AU595231B2

AU595231B2 - Substituted toluidines, a process for their preparation pharmaceutical formulations containing them, and their use as inhibitors of gastric acid secretion

Info

Publication number: AU595231B2
Application number: AU61745/86A
Authority: AU
Inventors: Andreas W. Herling; Hans-Jochen Lang; Gerhard Rackur; Manfred Rosner
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1985-08-24
Filing date: 1986-08-22
Publication date: 1990-03-29
Anticipated expiration: 2006-08-22
Also published as: NO169169C; JPH0791276B2; FI863382A; ES2001389A6; DK401586A; NZ217322A; IL79813A0; FI863382A0; NO863389D0; FI89910C; HUT44242A; HU199126B; EP0213474B1; FI89910B; PH24073A; IE59587B1; AU6174586A; PT83240B; PT83240A; AR243167A1

Description

Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE

SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: t Lodged: 6 595e2 3 Complete Specification Lodged: Accepted: Published: Priority: tJ 1 Jfl e j elated Art: 0 00 0 a 0o•0 Name of Applicant: 00 lddress of Applicant: 0 *0 Actual Inventor: *°^dress for Service 0 ft HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany HANS-JOCHEN LANG, GERHARD RACKUR, MANFRED ROSNER and ANDREAS W. HERLING EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: SUBSTITUTED TOLUIDINES, A PROCESS FOR THEIR PREPARATION PHARMACEUTICAL FORMULATIONS CONTAINING THEM, AND THEIR USE AS INHIBITORS OF GASTRIC ACID SECRETION The following statement is a full description of this invention, including the best method of performing it known to US

-U

am Il I I I -la- HOECHST AKTIENGESELLSCHAFT HOE 85/F 160 K Dr.WS/St Substituted toluidines, a process for their preparation, pharmaceutical formulations containing them, and their use as inhibitors of gastric acid secretion Benzimidazole derivatives having an analgesic action are disclosed in German Patent A 2,246,429, and those having an inhibitory action on gastric acid secretion are disclosed in, for example, German Patent A-2,548,340, European Patent A-5,129, German Patent A-3,240,248 and German Patent A-3,333,314. Further benzimidazole derivatives have been proposed in German Patent Application P 35 09 333.1 (HOE 85/F 046).

German Patent A-3,531,487 (publication date: March 13, 1986) and European Patent A-174,717 (publication date: 15 March 19, 1986) likewise relate to benzimidazole derivatives.

It has now been found, surprisingly, that certain substituted toluidines are highly active inhibitors of gastric acid secretion.

The present invention relates to o-toluidine derivatives of the formula

I

2 1

RI

25 R R 13 S..0 R 6

R

in which 1a) R1 and R are identical or different and denote hydrogen, (C 1

-C

12 )-alkyl, preferably

(C

1

-C

6 )-alkyl or (C3-C6)-cycloalkyl, in which 1 or 2 of the methylene groups can each be replaced by oxygen, imino, (C 1 2

C

4 )-akyimino and/or (C 1

-C

4 )-alkanoylimino, or denote (C 3 -C6)-akenyl,

(C

3

-C

6 )-akynyl, phenyl or phenyL-(C 1

C

3 )-aLkyl, in which phenyl can be mono-, di- or trisubstituted, preferably mono- or disubstituted, in each case with

(C

1

-C

3 )-alkyl, (C 1

-C

3 )-alkoxy, halogen and/or trifluoromethyl, or denote (C 1

C

6 )-alkanoyl, (C 1

-C

6 )-akoxycarbony, (C 1 C6)-alkyl-carbamoyl, trifluoroacetyl, benzyloxycarbonyl or another physiologically tolerated acid- or baselabile protective group, or a 2

R

1 and R2 together represent a methyene chain -ECH2)n- which can contain a double bond, in which n is 4, 5 or 6 and in which one methylene group can be replaced by oxygen, sulfur or NR 9 or together denote phthaloyl, b) R 3

R

4

R

5 and R are identical or different and represent hydrogen, halogen, cyano, nitro, t-ta a- t-nt (C 1

-C

6 )-alkyL-Y- or phenylin which Y denotes oxygen, sulfur, sulfinyl, sulfonyl 25 or -ECH2m-, with m= 0, 1 or 2, or represent -CO-R 10 -SO2NR 11

R

12 r 11 11 12 11 S212 -0-COR -NR -COR 12 -NR -S0 2

R

12 or -NR 11

R

12 or 1 3 c) R is as defined under al), and 4 5 6 S 30 R 4 R5 and R are as defined under and 2 3 R and R together represent a chain -ECH 2 Jm-X-, in which m is as defined above, and X is in the position of R3 and denotes methylene, oxygen, sulfur or NR or d 1

R

5 and R 6 are as defined under and R3 and R together represent a chain W, W representing -CCH 2 with p= 3 or 4, in which one or two methyLene groups can be 9 3 replaced by oxygen or NR or W, together with the two carbon atoms carrying these groups, forms a fused-on benzo system, or d 2

R

3 is as defined under b) or and R is as defined under and R and R 5 together represent a chain W which is as defined above, or d 3

R

3 is as defined under b) or and R is as defined under and

R

5 and R 6 together represent a chain W which is as defined above, 7 8 el) R 7 and R are identical or different and represent hydrogen or methyl, or e2) R -R 5 are as defined under al), a2), c), dl) and/or d 2 a d R is as defined under cl), and

R

6 and R 7 together represent a methylene chain -CCH2]m-, in which m is as defined above, Sf) R denotes hydrogen, (C 1

-C

3 )-alkyl or (C 1 20 C4)-alkanoyl, S 010 g) R denotes (C 1

-C

5 )-aLkyl, (C5 or C 6 cycloalkyl, hydroxyl, (C1-C 4 )-alkoxy or -NR1R 12 11 12 h R and R are identical or different and denote 0.

25 hydrogen, (C 1

-C

4 )-alkyl, or phenyl which can be mono-, di- or trisubstituted with (C1-C 3 )-alkyl, (C1-C 4 )-alkoxy, trifluoromethyl and/or halogen, or 11 12 h 2 R and 12 together represent a methylene chain 30 -ECH23q- in which q is 4 or and a methylene group can be replaced by oxygen i) A represents sulfur sulfinyl (SO) or sulfonyl (S02), k) R 13 and R 14 are identical or different and have the meanings defined for R3-R 6 under preferably these meanings with the exception of hydrogen, or adjacent radicals R13 rill* a~ -i -4- 4 and R 14 are defined as R 3 and R under dl) L) R 1 denotes hydrogen, or (C 1

-C

4 )-alkyl, k 6Ort and to their physiologically tolerated salts.

a.

«o Preferred compounds of the formula I are those in which

R

1 denotes (C 1

-C

4 )-alkyl, preferably methyl or ethyl, in particular ethyl,

R

2

R

7

R

8

R

2

R

7 R and R each represent hydrogen, one, preferably all, of the radicals R 3

R

4

R

5 and R 6 represents/ represent hydrogen, or one or two of these radicals represents/represent (C 1

-C

4 )-alkyl, and R 13 and R are identical or different, are preferably located in the and 6-position of the benzimidazole system, and denote

(C

1

-C

4 )-alkoxy, preferably methoxy or ethoxy, in particular methoxy.

20 Compounds of the formula I in which A denotes sulfur or sulfinyl, prepferably sulfinyl are particularly preferred.

7 R 8 Furthermore, compounds of the formula I in which R R and R15 each denote hydrogen, one of the radicals R 25 R 4

R

5 and R 6 denotes hydrogen, and R 13 or R 14 represents hydrogen, are preferred, in particular compounds of the formula I in which

R

1 and R 2 *s a a.

are identical or different and denote hydrogen, (C1-C3)-alkyl, (C3-C6)-cycloalkyL, allyl, propargyl, phenyl or phenyl-(C 1

-C

3 )-alkyl, both of which can be monosubstituted as defined above, (C 1

-C

3 )-alkanoyl or (C 1

-C

4 )-alkoxycarbonyl, or together with the nitrogen atom carrying them, represent pyrrolidino, pyrrolino, piperidino, piperazino, 3-(C 1

-C

3 )-alkylpiperazino, morpholino or thiomorpholino, R and R 2

N

1 ilr-- .i I "L~Lll~n"i~wuer~~nl;._; I i -r 5 R3 R4 5

R

6 R R, R 5 and R 6 are identical or different and denote hydrogen, (C 1

-C

4 )-alkyl, (C 1

-C

4 alkoxy or (C 1

-C

4 )-alkoxycarbonyl, or two adjacent radicals form a chain W defined above under dl)-d 3

R

7 and R 8 each denote hydrogen,

R

13 and R 14 are identical or different and denote hydrogen,

(C

1

-C

4 )-alkoxy, (C 1

-C

4 )-alkyl or trifluoromethyl, and

R

15 represents hydrogen or (C 1

-C

4 )-alkyl.

Special attention may be drawn to compounds of the formula I in which R and R 2 are identical or different and denote hydrogen, methyl, ethyl or phenyl-(C 1

-C

3 )-alkyl, 3 4 5 6

R

3 R R 5 and R are identical or different and denote hydrogen, (CI-C 4 )-alkyl or methoxy, or R and R 5 together represent

-CH=CH-CH=CH-,

S 20 R and R each denote hydrogen, 13 and R 14 are identical or different and denote hydrogen, methoxy, ethoxy, methyl or trifluoromethyl, preferably methoxy, ethoxy, methyl or tryfluoromethyl, and 25 R 15 denotes hydrogen or methyl, preferably hydrogen, Sin particular 2-(2-methylaminobenzylsulfinyl)benzimidazole.

Any chiral carbon or sulfur atoms which are present may occur both in the R and in the S configuration. In such S 30 cases, compounds of the formula I exist in the form of the pure enantiomers or as a mixture of stereoisomers (such as a mixture of enantiomers and a mixture of diastereomers).

Suitable salts are, in particular, alkali metal and alkaline earth metal salts, and salts of inorganic or organic acids such as, for example, HCL, HBr, H 2 S0 4 methanesulfonic acid, amidosulfonic acid and p-toluenesulfonic acid.

hL"L-LI Y~ P iLS~ -X I I -i i Chl~~ 6 An acid- or base-labile amino protective group of the aniline nitrogen atom is understood to be the ILkylcarbamoyl radicals which have already been mentioned, as well as

CF

3 CO, trimethylsilylethoxycarbonyl, urethane protective groups such as Boc, Bpoc, MOC and Pyoc, phthaloyl (cf., for example, Kontakte Merck 3/79, pages 14 and 16-19; SchrSder, Lubke, The Peptides, Vol. I, New York, London 1965, pages 3-50).

Alkyl and radicals derived therefrom, such as alkoxy, alkylthio, alkanoyl etc., can be straight-chain or branched.

The invention also relates to a process for the preparation of a compound of the formula I, which comprises a) reaction of a compound of the formula II E13 S

R

13 14 in which R13, R14 and R 1 5 are as defined above, and 1 Q denotes i. a leaving group or 25 i i. -SH, -S or -SO 2 with a compound of the formula III 2 1 3 2 II) hR 3

R

R 4: R6 in which R1, R 2

R

3

R

4

R

5

R

6

R

7 and R 8 are as defined above, and Q2 denotes, in the abovementioned case -SH, or -SOy and, in the abovementioned case ii., a leaving group, YL i~LI~-trl -1 7 b) reaction of a compound of the formula IV R13 Y NH 2 (IV)

SNH

2 in which R13 and R14 are as defined above, with a compound of the formula V 2 1 NR2 R 1 N

R

7 R3 C-A-COrR 16

(V)

RR

in which R 1

R

2

R

3

R

4

R

5

R

6

R

7

R

8 and A are as 16 defined above, and R represents an esterifying group, or S 20 c) for the preparation of a compound of the formula I in *1 2} which R and R each denote hydrogen, reduction of a compound of the formula VI R13 2NO R 7 144 NI j Jv S2 7 NR8 N: 1 4 115 R

R

S 30 in which R 3

R

4

R

5

R

6

R

7

R

8

R

13

R

14 and R15 are <4 *1 as defined above, and A represents a sulfur atom, oxidation, in the compounds of the formula I which have been obtained according to b) or c) and in which A represents or and/or R 3 to R 6 and/or R 1 3 and

R

14 represent radicals containing or to the corresponding -SO- or -SO2- group, alkylation or acylation of a compound of the formula I in which R1 and/or R 2 represents hydrogen, subjection of a compound of the 8 formula I in which R and/or R represents acyL to r 4 ry!.iting hydrolysis or hydrogenolysis, and conversion of a compound of the formula I, thus obtained, where appropriate into its physiologically tolerated salt.

When, in accordance with process variant which is preferred here, compounds of the formula II are reacted with compounds of the formula III, then Q or Q represents a leaving group which can be detached nucleophilically, such as Cl, Br, I, -OSO 2

CH

3 -0-S0 2

CF

3 or -0-S0 2

C

6

H

4 pCH3.

The reaction of a compound of the formula II with a compound of the formula III or its salts takes place in an inert solvent such as, for example, water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methylene chloride, acetone, ethyl acetate, dimethylformamide, acetonitrile, dimethylacetamide, dimethyl sulfoxide, or mixtures of these solvents. The reaction can be carried 0***0e out in the presence or absence of an inorganic or organic base, it being possible to use sodium or potassium hydroxide, carbonate, alkoxide, hydride or amide, ammonia, triethylamine, tributylamine or pyridine. The reaction tem- Sperature is between -20 and +150 0 C, preferably at 0-80 0

C.

Compounds of the formula II are known from the literature or can be prepared in analogy to known processes, for example by ring closure of appropriately substituted ophenylenediamines with carbon disulfide (for example German 30 Patent A-3,132,167).

*o The o-phenylenediamines required for this purpose are likewise known from the literature and are obtained by, for example, catalytic reduction of appropriately substituted o-nitroanilines.

Compounds of the formula III are likewise known from the literature or can be prepared in analogy to known processes.

i-lrr~-~l I Y-iL ii 9 In the esters of the formula V, used in process variant b),

R

16 represents an esterifying group, preferably (C 1

-C

6 alkyl or benzyl. The transesterification of the compounds of the formula IV with compounds of the formula V is carried out in analogy to the procedures described in Preston et al., Benzimidazoles and Congeneric Tricyclic Compounds, Part 1, New York, pages 10-13.

Tin(II) salts such as SnCL 2 have proved to be particularly suitable reducing agents for compounds of the formula VI. The reduction is particularly preferably carried out in aqueous medium or in mixtures of an aqueous phase with polar organic solvents under strongly acid conditions, for example in concentrated hydrochloric acid between 0 and 100 0 C, preferably between 20 and 80°C. The working up and isolation of the substance is preferably .o carried out under alkaline conditions in a manner known per se from the literature.

20 The 2-(2-nitrobenzylthio)benzimidazole derivatives used as starting materials are obtained in accordance with procedure a) ii. in a manner known per se by reaction of a 2-mercaptobenzimidazole of the formula II with a 2- S S.

nitrobenzyl halide, preferably with a 2-nitrobenzyl chlor- 25 ide or bromide derivative of the formula VII (Hal CL or Br).

R* 3 2 R R8 Hal R 6

(VII)

The compounds of the formula I which are thus obtained and in which A represents can, where R denotes hydrogen, be converted into physiologically tolerated salts with bases.

Compounds of the formula I with A= can furthermore be converted into those with A= -SO- or -SO 2 with suitable oxidizing agents.

i I

I

I 'I 10 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 0 C to +1500C, preferably at -10 0 C to Examples of suitable oxidizing agents are: hydrogen peroxide, peracids and peresters such as peracetic acid, trifluoroperacetic acid, monoperphthalic acid, m-chloroperbenzoic acid and its esters, ozone, dinitrogen tetroxide, iodosobenzene, N-chlorosuccinimide, 1-chlorobenzotriazole, sodium hypochlorite, potassium peroxodisulfate, t-butyl hypochlorite, tetrabutylammonium periodate or permanganate, sodium metaperiodate, selenium dioxide or manganese dioxide, ceric ammonium nitrate, chromic acid, chlorine, bromine, diazabicycloE2.2.2]octane-bromine complex, dioxane dibromide and pyridinium perbromide.

20 It is likewise possible to use isolated, where appropriate immobilized, oxidizing enzymes or microorganisms as oxidizing agents.

For oxidation to A= -SO- the oxidizing agents are used in 25 equimolar amounts, and where appropriate in a slight excess of 5-10 mol-%, or when oxidation to A= -S02- is desired they are used in greater excess and/or at a higher reaction temperature.

30 Compounds according to the invention which may be mentioned, S without restricting the invention to these, are: 11

H

7 1

R

8 R15 H A =S 3 N

/R

0e 9*e

S.

S

9** 9 9 S

S*

S 9 9* S 59 9 9 55 5 9 *5 *5 9 9* 95 Me Me Me Me Me Me Me Me Me Me Me Me Me Me

H

Me Me Me

H

Me Me

H

Me Me

H

Me

H

R

3

H

Me Me Me

H

Et Et

H

cl Cl Cl Cl

H

Me Me Me Me Me He

H

Et

H

Cl cl Cl

H

R 6

H

Me Me Me

H

Cl Cl R1 3

H

OMe o Et OMe

H

OMe OEt

H

OMe OEt OMe

H

OMe

H

OMe OEt

H

OEt

H

OMe

H

R

1 4

H

OMe

H

OMe

H

14

H

25 H' R 8 ,Rl 5

H

12

H

A wS Ri R2 j3 R 4 5 R6 R13 R 14 a 0 90

H

Me Me Me Me Me

H

Me Me

H

Me

H

Me Me Me

H

Me Me Me Me

H

Me Me Me Me Me

H

Me Me

H

Me .Me

H

Me

H

Br Br Br

H

OMe OMe OMe

H

OEt OEt OEt

H

F

H

Br

H

OMe OMe

H

OEt

H

F

H

COOEt COQEt COQEt

H

Br Br

H

OMe OMe OMe

H

OEt CEt OEt

H

F

H

OMe

H

F

H

QEt

H

OEt

H

CEt

H

OEt H1

H

OEt

H

QEt

H

OEt

H

OEt

H

H CODEt H COQEt H COOEt

SO

2 Me H

SO

2 Me H H SO2Me

V

13 7J;RsR 15m H A- S *t* 094

R'

3

H

Me Me Me Me Me

H

Me Me Me cl Cl Cl Cl Cl Cl

H

Br Br Cl Cl Cl OMe OMe

H

R

5

SO

2 Me S0 2 Me

SO

2 Me Me Me Me

H

Me Me Me Cl.

Cl Cl

H

Cl Cl Cl

H

Cl Cl Cl Cl Br Br OMe OMe OMe Cl Cl OMe OMe OMe OMe R1 3

H

OEt OEt

H

OEt

H

OEt

H

QEt

H

OEt

H

1 4

H

I 14 R'B, R5= H A S 4 0io r '.0 43 *I O 6 .1 3 0 i 0*L *1 3

R

1 Ri Me

H

Me

H

Me

H

Me

H

Me

H

Me Me Me Me Me Me Me Me Me

H

Me Me Me Me Me

H

Me Me

H

Me Me Me Me Me

R

H

R

3

H

Cl Cl Br Br Me Me

H

Cl Br Me Me

H

Et

H

Cl Cl

H

Br

H

R4

H

Me Me

H

Me

H

Et

H

Cl

H

Br

H

I

R5 OMe DEt OEt OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe CEt OMe OMe

H

Me Me

H

Et

H

Cl cl

H

K

H

Br

R

6 Cl

H

Me Me Me Me Cl

H

Me

H

Cl

H

R13 CEt

H

OEt OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe R14

H

OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe Me H OMe H H H OMe OMe -IL i 15

S

R 2. R3

R

5 6 1 3 1

H

cl Br Me Me

H

Me OMe OMe CEt O~e O~e *1 6@ eve 6O* Cl,.

'C

9 0

*OBO

t 0 see.

hi he Ph

C

Et H Et H t Et H .t H Et H st H H Et H H .Et H H H H cl H H c 1 O~e O~e OMe O~e OMe O~e O~e O~e O~e O~e O~e O~e Ome O~e O~e OMe CMe O~e OMe O~e Ome O~e O~e O~e CMe O~e O~e O~e O~e O~e O~e CMe Ome

ON.

O~e O~e OMe CM e Ome CMe ON e

ON.

CM.

O~e O~e

ON.

Ome Et Et Et Bt Et Et

H

Br

H

DM.

a.

0* C C 1 @0 It 0£ C

C

Ce

H

P

H

CODEt

ON.

DEt

H

ome

ON.

O~e

ON.

Oke

OM.

Ome H CODEt Ha CDt H Ome ON.

I .I 16 Rl R 2 R3 R R 6 ,13 1 st st H Et H Et H Et H Et H Et H H So 2 Me H H OMe ome H H SP 2 Me H D~e OMe Me H Me H O~e O~e Me Me H H O~e OMe H Me Mie H O~e O~e Me H Cl H Ome O~e Cl Cl H H O~e Ome

S

S.

S

S.

5* A mSO

R

2

R

3 R4 R -y 6 .R1 3 HI14 Et Et Et Et Et Et Et Et Et H COOzt H H H H CODEt H H SO 2 M H H H H SO 2 IeH Me H Me H Me Me H H H Me Me H Me H. Cl H Cl cl H H O~e O~e O~e O~e O~e O~e O~e O~e O~e ome O~e O~e O~e O~e O~e O~e O~e O~e

S.

S. S I 17 R 7RctR!= H Fl 1

R

2 R3 R 5 R 6

R

1 3 R1 Me H H OMe H H OMe OMe H H H H OMe H OMe OMe Me H H H OMe H OMe OMe Me H H H OEt H OMe OMe Me H F H H H OMe OMe ME H H F H H OMe OMe Me H H H F H OMe OMe Me H H H H F OMe OMe Me H H CODEt H H OMe OMe Me H H H COQEt H OMe OMe Me H H SO 2 Me H H O~e OMe Me H H H SO 2 Me H OMe OMe Me H Me H Me H OMe OMe Me H Me Me H H OMe OMe Me H H Me Me H OMe OMe oo9Me H Me H Cl H OMe OMe ME H cl c1 H H OMe OMe H H Cl H Cl H OMe OMe MeH0*H**H O~ Et H Cl H Cl H OMe OMe Et H Cl H Cle H OMe OMe H H Cl H OMe H OMe OMe *H H Hl G OMe H OMe OMe H H H Hl OMe Hl OMe OMe H H Hl H O~E CH OMe OMe H H Br H ~Et H OMe OMe Me H BH He Me He OMe OMe 0Me H H Me Me He H H H H OMe Me Me OMe OME Me H H Me OMe Me H H Me H H Me OMe Me OMe 0Me He H H Me OMe Me H H He H H Me OMe Me OMe OMe Me H H Me OMe Me H~ H f I 'II 18

R

7 A= S

R

1 R 2

R

3 R4 5 R 6

R

13 R14 Me Me Me Me Me

H

H H H H H H H H H H

-(OH

2 2

-CCH

2 2

-(OH

2 3

(OH

2 3

(CH

2 3-

-(OH

2 3 Cl Cl Me Me Cl

H

OMe OMe Cl Cl Me

H

OMe OH e

H

Me OMe :0e 0 .0 0 es 0 0 0 .00.

Ph H Ph H

(OH

2 4

-(OH

2 4 H H Me H Me H H H Me H Me H All H All H All H All H All H All H cPent H c~ent H cPent H

H

OMe

H

OMe

H

OEt OMe

H

OEt OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OEt

H

OEt

H

OMe

H

OMe

H

OM e

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe OMe

H

CEt

H

QEt

H

-(OH

2 4

H

-(CH2)4- H -(CH2)4- H H

-(OH

2 4 H

-(CH

2 4 H (Hir H H H H H H Me H H Me H 11 H H H H H H H H H H H H Me H L -7 -L I 'mm I I I I 19 R7,R 8 ,R15= H

R

1 R 2

R

3

R

H5 6 R1 3 1 0 0

S

0S*S

S..

S.

*5 *5 0 5 S. S S S *5

H

Me Me Me Me Me Me Me Me Me Me Me

H

Me Me

H

Me Me Me

H

Me Me Me

H

Me Me

H

Me Me

H

Me

H

Me Me Me

H

Et Et

H

Cl Cl Cl Cl

H

Me Me Me Me Me

H

Et

H

Cl Cl Cl

H

OMe OEt OMe

H

OMe OEt

H

OMe QEt OMe

H

OMe

H

OMe QEt

H

OEt

H

OMe

H

OMe

H

OMe

H

33 is evaporated in a rotary evaporator, and the residue is stirred with a little acetone, filtered off with

WEEWSOMMUNW,

20 R .7,8 A SO R2 R R4 R 5 R 6 R1 R 1 4 0 00 0 000 000000 00*0 00 0 0 .00.

00 00 Br Br Br

H

O~le OMe OMe

H

QEt OEt OEt

H

F

H

Br

H

OMe OMe

H

OEt

H

F

H

COQEt COQEt COQEt

H

Br Br

H

OMe OMe OMe

H

OEt QEt OEt

H

F

H

OMe

H

F

H

QEt

H

OEt

H

QEt

H

DEt

H

QEt

H

QEt

H

H~

H

OEt

H

00 00 H COOEt H COQEt H COOEt

SO

2 Me

H

SO

2 Me H H SO2Me

K

I v 21

R

7 ,R 8 R15=. H A -SO R R2 3 4 R5 R 6 R1 R 14 Me H H H SO 2 Me H H H Me H H H so 2 Me H QEt H H H H H S0 2 Me H QEt H H H Me H Me H H H Me H Me H Me H H H Me H Me H Me H GEt H Me H Me Me H H H H Me H Me H H Me H H Me H H Me Me H H H H H H H Me Me H H Me H H H Me Me H H H H Me H cl H H H Me H Me H Cl H H H Me H Me H Cl H OEt H H H Cl Cl If H H H :1 Me H Cl Cl H H H H H H Cl H Cl H H H Me H Cl H Cl H H H Me H Cl H Cl H QEt H Me H Cl H H cl H H H H H Cl Cl H H H *Me H H Cl Cl H H H Me H H H Cl Cl H H H H H H Cl Cl H H H H Br H Br H H H Me H Br H Br H H H *H H Cl H OMe H H H Me H Cl H OMe H H H Me H Cl H OMe H OEt H H H OMe H Cl H H H Me H OMe H Cl H H H H H H cl OMe H H H Me H H Cl OMe H H H H H H H OMe Cl H H Me H H H OMe Cl H H

R

7

,R

8 5 Rl5. H A SO 22 H~l R2 R H 5 R 6

R

13 R 1 4 00 Me

H

Me

H

Me

H

Me

H

Me

H

Me Me Me Me Me Me Me Me Me

H

Me Me Me Me Me

H

Me Me

H

Me Me Me Me Me Me HH H OMe QEt H H Cl H QEt H H H H Cl H OEt H H H H Br H OMe H H H H Br H OMe H H H H Me H OMe H H H H Me H OMe H H H H H Me OMe H H H H H Me OMe H H H H H H OMe Me H H H H H OMe Me H H H H H OMe Me OEt H H H H OMe Me OMe OMe H H H OMe Cl OMe OMe H Cl H OEt H OMe OMe H Br H OMe H 0Me OMe H Me H OMe H OMe OMe H Me H H H OMe OMe H H Me H H OMe OMe H H H Me OMe OMe H H H Me H OMe OMe H Et H H H OMe OMe H H Et H H OMe OMe H H H Et H OMe OMe H H H H Me OMe OMe H Cl H H H OMe OMe H Cl H H H OMe OMe H H Cl H H OMe OMe H H H Cl H OMe OMe H H H Cl H OMe OMe H H H H Cl OMe ome H Br H H H OMe OMe H H Br H H OMe OMe H H H Br H OMe OMe H OMe H H H OMe OMe 36 23 7H A mSO Ft 1 R2 13 t4 5 T6 R3 IM 1 .CMe OMe DEt OMe OMe Et Et Et Et Et Et Et 0 00 Et

H

OMe CM e OMe DMe OMe O~e O~e O~e ON e O~e CM e OMe O~e O~e DMe Ome O~e DMe OMe O~e O~e OMe O~e Ome O~e O~e O~e O~e O~e O~e CM e O~e O~e Ome CMe O~e O~e CM e CMe Cm a Cl H H H cl H H H H M Hr H H H Bre H H H H O~e H H H Ome H H O~e ovZ Et 0 Mt Et Et

H

O~e oEt

H

Ome Ome O~e Ome ON e O~e 'Ome O~e O~e O~e O~e O~e 37 -24- R7,R 8 ,R15. H A 2 Rl 4 R R 6 13 R 1 4 Me H H OMe H H OMe OMe HH H H OMe H OMe OMe Me H H H OMe H OMe OMe Me H H H OEt H OMe OMe Me H F H H H OMe OMe ME H H F H H OMe OMe Me H H H F H OMe OMe Me H H H H F OMe OMe Me H H CQOEt H H OMe OMe Me H H H COQEt H OMe OMe Me H H SO 2 Me H H OMe OMe Me H H H SO 2 Me H OMe OMe Me H Me H Me H OMe OMe Me H.e Me HH* Me H Me Me He H OMe OMe Me H Me Mec H OMe OMe ME H Me Hl H H OMe OMe Me H C 1 l H H OMe OMe E c1H...H Oe A H Cl H Cle H OMe OMe Me H cl H a Cl H OMe OMe EtH H Hl Hl Cl H O~e OMe H H Hl H OMe H O~e O~e H H*9H Ot H H Br H OMe H OMe OMe He H H Me Me He OMe O~e 0. HM H H H~ OMe Me OH H~ *pp H H H He OE He OH OH H H Br He Oe He O~e O~e Me H H Me OMe He H H Me H H Me OMe Me OMe O~e He H H Me OMe Me H~ H I I 25

R

7 1

R

8 R15. H tA= SO a.

a a *o a 9 99e 00 a n a *9C a V *9 9 0 a R 1 R 2 Me H Me H Me H Me H Me H I H -(CH2)i- F (CH2)r_ H

-(CH

2 a

-(OH

2 2 H

-(CH

2 3 H -(CH2)3 H

-(CH

2 3 H

-(CH

2 3 Ph H I Ph H I

-(OH

2 4

I

(CH2) 4- -(CH2)4- I -(CH2)I- I H H I Me H I Me H I H H I Me H I Me H I All H I All H I All H I All H I All H All H cPent H I cPent H I cPent H I

I

4 R 6 Cl OMe Cl Cl OMe Cl Me c1 Me Me Cl Me Cl Me Cl H H H H H H H H H H II H H H H H H H H OMe H H OMe H H H H H H H H H H H H H H Me H H OMe H

H

-(CH

2

H

-(CH2)f- H H -(CH2)9-- H (CH2) 4- H -(CH2)41- H H H H Me H H Me H H Hi H H H H H H H H H H H Me H R13

H

OMe

H

OMe

H

QEt OMe

H

OEt OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OEt

H

OEt

H

R14

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OEt

H

QEt

H

a 4 u a a a.

*9 9 a a a.

i. I-I 39 26 Abbreviations: Me Methyl Et Ethyl Ph Phenyl ALL Allyl cPent Cyclopentyl The new compounds of the formula I and their salts have valuable pharmacological properties.

They markedly inhibit gastric acid secretion and, furthermore, exhibit an excellent gastrointestinal protective action.

"Gastrointestinal protection" in this connection is understood to be the prevention and treatment of gastrointestinal disorders, in particular inflammatory gastrointestinal 20 disorders and lesions (such as, for example, gastric ulcer, duodenal ulcer, gastritis, hyperacid or drug-related irritable stomach), which may be caused by, for example, microorganisms, bacterial toxins, drugs (for example antiinflammatory and antirheumatic agents), chemicals (for example ethanol), gastric acid or stress situations.

I

Because of their excellent properties, the compounds of the formula I and their pharmacologically tolerated salts are as outstandingly suitable for use in human and veterinary medicine, being used, in particular, for the treatment and prophylaxis of gastrointestinal disorders and those disorders based on excessive gastric acid secretion.

S Thus the invention also relates to the compounds of the formula I, according to the invention, for use for the treatment and prophylaxis of the abovementioned disorders.

Likewise, the invention embraces the use of the compounds I 40 -27according to the invention for the preparation of medicaments which are used for the treatment and prophylaxis of the abovementioned disorders.

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

The medicaments are prepared by processes which are known per se and are familiar to those skilled in the art. The pharmacologically effective 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 content of active compound advantageously being between 0.1 and 96%.

f t The particular auxiliaries suitable for the desired medica- S 20 ment formulation are familiar to those skilled in the art on the basis of their knowledge. Apart from solvents, gelforming agents, suppository bases, tabletting auxiliaries and other vehicles for active compounds, it is possible to use, for example, antioxidants, dispersing agents, emulsifiers, defoaming agents, flavor corrigents, preservatives, solubilizers or colorants.

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

In general, it has proved advantageous in human medicine to administer the active compound or compounds in a daily dose on oral administration from about 0.01 to about 20 mg/ kg of body weight, where appropriate in the form of several, preferably 1 to 4, individual administrations, to achieve the desired result. It is possible on parenteral treatment for similar or (especially on intravenous administration of the active compounds) as a rule lower doses to be .1 1 1 x! 28 used. The establishment of the optimal dosage and mode of administration of the active compounds which are necessary in each case can easily be carried out by all those skilled in the art on the basis of their expert knowledge.

o OO .c o o•°9 9 9 9 o• 9.

9 If the compounds according to the invention and/or their salts are to be used for the treatment of the abovementioned disorders, it is possible for the pharmaceutical formulations also to contain one or more pharmacologically active constituents of other medicament groups, such as antacids, for example aluminum hydroxide and magnesium aluminate; tranquilizers such as benzodiazepines, for example diazepam; spasmolytics such as, for example, bietamiverine and camylofin; anticholinergics such as, for example, oxyphencylimine and phencarbamide; local anesthetics such as, for example, tetracaine .and procaine; and, where appropriate, enzymes, vitamins or amino acids.

For an oral administration form, the active compounds are mixed with the additives customary for this purpose, such as vehicles, stabilizers or inert diluents, and are converted by customary methods into suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, 25 alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. This can entail the formulation being carried out either as dry or moist granules. Examples of suitable oily vehicles or solvents are vegetable and animal oils, such as sunflower oil or fish liver oil.

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

9a 42 w sl i- I ~u*r -Y I- IUIIIII 29 Examples of suitable solvents for the new active compounds and the corresponding physiologically tolerated salts are: water, physiological saline solutions or alcohols, for example ethanol, propanol or glycerol, as well as sugar solutions, such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

The examples which follow are intended to illustrate the procedures according to the invention without restricting the invention to the substances mentioned here as representative.

Example 1: 2-(2-Aminobenzylthio)benzimidazole dihydrobromide g (0.1 mole) of 2-mercaptobenzimidazole are dissolved in 200 ml of anhydrous tetrahydrofuran, with magnetic stirring, and 29.4 g (0.11 mole) of 2-aminobenzyl bromide hydrobromide (from 2-aminobenzyl alcohol and 63% strength 20 aqueous hydrobromic acid, melting point 300 0 C) are added Sin portions. The mixture is stirred at room temperature for 1 hour and at 60-650C for 4 hours, then cooled to room temperature, and the precipitate is filtered off and the solid is washed several timf(s with tetrahydrofuran.

25 Colorless crystals, melting point 242 244 0 C (decomposition).

o Example 2: 2-(2-Trifluoroacetylaminobenzylthio)benzimidazole hydrobromide 1.4 g (0.005 mole) of 2 -trifluoroacetylaminobenzyl bromide (from 2-trifluoroacetylaminotoluene and N-bromosuccinimide in carbon tetrachloride in the presence of azobisisobutyronitrile under reflux, melting point 97-102°C) in 15 ml of ethanol are heated at 60°C with 0.75 g (0.05 mole) of 2mercaptobenzimidazole for 6 hours, the solvent is removed by distillation, and the residue is induced to crystallize i i ili 30 in a mixture of ethyl acetate and a Little acetone.

Colorless crystals, melting point 184 186 0

C.

Example 3: 2-(2-Aminobenzylthio)benzimidazole a) 13.4 g of 2-(2-aminobenzylthio)benzimidazole dihydrobromide are dissolved in 800 ml of hot methanol, and the mixture is filtered and 15 ml of triethylamine are added at room temperature. After addition of 400 ml of water, the mixture is stirred for 15 minutes at 0-10 0 C, and the precipitate is filtered off and washed with water.

Colorless crystals, melting point a) 144-1480C followed by crystallization b) 260-2620C (decomposition with development of red color) e*e* 20 b) 2.5 g of 2-(2-trifluoroacetylaminobenzylthio)benzimidazole hydrobromide are heated on a steam bath with a mixture of 70 ml of methanol, 30 ml of aqueous ammonia strength) and 30 ml of water until dissolution is complete. The solution is then stirred at room tempera- 25 ture for 2 hours, and most of the methanol is distilled *o out under waterpump vacuum, and the crystals are filtered off and washed with water.

Colorless crystals, melting point: identical to the figures indicated under a) (above).

S Example 4: 2-(2-Aminobenzylsulfinyl)benzimidazole 4.1 g of m-chloroperbenzoic acid are added in portions to 5.1 g of 2-(2-aminobenzylthio)benzimidazole in 300 ml of methylene chloride, with magnetic stirring at 0 to and then the mixture is stirred at 0-5 0 C for one hour and I -Y~ 31 at room temperature for a further hour. The crystalline precipitate is filtered off, washed with methylene chloride and dried in air, and then the product is suspended in a mixture of 200 ml of water and 50 ml of saturated aqueous sodium bicarbonate solution, and the mixture is stirred at room temperature for 1 hour, and the compound is filtered off and thoroughly washed with water.

Colorless crystals, melting point 175 176 0 C (decomposition) from acetonitrile.

Example 2-(2-Aminobenzylthio)benzimidazole a) 2-Phthalimidobenzyl bromide 60 g (0.25 mole) of 2-phthalimidotoluene, 45 g of Nbromosuccinimide (0.25 mole) and 0.3 g of azobisisobutyronitrile are suspended in 600 ml of CCL 4 and the mixture is heated to reflux for 2 hours. Then the precipitated succinimide is filtered off with suction at S 20 the boiling point, and the solvent is removed in a rotary evaporator. The crude benzyl bromide 80 g) is evaporated once more with toluene in a rotary evaporator, and is used without further purification in the next step.

b) 2-(2-Phthalimidobenzylthio)benzimidazole 40 g of 2-mercaptobenzimidazole are dissolved in 300 ml of DMF at room temperature, and 11 g of NaH are g added. After evolution of gas has ceased, the abovementioned crude benzimidazole 80 g) is added, and the S. reaction solution is stirred at 50 0 C for 30 min. The solution is then evaporated, water is added to the residue, and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried with Na 2

SO

4 and evaporated in a rotary evaporator. The oily residue is purified by filtration through a silica gel column using ether as mobile phase.

Melting point: 174 175 0

C.

c 32 c) 2 2 -Aminobenzylthio)benzimidazole 0.1 mole of phthalimido compound and 0.1 mole of hydrazine hydrate are stirred in 200 ml of ethanol at room temperature for one hour. The precipitated hydrazide is decomposed in an emulsion of 2N NaOH and methylene chloride, the amine which is formed going into the organic phase. This phase is separated off, washed with water, dried (Na 2

SO

4 and evaporated in a rotary evaporator. The oily residue is induced to crystallize by stirring with diisopropyl ether. The compound thus obtained is identical to the compound prepared in Example 3.

Example 6: 2-(2-Ethylaminobenzylsulfinyl)-5,6-dimethoxybenzimidazole a) 2-(2-Ethylaminobenzylthio)-5,6-dimethoxybenzimidazole 10.5 g of 5,6-dimethoxy-2-mercaptobenzimidazole are suspended in 250 ml of THF, and 15 g of 2-ethylaminobenzyl bromide hydrobromide are added in portions.

The mixture is stirred at room temperature for 6 hours, and then the precipitate is filtered off with suction, washed with THF and petroleum ether and dried under reduced pressure at about 80 0

C.

The resulting hydrobromide is introduced into 400 ml of 1% strength aqueous sodium hydroxide solution, and the mixture is then stirred at room temperature for 2 hours. The free base is filtered off with suction, washed with water and dried. Melting point 162°C I- (decomposition).

b) 2-(2-Ethylaminobenzylsulfinyl)-5,6-dimethoxybenzimidazole g of 85% m-chloroperbenzoic acid, dissolved in ml of methylene chloride, are added dropwise at room temperature, within 10 minutes, to 3.4 g of 2-(2ethylaminobenzylthio)-5,6-dimethoxybenzimidazole in 100 ml of methylene chloride, with stirring. The mixture is then stirred for 20 minutes, excess two-normal aqueous ammonia solution is added, and the organic phase is separated off. After drying over sodium sulfate, it -46- 33 is evaporated in a rotary evaporator, and the residue is stirred with a little acetone, filtered off with suction, recrystallized from acetone and dried.

MeLting point 168 0 C (decomposition).

Example 7: 2-(2-Amino-4,6-dimethyLbenzyLsuLf inyL )-5,6-dimethoxybenzimidazole sodium salt a) 2-(2-Amino-4,6-dimethylbenzylthio)-5,6-dimethoxybenzi m i d'azoLe 1.4 mL of thionyl chloride are added dropwise at -10 0

C,

to 2.3 g of 2-amino-4,6-dimethyLbenzy alcohol in 50 mL of anhydrous tetrahydrofuran. The mixture is stirred with exclusion of atmospheric moisture at -10 0 C, for a further 15 minutes, and the cold suspension is added dropwise to a solution of 3.1 g of 2-mercapto-5,6-dimethoxybenzimidazole in 40 mL of 2N sodium hydroxide solution and 50 mL of ethanol. After addition is com- 20 plete, the mixture is stirred at room temperature for a further 30 minutes, and then the solvent is removed by distillation in vacuo. Water is added to the resi- **due, and the solid is filtered off and taken up in 200 mL of methylene chloride. The slight precipitate 25 of unreacted 2-mercapto-5,6-dimethoxybenzimidazoe is filtered off and, after concentration of the filtrate, the crude 2-(2-amino-4,6-dimethyLbenzyLthio)-5,6-dimethoxybenzimidazole is isolated. The crude product thus obtained is, because of its instability, reacted further as rapidly as possible and without any further purification operation.

b) 2-(2-Amino-4,6-dimethyLbenzyLsufinyL)--5,6-dimethoxybenzimidazoLe sodium salt The crude product obtained in a) is dissolved in 50 mL of methylene chloride, and 40 mL of 0.5 N aqueous sodium bicarbonate solution are added. Then, at OoC, a solution of 1.6 g of 3-chLoroperbenzoic acid in 25 mL _L r-I 34 of methylene chloride is added dropwise to the stirred two-phase mixture and, after 30 minutes, the crystalline precipitate is filtered off, and the product is washed with diisopropyl ether. Colorless crystalline substance.

Melting point 165°C (decomposition).

Example 8: General procedure for the preparation of the free benzoimidazole derivatives from the benzimidazole sodium salts A mixture of equal parts of tetrahydrofuran and saturated NaHCO 3 solution is suitable for converting the sodium salts into the free sulfinyiLenzimidazoles of the general formula I. The organic phase is concentrated, and the crystalline product is washed with diisopropyl ether.

Example 9: 2-(Aminobenzylthio)benzimidazole S5.7 g of 2-(2-nitrobenzyl hio)benzimidazole are added to a stirred solution of 10.2 g of tin(II) chloride hydrate (SnCI 2 x 2H 2 0) in 50 ml of concentrated hydrochloric acid at room temperature. The reaction mixture is then stirred 25 at 60 0 C for 1 hour and, after cooling to room temperao ture, a solution of 35 g of sodium hydroxide in 500 ml of water is added. After extraction with methylene chloride, the organic phase is dried over sodium sulfate, and the solvent is removed by distillation under reduced pressure. Colorless crystals after column chromatography on silica gel using a mixture of methylene chloride and diethyl ether as mobile phase.

Melting point 149 0

C.

Eample 2 -(5-Trimethylsilylethoxycarbonylamino-1,2,3,4-tetrahydro- 6-naphthylmethylthio)benzimidazole The reaction mixture of 2.02 g of L- 4 35 methylsilylethoxycarbonylamino-1,2,3,4-tetrahydronaphthalene, 0.96 of 2-mercaptobenzimidazole, 1.7 g of triphenyiphosphine and 1.01 mL of diethyl azodicarboxylate is dissolved in 25 ml of anhydrous and degassed ttrahydrofuran, and the solution is stirred at room temperature under protective gas for 7 hours. The solvent is removed by distillation under reduced pressure, the residue is taken up in a mixture of cyclohexane and ethyl acetate the crystals of the hydrazodicarboxylic ester are filtered off, and the solvent is again completely removed by distillation. The product which is thus obtained is then purified by column chromatography using cyclohexane/ ethyl acetate as mobile phase on silica gel.

Colorless crystals, melting point 1650C.

Example 11: 2-(5-Trimethysiylethoxycarbonyamino-1,2,3,4-tetrahydro-6-naphthyLmethysufiny)benzimidazoLe The title compound is obtained in analogy to the procedure described in Example 4 from the compound of Example by oxidation with 3-chloroperbenzoic acid.

Colorless crystals, melting point 140-143 0

C.

25 Example 12: 2-(5-Amino-1,2,3,4-tetrahydro-6-naphthymethyLsuLfinyL)benzimidazole 453 mg of the compound of Example 11 are stirred with 1.04 g of tetrabutyammonium fluoride trihydrate in 20 mL S of acetonitrile under inert gas (nitrogen) at 450 for hours. The mixture is poured into ice-water, and the crystals which have separated out are filtered off and dried in a stream of air.

Colorless crystals, melting point 137 0 C (decomposition).

The following compounds of the formula I are prepared in an analogous procedure: "k -Allj

I_

C

SO S S 0 0 S S S S :0 to* .0 S S 5 5 5 S S S S S S t Table Ex-

RI

enple

N

2 3 R2 R3 R' F5 R' R R A '-o'oA 11

R

Melting point 0

C)

L 13 H H H H H H H H S

H

300 14 H H H H H H H H a) r'-/u If ff,3 295-297 H H H H H H Hi H 3 285 (decomp.) 16 H H H H H H H H so yi~r 122-130 (decomp.) 17 H H CH, H H H H H S

H

1. 124-125 2. 210 (decomp.) 18 H H C3

H

H H H H so 14I0-141 i i rl C C S S S S C S *0 S S S C S S S S S R *55 R C) S S R Table Continuation ample Ri

R

3

R

1 F~ R6 19 H C H 5 H H H H H H s 20-20 x 218r (decomp.) H C 2

H

5 H H H H H H s 280-290 21 H CAH H H H H H H so 230 (decornp. 22 H H HI H C"3 H H H S 2541 (decomp. v 2$f8r 23 H H H H C 3 H H H 3 1. 98-103 2. 250 .4 H H H H CH 3 H H H s 1841'(decomp.) I-0 0 *0 0 0 0 00 0 0 0 *D 0 0 *0 a .oo a a..

000 0 0 R13 Melting point R

C)

R

Table njtiwn.ation Example R 2 0 RI RH T6 A 7 -217-220- 2 5 C"3

CH

H H H H H H 21T-220 KI 2lr (decomp.)

H(

26 CH3 CH3 H H H H H 177-179 cr 27 CH3 CH3 H H H H H H SO 96-100 28 Clt H H H H H H H S 215 (decomp.) k~I~ 211r Hc 29 CH3 H H H H H H H S above 225 y~;F1 C3~ H H H H H H so0 139-11 a i a a a a.

a aa a) *aa a. a a a. a a

I

Table Continuation R 1 3

I

R

Example

R

2 R R 5 6H R 7

R

8 Melting point 0C) 31 H H H H H H H S 3-6C5 ;V 211IRr -5 2g 205 (decomp.) 32 H H H H H H H s above 240 (C2) 3 6

H

5

H

3 H H H H H H H 3 126-130 34 ~L H H H H H H H S 32-21Q

I

H H H H H H H H s A .2111gr (decomp.) 250-260 ~f~xZ~Br(decomp.)

H

36 H H H -CIPCH-CH=CH-H H H s

~I

iL_ ft..

ft ft ft.. 3*ft *9 ft ft ft ft.

ft ft ft ft* ft ft ft ft.

ft ft 3* ft ft 94.

ft .ft ft ft ft 0ft ft ft ft ft ftft ft ft ft ft .ftt ft ft ft ft ft. ft ft.. ft Table Continuation R13 Melting point A 11~ 5 R(

C

Ex- 1 R3g HT 8 37 H1 H H -CW-CH-CH-CH- H H H s 220-232 36 H H H -CHCH=C2H01- H H H so 215 (decomp.) 39 H H H HI 001311 H H 104 H H H H n H H H so 182 (decomp.) 41 H H H H H *H H s 9.' 150 (decomp.) 42 H H H H H H H H s 163 (decomp.) C a p p C a p 0 s*P p p 0c C 69 p a be p pa S P a p a. eta p p~e C* C P a P C 6* 4 p *c a S U as 4 a C 6 Table Continuat ion "A I R "elting point Ex- 1 ample R 43 H H H H H H H H ST 115 (decomp.) 44 H H H H H H H H SO 179 (decomp. H H H H H H H H s 120 (decomp. W cs n

OCAS

46. H H H H H H H H so 155 (decomp.) 47 H H H H H H H H SO;'C 158 (decomp.) H4 48 H H H H II H H H Il T1 1 a a. a 1 5**r OS 0 ar A. as R a 4 .4 .2 a r 0 Table Continuation Ex-

I

R2 R3 R R5 R6 R 7 R8 Melting point 19 (0 C) I 49 H H H H H H H H above I r 50 H H H H H H H H1 9 125 (decop.) 51 H H H H H H H H 3 Oil 52 H H H H H H H H so -d 120 (decomp.) .53 H H H H H H H H S Oil 54 H H H H H H H H -1 4ot Q-r 12T (decomp.) rC- I- i- 6 0 0 000 91 6 6~r 0 O 6 1 ia 4 4 0 690 *r 466 0 Table Continuation Example

R

1

R

2

R

3 R F R H 7 11 A Melting point 0

C)

226 (decomp.) C 2

H

5 C 2

H

5 H H CH 3 H H H S Hx Q H x2HRBr 56

C

2

H

5 C 2

H

5 H H CH3 H H H S OCH3 H OCH 3 11-113 (decomp.) 57

C

2

H

5 C 2

H

5 H H

CH

3 H H H S4 Q

H

152-153 (decomp.) 58

C

2 H

C

2

H

5 H H CH3 H H

HOCH

H SO CH 3 above 130 decomp.

59 CPS1 C 2

H

5 H H

CH

3 H H H SO

H

above 118 decomp.

H H H H C 3 H H H SU 227 3 1

P

U

U.

U

U U

U

o a 0* U Table Continuation ExampleR 4l 3

N

R R R T R A 115

R

Melting point 0C) 61 H H H H CH3 H H H SOYOCH 62 H H CH 3 H H H H H s Oj 3 276 63 H H CH 3 H H H H H so 4 C 177 H~a OCH 3 64 H H H H H H H S H 3 120 (decomp.) H H H H H CH3 H H so :a CH3 156 H

OCH

66 C 2

H

5 H Cu 3 H H H H H S 3 88

HI<

r. t

;I

C

**C

C C 0C 06: *0 :1 0 1.

C. C 0 *CC C 0 e *C Table Continuation Example R 2 3 R4 Tn 5 6 R R A Melting point 0

C)

I- 'I 67 C 2

H

5

H

OCH3 H H H H H so 3 (decomp.) 68 -CH 2 74- H H H H H H S .N 1 J:0 'j3 162 OCH 1 69 C 2

H

5

C

2

H

5 H H H H H H S yj( 3 113 H MN OCH3

C

2 HS H H H H CH 3 H H S y0 OC 3 276 1 1 -K7 3 r- 71 CA!!

C

2 .H H H H3 H SO N OcH3 97 3 N Z H3136 N3 (decomp.) (decomp.) 72

C

2 5 H H H H

CH

3 H SO N 11- 0000136-- Table Continuation S S S CS C C C S C CC C CCC CC S CS C C C 5 5 *SC S S S 5 C C R13 I. Melting point H-5 RI 17 ;"AN A (0OC

R

Ex- 1 2 ample H 1 73 CH3 H H H H C H H so H 3 161 (decomp.-) 74 H H H H H F H H so

Y

163 (decomp. 'H H H H H F H H S 98-101 76 CF 3 w0 H H H H H H H S Y71j§ 8~4187 77 CF~ P)C H H OH3H H H S 199-203 H~r 78 H CH 3 H H OCH 3 H H H SN 220 LI aii' s o *0 0

S

*0 0 *e* e

C

Table Continuation 13 Melting point R'e (C) I1 Ex- 1 ample R2

R

fl 8

A

c 79 H H H H CH H H S H H H H CH3 H H S AN OCHx2

HI

H 3 OCH3 N V~OCH 3 OCH3 x HBr

"OC-

H 3' r 153 (decomp.) 263-269 81 cE' 3 cx H H OCH3 H H S *248-250 82 H H H H CH 3 H H So N~a; 2 OCH3 H ,OCRJ 147-149 83 CH3 H H H H H H H S H 3 254 *(decomp.) 84 2 4 H H Cl 3 H H H S I7 ,11~x2 HBr

H

231-235 t Table Continuation 0 0 0* 0 0 0 0 0 0 a 0 0. R 13 NN Q.R% Melting point R15 0C)

R

Exn 3 n'4 n 5

R

6

H

7

A

-s-

C

2 5 H H H

C

3 H H s x2 HBr 192 (decomp.)

H

86-(C H H CU 3 H H H N 7rl (decomp.) H CCH3 87 CU 3

CU

3 H H H H U U S NOCa 3 117-122 H C! 3 88 -(CU 2 4 H H H H H H S 108-112

H

89C 2

H

5 H H H H H H H S above l18

H

-(CH

2 4 H H CU 3 U H H S H 142-145 a- C aOC H 3 ia.

Table Continuation *0 *0 9 4 9c 9 9 9

N

9 Melting point N 0

RC

Exl 2

H

3

T

1 a 6 R I 91 H -1?:H273- H H H H H S 225

H

92 CH3 3 H *H H H H H so 145-149 A H N OC R 3 93 -fCH274- H H H H H SO 3

H

above 150 (decomp.) 94

C

2 1 5 C 2

H

5 H H H H H H S 2 H 194 (decomp.) 32 HBr OCR9 3

C

2 5 C 2

H

5 H H H H H H S 7 x2 HBr 226 (decomp.)

H

96 C 2

H

5

C

2

H

H H H H H H S N- 0CF OC 3 OCH3

H

124-126 Ir: I Table Continuation 0 0 0 0 0 *0 a 0 0 0 0 Ex-l R2 R 3 R, II R 8 Melting po.int 0

C)

97 C 2 H 5

C

2

H

5 H H H H H H S 136-138

H

98C 2

H

5

C

2 H H H H H H H so nH3 134-136

H

99 C 2

H

5

C

2

H

5 H H ar 3 H H S OC\ 3 187 Hx2 HBr LI OCH3 (decomp.) 100 H H H

CH

3

OH

3

CH

3 H H so h:

H

140 (decomp.) 101 H H H CH13 0CH 3 013 H H SO Na 132 (decomp.) 102 H H H C3 H H H so OCH3

HOCH

157 (decomp.) Nti_, I I -r a L C _j Table Continuation

S

S S S S

S

Example flR SS 055 *IA N Q Melting point 115 R~Y14 (0c)

R

A Melin pon aI R3 R1 Hl fl7 i H CH3 CH3 H H H H SO N C 3 144-145 (decomp.

H

OCH

3 H 03 H H CH3 H SO N 3 144 (decomp.)

-OCHI

H

105 H H H 013 H 03 H H SO NOCR 3 165 (decomp.

OCH

3 .Na 106 H H CH3

C

2 A

H

H H SO N

II;'

158 (decomp.) Na salt: 167 (decomp.)

H

107 H H H H CH1(CH13)2 H H H SO N 161 (decomp.

Na' 108 H H H CH3 H H H H SO 164 (decomp.)

H

II~ PI~-C- Is~lCI*dllT1PB~BIIPI~Bb I I C I r Table Continuation 0 0 *o 0 0 0 00 0 0 0 0 0 0 0 00 0 000 0 *0* e 00 0 00 0 0 0 0 0 0 0 000 0 0 0 0* 0 0 Ex- 2 R3 ample R R R 5 R R8 A Melting point (oc)

C)

109 H H CH3 CH 3 H H H H SO N155 SNa salt: 165

H

110 H H CH 3 H CH 3 H H H SO Na sat152

H

111i H H CH3 H H CH 3 H H SO N126 sNa salt: 143

H

112 H H H CH3 3t 3 H H H SO- 155 N Na salt: 162

H

113 H H H (313 H CH 3 H H SO 170 N Na salt: 150

H

114 H H- H H CH 3 C3 H H SO N 126

H

Table Example 26 27 28 29 I rr- II 2x Tal n a Table Continuation *0 o *0 C C o a o o o R 13' 1,eting point

R

6 R I C)

R

Ex- R3 R -sl c 115 Benzyl H H Cl SO M2 H H S

H

180 (decomp.) 116 enzyl H H Cl S02

H

H H SO

N

H

210 (decomp.) 117 H H H Cl i 2 H H H S 206-209 O

H

118 H H H Cl 1 2 H H H SO 19 119 CH 3 H H H -702 H H H S 175-177 09

H

120 CH 3 H H H 12 H H so IN 178 'd H -i -cr Tal n a Table Continuation a a a a a a a a a a a a a. S oS a aaa a. a a. a a a a n a a a r S a a OS a a Example H H

H

3 R3 15 6 7 Melting point 0

SC)

I

121 H H N02 H H H H SO N

H

203-204 122 H H H OCR 3 H H H H SO 163-165 123 H H OCI 3 H H H H H So 143-145

H

124 CR 3 H H CF 3 H 0CH3 H H So N 176 125 CH3 H H CF 3 H OCR 3 H H s 110

H

Tab Examp.

37 38 39 41 42 126 H -M=M- H H H H H SO H1 205 (decom.p I

I

Tal n a Table Continuation S 5 S S 5 5 0 0 r C S S

S

OS 5 500 550 55 5* 0 5 5 0 0 S S S 050 S 0 0 55 0 Ex -1 2 ample R 5' jR B 8

A

13 i Melting point kPl 4 (0 C

R

3 1 B 5 i I- 127 H Z -LcH 2 7 4 H H H H S

N

H

70 (decomp.) 128 H =OCF 3

-LEH

2 7 4 H H H H SO N-6%D 202 (decomp.)

H

129 H z -LH 2 7 4 H H H H SO 7 200-201 HI I 130 H H H raj 7 H H H S Ni Il, 117 (decomp.)

N

131 H Z H -1ZH 2 7 4 H H H S 183-190

H

132 H H -0-LH 2 7 2 H H H S 201-202

H

Z= Bemzyloxycabonyl I r r 1 I i 0 0 0 *0 *0 *c 0 0 0 0 0 0 *0 0 *00 000 0 0 0 *0 0 0 0 0 0 0 0 0 0 000 0 0 0 Table Continuation Ex- 1 ampleR, R 2

R

3 R5 f 6 fT R 8

A

W6 Melting point R 0

C)

133 H Z H -Za 2 7 4 H H H so i1 209-209,5

H

134 H Z H H -fCH 2 7 4 H H S 209-211

H

135 H CH (3?2 H H -[cH 2 7 4 H H S A 109-111

H

136 H Z H H -[CH2 4 H H S02 196-197 137 Q H H H *H H F SO 205-205,5

H

138 H Z H H H H H H SO

CO,C,H,

70 (decomp.) Z= Benzyloxycarbonyl r Table Continuation I I r I I C

LI

I. I

I

*o I.

I II Sr I SI I~ I S i

I

ample R 2 rI 1 R 7

R

Melting point 0C 139 H H -LCCH 2 7 H H H S 210-211,

H

140 H -Lbi 2 7 4 H H H H SO 140-143 141 H H -9H 274- H H H H SO

N

137 (decomp.) 142 H COCF 3 -H27 H H F1 H S

IJO

143 H H H1 H H S I 1- 174

H

144 H Z H H H H H H S 159-161

H

TM- Trinethylsilyl, Z= Benzylaxyarbmnyl ~R ~saaaslslsss~Bep~~ ICla r .ri i Tal C Table Continuation 8t V a C C 5d B e V V S SC S es e ag SC C 0 a S c Se S S r et V C SS *SS S C S Ex 1- 2 ampleR R 145 H Z t 3 R 1 r F 6 RT R A Melting point 0

C)

N

H H H H H H C0 2

C

2

HS

146 H Z H H H H H H SO Nt 171-173

H

147 H H H H H H H H S N yOCH 3 150 (decomp.) H c.

~OH 3 160 (decomp.)

-N

148 H H H H H H R H .149 CH 3 O H H H H H H H S J rCH3 176 (decomp.)

H

150 CH 3 O H H H H H H H SO N- 3

H

z 1enzy1oxycaxony1

I

I IL r Sr t*i Table Continuation S b r S u 4* 5 S 5 34 55 5.5 .a Sw o 5. 5 5S 8 S 5 S S S 0 S S 4 5 R 13 Melting point R A N.7 PQ 0

R

Example R R Ft 3

R

1

R

151 CF 3 0D H H H H H H H. S OC 3 Oil

H

152 C~jMH H H H H H H SO

N

7 K- JH3 150(decomp.)

H

153 C 2

H

5 H H H H H H H S N Ii

OCR

3 150 (decomp.) 154 C 2

H

5 H H H H H H H

NZH

3 3-Chlorbenzoate: I0 .4 108 (decomp.)

H

155 CH 3 CO H H H H H H H S 185 (decomp.) H3 156 CH 3 0 H H *H H H H H SO 211 (deccmp.)

H

0 9 0 9 9 6 9 Table Continuation n1 3 Ex-8 Melting point ampl~el R R t R RT R A I

C)

rt .OcH3 157CH3 H H H H H H H S 230 (decomp.) H'I

OCH

3 H 3 158 a! 3 H H H H H H H so C.~<(CH3 140(decomp.) H 3 159 C 2

H

5 H H H H H H H S O 130 (decomp.) H 2C 160 C 9 5 H H H H H H H so j)~O 2 S 5 (decomp.)

HH

OCH CH CH 161 H H H H H H H H S 2 223 OCH 2

CH

2 CH 3 Oi 162 H H H H H H H H sQ ,OCH 2 C 2 CH 3 164 (decomp.) OCH CH CH H 2 7 ~tl I L Ir r Table Continuation a .a a a..

a B a a Example R 2 !I3 R 1

H

5

R

6 T Melting point (0C) 163 H H H H H H H H S 164 H H H H H H H H so 165 H H H H H H H H S 166 H HI H H H H H H so H3 H QCH 3 ~H3 0 2

H

H C 2

H

128 (decomp. 95 (decomp. 126 (decomp. 152 (decomp.) 167 H H H H H H H H S 270

H

168 H H H, H H H H H ,so 0

O)

178 (decomp.

II

.eT s e C Table Continuation Example R 1 R 2 R3

R

5 R R 7

R

8 N 1 AY 1)5

R

Melting point

C)

R

169 CH 3 0C H H H H H H H S MN 0 180 (decomp.)

H

170 QI 3 CO H H H H H H H SQ N

H

218 (decomp.) 171 C2H5 H H H H H H H S A 00" 141 (decomp.)

LI

172

C

2

H

5 H H H H H H H So 0

H

172 (decomp.) 173

C

2

H

5 H, H H H H H H S N

IC

140 (decomp.)

H

174

C

2

H

5 H H H H H H H so rN 104 (decomp.)

H

Ic~ i 4-rC- h~~

Claims

1. A compound of the formula I %NI 09 *040 o .1,0.0. *000 0 0 *0 0 9 0'~ 0* 0 in which R' an~d R' are identical or different and denote hydrogen, (C 1 C 1 2 )-alkyl or cy cl1o alk yl 1~~4~h ,r2=~=tcr~ :ai~nomd~oor denote (C -C )-alkenyl, (C 3 -C 6 )-alkynyl, phenyl or phenyl-(C 1 -C 3 )-alkyl, in which phenyl can be mono-. di- or trisubstituted, in each case with 3 )-alkyl, (C 1 -C 3 )-alkoxy, halooen and/or trifluoromethyl, or denote (C 1 -C 6 )-alkanoyl, (C 1 -C 6 alkoxycarbonyl, (C 1 -C 6 )-alkylcarbamoyl, trifluoroacetyl, benzyloxycarbonyl or another physiologically tolerated acid- or base-labile protective group, or a

2 )R1 and R 2together represent a methylene chain -[CH 2~ in which n is 4, 5 or 6 or together denote phthaloyl, b) R

3 R

4 R 5and R 6are identical or different and represent hydrogen, halogen, cyano, nitro, I t 64 **M *e I (C -C 6 )-alkyl-Y- or phenyl-Y-, in which Y denotes oxygen, sulfur, sulfinyl, sulfonyl or -[CH 2 with m=0, 1 or 2, or represents -CO-R 1 -SO 2 NR 1 1 R2 -0-COR -NR 1 1 -COR -NR-SO 2 R 1 2 or -NR 11 R12, or c) R 1 is as defined under a and R 4 R 5 and R 6 are as defined under and R 2 and R 3 together represent a chain -[CH 2 in which m is as defined above, and X is in the position of R 3 and denotes methylene, oxygen, sulfur or NR or d s 5 and R 6 are as defined under and R 3 and R 4 together represent a chain W, W representing -[CH 2 with p= 3 or 4, in which one or two methylene groups can be replaced by oxygen or NR 9 or W, together with the two carbon atoms carrying these groups, forms a fused-on benzo system, or d 2 R 3 is as defined under b) or and R6 is as defined under and R 4 and R 5 together represent a chain W which is as defined above, or d R 3 is as defined under b) or and R 4 is as defined under and R 5 and R 6 together represent a chain W which is as defined above, e R 7 and R 8 are identical or different and represent hydrogen or methyl, or e 2 R 1 -R are defined according to any one or more of a a d and d and R 8 is as defined under e and R 6 and R 7 together represent a methylene chain -[CH 2 in which m is as defined above, f) R 9 denotes hydrogen, (C -C 3 )-alkyl or (C -C alkanoyl, i i d'' F I k3 r L 1 65 g) R 1 0 denotes (C -C 5 )-alkyl, (C 5 or C 6 cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy or -NR 1 1 1 2 h R 11 and R 12 are identical or different and denote hydrogen, (Cl-C 4 )-alkyl, or phenyl which can be mono-, di- or trisubstituted with (C -C 3 )-alkyl, (Cl-C 4 )-alkoxy, trifluoromethyl and/or halogen, or h 2 R 11 and R 12 together represent a methylene chain -[CH in which q is 4 or 5, and a methylene group can be replaced by oxygen, i)A represents sulfur sulfinyl (SO) or sulfonyl (SO k) R 13 amd R 1 are identical or different and have the meanings defined for R 3 to R 6 under or 13 14 adjacent radicals R 13 and R are defined as R 3 and R 4 under d 1) R 1 5 denotes hydrogen, (C -C 4 )-alkyl, and its physiologically tolerated salts. No claim is made to compounds in which:- A is S or SO and 7 8 3 6 15 R R R 6 R 1 are hydrogen and a) R 1 and R 2 are both methyl and *13 R is hydrogen and 14 R is hydrogen, 5-Cl, 5-COOCH 5-OCH 4-CF 2

5-CO-C 6 H, 5-NH 2 and R 4 and R 5 are hydrogen b) R 1 and R 2 are both methyl and R 1 3 and R 1 4 are 5,6-di-Cl; 5,6-di-OCH 4,7-di-OCH 3 or form a fused benzo-ring in 5,6-position of the benzimidazole R 4 and R 5 are hydrogen c) R 1 and R 2 are both mythyl and R 5 is F, Cl, OCH 3 and .L1I1L- X ~l~-Ca ~Y il 65a R 4 R 3 and R 1 are hydrogen d) R 4 R 5 R 1 3 and R 1 4 are hydrogen and R 1 is hydrogen, CH cyclohexyl, phenyl, benzyl, 1,1- dimethylethyl; n-hexyl and R 2 is CH 3 e) R R R 3 and R 4 are hydrogen and a) R 1 is C2H5 and R 2 is CH 2 or C 3 H or b) R 1 and R 2 together represent a (CH 2 5 -chain f) R R and R 3 and R 4 are hydrogen and R 1 is hydrogen, CH, 3 cyrlohexyl, phenyl and R 2 is hydrogen a14 g) R 5 and R 4 are hydrogen and R 1 and R 2 are methyl and S. R 1 3 is 5-Cl and R 4 is OCH 3 2. A compound of the formula I according to claim 1 wherein when R 1 and R 2 are defined according to a, phenyl is mono or disubstituted. 3. A compound of the formula I according to claim 1 or 2 wherein R 1 3 and R 1 4 are identical or different and have R 3 R 6 meanings according to those defined for R to R under claim l,b). 4. A compound of the formula I as claimed in any one of claims 1 to 3, in which A represents sulfur or sulfinyl, R R8 and R 1 5 each denote hydrogen, one of the radicals R 3 R R 5 and R 6 denotes hydrogen, and R or R 1 4 represents hydrogen, and its physiologically tolerated salts. L I.-~U1CI i 66 A compound of the formula I as claimed in any one of claims 1 to 4, in which R and R 2 are identical or different and denote hydrogen, (C 1 -C 3 )-alkyl, (C 3 -C 6 )-cycloalkyl, allyl, propargyl, phenyl or phenyl-(Cl-C 3 )-alkyl, both of which can be monosubstituted as defined in claim 1, (C -C 3 )-alkanoyl or (C -C )-alkoxycarbonyl, or R 1 and R 2 together with the nitrogen atom carrying them, represent pyrrolidino, or piperidino, R 3 R 4 R 5 and R 6 are identical or different and denote hydrogen, (C 1 -C 4 )-alkyl, (C-C 4 )-alkoxy or (C -C )-alkoxycarbonyl, or two adjacent radicals form a chain W defined in claim 1 under d )-d 3 R R and R 8 each denote hydrogen, R 1 3 and R are identical or different and denote hydrogen, C (C -C 4 )-alkyl or trifluoromethyl, and R 1 5 represents hydrogen or (C -C 4 )-alkyl, and its physiologically tolerated salts. I a

6. A compound of the formula I as claimed in one of claims 1 to 5, in which R and R 2 are identical or different and denote hydrogen, methyl, ethyl or phenyl-(C -C 3 )-alkyl, S4 5 6 .R R R and R are identical or different and denote hydrogen, (C-C 4 )-alkyl or methoxy, or R 4 and R together represent -CH=CH-CH=CH-, R 7 and R 8 each denote hydrogen, R 1 and R 4 are identical or different and denote hydrogen, S. methyl or trifluoromethyl, and R denotes hydrogen or methyl, and its physiologically tolerated salts.

7. A compound of the formula I according to any one of claims 1-6 wherein R 15 is hydrogen.

8. A compound of the formula I as claimed in one of claims f^7~ 1, 3 and 4, in which 67 A represents sulfur or sulfinyl, and its physiologically tolerated salts.

9. 2-(2-Methylaminobenzylsulfinyl)benzimidazole and its physiologically tolerated salts.

A compound of the formula I as claimed in any one of claims 1 to 3, in which A represents or -SO-, R denotes (C 1 -C 4 )-alkyl, R 2 R R and R 5 each denote hydrogen, one of the radicals R 3 R 4 R and R 6 represents hydrogen, and R 1 and R" 4 are identical or different and denote (C -C 4 )-alkoxy, and its physiologically tolerated salts.

11. A compound of the formula I as claimed in any one of claims 1 to 3 and 10 wherein R 1 is methyl or ethyl.

12. A cormound of the formula I as claimed in any one of claims 1-3 or 10 and 11, in which A represents and its physiologically tolerated salts.

13. A compound of the formula I as claimed in any one of claims 1-3, 10, 11 or 12, in which R 3 R 4 R and R 6 each represent hydrogen, and its physiologically tolerated salts. C

14. A compound of the formula I as claimed in one of claims 1 to 3 and 10 to 13, in which R 1 3 and R 1 4 are located in the Pe* 5- and 6-position of the benzimidazole system, are identical or different, and denote methoxy or ethoxy, and R 1 denotes .ethyl, and its physiologically tolerated salts.

A compound of the formula I as claimed in any one of claims 1 to 3 and 10 to 14 in which R 1 and R 1 4 are methoxy.

16. 2-(2-Ethylaminobenzylsulfinyl)-5, 6-dimethoxybenzimidazole and its physiologically tolerated salts. 68

17. A compound of the formula I as claimed in one of claims 1 to 3, 10, 11, 12 or 14-15, in which one or two of the radicals R 3 RI R 5 and R 6 represents (represent) (C -C 4 alkyl, and its physiologically tolerated salts.

18. A process for the preparation of a compound of the formula I as claimed in one of claims 1 to 17, which comprises a) reaction of a compound of the formula II R 1 3 N N 5-R 1 I (II) S 1 5 in which R 13 R 14 and R1 5 are as defined in claim 1, &see and Q 1 denotes i. a leaving group or Op..o. ii. -SF, or -SO 2 with a compound of the formula III R 2 R 1 3 C-Q 2 (III) 8 V 1 2 3 4 5 6 78 in which R R R R R R R and R8 are as defined in claim 1, and SQ2 denotes, in the abovementioned case, -SH, or -SO 2 and, in the abovementioned case ii., a leaving group, b) reaction of a compound of the formula IV R 1 3 (IV) NH 2 I -I YI^I- .I_,-II1Xl~i~, 69 in which R 13 and R 14 are as defined above, with a compound of the formula V R 2 R 1 N R 3 N R 16 (V) R3 C-A- COOR 6 R R 6 R 8 R in which R, R, R R R, R, R 7 R 8 and A are as defined above, and R 16 represents an esterifying group, or c) for the preparation of a compound of the formula I in which R 1 and R 2 each denote hydrogen, reduction of a compound of the formula VI R 13 R *defined in claim 1. and A represents a sulfur atom, N R i c A r R RR 14 R in which R 3 ydr, R 4 R R 6 R 7 R R 1 3 R 1 4 and R 1 are as defined in claim i. and A represents a sulfur atom, oxidation, in the compounds of the formula I which have been obtained according to b) or c) and in which A represents or andor R 3 to R 6 and/or R 1 3 and R 1 4 represent radicals containing or to the corresponding -SO- or group, alkylation or acylation of a compound of the formula I in which R 1 and/or R 2 represents hydrogen, subjection of a compound of the formula I in which R 1 and/or R 2 represents acyl to deacylating hydrolysis or hydrogenolysis, and conversion of a compound of the formula I, thus obtained, where appropriated into its physiologically tolerated salt. LC~n F: ;S l; ix ~~lrilmr rr~i. r 70 L a compound of

19. A method of inhibiting gastric acid secretions comprising administering to a patient suffering therefrom a pharmacologically acceptable amount of a compound as claimed in any one of claims 1 to 17. A pharmaceutical agent comprising a compound as claimed in any one of claims 1 to 17 in.adjunct with L- S pharmaceutically acceptable ea~i e or excipients. R 8 and A n esterifying ala I in which a compound of DATED this 21st day of June 1989 HEOCHST AKTIENGESELLSCHAFT *o 9 00 9 5.5.9 9 5* S 0 WATERMARK PATENT TRADEMARK ATTORNEYS 50 Queen Street, MELBOURNE VIC. 3000. nd R' 5 are as sulfur atom, .iich have been a A represents R 1 4 represent onding -SO- or mpound of the its hydrogen, iich R 1 and/or rdrolysis or )f the formula iysiologically DBM:KJS:SC (1.34) 9090 0 99 9 @9 9 5 9. 9S o* a. 9 9 999 S