EP0772611A1

EP0772611A1 - Piperazine thiopyridines for controlling helicobacter bacteria

Info

Publication number: EP0772611A1
Application number: EP95927666A
Authority: EP
Inventors: Guido Hanauer; Wolfgang-Alexander Simon; Peter Zimmermann; Wolfgang Opferkuch; Bernhard Kohl; Gerhard Grundler; Jörg Senn-Bilfinger
Original assignee: Byk Gulden Lomberg Chemische Fabrik GmbH
Current assignee: Takeda GmbH
Priority date: 1994-07-20
Filing date: 1995-07-19
Publication date: 1997-05-14
Also published as: US5922720A; NZ290788A; WO1996002534A1; AU3162095A; CA2195443A1; AU702307B2; JPH10505328A

Abstract

Compounds having the formula (I), in which the substituents and symbols have the meanings given in the description, are useful for controlling helicobacter bacteria.

Description

PIPERAZINOTHIOPYRIDINE FOR CONTROLLING HELICOBACTER BACTERIA

Field of application of the invention

The invention relates to compounds which are to be used in the pharmaceutical industry as active ingredients for the production of medicaments.

Known technical background

European patent application 150 586 discloses 2- (pyridylmethylthio- or -sulfinyl) benzimidazoles, which can be substituted in the pyridine part of the molecule in the 4-position, inter alia, by al ylthio or arylthio radicals. Long-term gastric acid secretion inhibition is indicated for the compounds described. - In international patent application W089 / 03830 it is described that the same, as well as other structure-like compounds, are said to be suitable for the treatment of osteoporosis. - In the international patent application WO92 / 12976, substituted 2- (pyridylmethylthio- or -sulfinyl) benzimidazoles are described in a certain way, which are said to be effective against Helicobacter bacteria and for which it is furthermore disclosed that they are useful for the prevention and Treatment of a whole range of diseases of the stomach are said to be suitable. - International patent application WO93 / 24480 describes further 2- (pyridylmethylthio- or -sulfinyl) benzimidazoles which are substituted in a certain way and are said to be active against Helicobacter bacteria.

Description of the invention

The invention relates to compounds of the formula I (see attached formula sheet I), in which

R1 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl, R3 is hydrogen, 1-4C-alkyl, 1-4C-alkyl substituted by R4, 1-4C-A1-alkylcarbonyl, 2-4C-alkenylcarbonyl, halogen-1-4C-alkylcarbonyl, N (R14) R15-1-4C- means alkylcarbonyl, di-1-4C-alkylcarbamoyl or 1-4C-alkylsulfonyl,

R4 denotes hydroxy, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl or -N (R14) R15,

R5 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy,

R6 is a cycle or bicycle substituted by R8 and R9, which is selected from the group consisting of benzene, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, thiazoline, isothiazole, idazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole , Thiadiazole-1-oxide, oxadiazole, pyridine, pyridine-N-oxide, pyrimidine, triazine, pyridone, benzimidazole, imidazopyridine, benzothiazole and benzoxazole,

R7 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy,

R8 is hydrogen, 1-4C-alkyl, hydroxy, 1-4C-alkoxy, halogen, nitro, guanidino, carboxy, 1-4C-alkoxycarbonyl, 1-4C-alkyl or -N (R11) R12 substituted by RIO,

R9 denotes hydrogen, 1-4C-alkyl, hydroxy, 1-4C-alkoxy, halogen or trifluoromethyl,

RIO is hydroxy, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl or -N (R11) R12, where

Rll hydrogen, 1-4C-alkyl or -C0-R13 and

R12 represents hydrogen or 1-4C-alkyl, or wherein

R11 and R12 together and including the nitrogen atom to which both are attached represent a piperidino or morpholino radical,

R13 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy,

R14 1-4C alkyl and

R15 is 1-4C-alkyl, or wherein

R14 and R15 together and including the nitrogen atom to which both are attached represent a piperidino or morpholino radical,

W means CH or N,

X represents 0 (oxygen), N-1-4C-alkyl or S (sulfur),

Y means N or CH,

Z denotes 0 (oxygen), CO (carbonyl), S (sulfur) or SO-, m denotes a number from 2 to 5, n denotes the number 0, 1 or 2, r denotes a number from 0 to 5, u denotes a number from 0 to 3 and v denotes the number 0 or 1 and their salts, where

R6 is not benzene if R5 is hydrogen or 1-4C-alkyl and v is 0, r is not 0 if YN and Z is 0, S or S0 ₂ , Z is not SO- if u the number 0 and v the number 1, and where R6 does not signify a cycle or bicyclic bonded via N (nitrogen) if Z 0, S or S0 ₂ , v the number 1 and u the number 0.

1-4C-A1kyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

1-4C-Alkoxy represents a radical which, in addition to the oxygen atom, contains one of the 1-4C-alkyl radicals mentioned above. The methoxy and ethoxy radicals may be mentioned, for example.

Halogen in the sense of the present invention is bromine, chlorine and in particular fluorine.

1-4C-Alkylcarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the 1-4C-alkyl radicals mentioned above. For example, the acetyl radical may be mentioned.

2-4C-alkenylcarbonyl stands for a radical which, in addition to the carbonyl group, contains a 2-4C-alkenyl radical, for example a propenyl radical or a butenyl radical. For example, the acryloyl radical may be mentioned.

Halogen-1-4C-alkylcarbonyl stands for a radical which, in addition to the carbonyl group, contains a halogen-substituted 1-4C-alkyl radical. For example, the γ-chlorobutyryl radical may be mentioned. N (R14) R15-1-4C-alkylcarbonyl stands for a radical which, in addition to the carbonyl group, contains a 1-4C-alkyl radical substituted by -N (R14) R15. For example, the 3-dimethylamino-propionyl radical may be mentioned.

Di-1-4C-alkylcarbamoyl stands for a radical which, in addition to the carbonyl group, contains a di-1-4C-alkylamino radical. The di-1-4C-alkylamino radical is an amino radical which is substituted by two identical or different of the 1-4C-alkyl radicals mentioned above. Examples include the dimethylamino, diethylamino and diisopropylamino residues. Examples of the di-1-4C-alkylcarba oyl esters are the dimethylcarbamoyl and the diethylcarbamoyl radical.

1-4C-Alkylsulfonyl stands for a radical which, in addition to the sulfonyl group (-SO--), contains one of the 1-4C-alkyl radicals mentioned above. The methylsulfonyl radical may be mentioned as an example.

1-4C-Alkoxycarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the 1-4C-alkoxy radicals mentioned above. For example, the methoxycarbonyl and the ethoxycarbonyl radical may be mentioned.

Exemplary 1-4C-alkyl radicals substituted by R4 are 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, methoxycarbonylmethyl, carboxymethyl, 2-hydroxyethyl, methoxymethyl and 2-methoxyethyl -, the Dimethylaminomethyl- and the 2-Dimethylaminoethylrest called.

The following may be mentioned as cycles or bicycles R6, for example: phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 2-0xazolyl, 4-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 3-isothiazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, l, 2,3-triazol-4-yl, l, 2,5-thiadiazol-4-yl, l, 2,5- Thiadiazol-4-yl-l-oxide, l, 2,4-triazol-3-yl, tetrazol-5-yl, l, 3,4-thiadiazol-2-yl, l, 2,3-thiadiazol-4- yl, l, 3,4-oxadiazol-2-yl, 2-pyridyl, 4-pyridyl, 2-pyrimidinyl, l, 3,4-triazin-2-yl, 2-benzimidazolyl, 2-imidazopyridyl, 2-benzothiazolyl and 2-benzoxazolyl.

The substituents R8 and R9 can be attached at any conceivable position in the cycles or bicycles R6. Examples of radicals R6 substituted by R8 and R9 include: 4-methylphenyl, 3-dimethylaminomethyl phenyl, 3-piperidinomethylphenyl, 3-carboxymethylphenyl, 2-dimethylamino-methyl-5-methyl-3-furyl, 1-methylpyrrol-3-yl, 4,5-dimethyl-oxazol-2-yl, 3,5-dimethyl isoxazol-4-yl, 4,5-dimethyl-thiazol-2-yl, 4-methyl-5-carboxy-methyl-thiazol-2-yl, 1-methyl-imidazol-2-yl, 1-methyl-pyrazole- 3-yl, l- (2-dimethylaminoethyl) pyrazol-3-yl, 5-methyl-l, 3,4-oxadiazol-2-yl, 1-methyl-l, 2,3-triazol-4- yl, l-methyl-l, 2,4-triazol-3-yl, l- (2-dimethylaminoethyl) -l, 2,3-triazol-4-yl, l-methyl-tetrazol-5-yl, l- (2-dimethylamino-ethyl) -tetrazol-5-yl, l-carboxymethyl-tetrazol-5-yl, 5-methyl-l, 3,4-thia-diazol-2-yl, 5-trifluoromethyl-l, 3,4-thiadiazol-2-yl, l- (2-hydroxyethyl) tetrazol-5-yl, 2-amino-l, 3,4-thiadiazol-2-yl, 3-amino-l, 2,4- triazol-5-yl, 4-methyl-5-trifluoromethyl-l, 2,4-triazol-3-yl, 4-aminopyrimidin-2-yl, 3-methyl-2-furyl, 2-methyl-3- furyl, 5-methyl-2-furyl, 5-ethyl-2-furyl, 3-methoxy-2-furyl, 5-dimethylaminomethyl-2-furyl, 5-N-morpholinomethyl-2-furyl, 5-methoxymethyl-2- furyl, 5- Hydroxymethyl-2-furyl, 5-N-piperidino-methyl-2-furyl, 5-chloro-2-furyl, 5-fluoro-2-furyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl, 3-methyl-2-thienyl, 3-amino-2-thienyl, 3-guanidino-2-thienyl, 3-methoxy-2-thienyl, 2-methyl-3-thienyl, 5-dimethylaminomethyl-2-thienyl, 5- N-morpholinomethyl-2-thienyl, 5-methyl-2-pyrrolyl, 2,5-dimethyl-1-pyrrolyl, l, 5-dimethyl-2-pyrrolyl, l-methyl-2-pyrrolyl, 2-amino- 4-thiazolyl, 2-methyl-4-thiazolyl, 2-amino-5-methyl-4-thiazolyl, 4-methyl-5-thiazolyl, 2-dimethylaminomethyl-4-thiazolyl, 2-guanidino-4-thiazolyl, 2- Formylamino-4-thiazolyl, 2-N-morpholinomethyl-4-thiazolyl, 4-methyl-5-oxazolyl, 3-guanidino-l-pyrazolyl, 3-guanidino-4-pyrazolyl, 2-methyl-4-i idazolyl, 5 -Methyl-4-imidazolyl, 2-methyl-1-imidazolyl, 2-methyl-5-nitro-1-imidazolyl, 4,5-dimethyl-2-imidazolyl, 4-hydroxymethyl-5-methyl-1-imidazolyl , 3-methyl-l-pyrazolyl, 5-amino-l, 2,4-thiadiazol-3-yl, 4-methoxy-2-pyridinyl, 4-methoxy-3-methyl-2-pyridinyl and 3,4 -Dimethoxypyridinyl.

As residues -C _m H- _m - -C _r H _2r - and -CH, - straight-chain or branched residues come into question. Examples include pentylene, isopentylene (3-methylbutylene), neopentylene (2,2-dimethylpropylene), butylene, iso-butylene, sec-butylene, tert-butylene, propylene, Isopropylene, ethylene and (for -CH »- and -C H. -) the methylene residue.

The radicals -C _m H _2m - are preferably the ethylene- (-CH-CH--), the butylene- (-CH ₂ CH ₂ CH ₂ CH ₂ -) and in particular the propylene radical (-CH-CH-CHg-) to call. The radicals -CH »- are preferably the ethylene, propylene and methylene radicals. In a further preferred embodiment, r represents the number 0, so that the expression -CrHZ, r- disappears or represents a dash.

The radicals -C H »- are preferably the methylene, the ethylene and the propylene radical. In a further preferred embodiment, u represents the number 0, so that the expression -C H »- disappears or represents a hyphen and the radical R6 is bonded directly to the group Z.

In a further preferred embodiment, v stands for the number 0, so that the expression -Z-C H- disappears or represents a hyphen and the radical R6 is bonded directly to the group C H-.

Suitable salts for compounds of the formula I in which n denotes the number 0 are all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically compatible salts by processes known to the person skilled in the art. Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, Maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a - or polybasic acid and, depending on which salt is desired - be used in an equimolar or a different ratio.

For compounds of the formula I in which n is 1 and / or for compounds having a carboxy radical, salts with bases are also suitable as salts. Examples of basic salts are lithium, sodium, potassium, Calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidine salts are mentioned, with the bases being used here in salt production in an equimolar or a different ratio.

Compounds to be emphasized are those of the formula I (see attached

Formula I), wherein

Rl is hydrogen, 1-4C-alkoxy or halogen,

R2 represents hydrogen or halogen,

R3 is hydrogen, 1-4C-alkyl, 1-4C-alkyl substituted by R4, 1-4C-A1-alkylcarbonyl, 2-4C-alkenylcarbonyl, halogen-1-4C-alkylcarbonyl,

N is (R14) R15-1-4C-alkylcarbonyl, di-1-4C-alkylcarbamoyl or 1-4C-alkylsulfonyl, R4 is -N (R14) R15,

R5 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy, R6 denotes a cycle or bicyclus substituted by R8 and R9, which is selected from the group consisting of benzene, furan, thiophene,

Thiazole, imidazole, triazole, pyridine, pyrimidine and pyridone, R7 is hydrogen or 1-4C-alkyl, R8 is hydrogen, 1-4C-alkyl, hydroxy, 1-4C-alkoxy, halogen, nitro, guanidino, carboxy, l -4C-alkoxycarbonyl, RIO-substituted 1-4C-alkyl or -N (R11) R12, R9 is hydrogen, 1-4C-alkyl, hydroxy or fluorine, RIO carboxy, 1-4C-alkoxycarbonyl or -N (R11) R12 means, where R11 1-4C-alkyl and

R12 is hydrogen or 1-4C-alkyl, or where R11 and R12 together and including the nitrogen atom to which both are attached represent a piperidino or morpholino radical, R14 is 1-4C-alkyl and R15 is 1-4C-alkyl, or where R14 and R15 together and including the nitrogen atom to which both are attached represent a piperidino or morpholino radical, W denotes CH or N,

X represents 0 (oxygen), N-1-4C-alkyl or S (sulfur), Y represents N or CH,

Z represents 0 (oxygen), CO (carbonyl), S (sulfur) or S0 ₂ , m represents a number from 2 to 4, n denotes the number 0 or 1, r denotes a number from 0 to 3, u denotes a number from 0 to 2 and v denotes the number 0 or 1 and their salts, where

R6 is not benzene if R5 is hydrogen or 1-4C-alkyl and v is 0, r is not 0 if YN and Z is 0, S or SO ", Z is not SO- if u the number 0 and v the number 1, and where R6 does not mean a cycle or bicyclic bonded via N (nitrogen) if Z 0, S or SO-, v the number 1 and u the number 0.

Particularly noteworthy compounds are those of the formula I (see attached formula sheet I), in which

Rl is hydrogen, 1-4C-alkoxy or halogen,

R2 represents hydrogen or halogen,

R3 is hydrogen, 1-4C-alkyl substituted by R4, N (R14) R15-1-4C-alkylcarbonyl or 1-4C-alkylsulfonyl, R4 -N (R14) R15,

R5 denotes hydrogen, 1-4C-A1kyl or 1-4C-alkoxy, R6 denotes a cycle or bicyclus substituted by R8 and R9, which is selected from the group consisting of benzene, furan, thiophene,

Thiazole, imidazole, triazole, pyridine, pyrimidine and pyridone, R7 is hydrogen, R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen, nitro or R4-substituted 1-4C-alkyl, R9 is hydrogen, 1- 4C-alkyl or fluorine, RIO -N (R11) R12, where R11 is 1-4C-alkyl and R12 is 1-4C-alkyl, or where R11 and R12 are together and include the nitrogen atom to which both are bonded, represent a piperidino or morpholino radical, R14 denotes 1-4C-alkyl and R15 1-4C-alkyl, or wherein R14 and R15 together and including the nitrogen atom to which both are attached represent a piperidino or morpholino radical,

W means CH or N,

X represents 0 (oxygen) or S (sulfur),

Y means N or CH,

Z is 0 (oxygen), CO (carbonyl), S (sulfur) or SO-, m is a number from 2 to 4, n is 0 or 1, r is a number from 0 to 3, u is a number of 0 to 2 and v denotes the number 0 or 1 and their salts, where

R6 is not benzene when R5 is hydrogen or 1-4C-alkyl and v is 0, r is not 0 when Y is N and Z is 0, S or SO,

Z is not SO- if u is 0 and v is 1, and where

R6 does not mean a cycle or bicyclic bonded via N (nitrogen) if Z 0, S or S0 ₂ , v denotes the number 1 and u denotes the number 0.

Exemplary compounds are those of the formula I (see attached

Formula I), wherein

Rl is hydrogen,

R2 means hydrogen

R3 means hydrogen,

R5 denotes 1-4C-alkyl or 1-4C-alkoxy,

R6 denotes a cycle or bicyclic substituted by R8 and R9, which is selected from the group consisting of benzene, furan, thiophene,

Thiazole, pyridine and pyrimidine, R7 is hydrogen, R8 is hydrogen, 1-4C-alkyl, halogen or 1-4C- substituted by RIO

Alkyl means, R9 means hydrogen, RIO means -N (R11) R12, where R11 is 1-4C-alkyl and R12 1 -4C-alkyl means

W CH means

X S (sulfur) means

Y means N or CH,

Z denotes CO (carbonyl) or S (sulfur), m denotes the number 3, n denotes the number 0, r denotes a number from 0 to 3, u denotes the number 0 and v denotes the number 0 or 1 and their salts, in which

R6 is not benzene when R5 is 1-4C-alkyl and v is 0 and where r is not 0 when Y is N and Z is S.

One embodiment of the invention (embodiment a) are those compounds or those compounds of formula I to be emphasized, particularly emphasized and exemplified, in which v denotes the number 1, Z denotes CO (carbonyl), r denotes the number 0 and u denotes the number 0 .

A further embodiment of the invention (embodiment b) are those compounds or those compounds of formula I which are to be emphasized, particularly emphasized and exemplified, in which v denotes the number 1, ZS denotes (sulfur), YN denotes, r denotes the number 2 or 3 and u means the number 0 or 1.

A further embodiment of the invention (embodiment c) are those compounds or those compounds of formula I to be emphasized, particularly emphasized and exemplified, in which v denotes the number 0 and r denotes a number from 0 to 3.

Exemplary compounds according to the invention are listed in the following tables: Table 1

Compounds of the formula I (see attached formula sheet I) with W = CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2 = H, R3 = H, R7-H, n = 0, X = S, YN, v-0, R6 = 2-furyl and the following further substituent and symbol meanings:

Rl R5

Table 2

Compounds of the formula I (see attached formula sheet I) with W = CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2 = H, R3 = H, R7-H, n-0, XS, YN, v * 0, R6 = 4-methyl-5-thiazolyl and the following further substituent and symbol meanings:

Rl R5 m

Table 3

Compounds of the formula I (see attached formula sheet I) with W = CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2 = H, R3 = H, R7-H, n-0, X = S, Y « N, v> = 0, R6 = 1-methyl-5-tetrazolyl and the following further substituent and symbol meanings:

Rl R5 m r

H H

H

HHHHHH Table 4

Compounds of the formula I (see attached formula sheet I) with W = CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2 = H, R3 = H, R7-H, n »0, XS, YN, v- 0, R6 »4-pyridinyl and the following further substituent and symbol meanings:

R R5

Table 5

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2 = H, R3-H,

R7-H, n «0, X-S, Y-N, v-0, R6-l-imidazolyl and the following further substituent and symbol meanings:

m

Table 6

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n = 0, XS, YN, v- 0, R6 = 5-chloro-2-thienyl and the following further substituent and symbol meanings:

Rl R5 m r

Table 7

Compounds of the formula I (see attached formula sheet I) with W = CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n-0, XS, YN, v » 0, R6 = 2-methyl-5-nitro-l-imidazolyl and the following further substituent and symbol meanings:

£ 1 F_5 nι _

Table 8

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n-0, XS, YN, v = 0, R6 = 2-pyridine-3-carboxylic acid and the following further substituent and symbol meanings:

R5

Table 9

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n-0, XS, YN, v- 0, R6-2-thiazolyl and the following further substituent and symbol meanings:

fil E__ m c

Table 10

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H,

R7-H, n-0, X-S, Y-N, v-0, R6-2-imidazolyl and the following further substituent and symbol meanings:

Rl R5 m r

Table 11

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n = 0, XS, YN, v- 0, R6 = 5-nitro-l-imidazolyl and the following further substituent and symbol meanings:

Rl R5 r

Table 12

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n = 0, XS, YN, v- 0, R6-2-pyridinyl and the following further substituent and symbol meanings:

Rl R5

Table 13

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n-0, XS, YN, v- 0, R6 = 2-pyrimidinyl and the following further substituent and symbol meanings:

R

Table 14

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n-0, XS, YN, v- 0, R6-4-methyl -3-triazolyl and the following further substituent and symbol meanings:

R5 m

Table 15

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n-0, XS, YN, v- 0, R6-2-methyl-5-thiadiazolyl and the following further substituent and symbol meanings:

Rl R5 m r

Table 16 - Table 30

Compounds of formula I (see attached formula sheet I) as defined in Tables 1-15, but with Y-CH instead of Y-N.

Table 31

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n = 0, XS, YN, v = 0, R6 = phenyl and the following further substituent and symbol meanings:

Rl R5 m r

0 1 2 0 1 2 0 1 2 Table 32

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n-0, XS, YN, v- 0, R6-4-fluorophenyl and the following further substituent and symbol meanings:

Rl R5 m r

Table 33

Compounds of the formula I (see attached formula sheet I) with W = CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n-0, XS, YN, v « 0, R6 = 4-methylphenyl and the following further substituent and symbol meanings:.

Rl R5 r

0 1 2 0 1 2 0 1 2

Table 34

Compounds of the formula I (see attached formula sheet I) with W-CH, attachment of the substituent Rl in the 5-position on the benzimidazole, R2-H, R3-H, R7-H, n = 0, XS, YN, v « 0, R6 = 4-methoxyphenyl and the following further substituent and symbol meanings:

__! R5 m r

0 1 2 0 1 2 0 1 2

Tables 35-38

Compounds of formula I (see attached formula sheet I) as defined in Tables 31-34, but with Y-CH instead of YN. Table 39

Compounds of the formula I (see attached formula sheet I) with W-CH, Rl-H, R2-H, R3-H, R7-H, n = 0, v = 1, XS, R6 = phenyl and the following further substituents and symbol meanings:

R5 Y Z rn r u

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1 Table 40

Compounds of formula I (see attached formula sheet I) with W-CH, Rl-H, R2-H, R3-H, R7-H, n-0, v-1, XS, R6 = 2-furyl and the following others Substituent and symbol meanings:

5 Y m

Tabel le 41

Compounds of formula I (see attached formula sheet I) with W-CH, Rl-H, R2-H, R3-H, R7-H, n = 0, v = 1, XS, R6 = 4-fluorophenyl and the following wide ¬ Ren substituent and symbol meanings:

R Y Z Π

Table 42

Compounds of formula I (see attached formula sheet I) with W-CH, Rl-H, R2-H, R3-H, R7-H, n-0, v-1, XS, R6 = 5-chloro-2-thienyl and the following further substituent and symbol meanings:

R5 Y Z [n r u

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1 Table 43

Compounds of formula I (see attached formula sheet I) with W-CH, Rl-H, R2-H, R3-H, R7-H, n-0, v-1, XS, R6 = 2-methyl-5-nitro -l-imidazolyl and the following further substituent and symbol meanings:

R5 Y Z m r u

S 2 2 2

S 3 2 2

S 4 2 2

S 2 3 2

S 3 3 2

CO 2 0 2

CO 3 0 2

CO 4 0 2

CO 2 1 2

CO 3 1 2

S 2 2 2

S 3 2 2

S 4 2 2

S 2 3 2

S 3 3 2

CO 2 0 2

CO 3 0 2

CO 4 0 2

CO 2 1 2

CO 3 1 2

S 2 2 2

S 3 2 2

S 2 3 2

CO 2 0 2

CO 3 0 2

S 2 2 2

S 3 2 2

S 2 3 2

CO 2 0 2

CO 3 0 2 Tabel le 44

Compounds of formula I (see attached formula sheet I) with W-CH, Rl-H, R2-H, R3-H, R7-H, n-0, v-1, XS, R6 = 2-pyridinyl and the following others Substituent and symbol meanings:

R5 Y l Q r u

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1 Table e 45

Compounds of formula I (see attached formula sheet I) with W-CH, Rl-H R2-H, R3-H, R7-H, n = 0, v-1, XS, R6 = l-methyl-5-tetrazolyl and the following further substituent and symbol meanings:

R5 Y Z m r u

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1 Table 46

Compounds of formula I (see attached formula sheet I) with W-CH, Rl-H, R2-H, R3-H, R7-H, n »0, v-1, XS, R6 = 4-pyridinyl and the following others Substituent and symbol meanings:

R5 Y Z DI r u

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 4 2 0

S 2 3 0

S 3 3 0

CO 2 0 1

CO 3 0 1

CO 4 0 1

CO 2 1 0

CO 3 1 0

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1

S 2 2 0

S 3 2 0

S 2 3 0

CO 2 0 1

CO 3 0 1 Table 47

Compounds of formula I (see attached formula sheet I) with W-CH, Rl-H, R2-H, R3-H, R7-H, n-0, v-1, XS, R6-5-nitro-l-imidazolyl and the following further substituent and symbol meanings:

R5 Y Z Π r u

S 2 2 2

S 3 2 2

S 4 2 2

S 2 3 2

S 3 3 2

CO 2 0 2

CO 3 0 2

CO 4 0 2

CO 2 1 2

CO 3 i 2

S 2 2 2

S 3 2 2

S 4 2 2

S 2 3 2

S 3 3 2

CO 2 0 2

CO 3 0 2

CO 4 0 2

CO 2 1 2

CO 3 1 2

S 2 2 2

S 3 2 2

S 2 3 2

CO 2 0 2

CO 3 0 2

S 2 2 2

S 3 2 2

S 2 3 2

CO 2 0 2

CO 3 0 2 and the salts of the compounds listed in the tables above.

Another object of the invention is a process for the preparation of the compounds of formula I and their salts.

The process is characterized in that

a) mercaptobenzimidazoles of the formula II (see attached formula sheet II), in which W, Rl, R2 and R3 have the meanings given above, with picoline derivatives III (see attached formula sheet II), in which R5, R6, R7, X, Y, Z, m, r, u and v have the meanings given above and A represents a suitable leaving group, or is reacted

b) Compounds of the formula IV (see attached formula sheet II), in which W, Rl, R2, R3, R5, R7, X and m have the meanings given above, n, the number 0 and A represents a suitable leaving group, with compounds the formula V (see attached formula sheet II), wherein R6, Y, Z, r, u and v have the meanings given above, or that

c) Compounds of the formula VI (see enclosed formula sheet III), in which W, Rl, R2, R3, R5, R7 and n have the meanings given above and shark represents a halogen atom, with compounds VII (see attached formula sheet III), in which R6 , X, Y, Z, m, r, u and v have the meanings given above, or that

d) benzimidazoles of the formula VIII (see enclosed formula sheet III), in which Rl, R2, R3 and W have the meanings given above and A represents a suitable leaving group, with pyridines of the formula IX (see enclosed formula sheet III), in which R5, R6, R7, X, Y, Z, m, r, u and v have the meanings given above, and

(if compounds of the formula I with n-1 or 2 and / or Z = S0 _{2 are} the desired end products) that the compounds obtained are subsequently oxidized with n-0 and / or ZS, and / or that if desired, the compounds obtained are subsequently converted into the salts and / or that if desired, salts obtained are subsequently converted into the free compounds.

In the reactions listed above, the starting compounds can be used as such or, if appropriate, in the form of their salts.

Suitable leaving groups A include, for example, halogen atoms, in particular chlorine, or hydroxyl groups activated by esterification (for example with p-toluenesulfonic acid).

The reaction of II with III is carried out in suitable, preferably polar, protic or aprotic solvents (such as methanol, ethanol, isopropanol, dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile) with or without water. It is carried out, for example, in the presence of a proton acceptor. Alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium carbonate or tertiary amines such as pyridine, triethylamine or ethyldiisopropylain are suitable as such. Alternatively, the reaction can also be carried out without a proton acceptor, depending on the type of Starting compounds - if necessary, the acid addition salts can first be separated off in a particularly pure form. The reaction temperature can be between 0 ^* and 150 ^* C, in the presence of proton acceptors temperatures between 20 ^* and 80 ^* C and without proton acceptors between 60 ^* and 120'C - especially the boiling point of the solvents used - are preferred. The reaction times are between 0.5 and 30 hours.

The reaction of the compounds IV with the compounds V is carried out in a manner similar to the reaction of the compounds II with the compounds III, if desired with the addition of catalytic amounts of alkali iodide, e.g. Sodium iodide.

The reaction of the compounds VI with the compounds VII takes place in a manner known per se, as is known to the person skilled in the art for the production of sulfides from thiols and halogenated aromatics. The halogen atom shark is preferably a chlorine atom. The reaction of the compounds VIII with the compounds IX takes place in principle in an analogous manner to the reaction of the compounds II with the compounds III.

The oxidation of the sulfides to the sulfoxides or sulfones takes place under the conditions known to those skilled in the art for the oxidation of sulfides to sulfoxides or sulfones [see e.g. J. Drabowicz and M. Mikolajczyk, Organic preparations and procedures int. 14 (1-2), 45-89 (1982) or E. Block in S. Patai, The Chemistry of Functional Groups, Supplement E. Part 1, S. 539-608, John Wiley and Sons (Interscience Publication), 1980]. Suitable oxidizing agents are all reagents commonly used for the oxidation of sulfides to sulfoxides or sulfones, in particular peroxy acids, such as e.g. Peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid, magnesium monoperoxiphthalate or preferably m-chloroperoxybenzoic acid.

The reaction temperature is (depending on the reactivity of the oxidizing agent and degree of dilution) between -70 ^* C and the boiling point of the solvent used, but preferably between -30 ^* and +20 ^* C. Oxidation with halogens or with hypohalites has also proven advantageous. proven with aqueous sodium hypochlorite solution), which is conveniently carried out at temperatures between 0 ^* and 50 ^* C. The reaction is conveniently carried out in inert solvents, for example aromatic or chlorinated hydrocarbons, such as benzene, toluene, dichloroethane or chloroform, preferably in esters or ethers, such as ethyl acetate, isopropyl acetate or dioxane, or in alcohols, preferably isopro - panol, carried out.

The sulfoxides according to the invention are optically active compounds. Depending on the nature of the substituents, there may be additional chiral centers in the molecule. The invention therefore includes the enantiomers and diastereomers as well as their mixtures and racemates. The enantiomers can be separated in a manner known per se (for example by preparing and separating corresponding diastereoisomeric compounds) (see, for example, WO92 / 08716). Depending on the nature of the substituent R6, the sulfones (Z = S0 ₂ ) are also obtained in the oxidation to the sulfoxides n = 1 or sulfones n-2. In addition, the respective sulfides or sulfoxides or sulfones can be prepared by choosing suitable starting compounds or by using selective oxidizing agents.

Compounds II are e.g. known from W086 / 02646, EP 134400, EP 127763 or W093 / 24480. The compounds III can, for example, be prepared analogously to this, as described in the examples below.

The starting compounds required for the preparation of III can e.g. from the corresponding halogen compounds analogous to J. Med. Che. 14 (1971) 349.

The compounds IV, V, VI, VII, VIII and IX are likewise known or they can be prepared in an analogous manner from known starting compounds by processes known per se. For example, compounds of the formula VI are obtained by reacting compounds of the formula II with 4-halopyridines corresponding to compounds of the formula III. The compounds IV are obtained, for example (as also described in more detail in the examples below) by reacting compounds of the formula II with 4- (ω-haloalkylthio) pyridines corresponding to compounds of the formula III.

The following examples explain the invention in more detail without restricting it. The compounds according to the invention and the starting compounds can be prepared in a manner analogous to that described in the examples. The abbreviation RT stands for room temperature, h stands for hour (s), mp for melting point, dec. for decomposition. Examples

1. 2- (r3-Methyl-4-r3-r4- (2-pyrimidinyl) -piperazin-l-vπ-propylthio-2-pyridinimethylmethyllthiol-1H-benzimidazole

2 - {[[4- (3-Chloropropylthio) -3-methyl-2-pyridinyl] methyl] thio} -lH-benzimizazole (3 mmol) are mixed with N- (2-pyrimidinyl) piperazine (3.1 mmol), potassium carbonate (15 mmol) and sodium iodide (0.3 mmol) in acetonitrile (20 ml) stirred at 100'C for 36 h. The inorganic salts are filtered, concentrated and crystallized by adding water. The title compound is obtained; beige powder; Sch p. 100-103 ^* C; Educ. 81% of theory

2. 2- (ι ^r 3-methyl-4-r3-ι ^r 4- (2-pyridinyl j-piperazin-l-yn-propylthio ^ -pyridi- nvπmethvnthiol-lH-benzimidazole

Following the procedure given in Example 1), the title compound is obtained by reaction with N- (2-pyridinyl) -piperazine; M.p. 79-82'C; Educ. 75% of theory

3. 2-frr4-r3-r4- (5-chlorothiophen-2-yl-methv1) -piDerazin-l-vn-proDylthiol-3-methyl-2-pyridinyllmethyll-thiol-lH-benzi idazole

According to the procedure given in Example 1), N- (5-chlorothiophene-1-yl-methyl) -piperazine is obtained, after chromatography on silica gel (ethyl acetate / methanol / ammonia) and subsequent crystallization from dichloro than // diisopropyl ether the title compound; Mp 125 ^* C (decomposition); Educ. 84%.

4. 2- (r3-Methv1-4-r3-r4- (2-Pyridinv1thiθDroDyll-piDerazin-l-v11-propy1-thio-2-pyridinγπmethyllthioVlH-benzimidazole

Following the procedure given in Examples 1) and 3), the title compound is obtained with N- (2-pyridinylthiopropyl) piperazine; M.p .: 116-118'C; Educ. 29%. 5. 2- (7R4-r3-r4- (4-Fluorbenzoy1) ^{-piperidin-l-yll-propylthiol-3-py} methv1-2- ridinyllmeth ^y nthio -lH-benzimidazole

Following the procedure given in Examples 1) and 3), the title compound is obtained with 4- (4-fluorobenzoyl) piperidine; M.p. 126-129'C; Educ. 44%.

6. 2-f rr4-r3- (4-Benzoyl-piperidin-l-yl i-propylthiol-S-methyl ^ -pyridinium-nylImeth ^y πthiol-lH-benzimidazole-trihydrochloride

According to the procedure given in Examples 1) and 3), 4-benzoylpiperidine is obtained after conversion into the hydrochloride with conc. Hydrochloric acid in isopropanol the title compound; Mp 180-182 ^* C dec .; Educ. 63%.

7. 2- <Tr4-r3-r4- (5-dimethylaminomethyl-furan-2-v1-methyl) -piperazin-l-yll-propylthio1-3-methyl-2-pyridinyllmethvnthio) -lH-benzimidazole-pentahydrochloride

According to the procedure given in Example 1), 3) and 6), the title compound is obtained with N- (5-dimethylaminomethyl-furan-2-yl-methyl) -piperazine; Mp 150 "C decomp; yield 63%; colorless crystals.

8. 2-frr3-Methv1-4-r3-r4-r (4-methyl-thiazo1-5-y1) -2-ethvn-piperazin-l-vn-propylthiol-2-pyridinvnmethvnthiol-lH-benzimidazole-tri hydrochlo¬ rid

According to the procedure given in Example 1), 3) and 6), the title compound is obtained with N - [(4-methylthiazol-5-yl) -2-ethyl] -piperazine; Mp 120'C dec .; Educ. 57%.

9. 2- (rr4-r3-ι4-benzylpiperazin-l-yl j-propylthiol-S-methoxy ^ -pyridinvn-methyllthiol-lH-benzimidazole-tri vdrochloride

According to the procedure given in Example 1), 3) and 6), the reaction of 2 - {[[4- (3-chloropropylthio) -3-methoxy-2-pyridinyl] methyl] - thio) -lH-benzimidazole with N-benzylpiperazine and subsequent conversion into the hydrochloride the title compound; Mp 180'C dec .; colorless crystals; Educ. 59% of theory

10. 2- (7r4-r3- (4-BenzylDiperidin-l-yl j-propylthiol-S-methoxy ^ -dyridinyn-methylIthiol-1H-Benzi idazole

According to the procedure given in Example 1), the reaction of 2 - {[[4- (3-chloropropylthio) -3-methoxy-2-pyridinyl] methyl] thio) -lH-benzidazole with N-benzylpiperidine gives the Title link; beige powder; Mp 73-75'C (water-containing).

11. methyl lthio-1H-benzimidazole-tri hydrochloride

According to the procedure given in Examples 1), 3) and 6), reaction of 2 - ([[4- (3-chloropropylthio) -3-methoxy-2-pyridinyl] methyl] thio} -lH-benzimidazole is obtained with N-phenylpiperazine and subsequent conversion into the hydrochloride in acetone, the title compound; colorless crystals; mp 105'C decomp.; yield 73%.

12. 2- 4- r3- r4- (5-Ch1 orthiophene-2-yl -πιethyl i -piperazin-l-yl l -proDvI thiol -

0.7 g (1.28 mmol) 2 - {[[4- [3- [4- (5-chlorothiophen-2-ylmethyl) piperazin-l-yl] propylthio] -3-methyl-2 -pyridinyl] methyl] -thio) -lH-benzimidazole are dissolved in a mixture of 15 ml of dioxane and 2.57 ml (5.14 mmole) of 2 M NaOH. 1.63 ml (3.2 mmol) of 12% sodium hypochlorite solution are slowly added dropwise over 30 minutes. Then 2 ml of 1 M sodium thiosulfate solution are added. The mixture is stirred at RT for 10 min. The dioxane is drawn off. The residue is neutralized with sodium dihydrogen phosphate solution and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is mixed with ethyl acetate / methanol / conc. Ammonia = 8.5 / 1 / 0.5 chromatographed on silica gel. The title compound crystallizes on concentration. Educ. 0.3 g (42% of theory) mp 54-58'C. 13. 2-f rr4-r3-ι4-benzylpiperazin-l-yl) -propylthiol-S-methyl ^ -pyridinyll-methyllthiol-S-fluoro-lH-benzimidazole di hydrochloride

Following the procedure given in Example 1), the title is obtained by reacting 2 - {[[4- (3-chloropropylthio) -3-methyl-2-pyridinyl] methylthio) -5-fluoro-1H-benzimidazole with N-benzylpiperazine Compound as beige powder. 80%, m.p. 130-133'C.

14. 2-f rr4-r3-r4- (5-chlorothiophene-2-yl-methyl i-piperazin-l-VIl-propylthiol-S-methyl ^ -pyridinyn-methyn-thio ^' fS-fluoro-lH-benzimidazole

According to the procedure given in Example 1), reaction of 2 - {[[4- (3-chloropropylthio) -3-methyl-2-pyridinyl] methylthio) -5-fluoro-1H-benzimidazole with N- (5- Chlorothiophene-1-yl-methyl) -piperazine after chromatography on silica gel (ethyl acetate / methanol / ammonia - 19: 1: 0.1) and subsequent crystallization from diisopropyl ether, the title compound as a beige powder; Educ. 20%, mp 116-119 ^* C.

15. 2- (rr4-r3-r4- (5-chlorothiophen-2-yl-methyl) -piperazin-l-yl1-propy1thiol-3-methyl-2-pyridinyll-methyll-thio) -5.6-difluoro-lH- benzimidazole

According to the procedure given in Example 1), 2 - {[[4- (3-chloropropylthio) -3-methyl-2-pyridinyl] methylthio} -5,6-di-fluoro-1H-benzimidazole is reacted with N - (5-chlorothiophen-l-yl-methyl) -piperazine and subsequent crystallization from ethyl acetate the title compound as a beige powder; Educ. 50%, mp 79-82'C.

16. 2-frr4-r3-r4- (5-chlorothiophen-2-yl-methyl i-piperazin-l-yll-propylthiol-S-methyl ^ -pyridinyll-methyll-thiol-S-fluoro-e-methoxy-1H -benzimidazole difumarate

According to the procedure given in Example 1) is obtained by reacting 2 - ([[4- (3-chloropropylthio) -3-methyl-2-pyridinyl] methylthio) -5-fluoro-6-methoxy-1H-benzimidazole with N. - (5-chlorothiophen-l-yl-methyl) -piperazine after extraction with ethyl acetate, concentration of the organic extracts and subsequent crystallization with 2 equivalents of fumaric acid from hot acetone, the title compound as a beige powder; Educ. 45%, mp 141-146'C. Output connections

AI. 2-frr4- (3-chloropropylthiol-3-methyl-2-pyridinyllmethvnthio) -lH-benzimidazole

An equivalent of 2-chloromethyl-4- (3-chloropropylthio) -3-methylpyridine hydrochloride is added to a solution of 2-mercapto-1H-benzimidazole (1.5 g / 10 mmol) in 40 ml of ethanol and 21 ml of 1N sodium hydroxide solution (dissolved in 10 ml of water) was added dropwise at 40 ° C. in the course of 20 minutes. The mixture is then stirred for 2-3 hours at 50-60'C and for a further 3-4 hours at room temperature, ethanol is distilled off on a rotary evaporator (1 kPa / 40'C), extracted 3 times with 20 ml of dichloromethane, washed with 0.1 N sodium hydroxide solution, dries over potassium carbonate and completely evaporates in vacuo. For purification, the crude product is chromatographed on silica gel (dichloromethane / methanol 20: 1); the pure fractions collected are concentrated together in vacuo and crystallized from dichloromethane / diisopropyl ether. It is then recrystallized from methanol / toluene. Yield 2.67 g (74%) of the title compound as a colorless solid, mp. 112-114 * C.

A2. 2-chloromethyl-4- (3-chloropropylthio) -3-methylpyridine-hvdrochloride

a) 2,3-Dimethyl-4- (3-hydroxypropylthio) pyridine N-oxide

6 g (60%) NaH are added a little at a time to 50 ml of dry N-methylpyrrolidone (NMP), the mixture is stirred for 15 minutes, and 9.5 g (0.11 mol) of 3-hydroxypropyl mercaptan are added within 20 Min. Metered in and the mixture is stirred again for 30 minutes until the evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine-N-oxide in 100 ml of NMP is then added dropwise in the course of 20 minutes, and the reaction mixture is stirred at room temperature for 1 hour and then 1 h at 70'C and then 1 h at 100'C.

After the reaction is allowed to cool, diluted with 500 ml of water and extracted 4 times with 300 ml of dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate, concentrated and crystallized from toluene. After recrystallization from methanol / to toluene gives the title compound as a beige solid, mp. 106-107'C (sublimed): yield: 68% of theory

b) 2-Hydro ^χ ymethyl -4- (3-hvdroχypropyl thio, -3-methyl pyridine

The yellow oil obtained under a) is dissolved in 100 ml of acetic anhydride, and the mixture is stirred at 100'C for 2 h. After concentration in vacuo, the brown, oily residue is distilled in a Kugelrohr distillation apparatus and further reacted without purification.

The oily distillate is heated to reflux temperature in 100 ml of 2N sodium hydroxide solution and 100 ml of isopropanol with stirring for 2 hours, isopropanol is distilled off, the residue is extracted 3 times with 100 ml of dichloromethane each time, the combined organic phases are washed with water, dried over potassium carbonate and in vacuo constricted. 5.0 g of 2-hydroxymethyl-4- (3-hydroxypropylthio) -3-methylpyridine are obtained, which is reacted further without purification. Isopropanol can be used with conc. Hydrochloric acid produce a monohydrochloride of the title compound; M.p. 188-190'C (dec.).

c) 2-Chloromethyl -4- (3-ch1 orpropyl thio) -3-methyl pyridine-hydrochloride

5.0 g of the oil from b) are dissolved in dichloromethane (100 ml), 4 equivalents of thionyl chloride are added dropwise and the mixture is stirred at room temperature for 20 h. It is concentrated completely and 4.5 g of the title compound are obtained as an oily, gradually crystallizing residue. Crystallization from isopropanol / diisopropyl ether gives d. Title compound as a colorless solid; 142-144'C (dec.).

Bl. 2- rr4- (2-chloroethv1thio) -3-methv1-2-dyridinyl1methyllthio) -lH-benzimidazole

According to the example in AI. The procedure given is obtained by reacting 2-mercapto-1H-benzimidazole with 4- (2-chloroethylthio) -2-chloromethyl-3-methylpyridine hydrochloride and NaOH after crystallization from ethyl acetate to give the title compound (62% of theory) as a colorless solid, mp. 178-180'C. B2. 4- (2-Ch1 orethv1 thiol -2-ch1 ormethyl -3-methy1 pyridi n-Hvdrochl orid

a) 2, 3-Dimethyl -4- (2-hvdroethylyethyl thiθ jpyridi n-N-oxi d

According to the procedure given in Example A2.a), the title compound is obtained as an oily residue by reacting 4-chloro-2,3-dimethylpyridine-N-oxide with 2-mercaptoethanol and sodium hydride and is used in the subsequent step without further purification becomes.

b) 4- (2-Hydroχyethy1 thiθ j -2-hydroχymethy1 -3-methyl pyridine

According to the procedure given in Example A2.b), by reacting the oil obtained under a) with acetic anhydride and then saponifying with NaOH, the title compound is obtained as an oily residue which is used in the subsequent step without further purification.

c) 4- (2-Chloroethyl thio) -2-chloroethyl -3-methyl1 pyridine-hydrochloride

According to the procedure given in Example A2.c), the title compound is obtained as an oily residue by reacting the oil obtained under b) with thionyl chloride, which is used directly as a solution in ethanol for reaction with 2-mercaptobenzimidazole.

Cl. 2-frr4-f3-chloropropylthio) -3-methoxy-2-pyridinev11methynthio) -lH-benzimidazole dihydrochloride

2-Mercapto-1H-benzimidazole (10 g) and 2-chloromethyl-4- (3-chloropropylthio) - 3-methoxypyridine hydrochloride (1 equivalent) are stirred in 150 ml of isopropanol and 15 ml of water for 5 h at 80'C, cooled, filtered from the precipitated solid and recrystallized from isopropanol / water. The title compound is obtained as a light brown powder; M.p. 117-119 ^* C (dec.); Education: 67% of theory

C2. 2-Chloromethv1-4- (3-chloropropylthio) -3-methoxy pyridine hydrochloride

According to the procedure described in Example A2.a), b) and c, starting from 4-chloro-3-methoxy-2-methylpyridine-N-oxide, the title compound is obtained as a slowly crystallizing oil, which is directly reacted further. Dl. 2-frr4- (3-chloropropylthio) -3-methyl-2-pyridinyllmethy11thio) -lH-imi-dazo-f4.5-bl-pyridine-dihydrochloride

According to the example in Cl. The procedure described is obtained in the reaction of 2-mercapto-1H-imidazo [4,5-b] pyridine with 2-chloromethyl-4- (3-chloropropylthio) -3-methyl-pyridine hydrochloride as the title compound colorless powder; M.p. 186-188'C; Education: 88% of theory

El. 2-frr4- (3-chloropropylthio) -3-methyl-2-pyridinomethylthio -5-fluoro-lH-benzide idazole

According to the example in AI. The procedure given is obtained by reacting 5-fluoro-2-mercapto-1H-benzimidazole with 4- (2-chloroethylthio) -2-chloromethyl-3-methylpyridine hydrochloride and NaOH after crystallization from isopropanol to give the title compound (94% of theory .Th.) As a colorless solid with mp. 188-19rC.

Fl. 2-frr4- (3-chloropropylthio) -3-methyl-2-pyridinyllmethv1thio) -5.6-dif1u- or-1H-benzimidazole dihydrochloride

According to the example in AI. The procedure given is obtained by reacting 5,6-difluoro-2-mercapto-1H-benzimidazole with 4- (2-chloroethylthio) -2-chloromethyl-3-methylpyridine hydrochloride and NaOH after crystallization from ethyl acetate to give the title compound (90 % of theory) as a colorless solid with a melting point of 205 ^* C.

Eq. 2- (rr4- (3-Chloropropylthiθι-3-methy1-2-pyridinvπmethylthio) -5-fluorine-6-methoxy-1H-benzimidazole dihydrochloride

According to the example in AI. The procedure given is obtained by reacting 5-fluoro-6-methoxy-2-mercapto-1H-benzimidazole with 4- (2-chloroethylthio) -2-chloromethyl-3-methylpyridine hydrochloride and NaOH after crystallization from ethyl acetate the title compound (96% of theory) as a colorless solid, mp. 203-205'C. Industrial applicability

The excellent activity of compounds of the formula I and their salts against Helicobacter bacteria permits their use in human medicine as active ingredients for the treatment of diseases which are based on Helicobacter bacteria.

The invention therefore furthermore relates to a method for the treatment of mammals, in particular humans, who are suffering from diseases which are based on Helicobacter bacteria. The method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically tolerable amount of one or more compounds of the formula I and / or their pharmacologically tolerable salts.

The invention also relates to the compounds of the formula I and their pharmacologically tolerable salts for use in the treatment of diseases which are based on Helicobacter bacteria.

The invention also encompasses the use of compounds of the formula I and their pharmacologically tolerable salts in the preparation of medicaments which are used to combat diseases which are based on Helicobacter bacteria.

The invention further relates to medicaments for combating Helicobacter bacteria which contain one or more compounds of the general formula I and / or their pharmacologically tolerable salts.

Of the Helicobacter strains against which the compounds of the formula I have proven to be effective, the Helicobacter pyori strain should be mentioned in particular.

The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The pharmacologically active compounds of the formula I and their salts (active ingredients) are used as pharmaceuticals either as such or preferably in combination with suitable pharmaceutical auxiliaries, for example in the form of tablets, dragées, capsules, emulsions, suspensions. Pensions, gels or solutions are used, the active substance content advantageously being between 0.1 and 95%.

The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, tablet auxiliaries and other active ingredient carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyclodextrins) can be used.

The active substances can, for example, be administered parenterally (e.g. intravenously) or in particular orally.

In general, the active ingredients in human medicine are administered in a daily dose of about 0.2 to 50, preferably 1 to 30 mg / kg of body weight, optionally in the form of several, preferably 2 to 6, individual doses to achieve the desired result .

In this context, it should be mentioned as an aspect essential to the invention that the compounds of the formula I, in which n is the number 0, are effective against Helicobacter bacteria when administered, such doses which are below the doses used for education an inhibition of gastric acid secretion which suffices for therapeutic purposes would have to be used.

Compounds of the formula I in which n denotes the number 1 have, in addition to their activity against Helicobacter bacteria, also a pronounced inhibition of gastric acid secretion. Accordingly, these compounds can also be used to treat diseases which are based on increased gastric acid secretion.

The compounds according to the invention can also be administered in a fixed or free combination together with a substance which neutralizes gastric acid and / or inhibits gastric acid secretion and / or with a substance suitable for the classic control of Helicobacter pylori. Examples of substances which neutralize gastric acid are sodium hydrogen carbonate or other antacids (such as aluminum hydroxide, magnesium aluminate or magaldrate). Examples of substances which inhibit gastric acid secretion are H _? Blockers (e.g. cimetidine, ranitidine),

+ +

H / K -ATPase inhibitors (e.g. lansoprazole, omeprazole or in particular pantoprazole) as well as so-called peripheral anticholinergics (e.g. pirenzepin, telenzepin).

Substances which are suitable for the classic control of Helicobacter pylori are, in particular, antimicrobially active substances, such as, for example, penicillin G, gentamycin, erythromycin, nitrofurazone, tinidazole, nitrofurantoin, furazolidone, metronidazole and in particular amoxycilelin, or else bismuth salts such as eg called bismuth trustee.

Biological studies

The compounds of the formula I were tested for their activity against Helicobacter pylori based on that of Tomoyuki Iwahi et al. (Antimicrobial Agents and Chemotherapy, 1991, 490-496) the methodology described using Columbia agar (Oxoid) and with a growth period of 4 days. The approx. MIC 50 values listed in Table A below resulted for the compounds examined (the numbers of the compounds given correspond to the example numbers in the description).

TABLE A

Connection approx. MIC 50

No. (µg / ml)

1 ≤ 0.5

2 ≤ 0.5

3 ≤ 0.5

4 ≤ 0.5

5 ≤ 0.5

6 ≤ 0.5

7 <0.5

8 ≤ 0.5

9 <0.5

10 <0.5

11 ≤ 0.5

Claims

claims

1. Compounds of the formula I

wherein

R1 is hydrogen, 1-4C-A1kyl, 1-4C-alkoxy or halogen, R2 is hydrogen, 1-4C-A1kyl, 1-4C-alkoxy, halogen or trifluoroethyl,

R3 is hydrogen, 1-4C-alkyl, 1-4C-alkyl substituted by R4, 1-4C-A1-alkylcarbonyl, 2-4C-A1kenylcarbonyl, halogen-1-4C-alkylcarbonyl, N (R14) R15-1-4C- means alkylcarbonyl, di-1-4C-alkylcarbamoyl or 1-4C-alkylsulfonyl,

R4 denotes hydroxy, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl or -N (R14) R15,

R5 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy, R6 denotes a cycle or bicyclic substituted by R8 and R9, which is selected from the group consisting of benzene, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, Thiazoline, isothiazole, imidazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole, thiadiazole-1-oxide, oxadiazole, pyridine, pyridine-N-oxide, pyrimidine, triazine, pyridone, benzimidazole, imidazopyridine, benzothiazole and benzoxazol

R7 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy, R8 is hydrogen, 1-4C-alkyl, hydroxy, 1-4C-alkoxy, halogen, nitro, guanidino, carboxy, 1-4C-alkoxycarbonyl RIO is substituted 1-4C-alkyl or -N (R11) R12,

R9 is hydrogen, 1-4C-alkyl, hydroxy, 1-4C-alkoxy, halogen or trifluoromethyl, RIO is hydroxy, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl or -N (R11) R12, where R11 is hydrogen, 1-4C-A1kyl or -C0-R13 and R12 is hydrogen or 1-4C-A1 yl , or wherein R11 and R12 together and including the nitrogen atom to which both are attached represent a piperidino or morpholino radical, R13 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy, R14 is 1-4C-alkyl and R15 1-4C-A1kyl, or where R14 and R15 together and including the nitrogen atom to which both are attached represent a piperidino or morpholino radical, W is CH or N,

X represents 0 (oxygen), N-1-4C-alkyl or S (sulfur), Y represents N or CH,

Z is 0 (oxygen), CO (carbonyl), S (sulfur) or S0 ₂ , m is a number from 2 to 5, n is 0, 1 or 2, r is a number from 0 to 5, u is one Is from 0 to 3 and v is 0 or 1 and their salts, where R6 is not benzene if R5 is hydrogen or 1-4C-alkyl and v is 0, r is not 0 if YN and Z are 0, S or S0 ₂ , Z is not S0 ₂ when u is 0 and v is 1, and where R6 is not a cycle or bicyclic bond via N (nitrogen) when Z is 0, S or SO-, v is the number 1 and u is the number 0.

2. Compounds of formula I according to claim 1, wherein Rl is hydrogen, 1-4C-alkoxy or halogen, R2 is hydrogen or halogen,

R3 is hydrogen, 1-4C-alkyl substituted by R4, N (R14) R15-1-4C-alkylcarbonyl or 1-4C-alkylsulfonyl, R4 -N (R14) R15 means

R5 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy,

Thiazole, imidazole, triazole, pyridine, pyrimidine and pyridone, R7 is hydrogen, R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen, nitro or R4-substituted 1-4C-alkyl, R9 is hydrogen, 1- 4C-alkyl or fluorine, RIO -N (R11) R12, where R11 is 1-4C-alkyl and R12 is 1-4C-alkyl, or where R11 and R12 together and including the nitrogen atom to which both are bonded, represent a piperidino or morpholino radical, R14 denotes 1-4C-alkyl and R15 1-4C-alkyl, or wherein R14 and R15 together and including the nitrogen atom to which both are bonded represent a piperidino or morpholino radical, W CH or N means

X represents 0 (oxygen) or S (sulfur), Y represents N or CH,

Z is 0 (oxygen), CO (carbonyl), S (sulfur) or SO-, m is a number from 2 to 4, n is 0 or 1, r is a number from 0 to 3, u is a number of 0 to 2 and v denotes the number 0 or 1 and their salts, where R6 is not benzene if R5 is hydrogen or 1-4C-alkyl and v is 0, r is not 0 if YN and Z is 0, S or SO-, Z is not S0 ₂ when u is 0 and v is 1 and R6 is not a cycle or bicyclic bond via N (nitrogen) when Z is 0, S or SO -, v is the number 1 and u is the number 0.

3. Compounds of formula I according to claim 1, wherein Rl is hydrogen,

R2 means hydrogen

R3 means hydrogen,

R5 denotes 1-4C-alkyl or 1-4C-alkoxy,

Alkyl means R9 means hydrogen, RIO means -N (R11) R12, where R11 means 1-4C-alkyl and R12 means 1-4C-alkyl, W means CH, X means S (sulfur), Y means N or CH,

Z denotes CO (carbonyl) or S (sulfur), m denotes the number 3, n denotes the number 0, r denotes a number from 0 to 3, u denotes the number 0 and v denotes the number 0 or 1 and their salts, where R6 is not benzene when R5 is 1-4C alkyl and v is 0, and where r is not 0 when Y is N and ZS.

4. Compounds of formula I according to claim 1, wherein v denotes the number 1, Z denotes CO (carbonyl), r denotes the number 0 and u denotes the number 0.

5. Compounds of formula I according to claim 1, wherein v is 1, Z is S (sulfur), Y is N, r is 2 or 3 and u is 0 or 1.

6. Compounds of formula I according to claim 1, wherein v is the number 0 and r is a number from 0 to 3.

7. Compounds of formula I according to claim 1, wherein R5 is 1-4C-alkoxy and R6 is substituted by R8 and R9 benzene.

8. A process for the preparation of the compounds of formula I according to claim 1 and their salts, characterized in that

a) mercaptobenzimidazoles of the formula II (see attached formula sheet II), in which W, Rl, R2 and R3 have the meanings given in claim 1, with picoline derivatives III (see attached formula sheet II), in which R5, R6, R7, X, Y, Z, m, r, u and v have the meanings given in Claim 1 and A represents a suitable leaving group, or is reacted

b) Compounds of the formula IV (see attached formula sheet II), in which W, Rl, R2, R3, R5, R7, X and m have the meanings given in claim 1, n, the number 0 and A being a suitable leaving group represents, with compounds of the formula V (see attached formula sheet II), in which R6, Y, Z, r, u and v have the meanings given in claim 1, or that

c) compounds of the formula VI (see attached formula sheet III), in which W, Rl, R2, R3, R5, R7 and n have the meanings given in claim 1 and shark represents a halogen atom, with compounds VII (see attached formula sheet III), wherein R6, X, Y, Z, m, r, u and v have the meanings given in claim 1, or that

d) Benzimidazoles of the formula VIII (see enclosed formula sheet III), in which Rl, R2, R3 and W have the meanings given in claim 1 and A represents a suitable leaving group, with pyridines of the formula IX (see enclosed formula sheet III), in which R5, R6, R7, X, Y, Z, m, r, u and v have the meanings given in claim 1, and

(if compounds of the formula I with n = 1 or 2 and / or Z = S0 _{2 are} the desired end products) that the compounds obtained are subsequently oxidized with n-0 and / or ZS, and / or that If desired, the compounds obtained are subsequently converted into the salts and / or if desired, the salts obtained are subsequently converted into the free compounds.

9. Use of compounds of formula I according to claim 1 and / or their pharmacologically acceptable salts in the control of Helicobacter bacteria.

10. Use of compounds of formula I according to claim 1 and their pharmacologically acceptable salts for the manufacture of medicaments for combating Helicobacter bacteria.