FI89602B - Foerfarande Foer framstaellning av therapeutiskt anvaendbara substituerade tienoimidazolderivat - Google Patents

Description

! 89602

Process for the preparation of therapeutically useful substituted thienoimidazole derivatives

Thienoimidazole derivatives having an inhibitory effect on gastric acid secretion are known from EP-A1-234 485, EP-A2-201 094 and EP-A-237 248.

The invention relates to a process for the preparation of therapeutically useful substituted thienoimidazole derivatives of the formula I and their physiologically tolerable salts,

R I

ΥΎ l B

R2 H

wherein T is -S-, -SO- or -SO 2 -, R 1 and R 2 are the same or different and are hydrogen, (C 1 -C 6 alkyl, (C 1 -C 5) alkoxy, -O- [CH 2] O -CpH (2ptl.q) Halq, (C 1 -C 5) -alkoxycarbonyl, N, N-di- (C 1 -C 3) -alkylcarbamoyl, phenyl, benzyl or a substituted phenyl or benzyl group having the phenyl moiety has 1, 2, 3, 4 or 5 identical or different (C 1 -C 6) alkoxy substituents, and a) R 6 is hydrogen and R 8 is fluoro, chloro or bromo, or b) R 6 is (C 1 -C 6) alkyl and R 8 is fluorine, or c) R 6 is fluorine or bromine and R 8 is hydrogen, or d) R 6 is fluorine and R 8 is ((C 1-3) alkyl), or e) one of the substituents R 6 and R 8 is a group -O- [ CH2] o-CpH (2ptl_q | Halq and the other is hydrogen, halogen, (C1-C1) -alkyl or a group -O- [CH2-CpH2-] H1 is halogen, R 'is hydrogen , (C 1 -C 12) -alkyl, (C 1 -C 4) -alkoxy, 35-O- [CH 2 J-CpH 2] -hqq, or benzyloxy, the phenyl part of which may be substituted by 1, 2, 3, 4 or 5 with a similar or different substituent selected from halogen and trifluoro from methyl, 0 is 0, 1, 2 or 3, 5 pony, 2, 3, 4, 5, 6, 7 or 8, q is 0 or 1 up to (2p + 1), and T is preferably -SO .

Particularly preferred are compounds of formula I wherein T is -SO, R 1 and R 2 are the same or different and are hydrogen, (C 1 -C 3) alkyl, (C 1 -C 3) alkoxy or (C 1 -C 3) alkoxy. -C *) alkoxycarbonyl, and R 7 is hydrogen, (C 1 -C 3) alkyl or a halogenated alkoxy, alkenyloxy or alkynyloxy group of the formula -O- [CH 2] O-CpH (2ptl_q) Halq, (C 1 -C 6) -C 1-4 alkoxy or benzyloxy, and halogen is preferably fluoro, chloro or bromo, o is 0 or 1, p is 1 to 8 and q is from 0 or 1 to (2p + 1); compounds of formula 1 wherein T is -SO, R 1 and R 2 are the same or different and are hydrogen, (C 1 -C 3) -alkyl, and R 7 is hydrogen, (03-04) -alkoxy, a fluorinated n-alkoxy group, of formula -O- [CH 2] O -CpH (2pU_q) Halq, (C 1 -C 3) -alkyl, wherein halogen is fluorine, onon, pony - 5 and q is 0 or 1 up to (2p + 1) .

Of particular interest are 2- [3-methoxy-4- (2,2,2-trifluoroethoxy) -2-picolylsulfinyl] -1H-thieno-25 [3,4-d] imidazole, 2- [3-methoxy-4 - (2,2,3,3-tetrafluoropropoxy) -2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole, 2- [3-methoxy-4- (2,2,3,3, 3-pentafluoropropoxy) -2-picolylsulfinyl] -1H-thieno [3,4-d] imidazole, 2- [3-methoxy-4- (2,2,3,3,4,4,4- heptafluorobutoxy) -2-picolylsulfin-30-yl] -1H-thieno [3,4-d] imidazole, 2- (3-bromo-4-methoxy-2-picolylsulfinyl] -1H-thieno [3,4-d] imidazole , 2- (4-methoxy-5-bromo-2-picolylsulfinyl] -1H-thieno [3,4-d] imidazole and 2- (4-methoxy-5-chloro-2-picolylsulfinyl] -1H-thieno [3,4-d] imidazole.

3 89602

Alkyl and groups based thereon, such as, for example, alkoxy, alkyl mercapto, alkylsulfinyl, alkylsulfonyl, aralkyl or alkanoyl, may be straight-chain or branched.

5 Halogen is fluorine, chlorine, bromine or iodine.

Any chiral C and S atoms present may be in both the R and S configurations. In such cases, the compounds of formula I exist as pure enantiomers or as a mixture of stereoisomers (such as a mixture of enan-10 thiomers and a mixture of diastereomers).

Suitable salts are, in particular, alkali and alkaline earth metal salts and salts formed with physiologically acceptable amines.

The compounds of formula I are prepared according to the invention in such a way that

(a) compounds of formula II

R1

R2 H

wherein R 1 and R 2 are as defined above and X 1 is i) a leaving group or

ii) -SH, -S-M * or -SO 2 M *, wherein M * is a cation, is reacted with compounds of formula III

30 r7 1 | (III) X -c · -kx

I N

B

35 4 89602 wherein the groups R6, R7 and R8 are as defined above and X2 in the above case is i) -SH, -S-M * or -SO2-M * and in the above case ii) preferably a leaving group or OH, or

5 b) compounds of formula IV

R1 1 NH2

/ V

10 \ A

T NH2 R2

wherein the groups R1 and R2 are as defined above are reacted with compounds of formula V.

R7 i (v)

20 'I

9 / c ~ s — 9-

r -o ^ I N

B

wherein R6, R7 and R8 are as defined above and R9 is an esterifying group, i) the -S group (s) optionally present in the compounds of formula I are, if desired, oxidized to -SO or -SO2 group (s) , ii) the (S) -SO group (s) optionally present in the compounds of the formula I are, if desired, oxidized to the -SO 2 - group (s), and iii) the compounds of the formula I are, if desired, converted into their physiologically tolerable salts, steps i) to ii) can also be performed in the reverse order.

5 89 602 M * denotes cations, such as alkali, alkaline earth, ammonium or alkylammonium ions, in particular sodium or potassium ions.

When, according to the preferred process variant a), the compounds of the formula II are reacted with the compounds of the formula III, the group X1 or X2 is a leaving group which can be removed nucleophilically, such as Cl, Br, I, -O-SO2-CH3, -O-SO2 -CF3 or -O-SO2- (C6H4-pCH3).

The reaction of a compound of formula II with a compound of formula III or salts thereof is carried out in an inert solvent such as water, methylene chloride, methanol, ethanol, acetone, ethyl acetate, toluene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide in methyl sulfoxide or mixtures of these solvents, suitably in the presence of an inorganic or organic base such as, for example, sodium or potassium hydroxide, carbonate, alkoxide, hydride or amide, ammonia, triethylamine, tributylamine or pyridine at a temperature of -20 to + 150 C, preferably 0 to 80 ° C.

The compounds of the formula II are known compounds [see Cronowitz, "The Chemistry of Heterocyclic Compounds", Volume 44, "Thiophene and its Derivatives", Parts 1 to 3, New York, 1985-1986], or can be prepared according to known methods, e.g., by forming correspondingly substituted compounds of formula as defined above. Of 2,3-, 3,4- or 4,5-diaminothiophenes according to IV with corresponding sulfur compounds, such as carbon disulphide (e.g. DE-A-3 132 167).

The 2,3-, 3,4- or 4,5-diaminothiophenes required for this are either known from the literature or can be prepared using known methods. They are obtained, for example, by reduction of correspondingly substituted amino nitrothiophenes.

6 89602

In the esters of formula V used in process variant b), R 9 is an esterifying group, preferably (C 1 -C 4 alkyl or benzyl).

The reaction of a compound of formula IV with a compound of formula V according to process variant b) is carried out according to Preston et al .; using the method described in Benzimidazoles and Congeneric Tricyclic Compound, Part 1, New York, pages 10-13.

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

Compounds of formula I in which T is -S- may further be converted, using suitable oxidants, to compounds in which T is -SO- or -SO 2 -. In the same way, the -S groups in the substituents R1, R2 and R7 can also be oxidized.

This reaction is carried out in a suitable inert solvent such as, for example, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, toluene, ethyl acetate, acetic acid, trifluoroacetic acid, water, methanol, ethanol or mixtures of these. 20 to + 150 ° C, preferably -10 to + 40 ° C.

Suitable anoxides are hydrogen peroxide, peracids and peresters such as peracetic acid, trifluoroperacetic acid, monoperphthalic acid, m-chloroperbenzoic acid and their esters, ozone, nitrous oxide, sodium iodocyanide, iodosobenzene, N-chlorosuccinimide, 1-chlorosuccinimide, 30 phate, t-butyl hypochlorite, tetrabutylammonium periodate or permanganate, sodium metaperiodate, selenium and manganese dioxide, cerammonium nitrate, chromic acid, chlorine, bromine, diazobicyclo [2.2.2] octane-bromide bromide, 35-dioxide, dioxide, dioxide alkyl chloride, 2-arylsulfonyl-3-aryloxaziridine, 89602 7 titanium tetraisopropylate / tert-butyl hydrogen peroxide [optionally with the addition of a dialkyl ester of (D) or (L) -tartaric acid and a certain amount of water].

In addition, isolated, possibly immobilized oxidizing enzymes or microorganisms can be used as oxygen-free.

Oxygen-free ones are used in equimolar amounts, possibly also a small excess of 5-10 mol% when oxidizing to the T group -SO-, or using a larger excess or a higher reaction temperature if oxidizing to the T group -SO 2 -.

Intermediates of formula III can be prepared according to methods known to those skilled in the art, such as those described in "The Chemistry of Hetero-15 Cyclic Compounds - Pyridine and its Derivatives", Chapters 2 and 3; E. Klingsberg, ed. Interscience Publishers, 1962.

In addition to the synthesis of compounds of formula III wherein X 2 is a leaving group, compounds of formula III wherein X 2 is a hydroxyl group; Compounds of formula III in which X 2 is chlorine or bromine can be prepared e.g. by halogenation of the corresponding 2-picolines with N-bromo-succinimide, trichloroisocyanic acid [Chem. Ber. 120 (1987) ss. 649-651] or other haloamides such as N-chlorophthalimide.

Some methods for preparing compounds of formula III wherein X 2 is hydroxyl are described below. Their conversion to compounds of formula III in which X2 is a leaving group is carried out according to standard methods.

Compounds of formula III wherein X 2 is a hydroxyl group, one of R 6 and R 8 is bromine and the other is hydrogen can be obtained according to Scheme 1.

A mixture of compounds of formulas VII and VIII is obtained by known methods by bromination of 2-picoline 35 [cf. e.g., Bull. Soc. Chim. France (1972), pp. 2,466].

89602 8

For example, after N-oxidation and nitration with m-chloroperbenzoic acid, compounds IX and X are separated by crystallization or chromatography and purified.

Compounds of formulas IX and XIII in which R7 is alkoxy are in each case obtained from compounds of formulas IX and X and the corresponding alcoholates MR7, in which M is as defined above, and are reacted with e.g. acetic anhydride or (CF3CO) 2 O and then saponified to give compounds of formulas XII and XIV.

10

Scheme 1 “Jo- fe * 33 * JX?” R6, rB, h H3C CH3 <V1> tvil) (Vili)

20, -CPBS

v ../ νη, ΥΎ * TY

CH3 I ch3 I

0 0 (ix) (X) c * 3 ± hoch / ^ t o (x11 (XII) 30

* m- ^ IdT

CH3 hoch (^^ o 35 <XI Π) (XIV) 89602 9

Scheme 2 shows the synthesis of compounds of formula III wherein X 2 is a hydroxyl group, R 6 is hydrogen and R 8 is chlorine. Using known methods for decomposing carboxy-5-silicic acid derivatives of 6-methylnicotinic acid, the obtained 5-amino-2-picoline XV [cf.

J. Prakt. Chem. 133 (1932 <919)] are reacted according to reactions well known to those skilled in the art (Sand-Meyer reaction, N-oxidation, nitration, reaction with alcoholates, rearrangement with acetic anhydride, acetate saponification) to give compounds of formula XX.

Figure 2

15 2 NoNO 2 / HCl

AA -> IJ AJ

h3c H3C ^ H3C ** o lXV> <XV1) (XVII) 20 HN03 / H2504 R \ ^ ::: Y, CI MR7 '· a -2 · N'0H hoh ^ cw 25 0 0 (XV111) <X1X) Compounds of formula III wherein X 2 is a hydroxyl group, R 6 is hydrogen or methyl and R 8 is fluorine can be obtained as shown in Scheme 3.

Under Ullmann reaction conditions, compounds of formula VIII can be converted to 5-amino-2-picolines XV [cf.

35 Rec. Trav. Chim. 84 (1965) 7, p. 951-964].

10 89602

Compounds of formula XV are also obtained using decomposition reactions of carboxylic acid derivatives of 6-methylnicotinic acid of formula XXI. The synthesis of fluoro derivatives XXII is conveniently carried out under Schiemann reaction conditions as is known for compound XXII (R6 is H) [cf. J. Med. Chem. 13 (1970), p.

1 124].

The 4-nitro-5-fluoro-2-picolines of the formula XXIII are reduced, like the analogous 3-fluoroisomers, to the amino-10 derivatives XXIV [cf. Rocz. Chem. 41 (1967) (2), ss. 279-287] and converted to dihalides XXV.

Scheme 3 R 6 = H, CH 3 15 6 Br R 6 .., CO 2 x

Xt Jt? H3c (VI im 3 <χχπ x = N3, NH2 or NHNH2) nh3

CuSOj jr 20 4 / NOp NH2 EtONO / pfi / r6 i, f "fer Jcr Mg * J} h3c 0 25 (XV, <xx ,,> (xxnn

NH Y F R? F

06 L2 f NoNO2 / HCl „1. m-CPBSN

30 H3C 0 (XX] V> <xxv »Y - F, Cl) (XXVI) 'Vtf

2. NoOK

35 H0H2C

<XXV] 1) I.

89602 11 After N-oxidation, substitution with 4-halogen alcoholate R7 and rearrangement, preferably with acetic anhydride or trifluoroacetic anhydride, and acetate saponification, picolyl alcohols of formula 5 XXVII are obtained.

Similarly, corresponding compounds can be prepared in which R 6 is fluorine and R 8 is hydrogen or (C 1 -C 3) alkyl.

Compounds of formula III in which X 2 is a hydroxyl group and both R 6 and R 8 are fluorine or chlorine can be prepared e.g. according to Scheme 4.

Chart 4 15 7 7 mrt. yv "8 reduced's yVR8, ϋΓ1 '· LiilH4 ΑΧ (XXVI11, (XXIX) / (XXX) 20 Y = F, Cl) χ / o7 p7 1. m_CPBS r7

r6 * r8 R6 l rB 2. OcgO v R6. RB

"XX„ JX

25 (R02C) 2HC H H3C ™ H hOH2C

<XXXI) (XXXI 1) (XXXI 1) Using substitution reactions using nucleophiles such as amines and alcoholates, halogen derivatives XXVIII give compounds of formula XXIX, the reduction of which affords XXX [cf. J. Chem. Soc. (1965), p. 575].

Reaction of compounds of formula XXX with salts of malonic acid diesters affords esters of formula XXXI which are decarboxylated by acidic or basic hydrolysis in an acidic medium to substituted 3,5-dihalo-2-picolines of formula XXX.

Compounds of formula XXX may also be reacted with organometallic reagents such as methylmagnesium halides or methyllithium directly to give compounds XXXII.

By using nucleophilic substitution with C1-synto-10s, such as salts of maternal sounds or cyanides, compounds of formula XXX can also be used to obtain valuable substances which, by other reactions, give compounds of formula XXXIII.

15 Scheme 5 HO S 1- fl9s0 / Rx R '° v ^' · P ° C'3 vX, 20 H3CÖ 2 · NH3 "· h3cV * · ~~ CPe5„ 3CÖ (XXXIV) (XXXV) -i - ^ - x 1. -. (xxxvio; x - 0) 1. + 2.:(xxxv]b; X - 1) r7 p7, R 0, 1, pCpO RO 7

^ Λ e · no0h> xS

H0H2C / o o (XXXVI I) (XXXVI I I) 30

Compounds of formula III wherein X 2 is a hydroxyl group, R 6 is an alkoxy group and R 8 is hydrogen can be prepared according to Scheme 5.

i 89602 13

Maltol XXXIV is alkylated with an alkyl halide R'X in the presence of silver oxide to 3-alkoxypyran-4-ones which are reacted into 2-methyl-3-alkoxy-4-pyridones of formula XXXV with aqueous ammonia 5 [J. Org. Chem. 29 (1964), p. 776].

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

Using a similar reaction with 5-hydroxy-2-methyl-4-pyranone prepared from 5-hydroxy-2- (hydroxymethyl) -4-pyrone (kojic acid), isomeric compounds of formula XXXVIII are obtained in which R6 is hydrogen and R8 is alkoxy.

Using halogenating agents, e.g. POCl 3, the compounds of formula XXXV are converted to 2-methyl-3-alkoxy-4-chloropyridines which, with the alcohol R 7 H, give 4-alkoxy derivatives in the presence of a base.

The reaction of analogous N-oxides XXXVIb with alcoholates to give compounds of formula XXXVII is preferred.

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

: ·> RO 8 RO f '• Λ X) -> Λ • * - * · "3C' h h3C / ^

(XXXV) (XXXIX

3q R7 = (C1-C7) -alkoxy

Methods for the preparation of 3,4-dialkoxy-2-picolines and 4,5-dialkoxy-2-picolines are described in application-35 EP-A-166 287 and EP-A-208 452.

8 9 602 14

Compounds of formula III wherein X 2 is a hydroxyl group, one of the substituents R 6 and R 8 is an alkoxy substituent or a halogenated, preferably fluorinated alkoxy group R f, and the other is hydrogen, halogen, alkyl, alkoxy 5 or a halogenated, preferably fluorinated alkoxy group R f, can be prepared according to Scheme 6.

Figure 6 10

Rf ° x __.> RB

ΓΤ -> 1 · πι-CPBS

H3C ^ n ^ h3c 12 · nitration 'HN03 / H2SO4 (XXXX> (XXXX1) 15 NOp Λ R7

Rr0j2Rg Rf ° NI / RB

TT> TT -cpo—> h3c T 2 * Na0Hoq · 20 0 0 (X X X X1]) (XXXX111)

Rr \ A / RB

-.25 J | ] Rr = <CH2) d cpH (2p + 1_q) rq .8 hoh2c ^ o = 0 ^ '(XXXX1V) is * 9602

Compounds of formula XXXXI are obtained by coupling 3-hydroxy-2-picolines of formula XXXX to the corresponding halogenated olefins (e.g. CF2 = CF2 or CF2 = CC1F).

In addition, halogenated carbenes, e.g. CF2 from CHClF2, can be obtained from alkyl halides and bases, which can also be obtained by coupling compounds of formula XXXXI to the OH bond of 3-hydroxy-2-picolines [cf. J. Org. Chem. 25 (1960), p. 2,009]. 5-Trifluoromethoxy-2-picolin-10-n is obtained, e.g., in J. Org. Chem. 29 (1964), p. 1 and J. Med. Chem. 13 (1970), p. 1 124.

Isomeric 5-hydroxy-2-picolines can be reacted in a similar manner.

The methods of preparation described in the above schemes have the definitions given for substituents and variables at the beginning, unless otherwise specified in individual cases.

According to the invention, in addition to the thienoimidazole derivatives described in the working examples, for example also the compounds listed in the following Table 1 or their salts can be prepared.

The following abbreviations were used: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), hexyl (Hex), acetyl (Ac), phenyl (Ph), cyclo (c) and iso (i).

·. 25

table 1

T = SO

R1 R2 R6 R7 R8 30 ___ H H H OEt Cl H H H OPr Cl H H H OiPr Cl H H H OCH2Ph Cl 35 (continued ...) 16 89 602

R1 R2 R6 R7 R8 H H H 0 (CH2) 2OMe Cl 5 H H H OCH2CF3 Cl H H H OCH2CF2CF3 Cl H H H OEt Br H H H OPr Br H H H OCH2Ph Br 10 H H H 0 (CH2) 20Me Br H H H OCH2CF3 Br H H H OCH2CF2CF3 Br

H H H OCH2Ph F

H H H 0 (CH2) 2OMe F

15 H H H OCH2CF3 F

H H F OMe H

H H F OEt H

H H F OPr H

H H F OCH2Ph H

20 H H F 0 (CH 2) 2 OMe H

H H F OMe Me H H F OEt Me H H F OPr Me H H F OiPr Me .25 H H F OCH2Ph Me H H F 0 (CHj) 2OMe Me H H F OCH2CF3 Me

H H Me OEt F

H H Me OPr F

30 H H Me OCH2Ph F

H H Me 0 (CH2) 2OMe F

H H Me OCH2CF3 F

H H H OMe F

H H H OEt F

35 (continued ...) 17 8 9 6 0 2 R1 R2 R6 R7 R8

H H H OPr F

5 H H H OiPr F

H H Br OEt H

H H Br OPr H

H H Br OCH2Ph H

H H Br 0 (CH2) 20Me H

10 H H Br OCH2CF3 H

H H OCF3 OMe H

H H OCF3 OEt H

H H OCF3 OPr H

H H OCF3 OCH2Ph H

15 H H OCF3 O (CH2) 20Me H

H H OCF3 OCH2CF3 H

H H OCF2H OMe H

H H OCF2H OEt H

H H OCF2H OPr H

20 H H OCF2H 0 (CH2) 20Me H

H H OCF2CF2H OMe H

. :: H H OCF2CF2H OMe Me H H OCF2CF2H OEt Me

CH3 CH3 OCF2CF2H OMe H

: - .. 25 CH3 CH3 OCF2CF2H OMe Me

OCH2CF3 H OCF2CF2H OMe H

OCF2CF3 H OCF2CF2H OMe Me

OCH2CF3 H OCF2CF2H OCH2Ph H

OCH2CF3 H H OMe OCF2CF2H

30 OCH2CF3 H Me OMe OCF2CF2H

OCH2CF3CF3 H OCF2CF2H OMe H

OCH2CF2CF3 H OCF2CF2H OPr H

OCF2CF2H H OCF2CF2H OMe H

OCF2CF2H H OCF2CF2H OEt H

35 (continued ...) ie '* 9 602 R1 R2 R6 R7 R8

OCF2CF2H H OCF2CF2H OCH2Ph H

5 OCF2CF2H H OMe OMe OCF2CF2H

H H H OMe OCHF2 H H H OEt OCHF2 H H H OCH2Ph OCHF2 H H H 0 (CH2) 2OMe OCHF2 10 H H H OMe OCF3 H H H OEt OCF3

H H F OMe F

H H F OEt F

H H F OCH2Ph F

15 H H F 0 (CH2) 20Me F

H H Cl NPhMe H

H H Cl NPhMe Me H H H NPhMe Cl H H Me NPhMe Cl

20 H H F -NMe2 F

H H F -N ^ J F

H H F -N * '' O F

V_ / HH Cl -NMe2 Cl HH Cl -1 ^ 3 Cl 25 HH Cl -if- '0 Cl \ _ / ch3 ch3 och3 och2cf3 h ch3 ch3 och3 och2cf2cf2h h ch3 ch3 och3 och2cf2cf3 h ch3 ch3 och3 och2cf3c3 och2cf2cf2cf2cf2h 0CH3 H H H H OCH2CF3 H H H H H H oCH2CF2CF3 OCH2CF2CF2H OCH 3 OCH 3 OCH 3 H H H OCH2CF2CF2CF3 35 (continued ...) 89 602 19 R 1 R 2 R 6 R 7 r® OCH2CF2CF2CF2CF2H OCH 3 H H H 5 CH 3 CH 3 CH 3 OCH 3 H OCH2CF3 CH3 H och2cf2cf, OCH 3 H CH 3 CH 3 H OCH 3 och2cf2cf3 ch3 ch3 h och2cf2cf2cf3 och3 ch3 ch3 h och2cf2cf2cf2cf2h och3 10 och2cf3 h och3 och2cf3 h och2cf3 h och3 och2cf2cf3 h

H H 4-chlorobenzene-OCH3 H

yloxy

15 H H 4-fluorobenzene-OCH 3 H

yloxy

H H 2,4-difluoro-OCH3 H

benzyloxy 20

H H 3,5-difluoro-OCH3 H

benzyloxy

H H 4,6-dichloro-OCH 3 H

25 benzyloxy

H H 4,5-dichloro-OCH3 H

. . benzyloxy

30 H H 4-trifluoromethOCH 3 H

tyylibentsyylioksi

H H 3,5-bis-tri-OCH 3 H

fluorobenzyl-35 oxy

H H 4-fluorobenzene-OCH 2 CF 3 H

yloxy

40 H H 4-chlorobenzo-OCH2CF3 H

yloxy

H H 4-trifluoromethyl-OCH2CF3 H

style benzyloxy (continued ....) 45 20 8 9 602

R1 R2 R6 R7 R8

H H 3,5-bis-tri-OCH2CF3 H

5 fluoromethylbenzyloxy

CH3 CH3 4-trifluorometh-OCH2CF3 H

ethylbenzyloxy 10 H H H OCH 3 4-fluorobenzyloxy 15 H H H OCH 3 4 trifluoromethylbenzyloxy 20 H H H OCH 2 CF 3 4-fluorobenzyloxy 25 H H H OCH 2 CF 3 4-trifluoromethylbenzyloxy 30

The new compounds of the formula I and their salts have valuable pharmacological properties. They clearly inhibit the secretion of gastric acid and in addition have an excellent gastrointestinal protective effect.

35 "Gastrointestinal protective effect" in this context means the prevention and treatment of gastrointestinal diseases, in particular inflammatory diseases and injuries of the gastrointestinal tract (such as ulcus ventriculi, ulcus duodeni, gastritis or irritable stomach caused by hyperacidity or drugs). ), which may be caused, for example, by micro-organisms, bacterial toxins, drugs (eg anti-inflammatory and anti-rheumatic drugs), chemicals (eg ethanol), gastric acid or stressors.

89602 21

on the basis of its excellent properties tienoimidatsolit of formula I and their pharmacologically tolerable salts are very suitable for use in human and veterinary medicine, they are used for various 5-particular in the treatment and prophylaxis of gastric and intestinal disorders and of diseases caused by gastric acid secretion of too rich.

It was found that colon H * / K * -ATPase in vitro [cf. Gustin, Goodman; J. Biol. Chem. 256 (1981), ss.

10 10 651 to 10 656] strongly inhibit compounds formed by acid treatment of compounds of formula I according to the invention (e.g. in sodium acetate / HCl buffer having a pH of about 4 to 5.5). Such reaction products may also be formed in vivo as the compounds of formula I pass through the gastrointestinal tract. The extent to which they are formed depends on the substitution pattern and pH.

The colon H * / K * ATPase has a crucial effect on the electrolyte balance of the gastric mucosa. Thus, colon-20 H '/ K * -ATPase inhibitors, such as those mentioned above, may affect this balance and may be used in the treatment of diseases involving disturbed electrolyte balance.

The compounds of formula I or their acid-formed reaction products can thus be used in the treatment of diarrheal diseases. Examples of such diseases include inflammatory bowel diseases such as cholera, smallpox, travel diarrhea or other forms of secretory diarrhea; but also other intestinal diseases such as 30 local intestinal inflammation (morbus crohn), ulcerative colitis and local intestinal inflammation.

Medicaments containing one or more compounds of the formula I and / or their pharmacologically tolerable salts are prepared by a method known per se and known to the person skilled in the art. 89602 22 Pharmacologically active compounds (= active ingredient) prepared according to the invention are used as medicaments either as such or preferably together with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, suspensions or solutions, the active ingredient content being preferably between 0.1 and 96% .

Which excipients are used for the desired dosage forms will be readily apparent to those skilled in the art. In addition to solvents, gel-forming agents, suppository sticks, tablet excipients and other active ingredient carriers, for example, antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers or colorants can be used.

The active ingredients may be administered orally or parenterally, with oral administration being preferred.

In general, it has been found advantageous in human medicine to administer the active ingredient (s) for oral administration in a daily dose of from about 0.01 to about 20.0 mg / kg of body weight, possibly in several, preferably 1 to 4, single doses to achieve the desired results. When parenteral administration is used, 25 similar or (especially when using intravenous administration of the active ingredient) dosage may be used. The optimum dosage and method of administration of the active ingredient required in each case will be readily determined by a person skilled in the art on the basis of his skill.

If the compounds according to the invention and / or their salts are used for the treatment of the abovementioned diseases, the pharmaceutical preparations can additionally contain one or more pharmacologically active ingredients from other classes of drugs, such as antibiotics, for example ofloxacin, antacids, for example aluminum hydroxy-23 BS 602 di, magnesium aluminate, sucralfate and Bi-salts, sedatives such as benzodiazepines, for example diazepam, antispasmodics such as bietamiverine and camylofin, anticholinergics such as pirent-5-sepine, telencephrine, oxyphenicycline and fencarbamide, topical tencanamide, topical as well as possibly also gastrin antagonists, enzymes, vitamins or amino acids.

For oral use, the active compounds 10 are mixed with commonly used excipients such as carriers, stabilizers or inert diluents and brought into a suitable dosage form by conventional methods such as tablets, granules, capsules, aqueous, alcoholic or oily suspensions or aqueous, 15 into alcoholic or oily solutions.

As inert carriers, for example, gum arabic, magnesium oxide, magnesium carbonate, milk sugar, glucose or starch, in particular corn starch, can be used. In this case, the preparation can be carried out as both dry-20 granules and wet granules. Suitable oily carriers or solvents are, for example, oils of vegetable or animal origin, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous use, the active compounds or their physiologically tolerable salts are, if desired, brought into solution, suspension or emulsion with suitable substances, such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents for the new active compounds and the corresponding physiologically tolerable salts are, for example, water, physiological saline solutions or alcohols, e.g. ethanol, propanol or glycerin; in addition, sugar solutions, such as glucose or mannitol solutions, or also various mixtures of said solvents.

24 S 9 6 O 2

The following examples illustrate the methods of the invention, but do not limit the invention to these exemplified materials.

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

Example 1 a) 5-Chloro-2-picoline N-oxide 13.0 g of 5-chloro-2-picoline are stirred in 250 ml of methylene chloride at room temperature, stirring portionwise with 21.3 g of m- chloroperbenzoic acid (M-CPBS). After 2 hours, shake twice in each case with 200 ml of saturated aqueous NaHCO3 solution and then three times with 200 ml of saturated aqueous NaHCO3 solution. The hydrogen carbonate solution is extracted three times with 100 ml of methylene chloride each time, the combined organic phases are dried and the solvent is removed. Trituration with petroleum ether gives the title compound as crystals; mp. 73-76 ° C.

b) 4-Nitro-5-chloro-2-picoline N-oxide 20 12 g of 5-chloro-2-picoline N-oxide are transferred portionwise with cooling to a mixture of 40 ml of concentrated sulfuric acid and 40 ml of fuming nitric acid. . It is then heated to 35-40 ° C for 1 hour and to 65-70 ° C for 2 hours. After cooling, it is stirred in 250 g of ice, the pH is adjusted to 10-11 using 10 M sodium hydroxide and extracted with ethyl acetate. After removal of the solvent, the residue is treated with diisopropyl ether; mp. 115-117 ° C.

c) 4-Methoxy-5-chloro-2-glycoline N-oxide To a solution of sodium methylate prepared from 1.5 g of sodium and 150 ml of methanol at 3.5 ° C is added 3.5 g of 4-nitro -5-chloro-2-picoline N-oxide in 50 ml of anhydrous methanol. Allow to slowly warm to room temperature and then heat at reflux for 1 hour. The solvent is then removed by distillation under reduced pressure 89602, the residue is taken up in water, extracted with dichloromethane and the solvent is removed. Colorless crystals are obtained from diisopropyl ether; mp. 137-139 ° C.

5 d) 5-Chloro-2-hydroxymethyl-4-methoxypyridine 8.5 g of 3-chloro-4-methoxy-2-picoline N-oxide are dissolved in 16 ml of glacial acetic acid and added with stirring at 80 ° C to 24 ml. acetic anhydride. Heat to 100 to 120 ° C for 1.5 hours, then allow to cool to 80 ° C and drop by drop 40 ml of methanol. It is then evaporated under reduced pressure, the residue is taken up in 35 ml of water, 13.6 g of sodium hydroxide in small portions and 15 ml of dioxane, and this mixture is heated under reflux for 2 hours. After cooling, the mixture is extracted with dichloromethane, the solvent is removed and the residue is crystallized from diisopropyl ether. A solid having a m.p. is 78-80 ° C.

e) 5-Chloro-2-chloromethyl-4-methoxypyridine hydrochloride A solution of 4.5 g of 5-chloro-2-hydroxymethyl-4-methoxypyridine and 100 ml of dichloromethane is added dropwise at 0 ° C to a solution which contains 8.0 ml of thionyl chloride in 20 ml of dichloromethane and is then stirred for 2 hours at room temperature. The solvent is removed and the residue is crystallized from diethyl ether. Colorless crystals; mp. 136-137 ° C.

f) 2- (4-methoxy-5-chloro-2-picolyl mercapto) -1H-thieno [3,4-d] imidazole dihydrochloride 1.56 g of 2-mercaptothieno [3,4-d] imidazole and 2.3 g of 4-methoxy-5-chloro-2-picolyl chloride hydrochloride in 100 ml of ethanol is heated to 60 [deg.] C. for about 1 hour and then refluxed for 1.5 hours. After filtration, the crystalline substance is slurried in acetone, stirred for 1 hour at room temperature, the crystals are removed by suction filtration and air-dried; mp.

> 260 ° C.

26 39602 g) 2- (4-methoxy-5-chloro-2-picolylnercapto) -1H-thieno [3,4-d] imidazole 1.4 g of the title product of Example 1 f) are added after suspension in methanol (70 ml). at room temperature with stirring in 2 ml of triethylamine. The solution thus obtained is stirred for about 1 hour at room temperature, slurried with activated carbon, filtered and evaporated in vacuo. The residue is taken up in water and extracted with methylene chloride. After evaporation of the solvent, the residue is crystallized from diisopropyl ether; mp. 135-137 ° C.

h) 2- (4-methoxy-5-chloro-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole to 0.44 g of the title product of Example 1 g) in a two-phase mixture containing 70 ml of methylene chloride and 40 ml of an aqueous solution of KH 2 PO 4 / Na 2 HPO 4 buffer (pH 7.5), 0.308 g of m-chloroperbenzoic acid (85%) in 10 ml of methylene chloride are added dropwise with stirring at 0-5 ° C. After about 30 minutes, the organic phase is evaporated off and the residue is chromatographed on silica gel using a mixture of dichloromethane and ethylene acetate as eluent. The product is crystallized from the corresponding fractions with ethyl acetate; mp. 159 ° C (dec.) Or recrystallized from ethanol.

Example 2. 25 a) 3-Bromo-2-picoline N-oxide and 5-bromo-2-picoline N-oxide

According to Example 1 a), the title compounds are obtained from 43 g of a mixture of 3-bromo-2-picoline and 5-bromo-2-picoline and 60 g of m-chloroper-30 benzoic acid (85%). . The mixture of the title compounds is crystallized from diisopropyl ether; mp. 65-80 ° C (inaccurate).

b) 3-Bromo-4-nitro-2-picoline N-oxide and 5-bromo-4-nitro-2-picoline N-oxide 35 According to Example 1 b) 26.3 g of the title of Example 2 a) 27 89602 The compounds of H 2 SO 4 (50 mL) and HNO 3 (50 mL) are stirred for 7 hours at 60-65 ° C. Evaporation from the residue preferably crystallizes the 5-isomer using a mixture of ethyl acetate and diisopropyl ether (1: 1); mp. 133-135 ° C.

Chromatographic separation of the mother liquor using a mixture of toluene and ethyl acetate (1: 1) on silica gel elutes further 5-bromo-4-nitro-2-picoline N-oxide followed by 3-bromo-4-nitro-2 -picoline-10 N-oxide; mp. 111-113 ° C (from petroleum ether).

Example 3 a) 4-Methoxy-5-bromo-2-picoline N-oxide According to Example 1e), 8.2 g of the title compound are obtained from 4-nitro-5-bromo-2-picoline N-oxide and 0.87 g of Na in methanol. After evaporation of the dichloromethane, the residue is crystallized from diisopropyl ether; mp. 146-148 ° C.

b) 4-Methoxy-5-bromo-2-hydroxymethylpyridine According to Example 1 d), 6.6 g of 4-methoxy-5-bromo-2-picoline N-oxide are reacted with 7 ml of glacial acetic acid, 15 ml: with acetic anhydride, with 20 ml of methanol, with 20 ml of water, with 8 g of NaOH and with 20 ml of dioxane. The crude product is crystallized from isopropyl ether; mp. 80-82 ° C.

25 c) 4-Methoxy-5-bromo-2-chloromethylpyridine hydrochloride

According to Example 1 e) the title compound is obtained from 4.3 g of the title compound of Example 3 b) and 5.0 ml of thionyl chloride; mp. > 300 ° C (from di-30 isopropyl ether).

d) 2- (4-Methoxy-5-bromo-2-picolylmercapto) -1H-thieno [3,4-d] imidazole dihydrochloride 1.2 g of mercaptothieno [3,4-d] imidazole are suspended in 50 ml of ethanol. , is stirred in 2.0 g of 4-methoxy-5-bro-35 ml-2-chloromethylpyridine hydrochloride and stirred for 1 28 89 602 hours at 60 ° C. The solvent is removed and the residue is crystallized from diethyl ether; mp. > 300 ° C.

e) 2- (4-Methoxy-5-bromo-2-picolylmercapto) -1H-thieno [3,4-d] imidazole 5. 2.15 g of the title compound of Example 3 d) are mixed with 50 ml of methanol and 7 ml of to triethylamine. According to Example 1 g), the product crystallizes on stirring in water; mp. 165 ° C (dec.).

f) 2- (4-methoxy-5-bromo-2-picolylsulfinyl) -10H-thieno [3,4-d] imidazole

The title compound is obtained according to Example 1 h) from 1.1 g of the title compound of Example 3 e) and 0.725 g of m-chloroperbenzoic acid. When the residue is treated with a small amount of a mixture of diethyl ether and ethyl acetate (1: 1), the title compound crystallizes; mp. 140 ° C (dec.).

Additional product is obtained from the dark colored mother liquor by evaporation and immediate treatment with a small amount of ethyl acetate.

Example 4 a) 3-Bromo-4-methoxy-2-picoline N-oxide

According to Examples 1c) and 3a), 4.6 g of the title compound are obtained from 3-bromo-4-nitro-2-picoline N-oxide in 40 ml of methanol using a solution of sodium ethylate-25 prepared in 0 ml. 5 g of sodium and 20 ml of methanol; mp. 80-82 ° C (from diisopropyl ether).

b) 3-Bromo-4-methoxy-2-hydroxymethylpyridine 3.8 g of the title compound 30 of Example 4 a) are stirred for 1 hour at 80-85 ° C with 30 ml of acetic anhydride. According to Examples 1 d) and 3 b), 254 ml of methanol are mixed after evaporation with 30 ml of 5 M sodium hydroxide and 10 ml of dioxane. The product crystallizes from diisopropyl-35 ether; mp. 109-111 ° C.

89602 29 c) 3-Bromo-4-methoxy-2-chloromethylpyridine hydrochloride

According to Examples 1e) and 3c), 1.9 g of the title compound of Example 4b) are reacted with 2.5 to 5 ml of thionyl chloride. The product is crystallized from diisopropyl ether; mp. 142-144 ° C.

d) 2- (3-Bromo-4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole dihydrochloride 1.3 g of 2-mercaptothieno [3,4-d] imidazole in 50 ml Ethanol is stirred with 2.3 g of 3-bromo-4-methoxy-2-chloromethylpyridine hydrochloride with constant stirring and kept at 60 ° C for 30 minutes. The product is separated by suction filtration and dried in vacuo; mp. > 300 ° C.

e) 2- (3-Bromo-4-methoxy-2-picolyl mercapto) -1H-thieno [3,4-d] imidazole

According to Example 1 g), 2.4 g of the dihydrochloride of Example 4 d) in 50 ml of methanol are mixed with 2.9 ml of triethylamine. After evaporation and stirring with a small amount of water, the residue crystallizes; mp. 20 168 ° C (dec.).

f) 2- (3-Bromo-4-methoxy-2-picolylsulfinyl) -1H-tleno [3,4-d] imidazole

According to Example 1 h), 0.72 g of the title compound of Example 4 e) in 120 ml of dichloromethane and 50 ml of an aqueous solution of KH2PO4 / Na2HPO4 buffer (pH 7.5) are added dropwise. .44 g of m-chloroperbenzoic acid (85%) in 15 ml of dichloromethane. After evaporation of the organic phase, the residue is crystallized from ethyl acetate; mp. 160 ° C (polymerization?).

Example 5 a) 2-Methyl-3-methoxy-4-chloropyridine N-oxide II, 2 g of 3-methoxy-2-methyl-4 (1H) pyridone in 100 ml of phosphorus oxychloride are heated at reflux for 10 hours. It is then evaporated, stirred twice, each time with 30 ml of toluene, re-evaporated, taken up in 150 ml of water, adjusted to pH 11 with K2CO3, extracted with dichloromethane, washed with the organic phase with water, dried and the solvent removed.

5 A light brown oil (9 g) is obtained, using m-chloroperbenzoic acid in dichloromethane under normal conditions, to give the title compound; mp. 88-89 ° C (from petroleum ether).

b) 2-Methyl-3,4-dimethoxypyridine N-oxide To 8 g of the title compound of Example 5 a) in 100 ml of anhydrous methanol is added dropwise a solution of sodium methylate prepared from 1.14 g of sodium and 50 ml of: methanol, and heated at reflux for 20 hours, evaporated, stirred in water and extracted with dichloromethane. After evaporation, the title compound is obtained; mp. 111-113 ° C.

c) 3,4-Dimethoxy-2-hydroxymethylpyridine 5.8 g of the product described above are reacted according to Example 1 d) in a mixture of 10 ml of glacial acetic acid, 15 ml of acetic anhydride, 20 ml of methanol, 20 ml of water, 8 g of NaOH: a and 20 ml of dioxane; mp. 86-88 ° C (from diisopropyl ether).

d) 3,4-dimethoxy-2-chloromethylpyridine hydrochloride.25 g of the product obtained above are reacted according to Example 1 e) with 5 ml of thionyl chloride; mp. 150-151 ° C (dec.) (From diethyl ether).

e) 2- (3,4-Dimethoxy-2-picolyl mercapto) -1H-thieno- [3,4-d] imidazole According to Example 1 f) 1.56 g of 2-mercaptothieno- [3,4-d] imidazole 70 ml of ethanol are reacted with 2.3 g of 3,4-dimethoxy-2-chloromethylpyridine hydrochloride; mp. 148-150 ° C (dec.).

According to Example 1 g), 35 in 60 ml of methanol are then treated with 2.5 ml of triethylamine; mp. 141-142 ° C (dec.).

i 31 89602 f) 2-83 ,. 4-Dimethoxy-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole

According to Example 1 h), 0.75 g of the title compound of Example 5 e) are oxidized in a mixture of dichloromethane (100 ml) and an aqueous solution of KH 2 PO 4 / Na 2 HPO 4 buffer (50 ml; pH 7.5) with 0.55 g of m-chloroperbenzoic acid. After evaporation, crystallize from diethyl ether; mp. 139-140 ° C. Example 6 a) 2-Bromomethyl-3-fluoropyridine 1.11 g of 3-fluoro-2-picoline are dissolved in 50 ml of CCl 4, mixed with 3.6 g of N-bromosuccinimide and 0.1 g of with azobisisobutyronitrile and reflux with stirring. After cooling and filtration, the solvent is removed in vacuo. The expected molar peak, 189 m / e, is observed in the mass-15 spectrum of the impure product.

b) 2- (3-fluoro-2-picolylmercapto) -1H-thieno [3,4-d] imidazole 1.6 g of 2-mercaptothieno [3,4-d] imidazole and 1.9 g of 2-bromomethyl- 3-Fluoropyridine is stirred with 2.8 g of ground 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 using a mixture of cyclohexane and ethyl acetate as eluent. The Rf value of the product fraction is about 0.15.

c) 2- (3-Fluoro-2-picolylsulfinyl) -1H-thieno- [3,4-d] imidazole 530 mg of the compound obtained from the previous step are dissolved in 50 ml of CH2Cl2 and stirred at room temperature for 444 mg: with m-chloroperbenzoic acid for 4 hours. The solution is washed successively with NaHSO 3 solution, NaHCO 3 solution and water and dried over Na 2 SO 4. After removal of the solvent, the crude product obtained is separated by column chromatography [SiO 2; CHCl 2 / aze-35 work (7: 3)]. The product fractions are evaporated and taken up in di-S 9 6 O 2 32 isopropyl ether and filtered off; mp. 145 ° C; MS gives a molar peak at 282 m / e (M + H +).

The compounds of formula I shown in the following Examples 7-22 are obtained using the methods shown in Schemes 1-6.

Eg T R6 R7 R8 Sp. , ° C

10 7 S CH3 OCH3 F 170 - 173 8 SO CH3 OCH3 F from 145 (dec.) 9 SHH 0CHF2 (MS: M * = 313) 10 SO HH 0CHF2 116 (dec.) MS (DC1): M * + 1 = 329 15 11 SHH Cl 160 (dec.) 12 SO HH Cl 157 (dec.) 13 S 0CH3 HH 180 (dec.) 14 SO OCHj HH 85 - 90 (dec.) 15 SHH OCH3 112 - 114 20 16 SO HH OCH3 152 - 154 (dec.) 17 S OCHF2 HH 103 (dec.) M * = 313 18 S OCHFj HH 78 (dec.) M + H * = 330 25 19 S OCH2CF3 OCH2CF3 H 145 (dec.) M * = 443 20 SO OCH2CF3 0CH2CF3 h 154 (dec.) M + H * = 460 21 S OCF2CF2H OCH3 H oil 30 M + H * = 394 22 SO OCF2CF2H 0CH3 H 138 (dec.) M + H * = 410 8 S 6 D 2 33

Example 23 a) 2-Methyl-3-methoxy-4- (2,2,2-trifluoroethoxy) pyridine-1-n-oxide To 20 ml of trifluoroethanol is added at a temperature of 5 to 20 ° C all the time with stirring under a nitrogen atmosphere. g of tert-potassium butylate. After the mixture is warmed to 0 ° C, 5.2 g of 2-methyl-3-methoxy-4-chloropyridine N-oxide [the title compound of Example 5 a) are added portionwise. Heat at reflux for 3 hours, allow to cool to room temperature, add an additional 3.45 g of tert-potassium butylate and reflux for 2 hours. After the reaction mixture has cooled, 40 ml of water are added, the mixture is extracted with dichloromethane, dried over MgSO4 and the solvent is removed in vacuo. The crude oil-15 product obtained is allowed to react further.

b) 3-Methoxy-4- (2,2,2-trifluoroethoxy) -2-hydroxymethylpyridine 8 g of the title compound of Example 23 a) are dissolved in 16 ml of glacial acetic acid and stirred at 80 DEG C. for 24 ml. with acetic anhydride. Heat to 110 ° C for 2 hours, then cool to 80 ° C and add 40 mL of methanol dropwise to the reaction mixture. It is then evaporated in vacuo, the oily residue is added to 75 ml of 2M NaOH solution in NaOH and stirred for 30 min. After treatment with activated carbon and filtration, the mixture is evaporated in vacuo, the residue is taken up in 50 ml of water, extracted with dichloromethane, dried (MgSO4), evaporated and the residue is taken up in diisopropyl ether. Colorless crystals; mp. 107 - ... 30 108 ° C.

c) 3-Methoxy-4- (2,2,2-trifluoroethoxy) -2-chloromethylpyridine hydrochloride

A solution of 6.0 ml of thionyl chloride in 15 ml of dichloromethane is added dropwise to a mixture of 2.9 g of the product obtained above and 100 ml of dichloromethane at 0 [deg.] C. and then stirred for 2 hours. hours at room temperature. The solvent is removed and the residue is crystallized from diisopropyl ether. Colorless crystals; mp. 166-168 ° C.

5 d) 2- [3-methoxy-4- (2,2,2-trifluoroethoxy) -2-glycol mercapto] -1H-thieno [3,4-d] imidazole dihydrochloride 1.0 g of 2-mercaptothieno [ 3,4-d] Imidazole and 1.9 g of the product of the preceding paragraph are heated in 60 ml of ethanol 10 for about 1 hour at 60 ° C and then heated under reflux for 1.5 hours. After treatment with activated carbon, filtration and evaporation, the residue is crystallized from acetone; mp. from 188 ° C (dec.).

e) 2- [3-Methoxy-4- (2,2,2-trifluoroethoxy) -2-picolyl mercapto] -1H-thieno [3,4-d] imidazole 2.1 g of the title compound of Example 23 d) are stirred after suspension in methanol (80 ml) at room temperature in 4 ml of triethylamine. The solution thus obtained is stirred for about 1 hour at room temperature, slurried with activated carbon, filtered and evaporated in vacuo. When mixed with water, a colorless product crystallizes; mp. 147-148 ° C.

f) 2- [3-methoxy-4- (2,2,2-trifluoroethoxy) -2-picoylsulfinyl] -1H-thieno [3,4-d] imidazole to the title product of Example 23 e) (0, 75 g) in a two-phase mixture of 80 ml of methylene chloride and 40 ml of an aqueous solution of KH 2 PO 4 / Na 2 HPO 4 buffer (pH 7.5), 0.42 g of m-chloroperbenzoic acid (85 -%) in 10 ml of methylene chloride. After about 30 minutes, the organic phase is separated, dried, evaporated and the residue is crystallized from diethyl ether; mp. 135-137 ° C.

The following intermediates of formulas XXXXVI to XXXXVIII can be prepared, for example, according to Scheme 5 -35.

35 ss6 ° 2 R7 CH-.0 3 7 s hqc ^ n Φ o

XXXXVI

10 Example No. R7 M.p., ° C

24 OCH2CF2CF2H 40 - 42 25 OCH2CF2CF3 138 26 OCH2CF2CF2CF3 128 - 130 15 27 0CH2CF2CF2CF2CF2H oil (1 R7 CH-, 0 20 3

H0H2C N

XXXXVII

• 25

Example No. R7 mp, ° C

28 OCH2CF2CF2H 45 - 47 .30 29 OCH2CF2CF3 oil (1 30 OCH2CF2CF2CF3 68 - 70 31 OCH2CF2CF2CF2CF2H oil (1 was allowed to react directly S 9 6 O 2 36 R7 5 Ti] 'HCl

XXXXVIII

10 Example No. R7 Sp. , ° C

32 OCH2CF2CF2H 133 (dec.) 33 OCH2CF2CF3 155 34 OCH2CF2CF2CF3 161 - 163 15 35 OCH2CF2CF2CF2CF2H 132

The following compounds of formula I are obtained according to Examples 5 and 23.

20 7

R

^ yn \\ "if S ') -T-C-» r2> t h

B

Eg T R1 R2 R6 R7 R® Sp. , ° C

30 36 S H H 0CH3 OCH2CF2CF2H H 127 - 129 37 S H H 0CH3 OCH2CF2CF3 H 142 38 S H H 0CH3 OCH2CF2CF2CF3 H 133 - 135 39 S H H 0CH3 OCH2CF2CF2CF2CF2H H 110 40 SO H H 0CH3 OCH2CF2CF2H H 133 - 37 (Contd.

Eg T R1 R2 R6 R7 RH Sp. , ° C

41 SO HH OCH3 OCH2CF2CF3 H 137 (ha j.) 5 42 SO HH OCH3 OCH2CF2CF2CF3 H 113 - 115 43 SO HH OCH3 OCH2CF2CF2CF2CF2H H 103 (dec.) 44 SH phenyl HHH 153 - 157 45 SH phenyl H OCH3 H 182 - 185 46 SH phenyl CH3 OCH3 CH3 192 - 195 10 47 SH 4-methoxyphenyl HHH 141 - 143 48 SHH OCH3 H 170 - 173 49 SH CH3 OCH3 H 151 - 154 50 SH phenyl H OCH2CF2CF2CF3 H 216 15 51 SH 4-methoxyphenyl H OCH2CF2CF2CF3 H 203 52 S OCH3 CO2CH3 HHH 106 - 110 53 SH CON (C2H5) 2 HHH 102 - 104 • HC1 20 54 SO H phenyl HHH 137 - 141 55 SO HH OCH3 H 103 - 135 56 SO H CH3 0CH3 CH3 160 - 165 57 SO H 4-methoxyphenyl HHH 164-167: 25 (dec.) 58 SO HH OCH3 H 162-165 59 SO H CH3 OCH3 CH3 162-165 (dec.) 60 SO H phenyl H OCH2CF2CF2CF3 H 80 .30 61 SO H 4-methoxyphenyl H OCH2CF2CF2CF3 H 79

Claims (5)

A process for the preparation of therapeutically usable substituted thienoimidazole derivatives of formula I and their physiologically acceptable salts thereof T is -S-, -SO- or -SO 2 -, R 1 and R 2 are the same or different and represent hydrogen, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkoxy, -O- [CH 2] O- CpH (2pM.q) Halq, (C1-C4-alkoxycarbonyl, N, N-di- (C1-C4) -alkylcarbamoyl, phenyl, benzyl, or a substituted phenyl or benzyl group, which in the phenyl moiety contains 1 , 2, 3, 4 or 5 are the same or different (C 1 -C 6 -) alkoxy substituents, and a) R 6 is hydrogen and R 8 is fluorine, chlorine or bromine, or b) R 6 is (C 1 -C 3) alkyl and R 8 is fluorine, or c) R6 is fluorine or bromine and R8 is hydrogen, or d) R6 is fluorine and R8 is (C1-C2) alkyl, or e) one of the substituents R6 and R8 is the group -O-tCH2] O-CpH (2 (1.1.i ()) Halil and the other are hydrogen, halogen, (C1-C4 alkyl or the group -O- [CH2O-CpHUp11.]] Halq, Hai is halogen, R 7 is hydrogen, () -alkyl, (C 1 -C 4) alkoxy, -O- [CH 2] o-C p H (2 p, jq) Halq, or benzyloxy, which in the phenyl moiety may be substituted by 1, 2, 3, 4 or 5 are the same or different substituents selected from halogen and trifluoromethyl, 0, 0, 1, 2 or 3, beads, 2, 3, 4, 5, 6, 7 or 8, and q is 0 or 1 up to the value (2p + 1), characterized in that a) compounds having the formula II R1 <Vw (ii) 10. In R 2 H where groups R 1 and R 2 are as defined above and X 1 is i) a leaving group, or ii) -SH, -SM * or -SO 2 -M ', where M * is a cation, is reacted with compounds, having the formula III R7 RR rS 20 x2-c_X JINH wherein the groups R6, R7 and R8 are defined above and X2 is in the above-mentioned cases i) -SH, -SM * or -SO2-M * and in the above-mentioned case ii) preferably a leaving group or OH, or b) compounds having the formula IV 30. X / V 2 lTNH2 44 89602 wherein the groups R 1 and R 2 are as defined above are reacted with compounds having the formula V, Ί RVV8% I I (v) 9 -S -? - S Ry-0 / | NH 10 wherein groups R6, R7 and R8 are as defined above and R9 is an esterifying group, the i) -S group (s) optionally present in the compounds of formula 1 are oxidized, if desired, to a -SO - or -SO2 group (s), ii) -SO group (s), optionally present in the compounds of formula I, are oxidized, if desired, to a -SO2 group (s), and lii) the compounds of formula I are converted, if desired, into physiologically acceptable salts thereof, wherein steps i) - ii) may also be performed in reverse order. 2. A process according to claim 1, characterized in that a compound of formula I is prepared, wherein T is -SO-, or physiologically acceptable salts thereof. Process according to claim 1 or 2, characterized in that a compound of formula I is prepared, wherein R 1 and R 2 are the same or different and are hydrogen, (C 1 -C 2) -alkyl, (C 1 -C 2) - alkoxy or (C ^-C ^) alkoxycarbonyl, R6 and R8 are the same or different and denote the same as defined in paragraphs a) - e) of claims 1 and R7 is a halogenated alkoxy, alkenyloxy or alkinyloxy group of formula -O - [CH 2] O-CpH (2ptl_q) Or bromine, o is 0 or 1, p is 1 - 8 and q is 0 or 1 up to the value (2p + 1), or physiologically acceptable salts thereof. 4. A process according to any one of claims 1-3, characterized in that a compound of formula I is prepared, wherein R 1 and R 2 are the same or different and are hydrogen or (C 1 -C 2) alkyl, R 6 and R 8 are the same. or different and denotes the same as defined in paragraphs a) - e) of claims 1 and R7 is a fluorinated n-alkoxy group of the formula -O- [CH2] O-CpH (2p.1.q) Halq, wherein Hai is fluorine, o is 1, p is 1 - 5 and q is 0 or 1 up to the value (2p + 1), and physiologically acceptable salts thereof. Process according to claim 1, characterized in that 2- [3-methoxy-4- (2,2,2-trifluoroethoxy) -2-picolylsulfinyl] -1H-thieno [3,4-d] imidazole is prepared. 2- [3-methoxy-4- (2,2,3,3-tetrafluoropropoxy) -2-picolyl] -1H-thieno [3,4-d] imidazole, 2- [3-methoxy-4- (2) , 2,3,3-pentafluoropropoxy) -2-picolylsulfin-20-yl] -1H-thieno [3,4-d] imidazole, 2- [3-methoxy-4- (2,2,3,3,4 , 4,4-heptafluorobutoxy) -2-picolylsulfinyl] -1H-thieno [3,4-d] imidazole, 2- (3-bromo-4-methoxy-2-picolylsulfinyl) -1H-thieno [3,4-d] d] imidazole, 2- (4-methoxy-5-bromo-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole, 2- (4-methoxy-5-chloro-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole and its physiologically acceptable salts.