Alkyl and radicals derived therefrom, such as, for example, alkoxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl, aralkyL or alkanoyl, can be straight-chain or branched.

(C

6

-C

12 )-AryL is, for example, phenyl, naphthyl or biphenylyL, and phenyl is preferred.

(C

7

-C

1 1 )-Aralkyl is, for example, benzyl or phenethyl, 10 preferably benzyl. This correspondingly applies to radicals derived therefrom, such as aralkyloxy.

Halogen stands for fluorine, chlorine, bromine or iodine.

tgt at im 3 Suitable N -protective groups R are described, for example, in connection with substituted picolylsulfinylbenzimidazoles in EP-A-176,308 and EP-A2-221,041, and for thienoimidazole compounds in EP-A-234,485.

Preferred Ni"-protective groups are those which can be split off in the presence of acid, preferably in a pH range of about 1 6 and/or under physiological condi- S 20 tions.

Any chiral C and S atoms present can occur both in the R- and in the S-configuration. In such cases, the compounds of the formula I are in the form of the pure enantiomers or as a .terecisomer mixture (such as an enantiomer mixture and diastereomer mixture).

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

The invention furthermore relates to a process for the I I 8 preparation of compounds of the formula I, which comprises a) reacting compounds of the formula II x (II) R3 in which A, R, R 2 and 3 are as defined above and X i. denotes a leaving group or ii. denotes -SH, -S-M or -SO 2

-M

with compounds of the formula III

R

7 R4 R

R

E

(III)

R

in which R 4

R

5

R

6

R

7 and R 8 are as defined above and

X

2 in the abovementioned case i. denotes -SH, -S-M or

-SO

2 -M and in the abovementioned case ii. preferably denotes a Leaving group or OH, or b) reacting compounds of the formula IV NH2

(IV)

NH-R3 in which A, R, R 2 and 3 are as defined above, with compounds of the formula V

R

7 0 R4 R RB C- (V) R9- 0 in which R 4

R

5

R

6

R

7 and R are as defined above and R 9 stands for an esterifying group,

A

an~ U 9 i. if desired oxidizing any group(s) present in compounds of the formula I to (the) -SO- or -SO 2 group(s), ii. if desired oxidizing any -SO- group(s) present in compounds of the formula I to (the) -S02- group(s), iii. if desired acylating, alkylating or aralkylating compounds of the formula I in which R 3 stands for hydrogen, iv. if desired hydrolysing compounds of the formula I in S 10 which R does not denote hydrogen, and v. if desired converting compounds of the formula I into their physiologically tolerated salts, it also being possible for two or more of the measures i.-iv. to be carried out in a sequence other than that shown.

M stands for cations, such as, for example, alkali metal, alkaline earth metal, ammonium or alkylammonium ions, in particular sodium or potassium ions.

8; «If in accordance with the process variant preferred 20 here compounds of the formula II are reacted with compounds of the formula III, X 1 or X 2 stands for a leaving group which can be detached nucleophilically, such as CI, Br, I, -O-S0 2

-CH

3 -0-S0 2

-CF

3 or -0-S02-(C 6

H

4 -pCH 3 The reaction of a compound of the formula II with a compound of the formula III or salts thereof is carried out in an inert solvent, such as, for example, water, methylene chloride, methanol, ethanol, acetone, ethyl acetate, toluene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or mixtures of these solvents, advantageously in the presence of an 10 inorganic or organic base, such as, for example, sodium or potassium hydroxide, carbonate, alkoxide, hydride or amide, ammonia, triethylamine, tributylamine or pyridine, at -20 to +150 0 C, preferably at 0 The compounds of the formula II are known compounds (see, for example, Gronowitz, "The Chemistry of Heterocyclic Compounds", Volume 44, "Thiophene and its Derivatives", Parts 1-3, New York 1985-6) or they can be prepared analogously to known processes, for example by cyclization of correspondingly substituted 3,4- or thiophenes of the formula IV defined above with corresponding sulfur compounds, such as carbon disulfide (for 1 example DE-A-3,132,167).

r The 3,4- or 4,5-diaminothiophenes required for this are either known from the literature or can be prepared analogously to known processes. They are obtained, for example, by reduction f correspondingly substituted aminonitrothiophenes.

In the esters of the formula V used in process variant R stands for an esterifying group, preferably

(C

1

-C

6 )-alkyl or benzyl.

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

If R 3 denotes hydrogen, the compounds of the formula I thus obtained can be converted into physiologically tolerated salts.

Compounds of the formula I where T can furthermore be converted into those where T -SO- or -SO2- with suitable oxidizing agents. groups in the substituents

MMMMMMM_

1 2 7 11 R R and R can also be oxidized in the same way.

This reaction is carried out in a suitable inert solvent, such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, ethyl acetate, acetic acid, trifluoroacetic acid, water, methanol, ethanol or mixtures thereof, at -20°C to +150°C, preferably at -10 0 C to +40 0

C.

Possible oxidizing agents are, for example: hydrogen peroxide, peracids and peresters, such as peracetic acid, trifluoroperacetic acid, monoperphthalic acid, m-chloro- J r. perbenzoic acid and esters thereof, ozone, dinitrogen ;tetroxide, iodosobenzene, N-chlorosuccinimide, 1-chloro- S benzotriazole, sodium hypochlorite, sodium brcmite, potassium peroxodisulfate, t-butyl hypochlorite, tetra- J l 15 butylammonium periodate or permanganate, sodium meta- 2 of periodate, selenium dioxide or manganese dioxide, cerium ammonium nitrate, chromic acid, chlorine, bromine, diazabicyclo[2,2,2]octane-bromine complex, dioxane dibromide, Spyridinium perbromide, sulfuryl chloride, 2-arylsulfonyl- 'i 20 3-aryLoxaziridines and titanium tetraisopropyLate/tert.butyl hydroperoxide (if appropriate with the addition of dialkyL esters of or (L)-tartaric acid and a defined amount of water).

Isolated and if appropriate immobilized oxidizing enzymes or microorganisms can also be used as the oxidizing agent.

The oxidizing agents are used in equimolar amounts, and also if appropriate in a slight excess of 5 10 mol Z in the case of oxidation to T -SO- or in a Larger excess and/or at a higher reaction temperature if oxidation to T -SO 2 is required.

The invention furthermore relates to novel intermediates of the formula III. They can be prepared by methods Tl(- T.i i 12 which are known to the expert, such as are described, for example, 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 for- 2 mula III, in which X denotes a leaving group, from com- 2 pounds of the formula III, in which X denotes a hydroxyl group, the compounds of tha formula III, in which X denotes chlorine or bromine, can be prepared, for example, by halogenation of the corresponding 2-picolines with Nbromosuccinimide, trichloroisocyanuric acid (Chem. Ber.

120, 649-651 (1987)) or other N-halogenoamides, such as N-chlorophthalimide.

Ir c 't Without Limiting the invention to the following examples, S 15 some preparation processes for the compounds of the formula III in which X 2 denotes hydroxyl are described below. They are converted into compounds of the formula 2 III, in which X denotes a Leaving group, by standard methods.

Compounds of the formula III in which X 2 denotes a Shydroxyl group, one of the substituents R 6 and R denotes bromine and the other denotes hydrogen can be obtained in accordance with equation 1.

.1 A mixture of the compounds of the formula VII/VIII is obtained by bromination of 2-picoline by known processes for example, Bull. Soc. Chim. France 2466, 1972).

After N-oxidation, for example with m-chloroperbenzoic acid, and nitration, the compounds IX and X are separated by crystallization or chromatography and prepared in a pure form.

The compounds of the formulae XI and XIII in which R7 denotes alkoxy are in each case obtained from the Lb, 13 compounds of the formulae IX and X and the corresponding alcoholates MR 7 in which M is as defined on page 9, and are reacted, for example, with acetic anhydride or

(CF

3

CO)

2 0 with subsequent hydrolysis of the acetates to give the compounds of the formulae XII and XIV.

Equation 1: R R H3C~ R

R

6

,RB-H

"2 0 H2504/503

H

3

SC

R

6

CH

*8s.W 4

I

8 4 o t 4 el

I

88**( 84 1

(VI)

1. m-CPBS 2. HN03/H 2 50 4 (VII) (VIII)

(IX)

MR

7 R7 Br- J RB

CH

3 0 21. Nto0/H(0 2. NoOH

(X)

R7H HOCH2

N

u

(IX)

a t I t r i

MR

7

(XI)

R

7

CH

3 0

(XIII)

1 Ac 2 0/(e0H) 2. NoOH

(XI)

(XIV)

The synthesis of compounds of the formula III in which X denotes a hydroxyl group, R 6 denotes hydrogen and R 8 denotes chlorine is shown in equation 2. The 5-amino-2picoline XV obtainable by known processes via degradation reactions of carboxylic acid derivatives of 6-methylnicotinic acid (cf. J. Prakt. Chem. 133 [19323 19) is reacted by reactions familiar to the expert (Sandmeyer -14 reaction, N-oxidation, nitration, reaction with alcoholates, rearrangement with acetic anhydride, acetate hydrolysis) to give compounds of the formula XX.

Equation 2: NH2 NoN0 2 /HCI R- CCI P5 RCI CuCI 1 J -CPBS

H

3 C H 3 C H 3

C

0 (XV) (XVI) (XVII) N0 2

R

7

R

7 R C R Ci CI 4 HN0 3

/H

2 50 MR 7 7 1 RcO/(AcOH)NoR C' S- 2. NoOH SHC H3C HOH2 C

N

0 0 (XVIII) (XIX) (XX) t rr '2 Compounds of the formula III in which X 2 denotes a 6 8 hydroxyl group, R denotes hydrogen or methyl and R 10 denotes fluorine can be obtained as shown in equation 3.

The compounds of the formula VIII can be converted into 5-amino-2-picolines XV under the conditions of the Ullmann reaction (cf. Rec. Trav. Chim. 84 951-64 (1965)).

The compounds XV are Likewise accessible via degradation reactions of carboxylic acid derivatives of 6-methylnicotinic acid of the formula XXI. The synthesis of the fluorine derivatives XXII is advantageously carried out under the conditions of the Schiemann reaction, as is known for XXII (R 6 H) (cf. J. Med. Chem. 13, 1124 (1970)).

The 4-nitro-5-fluoro-2-picolines of the formula XXIII are reduced, as is known for the analogous 3-fluorine isomers, to the amino derivatives XXIV (cf. Rocz. Chem.

41 279-87 (1967)) and these are converted into r C 15 the dihalides XXV.

Equation 3: R6= H, CH 3

H

3 (V I II H 3 C!C (XX I (X N 3

NH

2 *den' NHNH 2

NH

3 CuSO.

4 z R

NH

2

H

3

(XV)

EtONO/ 1. M CPBS' 2. HNO Fe /AcOH

H

3 C 4 0 (XXI II) (XXII F

YR

NoNO 2 /HCI NoNO 2 .M7 1

H

3 C

H

3

C-

0 xX I V) (XXV, Y F, CI) XXVI 9 C r 2. NcO Rii/t

HOH

2

C

(XXV1I C C

C

After N-oxidlation, replacement of the 4-halogen by alco- 5 hoLate R 7and rearrangement, preferably with acetic anhydride or triftuoroacetic anhydride, and acetate hydrolysis, the picolyL aLcohoLs of the formula XXVII are obtained.

The corresponding compounds where R6=fluorine and R8= H or (Cl-C3)-aLkyt can be prepared in an anaLogous manne r.

Compounds of the formula III in which X 2 denotes a hydroxyL group and both R6and R8denote fluorine or i ~--rC 16 chLorine can be obtained, for example, in accordance with equation 4: Equation 4:

R

6 Y

R

6 Re reiction R6 S zB.LA RI Re Y)Y Y 4d

YH

(XXVIllI (XXIX) (XXX) Y F, CI) 7 R 7 1. m-CPBS R 7 R 8 6 RB 2. Ac20 R6 e

(RO

2

C)

2 HC H 3 C H HOH2C xxxI) (xxx I (XXXI II) Replacement reactions with nucleophies, such as, for example, amines and alcoholates, on the halogen derivatives XXVIII lead to compounds of the formula XXIX, reduction of which gives XXX, cf. J. Chem. Soc. 1965, 575. Esters of the formula XXXI can be obtained by reaction of compounds of the formula XXX with salts of malonic acid diesters, and these decarboxylate following acid or alkaline hydrolysis in an acid medium to give the substituted 3,5-dihalogeno-2-picoires.of the formula

XXXII.

The compounds of the formula XXX can also be reacted directly with organometallic reagents, such as, for example, methylmagnesium halides or methyllithium, to give XXXII.

Useful substances can also be obtained from compounds of the formula XXX by nucleophilic replacement with Clsynthones, such as, for example, salts of dithianes or cyanides, and these lead to compounds of the formula XXXIII via further reactions.

17 Compounds of the formula III in which X 2 denotes a hydroxyl group, R 6 denotes an alkoxy radical and R denotes hydrogen can be prepared in accordance with equation Equation HO 1. e020/R'X R'O 1. POCI R' HO

POCX

3 2. NH 3 o. 2. m-CPBS

H

3 C 3 C H H 3 C ,4 (XXXIV) (XXXV)( 1.:(XXXV]o X 0) 1.+2.:(XXXVlb X 1) p R7 MR7

R

'O Me 1_n° R O R7 2. NaOH C H3C HOH 2

C

0 0 (XXXVIl) (XXXV11 SMatol XXXIV is alkylated with an alkyl halide R'X in the presence of silver oxide to give 3-alkoxy-pyran-4-ones, which are reacted with aqueous ammonia to give 2-methylt 3-alkoxy-4-pyridones of the formula XXXV Org. Chem.

29, 776 (1964)).

Substituted 3-benzyloxy derivatives can be obtained in an analogous manner by alkylation of maltol with the corresponding benzyl halides.

The compounds isomeric to the compounds of the formula XXXVIII where R 6 hydrogen and R 8 alkoxy are obtained by analogous reactions with 5-hydroxy-2-methyl-4-pyranone, prepared from Kojic acid.

The compounds of the formula XXXV are converted into 2-methyl-3-alkoxy-4-chloropyridines with a halogenating agent, for example POCL 3 and 4-alkoxy derivatives are obtained from these with an alcohol R 7 H in the presence of a base.

J

~ra ~d~ 18 The reaction of the analogous N-oxides XXXVIb'with alcoholates "o give compounds of the formula XXXVII is advantageous.

Compounds of the formula XXXV can also be alkylated directly in the presence of silver oxide to give compounds of the formula XXXIX.

R'O, R 7 H3C

H

3 C H

H

3

C

(XXXV)

(XXXIX

R7

(CI-C

7 )-alkoxy) Processes for the preparation of 3,4-dialkoxy-2-picolines and 4,5-dialkoxy-2-picolines are described in EP-A- 166,287 and EP-A-208,452.

Compounds of the formula III in which X 2 denotes a hydroxyl group, one of the substituents R 6 and R 8 denotes an alkoxy substituent or a halogenated, preferably fluorinated, alkoxy radical Rf and the other can be 15 hydrogen, halogen, alkyL, alkoxy or a halogenated, preferably fluorinated alkoxy radical Rf, can be prepared in accordance with equation 6: r t.

i i r I r *r I .t Ii *r I

I

*0 S 0

I)

i 19 Equation 6: HO RE

H

3

C

(XXXX)

Ry 02 Re H3 0 r 0 (XXXXJ I) f0 RE

H

3

C

(XXXX I

MR

7 1VrX R

H

3 C 4, 0 ,y-CP6S 2. nitraticn HN0 3 /112S04 1 H A0e.) 2. NoOH aq.

t t t r 11 9 41 *0 9* 9 0 i (XXXXI II Rf- (CH 2 0 CPH(2p+j.q)Fq 0 -0,1, 2

C

(XXXXIV)

5 Compounds of the formula XXXXI are obtained by adding 3-hydroxy-2-picolines of the formula XXXX onto correspondingly halogenated olefins (for example CF 2

=CF

2 or

CF

2

=CCIF).

Halogenated carbenes can furthermore be produced from 10 alkyl halides and a base, for example CF 2 from CHCIF 2 and these Likewise lead to compounds of the formula XXXXI by insertion into the OH bond of the 3-hydroxy-2-picolines (cf. J. Org. Chem. 25, 2009 (1960)). fluoromethoxy-2-picoine is obtained as is described, for example, in J. Org. Chem. 29, 1 (1964) and J. Med. Chem.

13, 1124 (1970).

The isomeric 5-hydroxy-2-picoines can be reacted in an analogous manner.

In the preparation processes shown in the above equations, the substituents and variables have the definitions given above, unless defined otherwise in an individual case.

In addition to the thienoimidlazole derivatives described in the illustrative examples, the compounds of the general formuLa I which are summarized in the following Table 1 and salts thereof, for example, are also obtained according to the invention.

Abbreviations used: methyl ethyl propyL butyl hexyL (Hex), acetyL phenyl cycLo iso Mi.

Table

,TS

p 2 R 1 R R 3

R

4 R 5

R

6

R

7 R8 tHH H H H H OEt C 1 HH H H H *H O~r Cl H irK H H H H H H OiHPh Cl H H H H H H O(CH 2 hO~ Cl H HH H OCH 2 2 O3 Cl H H H H H H OCH 2 CF2 3 Cl H H H H H H OCHCFCF Br H H H H H H O~t Br H H H H H H OCPh Br H H H H H H O(CH 2 hO~ Br H H H H H H OCH 2 2 O3 Br H H H H H H OCH 2 CF2 3 Br H H H H H H OCH 2 CFCF Br H H H H H H O(CH 2 hO~ F

IR

HH

IH

H

H

H

H

21 Tabte, Continuation

R

s R2 T SO

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

OCH

2

CF

3 OMe OEt OPr

OCH

2 Ph

O(CH

2 2 OMe OMe OEt OPr OiPr

OCH

2 Ph

O(CH

2 2 OMe

OCH

2

CF

3 OEt OPr

OCH

2 Ph

O(CH

2 2 OMe

OCH

2

CF

3 OMe OEt OPr OiPr I I I 22 TabLe, Continuation

R

1 p 2 T =SO

HI

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

CH

3

CM

3

OCH

2

CF

3 0CH 2

CF

3 H2

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

CM

3

CH

3

H

H

Br Br Br Br Br

OCF

3

OCF

3

OCF

3

OCF

3

OCF

3

OCF

3

OCF

2

H

OCF

2

H

OCF

2

H

OCF

2

H

OCF

2

CF

2

H

OCF

2

CF

2

H

OCF

2

CF

2

H

OCF

2

CF

2

H

OCF

2

CF

2

H

C)CF

2

CF

2

H

OCF

2

CF

2

H

OEt H OPr H

OCH

2 Ph H 0(CH 2 2 OMe H

OCH

2

CF

3

H

O)M. H C)Et H OPr H

OCM

2 Ph H 0(CH 2 2 OMe H

OCH

2

CF

3

H

OMe H OE', H O~r H

O(CH

2 2 OMe H OMe H OMe Me OEt Me OMe H ON. Me Ome H We. Me

R

3

R

4 R5 R 6 R a

I'

I 23 TabLe, Continuation

R

2 T SO RR2 R 3

R

4

R

5 R6j 7

R

OCH

2

CF

3

OCH

2

CF

3

OCH

2 >CFi

OCH

2

CF

3

CF

3

~>OCH

2

CF

2

CF

3

O)CF

2 CF H

OCF

2

CF

2

H

OCF

2

CF

2

H

HC2C2

H

H

H

H

H

H

H

H

H

H

OCF

2

CF

2

H

H

Me

O)CF

2

CF

2

H

OCF

2

CF

2

H

OCF

2

CF

2

H

OCF

2

CF

2

H

OCF

2

CF

2

H

OMe

H

H

H

H

H

H

F

F

F

F

cl

OCH

2 Ph H OMe OCF 2

CF

2

H

OMe OCF 2

CF

2

H

OMe H OPr H OMe H OEt H

OCH

2 Ph H OMe OCF 2

CF

2

H

OMe OCHF 2 OEt

OCHF

2

OCH

2 Ph OCHF 2

O(CH

2 2 OMe OCF 3 OMe

OCF

3 OEt OCF 3 OMe F OEt F

OCH

2 Ph F

O(CH

2 2 OMe F NPh?4e H H H H H cl hte NPhMe 24 Table, Continuation

R

1 T =SO

R

2 Rl R2 R 3 H H H H H H H H H H H H R R 5

R

6 R7R 8 NPh~e NPhMe -NMe 2 -N 0 H H F H H H H F H H H H cl H H H H cl -Me2

H

CH

3

CH

3

CH

3

CH

3

CH

3

H

H

H

H

H

CH

3

CH

3

H

CH

3

CH

3

CH

3

CH

3

CH

3

H

H

H

H

H

CH

3

CH

3 Cl

OCH

OCH

OCH

OCH

OCH

H

H

H

H

H

H

H

-0D 3 OCH 2

CF

3 3 OCH 2

CF

2

CF

2

H

3 OCH 2

CF

2

CF

3 3 OCH 2

CF

2

CF

2

CF

3 .3 OCH 2

CF

2

CF

2

CF

2

CF

2

H

OCH

2

CF

3

OCH

2

CF

2

CF

2

H

OCH

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

2

CF

2

H

OCH

2

CF

3

OCH

2

CF

2

CF

2

H

Cl 'Cl

H

H

H

H

H

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

OPP-

25 TabLe, Continuation

R

1

R

2

SO

R2 R 3 R4 R 5

R

6 R R

CH

3

CM

3

CH

3

OCH

2

CF

3

OCH

2

CF

3

H

CM

3

CM

3

CM

3

H

H

H

H

H

H

0CM:

OCH:

4-chior zyLoxy

OCH

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

2

CF

2

H

OCH

2

CF

3 3 CH 2

CF

2

CF

3 oben- 0CM 3 -t r

(C

t Cr

C

t S

C

OCH

3

OCH

3

OCH

3

H

H

H

H

H

H H H H 4-fLuorobenzyLoxy H H H H 2,4-diftuorobenzytoxy H H H H 3,5-difLuoroberizyLoxy H H H H 4,6-dichtorobenzyLoxy H H H H 4,5-dichiorobenzyLoxy H A H H 4-trifLuoromet hy IbenzyLoxy H H H H 3,5-bis-trif LuoromethyLbenzy Lox>' H H H H 4-fLuorobenzyLoxy H H H H 4-chiorobenzyLoxy H H H H 4-triftLuoromethyLbenzyLoxy 0CM 3 0CH 3 0CM 3 0CM 3

OCH

3 0CM 3 0CH 3

OCR

2 CF 3 0CM 2

CF

3

OCH

2

CF

3 him.- I I I 26 TablLe, Continuation

R

2 T SO RR2 R 3 R R R 6 R R 8

CH

3 H H H H 3,5-bis-trifLuoromethyLbenzy Loxy

CM

3 H H H 4-trifLuoromethylbenzyLoxy H H H H H H H H .H H

OCH

2

CF

3 0CM 2

CF

3 0CM 3 0CM 3 C f C r T Q

H

H

4-f LuorobenzyLox>, 4-t ri f LuoromethylbenzyLox>, H H H H H H H H

OCM

2

CF

3 4-f LuorobenzyLoxy OCh 2

CF

3 '4-ti-' fLuoromethylbenzyLox y C t'.

The novel compounds of useful pharmacological the formula properties.

I and their salts have They cLearly inhibit gastric acid secretion and moreover have an exceLLent effect of protection of the stomach and intesti'ne.

"Protection of the stomach and intestine" in this connection is understood as the prevention and treatment of gastrointestinaL diseases, in particuLar gastrointestinal inflammatory diseases and Lesions (such as, for exampLe, 27 Ulcus ventricui, ULcus duodeni, gastritis, irritated stomach of hyperacid or medicamentous origin), which can be caused, for example, by microorganisms, bacterial toxins, medicaments (for example antiinflammatories and antirheumatics), chemicals (for example ethanol), gastric acid or stress situations.

On the basis 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 medicine, and they are used in particular for the treatment and prophylaxis of diseases of the stomach and intestine and those diseases based on excessive gastric acid secretion.

It has been found that colon H+/K+-ATPase (cf. Gustin, Goodman, J. Biol. Chem. 256 [19813 10651-10656) is also greatly inhibited in vitro by compounds which are formed when the compounds of the formula I according to the invention are treated with acid (for example with sodium Sacetate/HCl buffer with a pH of about Such cont t e t 20 version products can also be formed in vivo during pas- Ssage of the compounds of the formula I through the gastrointestinal tract. The extent to which they are formed depends on the substitution pattern and on the pH.

SColon H+/K+-ATPase is attributed a decisive influence S 25 on the electrolyte equilibrium on the intestinal mucosa.

Colon H+/K+-ATPase inhibitors, such as those mentioned above, can therefore intervene in this equilibrium and be used for the treatment of diseases with disturbed electrolyte equilibrium.

The invention thus also relates to the use of compounds of the formula I or acid conversion products thereof in the treatment of diarrhea diseases. Examples of such diseases are inflammatory intestinal diseases, such as cholera, paratyphoid, travellers' diarrhea or other forms

J

28 of secretory diarrhea, and also other intestinal diseases, such as Morbus Crohn, Colitis ulcerosa and regional enteritis.

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

The invention thus also relates to the compounds of the formula I according to the invention for use in the treatment and prophylaxis of the abovementioned diseases.

ft( 10 The invention Likewise relates to the use of the compounds according to the invention in the preparation of r medicaments which are used for the treatment and prophylaxis of the abovementioned diseases.

t r 1 The invention furthermore relates to medicaments containing one or more compounds of the general formula I and/or pharmacologically tolerated salts thereof.

c The medicaments are prepared by processes which are known per se and with which the expert is familiar. The pharmacologically active compounds active compounds) according to the invention are used as medicaments either as such or, preferably, in combination with suitable pharmaceutical auxiliaries in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 96X.

The expert is familiar, on the basis of his knowledge, with the auxiliaries which are suitable for the desired medicament formulations. In addition to solvents, gelforming agents, suppository bases, tablet auxiliaries and other active compound excipients, it is also possible to use, for example, antioxidants, dispersing agents, emulsifiers, foam suppressants, flavor correctants, 29 preservatives, solubilizing agents or dyestuffs.

The active compounds can be administered orally or parenterally, oral administration being preferred.

In general, it has proved advantageous in human medicine to administer the active compound or compounds, in the case of oral administration, 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, in order to achieve the desired result. In the case of parenteral administration, similar or (especially in the case of intravenous administration of the active compounds) as a rule lower dosages can be used. The particular optimum dosage required and the mode of administra- Stion of the active compounds can easily be specified by any expert on the basis of his technlical knowledge.

If the compounds according to the invention and/or their salts are to be used for the treatment of the abovementioned diseases, the pharmaceutical formulations can also contain one or more pharmacologically active constituents from other groups of medicaments, such as antibiotics, for example ofloxacin, antacids, for example aluminum hydroxide, magnesium aluminate, sucralfate and Bi salts, tranquillizers, such as benzodiazepines, for example diazepam; spasmolytics, such as, for example, bietamiverine and camylofin; anticholinergics, such as, for example, pirenzepine, telenzepine, oxyphencyclimine and phencarbamide; Local anesthetics, such as, for example, tetracaine and procaine; and if appropriate also gastrin antagonists, enzymes, vitamins or amino acids.

For the oral use form, the active compounds are mixed with the additives customary for this, such as excipients, stabilizers or inert diluents, and are brought into suitable presentation forms, such as tablets, coated tablets, pushfit capsules, aqueous, alcoholic or oily suspensions or 30 aqueous, alcoholic or oily solutions, by customary methods.

Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, Lactose, glucose or starch, in particular maize starch. The mixtures can thereby be formulated either as dry or as moist granules. Possible oily excipients or solvents are, for example, vegetable and animal oils, such as sunflower oil or cod-Liver oil.

For subcutaneous or intravenous administration, the active compounds or physiologically tolerated salts thereof are dissolved, suspended or emulsified, if appropriate with the substances customary for this, such as solubilizing agents, emulsifiers or other auxiliaries. Possible solvents for the novel active compounds and the corresponding physiologically tolerated salts are, for example: water, physiological saline solutions or alcohols, for example ethanol, propanol or glycerol, and in addition also sugar solutions, such as glucose solutions or mannitol solutions, or also a mixture of the various solvents mentioned.

The following examples are intended to illustrate the 20 procedures according to the invention without Limiting the invention to the substances mentioned here as representatives.

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

5-Chloro-2-picoline a) 5-Chtoro-2-picotine N-oxide 21.3 g of m-chloroperbenzoic acid (m-CPBA) are added in portions to 13.0 g of 5-chloro-2-picoline in 250 ml of methylene chloride at room temperature, with stirring. After 2 hours, the mixture is extracted twice by shaking with 200 mL of saturated aqueous NaHCO 3 solution each time and then three times by i -31shaking with 200 mL of saturated aqueous NaHS03 solution each time. The bicarbonate solution is extracted three times with 100 ml of methylene chloride each time and the combined organic phases are dried and freed from the solvent. After trituration with petroleum ether, the crystalline title compound is obtained, melting point 73-76 0

C.

b) 4-Nitro-5-chLoro-2-picoLine N-oxide 12 g of 5-chloro-2-picoline N-oxide are introduced in portions into a mixture of 40 mL of concentrated sulfuric acid and 40 ml of fuming nitric acid, with cooling. The mixture is then heated at 35 to 40 0

C

for 1 hour and at 65 to 70°C for 2 hours. After S cooling, it is stirred with 250 g of ice, brought to pH 10 to 11 with 10 N sodium hydroxide solution and tj extracted with ethyl acetate. After being freed from the solvent, the residue is treated with diisopropyL ether, melting point 115-117 0

C.

c) 4-Nethoxy-5-chLoro-2-picoline N-oxide 3.5 g of 4-nitro-5-chloro-2-picoline N-oxide in 50 ml of anhydrous methanol are added at -10 0 C to a sodium methylate solution prepared from 1.5 g of sodium and 150 mL of methanol. The mixture is allowed to warm slowly to room temperature and is then heated under reflux for 1 hour. The solvent is now distilled off under reduced pressure, water is added to the residue, the mixture is extracted with methylene chloride and the solvent is stripped off. Colorless crystals from diisopropyl ether, melting point 137-139 0

C.

d) 5-Chloro-2-hydroxymethyL-4-methoxypyridine g of 3-chloro-4-methoxy-2-picoline N-oxide are dissolved in 16 ml of glacial acetic acid, and 24 ml of acetic anhydride are added at 80 0 C, with stirring.

The mixture is heated at 110 to 120 C for 1.5 hours and then allowed to cool to 80°C and 40 ml of 32 methanol are added dropwise. The mixture is then concentrated under reduced pressure, 35 ml of water, 13.6 g of caustic soda, in small portions, and 15 ml of dioxane are then added to the residue and this mixture is heated under refLux for 2 hours. After cooling, it is extracted with methyene chloride, the solvent is driven off and the residue is made to crystallize with diisopropyl ether. Solid, melting point 78- 0

C.

e) 5-Chtoro-2-chLoromethyL-4-methoxypyridine hydrochloride A solution of 8.0 mL of thionyl chLoride in 20 mL of methytene chloride is added dropuise to a mixture of Goo 64.5 g of 5-chLoro-2-hydroxymethy-4-methoxypyridine 0" and 100 mL of methylene chloride at 0OC and the mix- *Gob 15 ture is then stirred at room temperature for 2 hours.

a The solvent is driven off and the residue is made to crystallize with diethy ether. Colorless crystals, melting point 136-137C.

f) 2-(4-Nethoxy-5-chLoro-2-picolyLeercapto)-1H-thieno- (3,4-dliaidazoLe dihydrochLoride 1.56 g of 2-mercapto-thieno[3,4-d3imidazoLe and 2.3 g of 4-methoxy-5-chLoro-2-picoLyL chloride hydrochleride are heated at 60 0 C in 100 ml of ethano for about 1 hour and then heated under reflux for 1.5 hours. After 25 filtration, the crystalline substance is suspended in acetone, the suspension is stirred at room temperature for 1 hour and the crystals are filtered off with suction and dried in air, melting point 260oC.

SThe filtrate is treated with animal charcoal and concentrated in vacuo and the residue is made to crystal- Lize with acetone, melting point 2600C g) 2-(4-Nethoxy-5-chLoro-2-picoLyLmercapto)-IH-thieno- E3,4-dJimidazote 1.4 g of the title compound from Example I f) are i 33 suspended in 70 ml of ethanol and 2 mL of triethylamine are added at room temperature, with stirring.

The solution thus obtained is stirred at room temperature for about 1 hour, a suspension is formed with active charcoal, the mixture is filtered and the filtrate is concentrated in vacuo. Water is added to the residue and the mixture is extracted with methylene chloride. After evaporation of the solvent, the residue is made to crystallize with diisopropyl ether, melting point 135-137 0

C.

h) 2-(4-Methoxy-5-chloro-2-picolylsulfinyL)-1H-thieno- E3,4-d]imidazoLe t 0.308 g of m-chloroperbenzoic acid (85% pure) in 10 ml of methylene chloride is added dropwise to 0.44 g of r 15 the title compound of Example 1 g) in a two-phase mixture of 70 mt of methylene chloride and 40 ml of aqueous KH2PO 4 /Na2HPO 4 buffer solution (pH at 0 to 5°C, with stirring. After about 30 minutes, the organic phase is concentrated and the residue is S 20 chromatographed on silica gel using methylene chloride/ethyl acetate. The product is made to crystallize Sfrom the corresponding fractions with ethyl acetate, melting point 159°C Edecomposition], or is recrystallized from ethanol.

Example 2 a) 3-Bromo-2-picotine N-oxide and 5-bromo-2-picoLine Noxide The title compounds are obtained analogously to Example 1 a) from 43 g of a mixture consisting of 3bromo-2-picoline and 5-bromo-2-picoline with 60 g of m-chLoroperbenzoic acid (85% pure). The mixture of the title compounds is made to crystallize with diisopropyL ether, melting point 65-80 0 C (not sharp).

S It 34 b) 3 -Bromo-4-nitro-2-picoine N-oxide and 5-bromo-4nitro-2-picoLine N-oxide 26.3 g of the title Compounds from Example 2 a) are stirred in 50 mt of H 2

SO

4 50 ml of HNO3 at 60 to 65oC for 7 hours, analogously to Example I b).

The 5-isomer, melting point 133-135 0 C, is preferentially crystallized from the evaporation residue with a mixture of ethyl acetate and diisopropyl ether (1 On chromatographic separation of the mother liquor with toluene ethyl acetate (1 1) on silica gel, further 5-bromo-4-nitro-2-picoline N-oxide is first eluted, followed by 3-bromo-4-nitro-2-picoline N-oxide, melting point 111-113 0 C (from petroleum S ether).

Example 3 a) 4-Nethoxy-5-bromo-2-picoLine N-oxide The title compound is obtained from 8.2 g of 4-nitro- 5-bromo-2-picoline N-oxide and 0.87 g of Na in methanol analogously to Example 1 After evaporation of the methylene chloride, the residue is made to crystallize with diisopropyl ether, melting point 146- 148 0

C.

b) 4-Methoxy-5-bromo-2-hydroxymethylpyridine 6.6 g of 4-methoxy-5-bromo-2-picoline N-oxide are reacted with 7 ml of glacial acetic acid, 15 mL of acetic anhydride, 20 ml of methanol, 20 ml of water, 8 g of NaOH and 20 ml of dioxane analogously to Example 1 The crude product is made to crystallize with diisopropyl ether, melting point 80-82oC.

c) 4 -Methoxy-5-bromo-2-chloromethyLpyridine hydrochLoride The title compound is obtained from 4.3 g of the title compound from Example 3 b) and 5.0 ml of thionyl chloride art.logously to Example 1 melting point I i I 35 300 0 C (from diisopropyl ether).

d) 2-(4-Nethoxy-5-bromo-2-picoymercapto)-1H-thieno[3,4d3imidazoLe dihydrochLoride 1.2 g of 2-mercapto-thienoE3,4-d3imidazoLe are suspended in 50 mL of ethanoL, 2.0 g of 2-chLoromethyLpyridine hydrochloride are added and the mixture is stirred at 60 0 C for 1 hour. It is freed from the solvent and the residue is made to crystal- Lize with diethyL ether, melting point 300 0

C.

e) 2-(4-Methoxy-5-bromo-2-picotyLmercapto)-1H-thieno[ 3 4 d]imidazoLe 7 mL of triethylamine are added to 2.15 g of the title compound from Example 3 d) in 50 ml of methanol.

Analogously to Example 1 the product crystallizes on addition of water, melting point 165 0 C Edecomposition3.

f) 2-(4-Nethoxy-5-bromo-2-picoLyLsuLfinyL)-1H-thieno[3,4d]imidazoLe The title compound is obtained analogously to Example 1 h) from 1.1 g of the title compound from Example 3 e) and 0.725 g of m-chorobenzoic acid. On treatment of the residue, the title compound crystallizes from a Little diethyL ether/ethyl acetate (1 1), melting point 140 0 C (decomposition3.

Further product is obtained from the mother liquor, which becomes dark in color, by evaporation and immediate treatment with a little ethyl acetate.

Example 4 a) 3-Bromo-4-methoxy-2-picoLine N-oxide The title compound is obtained analogously to Examples 1 c) and 3 a) from 4.6 g of 3-bromo-4-nitro-2-picoLine N-oxide in 40 ml of methanol with a sodium methylate 36 solution prepared from 0.5 g of sodium and 20 mL of methano, melting point 80-82 0 C (from diisopropyl ether).

b) 3-Bromo-4-methoxy-2-hydroxyethypyridine 3.8 g of the title compound from Exiplie 4a) are stirred with 30 mL of acetic anhydride at 80-85 0 C for 1 hour. 25 mL of methanol and, after concentration, ml of 5 N sodium hydroxide solution and 10 mL of dioxane are added, analogously to Examples 1 d)/3 b).

The product crystallizes from diisopropy ether, melting point 109-111 0

C.

c) 3-Bromo-4-methoxy-2-chtoromethyLpyridine hydrochloride 1.9 g of the title compound of Example 4 b) are reacted with 2.5 ml of thionyl chloride analogously to Examples 1 e) and 3 The product is made to crystallize with diisopropy ether, melting point 142- 144 0

C.

d) 2-(3-Bromo-4-methoxy-2-picotyLmercapto)-IH-thieno[ 3 4 d3imidazoLe dihydrochLoride 2.3 g of 3-bromo-4-methoxy-2-chLoromethyl-pyridine hydrochloride are added to 1.3 g of 2-mercapto-thieno- C3,4-dlimidazoLe in 50 mL of ethanoL, with stirring, and the mixture is kept at 60 0 C for 30 minutes. The product is filtered off with suction and dried in vacuo, melting point 300 0

C.

e) 2-(3-Bromo-4-methoxy-2-picotylmercapto)-IH-thieno[ 3 4 d imidazoLe 2.9 ml of triethylamine are added to 2.4 g of the dihydrochloride from Example 4 d) in 50 ml of methano analogously to Example 1 After concentration and addition of a little water, the residue crystaLLizes, melting point 168 0 C tdecomposition].

r f 37 f) 2-(3-Bromo-4-methoxy-2-picotylsuLfinyL)-1H-thieno[ 3 ,4d3imidazoLe 0.44 g of m-chloroperbenzoic acid (85% pure) in 15 ml of methylene chloride are added dropwise to 0.72 g of the title compound from Example 4 e) in 120 ml of methylene chloride and 50 ml of aqueous KH 2

PO

4 /Na 2

HPO

4 buffer solution (pH 7.5) analogously to Example 1 h).

After concentrati.on of the organic phase, the residue is made to crystallize with ethyl acetate, melting point 160 0 C (polymerization?).

Example a* a) 2-NethyL-3-methoxy-4-chLoro-pyridine N-oxide ,1 a 11.2 g of 3-methoxy-2-methyl-4(1H)-pyridone are heated under reflux in 100 ml of phosphorus oxychloride for 15 10 hours. The mixture is then concentrated, 2 portions of 30 ml each of toluene are added and the mixture is concentrated each time, the residue is taken up in 150 ml of water, the mixture is brought to pH 11 with K 2

CO

3 and extracted with methylene chloride and 20 the organic phase is washed with water, dried and freed from the solvent.

a 4 The title compound is obtained from the pale brown oil (9 g) with m-chloroperbenzoic acid in methylene chloride under standard conditions, melting point 88-89 0

C

25 (from petroleum ether).

b) 2-Methyl-3,4-dimethoxy-pyridine N-oxide A sodium methylate solution prepared from 1.14 g of sodium and 50 ml of methanol is added dropwise to 8 g of the title compound from Example 5 a) in 100 ml of anhydrous methanol, the mixture is heated at the boiling point for 20 hours and concentrated, water is added, the mixture is extracted with methylene chloride and the extract is concentrated to give the title compound, melting point 111-113 0

C.

f heprdut esri~dabvear racedi c) 3,4i-Disethoxy-2-hydrcxymethyL-pyridine mLof g~ca ctcai,15 nit of acetic anhydmL of methanol, 20 ml of water, 8 g of NaOH and 20 ml of dioxane analogously to Example 1 dl), melting point 86-88 0 C (from diisopropyl ether).

d) 3,4-D imethoxy-2-ch- ,oromethyL-pyridine hydrochtoridle 3.4 g of the above product are reacted with 5 ml of thionyl chloridle analogously to Example 1 MeLting point 150-151 0 C [dlecomposition) (from dliethyL ether).

e) 2-(3,4-Dimethoxy-2-picotytmercapto)-1H-thienoE3,4-dJimidazote 1.56 g of 2-mercaptothienoE3,4-dimidazoLe in 70 ml of ethanol are reacted with 2.3 g of 3,4-dimethoxy-2chLoromethyt-pyridine hydrochLoridle analogously to Example 1 f).

Melting point 148-150 0 C [dlecomposition).

The product is then treated with 2.5 ml of triethyLamine in 60 nil of methanol analogously to Example 1 g).

Melting point 141-142 0 C [dlecomposition).

f) 2-(3,4-Dimethoxy-2-picotytsutfinyt)-1H-thienoE3,4imidazole 0.75 g of the title compound from Example 5 e) is oxidized with 0.55 g of m-chLoroperbenzoic acid in 100 ml of methyLene chloridle and 50 ml of Na 2

HPO

4

IKH

2

PO

4 buffer solution (pH analogously to Example 'i After the mixture has been concentrated, the residue is made to crystallize with dliethyL ether, melting point 139-140 0

C.

ExaupLe 6 a) 2-BrouomethyL-3-ftuoropyridine 1.11 g of 3-fLuoro-2-picoLine are dissolved in 50 ml of CCd 4 3.6 g of N-brouiosuccinimidle and 0.1 g of L. 1~L-~ S 4I 4C 4', 44'C 4 4

I

39 azobisisobutyronitrile are added and the mixture is stirred for 2 hours while boiling under reflux. After cooling and filtration, the solvent is removed in vacuo. The crude product shows the expected molecular peak of 189 m/e in the mass spectrum.

b) 2-(3-Fluoro-2-picolylaercapto-1H-thieno[3,4-d3imidazole 1.6 g of 2-mercapto-thieno[3,4-d]imidazole and 1.9 g of 2-bromomethyl-3-fluoropyridine are stirred with 2.8 g of powdered anhydrous K 2

CO

3 in about 100 ml of acetone for 4 hours, without cooling. After filtration and removal of the solvent in vacuo, the crude product is purified by column chromatography on silica gel with a mobile phase mixture of cyclohexane/ethyl acetate.

The product fraction has an Rf of about 0.15.

c) 2-(3-FLuoro-2-picoLylsulfinyl-1H-thieno[3,4-d]imidazoLe 530 mg of the compound from the preceding stage are dissolved in 50 ml of CH 2

CL

2 and the solution is stirred with 444 mg of m-chloroperbenzoic acid at room temperature for 4 hours. The solution is washed 20 successively with NaHSO 3 solution, NaHCO 3 solution and H20 and dried with Na 2

SO

4 The crude product obtained after removal of the solvent is subjected to column chromatography (Si02; CH 2

CI

2 acetone 7/3).

The product fractions are concentrated and the residue is stirred with diisopropyl ether and filtered off.

Melting point 145°C; MS gives a folecular peak of 282 m/e; (M+H) The compounds of the formula I in the following Examples 7 to 22 are obtained by procedures analogous to those shown in Equations 1 to 6: 0 Ex.

7 8 9 R6

CH

3 CH3

H

H

H

H

QCH

3

OCH

3

H

H

OCHF

2

OCHF

2

OCH

2

CF

3

OCH

2

CF

3

OCF

2

CF

2

H

OCF

2

CF

2

H

R

7

OCH

3

OCH

3

H

H

H

H

H

H

H

H

H

H

OCH

2

CF

3

OCH

2

CF

3

OCH

3

OCH

3 F8

F

F

OCHF2 OCHF2 Cl Cl

H

H

OCH

3

OCH

3

H

H

H

H

H

H

MeLtina point 170-173 0

C

ab 145 0 C Cdeconp.j (MS: M=313) 116 0 C Edeconip.] MS(DCl): M++1=329 160 0 C [cdecomp.j 157 0 C tdecomp.1 180 0 C Tdecomp.j 85- 90 0 C cIecomp.] 112-114 0

C

152- 54 0 CIdecornp.) 103 0 C [decomp.];M+=313 78 0 C fdeconp.j;M+H+=330 145 0 C tdeconp.;M+=443 154C Ideconp.];M+H+=46O 01 ;M+H+=394 138*C [ceconp.) ;M+H+=410 9 9a a* 9r 9 9L 1 9 9 It 9 It Sit D 9 4

I~

0 9 09 9 R, R 2 R 4 and R are in each case hydrogen ExampLe 23 a) 2-Methyt-3-methoxy-4-2,2,2-tr iftuoroethoxy)pyr idine N-oxide 6.7 g of potassium tert.-butylate are added in portions to 20 ml of trifLuoroethanol at -20 0 C, with stirring and under a nitrogen atmosphere. After the mixture has been warmed to OOC, 5.2 g of 2-methyL- 3-methoxy-4-chloro-pyridine N-ox ide (title compound from Example 5 a) are added in portions. The mixture is heated under refLux for 3 hours and alLowed to cool to room temperature, a further 3.45 g of potassium tert.-butyLate are added and the mixture is heated under reflux for 2 hours. After cooling, 40 ml of water are added to the reaction mixture, the mixture 1 s -41 is extracted with methylene chloride and the extract is dried over MgSO 4 and freed from the solvent in vacuo. The oily crude product obtained is reacted further.

b) 3-Nethoxy-4-(2,2,2-trifluoroethoxy)-2-hydroxy-methylpyridine 8 g of the title compound from Example 23 a) are dissolved in 16 mL of glacial acetic acid, and 24 ml of acetic anhydride are added at 80 0 C, with stirring.

The mixture is heated at 110 0 C for 2 hours and then cooled to 80 0 C, and 40 ml of methanol are added Sdropwise to the reaction mixture. The mixture is then concentrated in vacuo, the oily residue is added to ml of 2 N methanolic NaOH and the mixture is stirred for 30 minutes. After treatment with active charcoal and filtration, the filtrate is concentrated in vacuo, 50 ml of water are added to the residue, the mixture is extracted with methylene chloride, the extract is dried (MgSO 4 and concentrated and the tC S 20 residue is treated with diisopropyl ether. Colorless S'crystals, melting point 107-108 0

C.

c) 3-Hethoxy-4-(2,2,2-trifluoroethoxy)-2-chloromethylpyridine hydrochloride A solution of 6.0 ml of thionyl chloride in 15 ml of methylene chloride is added dropwise to a mixture of 3.9 g of the above product and 100 ml of methylene chloride at O°C and the mixture is then stirred at room temperature for 2 hours. The solvent is driven off and the residue is made to crystallize with diisopropyl ether. Colorless crystals, melting point 166- 168°C.

d) 2-(3-Methoxy-4-(2,2,2-trifluoroethoxy)-2-picolyltercapto)-lH-thieno[3,4-d3inidazole dihydrochloride g of 2-mercapto-thieno[3,4-d]imidazole and 1.9 g of the above product are heated at 60 C in 60 ml of 42 ethanol for about 1 hour, and the mixture is then heated under reflux for 1.5 hours. After treatment with active charcoal, filtration and concentration, the residue is made to crystallize with acetone.

Melting point from 188 0 C (decomposition).

e) 2-(3-Methoxy-4-(2,2,2-trifluoroethoxy)-2-picolylmercapto)-1H-thienoE3,4-d]iidazole 2.1 g of the title compound from Example 23 d) are suspended in 80 ml of methanol, and 4 ml of triethylamine are added at room temperature, with stirring.

The solution thus obtained is stirred at room temperature for about 1 hour, a suspension is formed with active charcoal, the suspension is filtered and the filtrate is concentrated in vacuo. On adding water, 15 the colorless product crystallizes. Melting point 147-148 0

C.

f) 2 -(3-Methoxy-4-(2,2,2-trifluoroethoxy)-2-picolylsulfinyl)-1H-thieno[3,4-dimidazole 0.42 g of m-chloroperbenzoic acid (85% pure) in 10 ml of methylene chloride is added dropwise to 0.75 g of the title compound from Example 23 e) in a two-phase mixture of 80 ml of methylene chloride and 40 ml of aqueous KH 2

PO

4 /Na 2

HPO

4 buffer solution (pH at 0 to 5 0 C, with stirring. After about 30 minutes, the organic phase is separated off, dried and concentrated and the residue is made to crystallize with diethyl ether. Melting point 135-137°C.

The following intermediates of the formulae XXXXVI- XXXXVIII can be prepared, for example, analogously to Equation I I

I

i I 43 CH R 7 0 xxxxv I ExarrpLe 24 26 27

OCH

2

CF

2

CF

2

H

OCH

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

2

CF

2

H

FeLting point 40-42 C 138 C 128-130 0

C

0 i L1* C

H

3 0:

HOH

2

C

xxxxv] I Exarypfe NoD.

28 29 31

OCH

2

CF

2

CF

2

H

OCH

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

2

CF

2

H

Me~ting point 45-411 C OiL* 68-70 0

C

OiL* was reacted directLy 44

CIH

2

C

xxxxv] I I ExampLe NoD.

32 33 34 OCH 2

CF

2

CF

2

H

OCH

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

3

OCH

2

CF

2

CF

2

CF

2

CF

2

H

Me1ting point 133 OC decomposition 155 OC 161-163 OC 132 *C The foLLowing compounds of the formula I analogously to Examples 5 and 23: 7-C7 p 2 I H

H

are obtained ExarpLe 36 37 38 39 41 4 42 43 44

T

S

S

S

S

so so so so

S

S

H2

H

H

H

H

H

Phenyl Phenyl

R

6

OCH

3

OCH

3 OCHi 3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

H

H

RC7 F C 2

OCH

2

CF

2 CF2H

OCH

2

CF

2

CF

2

C

3

OCH

2

CF

2

CF

2

CF

2

F

2

OCH

2

CF

2

CF

2 CFC2

OCH

2

CF

2 CF2H

OCH

2

CF

2

CF

2

C

3

OCH

2

CF

2

CF

2 CF3C 2

H

OCH

3 Metting point( *C) 127- 129 142 133- 135 110 133-135 137 decomposition 113- 115 103 decomposition 153- 157 182- 185 45

R

6

R

7 Exanp Le T

I(

0

C)

H

H

H

H

H

H

OCH

3

H

Phenyl CH 3 00H 3 4-Methoxy- H H

CH

3 192-195 H 141-143 phenyl.

if It Phenyl 4- Methoxypheny.

CO

2

CH

3

CON(C

2

H

5 2 H OCH 3 H 170-173

CH

3

OCH

3

CH

3 151-154 H OCH 2

CF

2

CF

2

CF

3 H 216 H OCH 2

CF

2

CF

2

CF

3 H 203

H

H

Pheniyl H H H OCH 3 to

CH

3

OCH

3 4-Methoxy- H H phtyo H OCH 3 to

CH

3

OCH

3 H 106-110 H 102-104 .HC1 H 137-141 H 130-135

CH

3 160-165 H 164-167 decomposition H 162-165

CH

3 162-165 decomposi tion so H so H so H so H Phenyl H 4-Methoxy- H phenyl

OCH

2

CF

2

CF

2

CF

3

H

OCH

2

CF

2

CF

2

CF

3

H

H

R

3 ExarrpLe T R No.

R

6

R

7

(OC)

62 S -CH 2

SCH

2

H

63 S CO 2

CH

3

CO

2

CH

3

H

64 SO CO 2

CH

3 C0 2 CHi 3

H

So CO 2

CH

3

CO

2

CH

3

H

H H

OCH

3

H

OCII

3

H

H H 186- 188 156- 159 140 decomposition 146- 149 y

I

Chemical stability of 2-r(2-Pyridylmethyl)sulfinyllH-thienoimidazoles reflative to the parent compound 1 determined in buffered acetonitrile solution, pH io as stable as 1 more unstable more stable furthermore stable 7 -20 h) 0,5 7 h) 20 40 h) 40 150 h) 4, I 99 4 409 I 04 99 0 9941 a 9 a a. a 4* 9 ra *0 I 4* a aa Ia 04 .4,4 Compound ER' 1R2 JR3 1R4 IR I Rd 1R7 ERD B aiit 1H H H H H H H H 0 2 H H H H H 00H, H H 3 H H H H H H H OCH 3 4 H H H H H F H H1 5 H H H H H Br OCH, H 6 H H H H H H OCH, H 7 H H H H H CH~, OCH, H 8H H H H H H H ci 9 H H H H H CH, OCH, F 10 H H H H H H _Ph-cH 2 o- H 11 H H H H H F -OCH 2 CF, CH, 12 CH, CH, H H H H H CH, 0

Claims (1)

1. 46- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A compound of the formula I havi 9 g itcrese s+e a pU7.i. R 7 SR R 8 A nJ I N N R3 R in which 1 1 A stand for b) S or c) I R R ST denotes or -SO-, R 1 and R 2 are identical or different and denote hydrogen, (C 1 -C 4 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, N,N-di-(C -C 4 alkylcarbamoyl, phenyl, or, if A is as defined above I under can also together denote -[CH2] n wherein one y CH 2 group is optionally replaced by S, or denote a substituted Phenyl which carries 1, 2, 3, 4 or identical or different (C 1 -C 4 )-alkoxy substituentes R 3 denotes hydrogen, (C 1 -C 6 )-alkanoyl, (Ci-C 6 )alkylcarbomyl, (C 1 -C 6 )-alkoxycarbonyl, benzyloxycarbonyl or other physiologically tolerated Nim-protectiVe group; R 4 and R 5 denote hydrogen a) R 6 denotes hydrogen and R 8 denotes fluorine, chlorine or bromine, or b) R 6 denotes (CI-C 3 )-alkyl and R8 denotes fluorine, or -47- c) R 6 denotes fluorine or bromine and Rdenotes hydrogen, or d) R 6 denotes4 I- I rtve and R 8 denot e 'J"KjI e) one of the substituentes R6and Radenotes the radical -0OICH 2 H( 2 p+l.q)Halq and the other denotes hydrogen, 0 4D Hal denotes halogen, 07 denotes hydrogen, (C 1 -C 4 )-alkoxy or 0-[C21o p (2p+l-q)aq, n-is 3 or 4, 0 is 0or p is 1, 2, 3, 4, 5 or 6 and q isO0 or i to 2 p+i), arnd physioLogicaL~y toLerated saLts thereof, with the proviso that the compounds 5-methyL-2-(Z-pyridytmethyLth io)-3H-th ienoE2,3-dJ imida- Szo Le 5-ehLZ(4mtoy2prdLmtyti)3-heo EZ,3-dJ imidazoLe, 2-(pyridyL)methyLthio-3H-thieloC2,3-dliruidazoLe, 2-((4-methoxy-2-pyridyL)methyLthio)-3H-thiefloCZ, 3 imidazoLe, 5-ctLZ(4mtoy35dmehL2prdLmtyti) 3H-thieno-E2,3-d~imidazoLe, iethyL (4-uetthoxy-35-dimethyL-2pyridyL )methyLthio)- 3H-thienoE2,3-dinidazoLe-5-carboxyLate, 48 -ace tyL-Z-((C4-me tho xy-Z-pyr idyL )me thyLth io )-3H-th jeno-. C2,3-d) imidazoLe, 5-acetyL-2-(2-pyridyL)methyLthjo-3H-thienoC2,3-dlimida- z oLe and the corresponding suLfinyL compounds are excluded. 2. A compound of the formuLa I as cLaimed in claim 1, in, which A is as defined under in claim 1, or a physio- LogicaLLy tolerated salt thereof. 3. A compound of the formula I as claimed in either of claims 1 and Z, in which T stands for or a physio- LogicaLLy tolerated saL t thereof 4. A compound of the formuLa I as claimed in one or more of cLaims 1 to 3, in which R 1and R 2 are identicaL or different and denote hydrogen, (Ci-C 4 )-aLkoxy or (Cl-C4)- aLkoxycarbonyL, R 3is as defined in cLaim 1, Rand R 5 each denote hydrogen, R 6 and R a are identicaL or different and are as defined in cLaim. 1 'under a) and R 7 denotes hydrogen, a7-.radiaiof~ the formula 0- CH 2 1o-CpH( 2 p+l.q)Hal q or (C 1 -C 3 )-alkoxy, in which halogen preferably denotes fluorine, o s 0 or 1, p is 1 to 4 and q is 0 or 1 to (2p+1) or a physiologically tolerated salt thereof. -49- A compound of the formuLa I as claimed in one or more of claims 1 to 4, in which R A C 4 .A At r: t S 4 4 4 At .A .en n nd h d rnC o r (C 1 C Lk OXY,, R 3is as defined in claim 1, R 4, and R5 each denote hydrogen, o 6 8 R and R a re identical or different and are as def ined in c La im 1 under a) e) and 0 k Rdenotes hydrogen, (C 1 -C 2 )-alkoxy, a fluorinated n..alkoxy or a radicalof the formula -0-(CH 2 ]o-CPH( 2 p+ 1 .q)Hlj in which halogen denotes fluorine, o is 1, p is 1 to 4 and q is 0 or 1 to or a phys iologically tolerated salt thereof. 6. 2-13-?iethoxy-4-(Z,2,2-tr ifLuoroethoxy)-2-picoLyLs.uL- finyLJ-1H-thienoC3,4-d] imidazoLe, 2-C3-Methoxy-4-(2,,2,33-tetrafLuoropropoxy)-2-p ic o L YL- suLfinyL]-iH-thienoC3,4-dlimidazoLe, 2-E3-MethoxY-4-(2,2,3,3,3-pentafLuoropropoxy)-a-picoLyL- suLf inyL]-lH-thienoC3,4-dJ iridazoLe, 2-E3-Methoxy-4-(2,2,3,3-,4,4, -heotafLuorobutoxy icoLyL- suLfinylJ-IH-thienoC3,4-dlimidazoLe, 2-(3-Bromo-4-methoxy-a-pico 1 .ylsuLfinyL )-1H-thienoC3,4-dJ- im*ida zo Ie,. Z-(4-Methoxy-5-broruo-Z-picoLyLsuLfinyL)-lH-thienoE3,4-d3- isidazoLe., Z-(4-Methoxy-5-chLoro-2-picoiyLsuLfinyL)-lH-thieno[3,4-dJ- imidazole. or a physiologically tolerated salt thereof. T T I 50 7. A process for the preparation of a compound of the formula I s caleme4 In l cli'l. a) reacting a comoound of the formula II Nx (II) It t t 4 II C in which A, R 02 34 3 r as efi i :Lei 1 a d X I i. denotes a Leaving group or ii. denotes -SH, -SM or -S0 2 -M M standing for a cation, with a comoound of the formula III fS 64 R RS I p 4 2 (III) I in which R 4 R R 6 R 7 and R are as defined in claim 1 and X in the abovementioned case i. denotes -SH, -SM or -SO 2 -M and in the abovementioned case ii. preferably denotes a Leaving group or OH, or b) reacting a compotnd of the formula IV ,NH 2 A NHi-R3 in which A, R R and R 3 are as defined in claim 1, with a compound of the formula V R 0 Re-R NC I (IV) (V) RS 5 7 8 in which R R 5 6 R 7 and R8 are as defined in claim 1 and R 9 stands for an esterifying group, 51 i. if desired oxidizing- any group(s) present in a sI- -P. compound of the formula I to t4w4) -SO -r i if desired oxdi~im9--*-5-group~z P 5 g 1t 3 M fi if desired acylating, alkylating or artlkylating a compound of the formula I in which R' stands for hydrogen, i if desired hydrolysing a compound-of the formula I in 3 Swhich R does not denote hydrogen, and tt 44 S if desired converting a compound of the formula I into its physiologically tolerated s,-Lts, it also being possible for two or more of the measures i.-iv. to be carried out in a sequence other than that shown. 8. A medicament containing a compound as claimed -in one or more of claims 1 to 6 ii adjunct with pharmaceutically acceptable carriers or excipients. Amedcc/zel 9. A process for the preparation of a-agen as claimed in claim which consists bringing a compound as claimed in one or more of claims 1 to 6 into a suitable presenta- tion form together with a physiologically acceptable ex- cipient and if appropriate other additives, auxiliaries and/or preservatives. DATE) this 19th day of December, 1990. ECBST AKTIENGELLSCAFT WATERMARK PATENT TRADE MARK ATTORNEYS "THE ATRIUM", 2ND FLOOR 290 BURWOOD RAD BAWTSCRN VIC. 3122.