7-SUBSTITUTED BENZIMIDAZOLES AND THEIR USE AS INHIBITORS OF GASTRIC ACID SECRETION

BENZIMIDAZOLES A SUBSTITUTION 7 ET UTILISATION DE CES DERNIERS EN TANT QU'INHIBITEURS DE LA SECRETION D'ACIDE GASTRIQUE

English Abstract

The invention provides compounds of the formula (1), in which the substituents
and symbols are as defined in the description. The compounds inhibit the
secretion of gastric acid.

French Abstract

La présente invention concerne des composés représentés par la formule (1), dans laquelle les substituants et les symboles sont tels que définis dans le descriptif. Ces composés inhibent la sécrétion d'acide gastrique. Formule (1)

Claims

-39-
Claims
We claim:
1 A compound of the formula 1
<IMG>
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl, flu-
oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,

-40-
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O (oxygen) or NH and
Y has either the meaning -CH2-Ar
wherein
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
or Y denotes the group gp
<IMG>
wherein
Z has the meaning -CHR8- or -CHR8-CHR9-
where in, Ar and/or in the group gp
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-
alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy,
aryl-1-
4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-
alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-
4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl or hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-
1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy
R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-

-41-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,
and wherein
aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
and its salts.
2. A compound of the formula 1 as claimed in claim 1,
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl,
fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,

-42-
X is O (oxygen) or NH and
Y has either the meaning -CH2-Ar
wherein
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
or Y denotes the group gp
<IMG>
wherein
Z has the meaning -CHR8- or-CHR8-CHR9-
where in, Ar and/or in the group gp
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-
alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy,
aryl-1-
4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-
alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-
4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl or hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-
1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy
R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,
and wherein

-43-
aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
with the proviso that R3 does not have the meaning hydrogen when R1 and R2
have the
meanings hydrogen or 1-4C-alkyl and Y denotes CH2-phenyl or a CH2-phenyl
substituted by a
1-4C-alkoxy radical,
and its salts.
3. A compound of the formula 1 as claimed in claim 1,
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl,
fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,

-44-
X is O (oxygen) or NH and
Y has either the meaning -CH2-Ar
wherein
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
or Y denotes the group gp
<IMG>
wherein
Z has the meaning -CHR8- or -CHR8-CHR9-
where in, Ar and/or in the group gp
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-
alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy,
aryl-1-
4C-alkoxy, trifluoromethyl, fluoro-l-4C-alkoxy, nitro, amino, mono- or di-1-4C-
alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-
4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl or hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-
1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy
R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,
and wherein

-45-
aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
with the proviso that R3 does not have the meaning hydrogen or halogen when R1
denotes
hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl, R2 denotes hydrogen, 1-4C-alkyl
or 3-7C-
cycloalkyl-1-4C-alkyl and Y denotes CH2-Ar,
and its salts.
4. A compound of the formula 1 as claimed in claim 1, characterized by the
formula 1 a
<IMG>
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl, flu-
oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,

-46-
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O (oxygen) or NH,
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
fluoro-l-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino,
1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
Aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
and its salts.
5. A compound of the formula 1 a as claimed in claim 4,
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl,
fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

-47-
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O (oxygen) or NH,
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
fluoro-l-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino,
1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
Aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
with the proviso that R3 does not have the meaning hydrogen when R1 and R2
have the
meanings hydrogen or 1-4C-alkyl and Ar is phenyl or a phenyl substituted by a
1-4C-alkoxy
radical,
and the salts of these compounds.
6. A compound of the formula 1 a as claimed in claim 4,

-48-
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl,
fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl; aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O (oxygen) or NH,
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,

-49-
fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino,
1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
Aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
with the proviso that R3 does not have the meaning hydrogen or halogen when RI
denotes
hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl and R2 denotes hydrogen, 1-4C-
alkyl or 3-7C-
cycloalkyl-1-4C-alkyl,
and its salts
7. A compound of the formula 1 as claimed in claim 1, characterized by the
formula 1b
<IMG>
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-14C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-l-4C-
alkyl,
fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and

-50-
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O(oxygen) or NH and
Z has the meaning -CHR8- or-CHR8-CHR9-
where
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-
alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbomyl, halogen,
trifluoromethyl or
hydroxy,
R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-
alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy
R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-
alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,
and wherein

-51-
aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
and its salts.
8. A compound of the formula 1a as claimed in claim 4, characterized by the
formula 1a-1
<IMG>
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-
1-4C-alkyl,
R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1-4C-alkoxy-1-4C-alkyl
R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,
cyano, the
group -CO-NR31R32, the group SO2-NR31R32 or the group Het,
where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-
cycloalkyl or
amino and
R32 is hydrogen or 1-7C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol and dihydroimidazol,
where
R33 is hydrogen or 1-4C-alkyl,
R34 is hydrogen or 1-4C-alkyl
R35 is hydrogen or 1-4C-alkyl
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-
alkoxycarbonyl, trifluoro-
methyl, fluoro-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-
alkoxycarbonylamino,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and
X is O (oxygen) or NH,
and its salts.

-52-
9. A compound of the formula 1a-1 as claimed in claim 8, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 the group -CO-NR31R32,
where
R31 is 1-4C-alkyl and
R32 is 1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyrrolidino
group,
R4 is 1-4C-alkyl
R5 is 1-4C-alkyl,
X is NH,
and their salts.
10. A compound of the formula 1a-1 as claimed in claim 8, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 the group -CO-NR31R32,
where
R31 is 1-4C-alkyl and
R32 is 1-4C-alkyl,
R4 is 1-4C-alkyl
R5 is 1-4C-alkyl,
X is NH,
and its salts.
11. A compound of the formula 1b as claimed in claim 7, characterized by the
formula 1b-1
<IMG>
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-
1-4C-alkyl,
R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1-4C-alkoxy-1-4C-alkyl
R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,
cyano, the
group -CO-NR31R32, the group SO2-NR31R32 or the group Het,
where

-53-
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-
cycloalkyl or
amino and
R32 is hydrogen or 1-7C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol and dihydroimidazol,
where
R33 is hydrogen or 1-4C-alkyl,
R34 is hydrogen or 1-4C-alkyl
R35 is hydrogen or 1-4C-alkyl
R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
R5 is hydrogen or 1-4C-alkyl,
R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-
7C-cycloalkyl-
1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-
alkoxy-1-
4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-l-4C-alkoxy-1-4C-
alkoxy, 1-
4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-
4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-
alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-
alkylcarbonyloxy
X is O (oxygen) or NH,
and its salts.
12. A compound of the formula 1b-1 as claimed in claim 11, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is the group -CO-NR31R32,
where
R31 is 1-4C-alkyl,
R32 is 1-4C-alkyl
R4 is hydrogen
R5 is hydrogen,
R8 is hydroxyl
X is O (oxygen)
and its salts.
13. A medicament comprising a compound as claimed in claim 1 and/or a
pharmacologically ac-
ceptable salt thereof together with customary pharmaceutical auxiliaries
and/or excipients.

-54-
14. The use of a compound as claimed in claim 1 and its pharmacologically
acceptable salts for
the prevention and treatment of gastrointestinal disorders.

Description

CA 02566821 2006-11-14
WO 2005/111000 PCT/EP2005/052196
-1-
Description
Title
7-SUBSTITUTED BENZIMIDAZOLES AND THEIR USE AS INHIBITORS OF
GASTRIC ACID SECRETION
Technical field
The invention relates to novel compounds which are used in the pharmaceutical
industry as active
compounds for the production of medicaments.
Background Art
In the European patent application EP 0266326 (which corresponds to US Patent
5,106,862), ben-
zimidazole derivatives having a broad variety of substituents are disclosed
which are said to be ac-
tive as anti-ulcer agents. In the intemational patent application WO 97/47603
(which corresponds
to the US Patent 6,465,505), benzimidazole derivatives having a very specific
substitution pattem
are disclosed, which are said to be suitable for inhibition of gastric acid
secretion and thus can be
used in the prevention and treatment of gastrointestinal inflammatory
diseases.
Torigoe et al. describe in Phytochemistry, 1972, 11, 1623 the cytokinin
activity of azaindene,
azanaphtalene, naphtalene and indole derivatives in the tobacco pith callus
bioassay.
Dincer et aI. describe in Indian Joumal of Chemistry, Section B, 1995, 34
(11), 982 the synthesis of
4-(substituted benzylamino)benzimidazole derivatives which compounds are
expected to give an
insight into the relationship between their structures and cytokinin activity.
The US Patent 6,083,961 describes benzimidazole oompounds which have
activities as bradykinin
antagonists and are said to be useful for treating several diseases such as
allergy, inflammation,
autoimmune disease, shock, pain or the like.
Brauninger et aI. describe in Archiv der Pharmazie, 1966, 299 (3), the
synthesis of some benzimi-
dazole derivatives and their kinetin activity.
In the Intemational patent application WO 04/054984, 4-substituted
benzimidazole derivatives hav-
ing a broad variety of substituents are disclosed, which compounds are useful
in the prevention and
treatment of gastrointestinal disorders.
In the intemational patent application WO 94/18199 (which corresponds to US
Patent 5,665730),
imidazopyridine derivatives and their use in treating gastrointestinal
diseases is disclosed.

CA 02566821 2006-11-14
WO 2005/111000 PCT/EP2005/052196
-2-
Disclosure of Invention
Technical problem
A whole series of compounds are known from the prior art which inhibit gastric
acid secretion
by blockade of the H+/K+-ATPase. The compounds designated as proton pump
inhibitors
(PPI's), for example omeprazole, esomeprazole, lansoprazole, pantoprazole or
rabeprazole,
bind irreversibly to the H+/K+-ATPase. PPI's are available as therapeutics for
a long time al-
ready. A new class of compounds designated as reversible proton pump
inhibitors (rPPI's) or
as acid pump antagonists (APA's) bind reversibly to the H+/K+-ATPase. Although
rPPI's or
APA's are known for more than 20 years and many companies are engaged in their
develop-
ment, no rPPI or APA is at present available for therapy. The technical
problem underlying the
present invention is therefore to provide acid pump antagonists which can be
used in therapy.
Technical solution
The invention relates to compounds of the formula 1
R3 / N
\>R1 (1)
~ N
'X R2
in yrhich
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-l-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1 -4C-
alkyl, flu-
oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and

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Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O(oxygen) or NH and
Y has either the meaning -CH2-Ar
wherein
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyi, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
or Y denotes the group gp
R4
R5~(gp)
z
wherein
Z has the meaning -CHR8- or -CHR8-CHR9-
where in, Ar and/or in the group gp
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-
alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy,
aryl-1-
4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-
alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-
4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl or hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-

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alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-l-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-l-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-
1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-alkylcarbonyloxy
R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-alkylcarbonyloxy,
and wherein
aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
and the salts of these compounds.
1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4
carbon atoms. Ex-
amples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl,
propyl, isopropyl,
ethyl and the methyl group.
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and cycloheptyl, of
which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl
groups,
which is substituted by one of the aforementioned 3-7C-cycloalkyl groups.
Examples
which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the
cyclohexylethyl group.
1-4C-Alkoxy represents groups, which in addition to the oxygen atom contain a
straight-chain
or branched alkyl group having I to 4 carbon atoms. Examples which may be
mentioned are
the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and
preferably the ethoxy
and methoxy group.
1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups,
which is sub-
stituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may
be mentioned
are the methoxymethyl, the methoxyethyl group and the butoxyethyl group.

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1-4C-Alkoxycarbonyl (-CO-1-4C-alkoxy) represents a carbonyl group, to which
one of the
aforementioned 1-4C-alkoxy groups is bonded. Examples which may be mentioned
are the
methoxycarbonyl (CH3O-C(O)-) and the ethoxycarbonyl group (CH3CH2O-C(O)-) .
2-4C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to
4 carbon at-
oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl
and the 2-
propenyl group (allyl group).
2-4C-Alkynyl represents straight-chain or branched alkynyl groups having 2 to
4 carbon atoms.
Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably
the 2-
propynyl, group (propargyl group).
Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups,
which is substi-
tuted by one or more fluorine atoms. An example which may be mentioned is the
trifluoro-
methyl group.
Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl groups, which are
substituted by a
hydroxy group. Examples which may be mentioned are the hydroxymethyl, the 2-
hydroxyethyl
and the 3-hydroxypropyl group.
1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group
contains one of
the aforementioned 1-4C-alkyl groups. An example which may be mentioned is the
acetyl
group.
Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by
one or by two
- identical or different - groups from the aforementioned 1-4C-alkyl groups.
Examples which
may be mentioned are the dimethylamino, the diethylamino and the
diisopropylamino group.
Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl
group, which
is substituted by a mono- or di-1-4C-alkylamino groups. Examples, which may be
mentioned,
are the dimethylamino-methylcarbonyl and the dimethylamino-ethylcarbonyl
group.
Fluoro-2-4C-alkyl represents a 2-4C-alkyl groups, which is substituted by one
or more fluorine
atoms. An example which may be mentioned is the 2,2,2-trifluoroethyl group.
Aryl-1-4C-alkoxy denotes an aryl-subsfituted 1-4C-alkoxy radical. An example
which may be
mentioned is the benzyloxy radical.

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Aryl-1-4C-alkoxy-1-4C-alkyl denotes one of the aforementioned 1-4C-alkyl
groups, which is
substituted by one of the aforementioned aryl-1-4C-alkoxy radicals. An example
which may be
mentioned is the benzyloxymethyl radical.
Halogen within the meaning of the invention is bromo, chloro and fluoro.
1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy
groups, which is
substituted by a further 1-4C-alkoxy group. Examples which may be mentioned
are the groups
2-(methoxy)ethoxy (CH3-O-CH2-CH2-O-) and 2-(ethoxy)ethoxy (CH3-CH2-O-CHa-CH2-O-
).
1-4C-Alkoxy-1-4C-alkoxy-1-4C-aIkyl represents one of the aforementioned
1-4C-alkoxy-1-4C-alkyl groups, which is substituted by one of the
aforementioned 1-4C-alkoxy
groups. An example which may be mentioned is the group 2-(methoxy)ethoxymethyl
(CH3-O-CH2-CH2-O-CH2-).
Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl
groups, which
is substituted by a fluoro-1-4C-alkoxy group. Fluoro-1-4C-alkoxy in this case
represents one of
the aforementioned 1-4C-alkoxy groups, which is completely or mainly
substituted by fluorine.
Examples of completely or mainly fluoro-substituted 1-4C-alkoxy groups which
may be men-
tioned are the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-
propoxy, the 1,1,1-
trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-
1-butoxy, the 4,4,4-
trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the
1,2,2-trifluoroeth-
oxy, in particular:the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy,
the trifluoromethoxy
and preferably the difluoromethoxy group. Examples of fluoro-1-4C-alkoxy-1-4C-
alkyl radicals
which may be mentioned are 1,1,2,2-tetrafluoroethoxymethyl, the 2,2,2-
trifluoroethoxymethyl,
the trifluoromethoxymethyl, the 1,1,2,2-tetrafluoroethoxyethyl, the 2,2,2-
trifluoroethoxyethyl,
the trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the
difluorometh-
oxyethyl radicals.
1-7C-Alkyl represents straight-chain or branched alkyl groups having I to 7
carbon atoms. Ex-
amples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl),
hexyl, isohexyl
(4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-
methylbutyl), neopentyl
(2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl,
isopropyl, ethyl and the
methyl group.
2-4C-Alkenyloxy represents groups, which in addition to the oxygen atom
contain one of the
abovementioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the
2-
butenyloxy, 3-butenyloxy, 1-propenyloxy and the 2-propenyloxy group (allyloxy
group).

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Carboxy-1-4C-alkyl represents 1-4C-alkyl groups which are substituted by a
carboxyl group.
Examples, which may be mentioned, are the carboxymethyl and the 2-carboxyethyl
group.
1-4C-Alkoxycarbonyl-1-4C-alkyl represents 1-4C-alkyl groups, which are
substituted by one of
the abovementioned 1-4C-alkoxycarbonyl groups. Examples, which may be
mentioned, are
the Methoxycarbonylmethyl and the ethoxycarbonylmethyl group.
Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical. An example
which may be men-
tioned is the benzyl radical.
1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-
alkylcarbonyl group is
bonded. Examples which may be mentioned are the propionylamino (C3H7C(O)NH-)
and the
acetylamino group (acetamido group) (CH3C(O)NH-).
1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by
one of the
aforementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned,
are the
ethoxycarbonylamino and the methoxycarbonylamino group.
1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of
the aforemen-
tioned 1-4C-alkoxy-1-4C-alkoxy groups is bonded. Examples which may be
mentioned are the
2-(methoxy)ethoxycarbonyl (CH3-O-CH2CHa-O-CO-) and the 2-
(ethoxy)ethoxycarbonyl group
(CH3CH2-O-CH2CH2-O-CO-).
1-4C-Alkoxy-l-4C-alkoxycarbonylamino represents an amino group, which is
substituted by
one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Examples
which may be
mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-
(ethoxy)ethoxycarbonylamino
group.
2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to
7 carbon at-
oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl,
the 2-
propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups
are preferred.
2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to
7 carbon at-
oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl,
the 2-
propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups
are preferred.
Oxo-substituted 1-4C-alkoxy represents a 1-4C-alkoxy group, which instead of a
methylene
group contains a carbonyl group. An example which may be mentioned is the 2-
oxopropoxy
group.

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3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy
and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy
are preferred.
3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy
groups, which
is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples
which may be
mentioned are the cyclopropylmethoxy, the cyclobutylmethoxy and the
cyclohexylethoxy
group.
Hydroxy-1-4C-alkoxy represents aforementioned 1-4C-alkoxy groups, which are
substituted by
a hydroxy group. A preferred example which may be mentioned is the 2-
hydroxyethoxy group.
1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-
alkoxy
groups, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-
alkoxy groups. A
preferred example which may be mentioned is the methoxyethoxyethoxy group.
3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy
groups,
which is substituted by one of the aforementioned 3-7C-cycloalkoxy groups.
Examples which
may be mentioned are the cyclopropoxymethoxy, the cyclobutoxymethoxy and the
cyclohexy-
loxyethoxy group.
3-7C-Cycloalkyl-1-4C-alkoxy-1 -4C-alkoxy represents one of the aforementioned
1-4C-alkoxy
groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl-1-4C-
alkoxy
groups. Examples which may be mentioned are the cyclopropylmethoxyethoxy, the
cyclobu-
tylmethoxyethoxy and the cyclohexylethoxyethoxy group.
1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to
an oxygen
atom. An example which may be mentioned is the acetoxy group (CH3CO-O-).
1-4C-Alkylcarbonyloxy-1-4C-alkyl represents one of the aforementioned 1-4C-
alkyl groups,
which is substituted by one of the aforementioned 1-4C-alkylcarbonyloxy
groups. An example
which may be mentioned is the acetoxymethyl group (CH3C0-O-CH2).
Halo-1-4C-alkoxy represents 1-4C-alkoxy groups which are completely or mainly
substituted
by halogen. "Mainly" in this connection means that more than half of the
hydrogen atoms in
the 1-4C-alkoxy groups are replaced by halogen atoms. Halo-1-4C-alkoxy groups
are primarily
chloro- and/or in particular fluoro-substituted 1-4C-alkoxy groups. Examples
of halogen-
substituted 1-4C-alkoxy groups which may be mentioned are the 2,2,2-
trichloroethoxy, the
hexachloroisopropoxy, the pentachloroisopropoxy, the 1,1,1-trichloro-3,3,3-
trifluoro-2-propoxy,
the 1,1,1-trichloro-2-methyl-2-propoxy, the 1,1,1-trichloro-2-propoxy, the 3-
bromo-1,1,1-
trifluoro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-butoxy, the 4-bromo-3,3,4,4-
tetrafluoro-1-

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butoxy, the chlorodifluoromethoxy, the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-
trifluoromethyl-
2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the
2,2,3,3,4,4,4-
heptafluoro-l-butoxy, the 4,4,4-trifluoro-l-butoxy, the 2,2,3,3,3-
pentafluoropropoxy, the per-
fluoroethoxy, the 1,2,2-trifluoroethoxy, in par6cularthe 1,1,2,2-
tetrafluoroethoxy, the
2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy
group.
Mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy represents a 1-4C-
alkylcarbonyloxy group,
which is substituted by one of the aforementioned mono- or di-1-4C-alkylamino
groups. Ex-
amples, which may be mentioned, are the dimethylamino-methylcarbonyloxy and
the
dimethylamino-ethylcarbonyloxy group.
1-4C-Alkoxy-1-4C-alkylcarbonyloxy represents one of the aforementioned 1-4C-
alkylcarbonyloxy radicals which is substituted by one of the aforementioned 1-
4C-alkoxy
groups. An example, which may be mentioned, is the methoxymethylcarbonyloxy
group.
Suitable salts of compounds of the formula 1 are - depending on the
substitution - in particular
all acid addition salts. Particular mention may be made of the
pharmacologically acceptable
salts of the inorganic and organic acids customarily used in pharmacy. Those
suitable are wa-
ter-soluble and water-insoluble acid addition salts with acids such as, for
example, hydrochlo-
ric 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, em-
bonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-
hydroxy-2-naphthoic
acid, where the acids are employed in the salt preparation in an equimolar
ratio or in a ratio
differing therefrom, depending on whether the acid is a mono- or polybasic
acid and on which
salt is desired.
Pharmacologically unacceptable salts, which can be initially obtained, for
example, as process
products in the preparation of the compounds according to the invention on an
industrial scale,
are converted into pharmacologically acceptable salts by processes known to
the person
skilled in the art.
It is known to the person skilled in the art that the compounds according to
the invention and
their salts can, for example when they are isolated in crystalline form,
comprise varying
amounts of solvents. The invention therefore also embraces all solvates and,
in particular, all
hydrates of the compounds of the formula 1, and all solvates and, in
particular, all hydrates of
the salts of the compounds of the formula 1.
One embodiment (embodiment 1) of the invention relates to compounds of the
formula 1, in
which

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-1 -
X is 0 (oxygen)
R1, R2, R3 and Y have the meanings as indicated in the outset,
and the salts of these compounds.
Another embodiment (embodiment 2) of the invention relates to compounds of the
formula 1,
in which
XisNH,
R1, R2, R3 and Y have the meanings as indicated in the outset,
and the salts of these compounds.
Another embodiment (embodiment 3) of the invention relates to compounds of the
formula 1,
in which
R3 is hydrogen,
R1, R2, X and Y have the meanings as indicated in the outset,
and the salts of these compounds.
Still another embodiment (embodiment 4) of the invention relates to compounds
of the for-
mula 1, in which R3 does not have the meaning hydrogen,
R1, R2, X and Y have the meanings as indicated in the outset,
and the salts of these compounds.
Still another embodiment (embodiment 5) of the invention relates to compounds
of the for-
mula 1, in which
R3 is halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-
alkyl, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-
alkyl,
cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-l-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,

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nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R1, R2, X and Y have the meanings as indicated in the outset,
and the salts of these compounds
The invention also relates to compounds of the formula 1,
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 14C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl,
fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-1 -4C-
alkyl or 3-7C-
cycloalkyl, amino and .w
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,

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R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O(oxygen) or NH and
Y has either the meaning -CH2-Ar
wherein
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
or Y denotes the group gp
R4
R5 (gp)
7z
wherein
Z has the meaning -CHR8- or-CHR8-CHR9-
where in, Ar and/or in the group gp
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-
alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy,
aryl-1-
4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-
alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-
4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-aikyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl or hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-l-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-l-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-
1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy
R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-l-4C-alkoxy, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-

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alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,
and wherein
aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
with the proviso that R3 does not have the meaning hydrogen when R1 and R2
have the
meanings hydrogen or 1-4C-alkyl and Y denotes CH2-phenyl or a CH2-phenyl
substituted by a
1-4C-alkoxy radical,
and the salts of these compounds.
The invention also relates to compounds of the formula 1,
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl, flu-
oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31 R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

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R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O(oxygen) or NH and
Y has either the meaning -CH2-Ar
wherein
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
or Y denotes the group gp
R4
R5 (gp)
'?~7z
wherein
Z has the meaning -CHR8- or -CHR8-CHR9-
where in, Ar and/or in the group gp
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-
alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy,
aryl-1-
4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-
alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-
4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl or hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-
1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy
R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-

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4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1 -4C-alkylamino-1 -4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,
and wherein
aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
with the proviso that R3 does not have the meaning hydrogen or halogen when R1
denotes
hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl, R2 denotes hydrogen, 1-4C-atkyl
or 3-7C-
cycloalkyl-1-4C-alkyl and Y denotes CH2-Ar,
and the salts of these compounds.
In one aspect, the invention relates to compounds of the formula 1a
R3 / N
C
>R1
I
~ N
x R2
~ (1 a)
Ar
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C=cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl,
fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where

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R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O(oxygen) or NH,
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino,
1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
Aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
and the salts of these compounds.
In a further aspect, the invention relates to compounds of the formula 1a, in
which
RI is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl, flu-
oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het,
where

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R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is Q(oxygen) or NH,
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyn=olyl,: pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyi, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino,
1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
Aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
with the proviso that R3 does not have the meaning hydrogen when R1 and R2
have the
meanings hydrogen or 1-4C-alkyl and Ar is phenyl or a phenyl substituted by a
1-4C-alkoxy
radical,

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and the salts of these compounds.
In a further aspect, the invention relates to compounds of the formula 1 a, in
which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl, flu-
oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-N R31 R32, the group SO2-NR31 R32 or the group
Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 14C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, induding the nitrogen atom to which both are bonded, are
a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihydroi-
soxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
X is O(oxygen) or NH,
Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7,
which is se-
lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,
imidazolyl, 1,2,3-
triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl,
thiazolyl, isoxa-
zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-

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alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino,
1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen,
Aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
with the proviso that R3 does not have the meaning hydrogen or halogen when R1
denotes
hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl and R2 denotes hydrogen, 1-4C-
alkyl or 3-7C-
cycloal kyl-1-4C-alkyl,
and the salts of these compounds.
In another aspect, the invention relates to compounds of the formula 1 b
R3 N
\>-R1
R4 N
R5 / x R2 (1 b)
z
in which
R1 is hydrogen, 14C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-
alkoxy, 1-4C-
alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-
4C-alkyl,
hydroxy-l-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-l-4C-
alkyl
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
1-4C-
alkoxycarbonyl, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyl, hydroxy-1-4C-
alkyl,
fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-
1-4C-alkyl,
1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-
1-4C-
alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het,
where
R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-
alkyl or 3-7C-
cycloalkyl, amino and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-l-4C-alkyl,
or where
R31 and R32 together, induding the nitrogen atom to which both are bonded, are
a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and

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Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group
consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol,
isoxazol, dihy-
droisoxazol, pyrazol and tetrazol
where
R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-
alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy,
aryl-1-
4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-
alkoxycarbonylamino or sulfonyl,
R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl
or hydroxy,
R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl
or hydroxy,
X is O(oxygen) or NH and
Z has the meaning -CHR8- or-CHR8-CHR9-
where
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,
1-4C-alkyl-
carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-
alkoxycarbonyl-1-4C-
alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy,
trifluoromethyl,
fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-
alkoxycarbonylamino or sulfonyl,
R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
trifluoromethyl or
hydroxy,
R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alk6xy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-
alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy
R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-
substituted 1-4C-
alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-
4C-
alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-
alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-
4C-
alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-
alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,
and wherein

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aryl is phenyl or substituted phenyl with one, two or three same or different
substituents from
the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,
trifluoro-
methyl, nitro, trifluoromethoxy, hydroxy and cyano,
and the salts of these compounds.
The compounds of the formula 1 b have up to three chiral centers in the parent
structure. The
invention thus relates to all conceivable stereoisomers in any desired mixing
ration to one an-
other, including the pure enantiomers, which are a preferred subject of the
invention.
Among the compounds of the formula I a, preferred compounds are those of the
formula 1 a-1
R3 / N
C
I
~>-R1
\ N
X R2
(1 a-1)
R5 R4
in which
RI is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-l-4C-alkyl or 1-4C-alkoxy-
1-4C-alkyl,
R2 is hydrogen,l-4C-alkyl, hydroxy, 1-4C-alkoxy or aryi-1-4C-alkoxy-1-4C-alkyl
R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkyl,
cyano, the
group -CO-N R31 R32, the group SO2-NR31 R32 or the group Het,
where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-
cycloalkyl or
amino and
R32 is hydrogen or 1-7C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
tolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol and dihydroimidazol,
where
R33 is hydrogen or 1-4C-alkyl,
R34 is hydrogen or 1-4C-alkyl
R35 is hydrogen or 1-4C-alkyl
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-
alkoxycarbonyl, trifluoro-
methyl, fluoro-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-
alkoxycarbonylamino,

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R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and
X is O(oxygen) or NH,
and the salts of these compounds.
Among the compounds of the formula 1 a, particularly preferred compounds are
those of the
formula 1 a-1
where
R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl,
R2 is hydrogen or 1-4C-alkyl,
R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,
or the group -
CO-NR31 R32,
where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-
7C-cycloalkyl
and
R32 is hydrogen or 1-7C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group,
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-
alkoxycarbonyl, trifluoro-
methyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-
alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino,
R5 is hydrogen, 1-4C-alkyl or.1-4C-alkoxy and
X is O(oxygen) or NH,
and the salts of these compounds.
Emphasis is given to those compounds of the formula 1a-1, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-
NR31R32,
where
R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-
7C-cycloalkyl
and
R32 is hydrogen or 1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group,
R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino,
R5 is 1-4C-alkyl,

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X is O(oxygen) or NH,
and their salts.
Emphasis is also given to those compounds of the formula 1a-1, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-
NR31R32,
where
R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-
7C-cycloalkyl
and
R32 is hydrogen or 1-4C-alkyl,
R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino,
R5 is 1-4C-alkyl,
X is 0 (oxygen) or NH,
and their salts.
Particular emphasis also given to compounds of the formula 1a-1, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 the group -CO-NR31R32,
where
R31 is 1-4C-alkyl and
R32 is 1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyrrolidino
group,
R4 is 1-4C-alkyl
R5 is 1-4C-alkyl,
X is NH,
and their salts.
Particular emphasis is also given to compounds of the formula 1a-1, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 the group -CO-NR31R32,
where
R31 is 1-4C-alkyl and
R32 is 1-4C-alkyl,
R4 is 1-4C-alkyl

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R5 is 1-4C-alkyl,
X is NH,
and their salts.
Among the compounds of the formula I b, preferred compounds are those of the
formula 1 b-1
I ~-R1
R3 ':; N
R4 N
R2
R5 X (1b-1)
R8
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-
1-4C-alkyl,
R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1 -4C-alkoxy-1 -4C-
alkyl
R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,
cyano, the
group -CO-NR31 R32, the group SO2-NR31 R32 or the group Het,
where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-
cycloalkyl or
amino and
R32 is hydrogen or 1-7C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpipera;dno, morpholino,
aziridino or azetidino
group and
Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from
the group con-
sisting of oxadiazol, dihydrooxazol and dihydroimidazol,
where
R33 is hydrogen or 1-4C-alkyl,
R34 is hydrogen or 1-4C-alkyl
R35 is hydrogen or 1-4C-alkyl
R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
R5 is hydrogen or 1-4C-alkyl,
R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-
7C-cycloalkyl-
1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-
alkoxy-l-
4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cyctoalkyl-1-4C-alkoxy-1-4C-
alkoxy, 1-
4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-
4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-l-4C-
alkylcarbonyloxy, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-
alkylcarbonyloxy
X is O(oxygen) or NH,

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and their salts.
Particularly preferred compounds of the formula 1 b-1 are those, in which
R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl,
R2 is hydrogen or 1-4C-alkyl,
R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,
or the group -
CO-NR31 R32,
where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-
7C-cycloalkyl
and
R32 is hydrogen or 1-7C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded,
are a pyr-
rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino,
aziridino or azetidino
group,
R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
R5 is hydrogen or alkyl,
R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-
7C-cycloalkyl-
1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-
alkoxy-1-
4C-alkoxy, 3-7C-cycloalkoxy-l-4C-alkoxy, 3-7C-cycloalkyl-l-4C-alkoxy-l-4C-
alkoxy, 1-
4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-
4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-
alkylcarbonyloxy, 1-4C-a(koxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-
alkylcarbonyloxy
X is O (oxygen) or NH,
and their salts.
Still particularly preferred compounds of the formula 1 b-1 are those, in
which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31
R32,
where
R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-
7C-cycloalkyl
and
R32 is hydrogen or 1-4C-alkyl,
R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
R5 is hydrogen,
R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-
7C-cycloalkyl-
1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-
alkoxy-1-
4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-
alkoxy, 1-

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4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-
4C-
alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-
alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-
alkylcarbonyloxy
X is O(oxygen) or NH,
and their salts.
Still particularly preferred compounds of the formula 1 b-1 are those, in
which
RI is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31
R32,
where
R31 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-
7C-cycloalkyl
and
R32 is hydrogen or 1-4C-alkyl,
R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
R5 is hydrogen,
R8 is hydroxyl or 1-4C-alkoxy
X is O(oxygen) or NH,
and their salts.
Emphasis is given to compounds of the 1 b-1, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is the group -CO-NR31 R32,
where
R31 is 1-4C-alkyl,
R32 is 1-4C-alkyl
R4 is hydrogen
R5 is hydrogen,
R8 is hydroxyl
X is 0 (oxygen)
and their salts.
The compounds of the general formula I a can be obtained as depicted in scheme
I by react-
ing substituted benzimidazole compounds of formula 2 with compounds of formula
3, wherein
L is a suitable leaving group like for example a suitable halogen atom, like
for example chlo-
rine.
Scheme 1:

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R3 N N
~>--R1 + >---R1
N Ar N
XH R2 R2
2, X= O, N H 3 qr
1a,X=0,NH
Another method for the preparation of compounds of the formula I a where X =
NH consists of
reacting substituted benzimidazole compounds of the general formula 2 where X=
NH with
substituted ketones of the formula 4 and subsequent reduction of the resulting
imine interme-
diate by suitable reducing agents, like for example sodium borohydride
(reductive amination,
scheme 2).
Scheme 2:
R3 I ~ N~R1 + /O R3 ~> -R1
~ N Arr/ N
XH R2 R2
2,X=NH 4 ,qr
1a,X=NH
Analogously, compounds of the general formula 1 b are obtained by reacting
substituted ben-
zimidazoles of formula 2 with 1,2-epoxyindanes of the formula 5, carrying any
desired sub-
stituent R4 and R5 (cf. scheme 3 for a compound 1 b-1). 1,2-Epoxyindan is
described for ex-
ample in W. F. Whitmore; A. I. Gebhart, J. Am. Chem. Soc. 1942, 64, 912. In
general, substi-
tuted alkyl-, alkoxy- or halogeno-epoxyindanes can be prepared from the
corresponding sub-
stituted indenes by methods known from literature (e.g. epoxidation).
Scheme 3:
R3 R4 R3 / CN
R1
\ I ~>-R1 + I / -~ R4 ( N~
XH R2 R5 rac. R5 ~ ..X R2
N
2,X=0,NH 5 OH
1b-1, X = O, NH
The starting compounds of the formula 2 where X 0 can be obtained for example
according
to the reaction sequence as shown in scheme 4. Compounds of the formula 6 can
be
deprotonated using a suitable base, like for example n-butyllithium, followed
by reaction with a

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suitable R2 precursor R2-Lg, whereby that precursor R2-Lg is a R2 group
substituted with a
suitable leaving group Lg, like a halogen atom, for example an iodine atom.
This reaction
leads to compounds of the formula 7 which can be converted by methods known to
the expert
to the desired compounds of the formula 2 with X= (oxygen).
Scheme 4:
H R3
R3 / N 1. base / N R3 N
\ I ~ -R1 2. R2-Lg \ ~ \R1 \R1
N N N
O ~
r O ~ OH ~
Ph 6 ~ 2,X=O
Compounds of the formula 6 can be prepared from compounds of the formula 8 for
example
following the reaction sequence shown in scheme 5.
Scheme 5:
NOz NOZ R3 / NOz
I
\
NHz NHz NHz
OH O O
g ~ 9 10
Ph Ph
R1
O-
R3 / NHz O- 12 R3 / CN
I R1 ~ ~R1
-~ \ NHz \ N
O O
~ 11 ~ 6
Ph Ph
3-Nitro-2-aminophenol can be reacted in a first step with a suitable benzyl
derivative, for ex-
ample benzylchloride, to form the reaction product of the formula 9 which is
known for exam-
ple from J. Heterocyclic Chem. (1983), 20, 1525). Into the compound of the
formula 9 a sub-
stituent R3 can be introduced, for example a bromine substituent can be
introduced by a bro-
mination reaction using a suitable bromination reagent, like for example N-
bromosuccinimide.
Subsequent reduction of the compound of the formula 10 under standard
conditions, for ex-
ample using hydrazine N2H4 in the presence of FeC13, leads to the formation of
compounds of
the formula 11 which can be transformed to the benzimidazole derivatives of
the formula 6 by
methods known to the expert, for example by a cyclization reaction with a
diketone of the for-
mula 12.
The starting compounds of the formula 2 where X = NH can be obtained for
example accord-
ing to the reaction sequence as shown in scheme 6. Starting from substituted
dinitrochlorben-
zenes of the formula 13, reaction with primary amines of the formula 14 leads
to compounds

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of the formula 15 (L. A. Summers, Austr. J. Chem. 1965, 18, 1695-1698) that
are reduced to
phenylenediamines of the formula 16 by methods known to the expert. The
benzimidazoles of
the formula 2 are then obtained by a cyclization reaction of compounds of the
formula 16, for
example with a diketone of the formula 12 to give compounds of the formula 17,
and subse-
quent reduction of the N02-group by catalytic hydrogenation or any other
method known from
literature (scheme 6).
Scheme 6:
R3 INO2 R2-NH2 R3 INO2 R3 NH2
14 ~
\ Ci -y ~ yLNR2 - ~ I NR2
NO2 NOZ H NO2 H
13 15 16
R1
O
O 12 R3 / N R3 / N
R1 ~ I N~R1 ~ ~ N>--R1
NOZ R2 NH2 R2
17 2,X=NH
The reaction steps outlined above are carried out in a manner known per se, e.
g. as de-
scribed in more detail in the examples. The derivatization, if any, of the
compounds obtained
according to the above Scheme 1, 2 and 3 (e.g. conversion of a group R3 into
another group
R3, or of R2 = H into another group R2, or conversion of a hydroxyl group into
an alkoxy or
ester group) is likewise carried out in a manner known per se. If compounds
where R3 =
-CO-1-4C-alkoxy or R3 =-CO-NR31 R32 are desired, an appropriate derivatization
can be per-
formed in a manner known per se (e. g. metal catalysed carbonylation of the
corresponding
bromo compound or conversion of an ester into an amide) at the stage of the
benzimidazoles
of the formula 2 (scheme 1, 2 and 3), or at a later point in time.

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Advantageous effects
The excellent gastric protective action and the gastric acid secretion-
inhibiting action of the
compounds according to the invention can be demonstrated in investigations on
animal ex-
perimental models. The compounds of the formula 1 according to the invention
investigated in
the model mentioned below have been provided with numbers which correspond to
the num-
bers of these compounds in the examples.
Testing of the secretion-inhibiting action on the perfused rat stomach
In Table A which follows, the influence of the compounds of the formula I
according to the in-
vention on the pentagastrin-stimulated acid secretion of the perfused rat
stomach after in-
traduodenal administration in vivo is shown.
Table A
Dose Inhibition of
No. ( mol/kg) acid secretion
i.d. (%)
1 1 > 50
2 1 > 50
3 1 > 50
Methodologv
The abdomen of anesthetized rats (CD rat, female, 200-250 g; 1.5 g/kg i.m.
urethane) was
opened after tracheotomy by a median upper abdominal incision and a PVC
catheter was
fixed transorally in the esophagus and another via the pylorus such that the
ends of the tubes
just projected into the gastric lumen. The catheter leading from the pylorus
led outward into
the right abdominal wall through a side opening.
After thorough rinsing (about 50-100 ml), warm (37 C) physiological NaCl
solution was con-
tinuously passed through the stomach (0.5 mi/min, pH 6.8-6.9; Braun-Unita I).
The pH (pH
meter 632, glass electrode EA 147; ~= 5 mm, Metrohm) and, by titration with a
freshly pre-
pared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCI
were deter-
mined in the effluent in each case collected at an interval of 15 minutes.
The gastric secretion was stimulated by continuous infusion of 1 g/kg (= 1.65
ml/h) of i.v.
pentagastrin (left femoral vein) about 30 min after the end of the operation
(i.e. after determi-

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nation of 2 preliminary fractions). The substances to be tested were
administered intraduode-
nally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous
pentagastrin infusion.
The body temperature of the animals was kept at a constant 37.8-38 C by
infrared irradiation
and heat pads (automatic, stepless control by means of a rectal temperature
sensor).
Mode(s) for Carrying Out the Invention
The examples below serve to illustrate the invention in more detail without
limiting it. Further com-
pounds of the formula 1 whose preparation is not described explicitly can
likewise be prepared in an
analogous manner or in a manner known per se to the person skilled in the art,
using customary proc-
ess techniques. The compounds named expressly as examples, and the salts of
these compounds,
are preferred subject matter of the invention. The abbreviation min stands for
minute(s), h stands for
hour(s), m.p. stands for melting point and ee for enantiomeric excess.
1. Final Compounds of the formula 1
1. 7-(trans-2,3-Dihydro-2-hydroxy-l-indenyloxy)-5-(N, N-dimethylaminocarbonyl)-
1,2-d imethyl-
1H-benzimidazole
To a suspension of 0.38 g (1.63 mmol) 7-hydroxy-1,2-dimethyl-lH-benzimidazole-
5-carboxylic acid
dimethylamide and 0.8 g (6.1 mmol) 1,2-epoxyindane in 4 ml methanol and 1 ml
water were added
0.45 ml triethylamine and the mixture was heated to 70 C for I h. The cooled
solution was partitioned
between dichloromethane and water. The organic layer was separated, dried over
anhydrous magne-
sium sulphate and evaporated. Purification of the residue by column
chromatography on silica gel
using dichloromethane:methanol (13:1) and crystallization from ethyl acetate
yielded 0.45 g (76 %) of
the title compound as a colourless solid (m.p. 230 C).
2. 6-(N, N-d imethylam inocarbonyl)-4-(2,6-d imethyl-benzylam ino)-2,3-d
imethyl-3H-
benzimidazole
To a solution of 0.54 g (1.56 mmol) 6-(N,N-dimethylaminocarbonyl)-4-(2,6-
dimethyl-benzylidene-
amino)-2,3-dimethyl-3H-benzimidazole in 10 ml methanol were slowly added 0.09
g (2.38 mmol) so-
dium borohydride. After 10 min, the reaction mixture was partitioned between
saturated aqueous am-
monium chloride and dichloromethane. The organic layer was separated, dried
over anhydrous mag-
nesium sulphate and evaporated. Purification of the residue by crystallization
from ethyl acetate/n-
heptane yielded 0.52 g (95 %) of the title compound as a colourless solid
(m.p. 187-188 C).
3. 4-(2,6-Dimethyl-benzylam ino)-2,3-d imethyl-6-(N-pyrrolidinocarbonyl)-3H-
benzimidazole

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To a solution of 0.5 g (1.94 mmol) 4-amino-2,3-dimethyl-6-(N-pyn-
olidinocarbonyl)-3H-benzimidazole
and 0.39 g (2.9 mmol) 2,6-dimethylbenzaldehyd in 15 ml dichloromethane and 5
ml acetic acid were
added 0.82 mg (3.9 mmol) sodium triacetoxyborohydride. After 2 h, TLC
indicated incomplete reaction
and the mixture was evaporated to dryness. The residue was diisolved in 20 ml
methanol and treated
with excess sodium borohydride. After complete reaction, mixture was
partitioned between saturated
aqueous ammonium chloride and dichloromethane. The organic layer was
separated, dried over an-
hydrous magnesium sulphate and evaporated. Purification of the residue by
column chromatography
on silica gel using dichloromethane:methanol (20:1) and crystallization from
ethyl acetate/n-heptane
yielded 0.41 g (56 %) of the title compound as a colourless solid (m.p. 188-
189 C).
II. Starting Compounds
A. 2-Be nzyl oxy-4-b romo-6-n itro-a n i l i n e
To a suspension of 50 g (325 mmol) 2-amino-3-nitrophenol, 45 g (325 mmol)
potassium carbonate
and 2 g (13 mmol) sodium iodide in 400 ml ethanol were added 47 ml (408 mmol)
benzyl chloride and
the mixture was heated to 80 C. After 2 h, the reaction mixture was cooled
down and the solvent was
evaporated. The residue was dissolved in ethyl acetate and extracted with
water. The organic layer
was dried over anhydrous magnesium sulphate and evaporated. Coevaporation with
dichloromethane
led to a dark brown oily residue which was dissolved in 400 ml acetonitriie.
After addition of 63.4 g
(356 mmol) N-bromosuccinimide, the reaction mixture was refluxed for I h.
After cooling down, 400 g
silica gel were added and the mixture was evaporated to dryness. The resulting
solid was put on a
column and the product was eluted with ethyl acetateaight petroleum ether
(4:1). Evaporation::of the
eluent left a solid which was recrystallized from ethyl acetateln-heptane to
give 62 g (59 %) of the title
compound as a red solid (m.p. 90 C).
B. 2-Ami no-3-benzyloxy-5-bromo-an i l i ne
To a suspension of 3.23 g (10 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline in 60
ml methanol and 15 ml
concentrated hydrochloric acid were added 2.23 g (40 mmol) iron filings in
small portions at 60 C.
After 10 min, the mixture was cooled down and neutralized with 6N aqueous
sodium hydroxide. Acti-
vated charcoal was added and the suspension was filtered. The filtrate was
partitioned between di-
chloromethane and water. The organic layer was dried over anhydrous magnesium
sulphate and
evaporated. Crystallization of the residue from ethyl acetate/n-heptane
yielded 2.05 g (70 %) of the
title compound as a colourless solid (m.p. 108 C).
C. 4-Benzyloxy-6-bromo-2-methyl-1 H-benzimidazole
To a suspension of 2.0 g (6.82 mol) 2-amino-3-benzyloxy-5-bromo-aniline in 20
ml ethanol were
added 5 ml 5N hydrochloric acid. The reaction mixture was hetaed to 60 C and
1.41 ml (13.6 mol)

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2,4-pentanedione were added in one portion. After refluxing 1 h, the mixture
was cooled down and
neutralized with 6N aqueous sodium hydroxide. The mixture was partitioned
between dichloromethane
and water. The organic layer was dried over anhydrous magnesium sulphate and
evaporated. Crystal-
lization of the residue from ethyl acetateln-heptane yielded 2.12 g (98 %) of
the title compound as a
colourless solid (m.p. 174 C).
D. 7-Benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide
To a suspension of 2.0 g (6.3 mmol) 4-benzyloxy-6-bromo-2-methyl-IH-
benzimidazole in 30 ml di-
methylamine (3.2M solution in tetrahydrofuran) were added 210 mg (0.95 mmol)
palladium(II) acetate
and 495 mg (1.9 mmol) triphenylphosphine. The mixture was transferred to an
autoclave and carbon-
ylated (5 bar carbon monoxide pressure, 120 C) for 16 h. The reaction mixture
was cooled down and
evaporated. Purification of the residue by column chromatography on silica gel
using dichloro-
methane/methanol (13:1) yielded 1.53 g(79 %) of the title compound as a a
light brown oil, which was
used without further purification in the next step.
E. 7-Benzyloxy-1,2-dimethyl-1 H-benzimidazole-5-carboxylic acid dimethylamide
To a solution of 1.53 g (4.7 mmol) 7-benzyloxy-2-methyl-3H-benzimidazole-5-
carboxylic acid di-
methylamide in 25 ml dried tetrahydrofuran were slowly added 3.1 ml (5 mmol) n-
butyllithium (1.6M in
hexanes) at -78 C. After adding 0.32 ml (5.1 mmol) methyl iodide, the
reaction mixture was allowed
to warm to room temperature. After 16 h, the mixture was partitioned between
dichloromethane and
water. The organic layer was separated, dried over anhydrous magnesium
sulphate and evaporated.
Purification of the residue by column chromatography on silica gel using
dichloromethane/methanol
(13:1) and crystallization of the residue from ethyl acetate/n-heptane yielded
0.79 g (52 %) of the title
compound as a colourless solid (m.p. 117-118 C).
F. 7-Hydroxy-1,2-dimethyl-lH-benzimidazole-5-carboxylic acid dimethylamide
A solution of 0.7 g (2.2 mmol) 7-benzyloxy-1,2-dimethyl-lH-benzimidazole-5-
carboxylic acid di-
methylamide in 25 ml methanol and 0.1 ml acetic acid was hydrogenated over
0.25 g 10% Pd/C (25
C, 1 bar Hz) for 16 h. The catalyst was filtered off and the filtrate was
evaporated. The residue was
crystallized from ethyl acetate to give 0.44 g (87 %) of the title compound as
a colourless solid (m.p.
209 C).
G. 4-Methylamino-3,5-dinitrobenzene-carboxylic acid
25.0 g(101 mmol) 4-chloro-3,5-dinitrobenzene-carboxylic acid were slowly added
to 120 ml aqueous
methylamine (40 %) and the mixture was heated to reflux. After I h, the
mixture was cooled down and
evaporated to dryness. The residue was dissolved in water and the pH was
adjusted to pH w 5 by add-

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ing 6N hydrochloric acid. The precipitate was collected, washed with water and
dried to yield 21.6 g
(90 %) of the title compound as a yellow solid (m.p. 184-188 C).
H. 1,2-Dimethyl-7-nitro-1 H-benzimidazole-5-carboxylic acid
To a suspension of 4.0 g (16.6 mmol) 4-methylamino-3,5-dinitrobenzene-
carboxylic acid in 50 ml
ethanol were added 40 ml 2N aqueous ammonium polysulfide. After 1 h, excess
ethanol was evapo-
rated and the residue was neutralized with 6N hydrochloric acid. The solids
were filtered off and the
filtrate was evaporated to dryness. The residue was suspended in 100 ml
ethanol and 20 ml 5N hydro-
chloric acid. To the boiling mixture were added 4.1 ml (40 mmol) 2,5-
pentanedione. After 4 h, the sol-
vent was removed and the residue was diluted with water and neutralized with
40% aqueous sodium
hydroxide. The precipitate was collected and suspended in 30 ml methanol and
10 ml water. To the
mixture were added 0.96 g (40 mmol) lithium hydroxide and the suspension was
heated to 70 C. After
30 min, the pH of the reaction mixture was adjusted to pH - 6 by adding 4N
hydrochloric acid. Excess
methanol was removed and the precipitate was collected and washed with water
to yield 0.8 g (21 %)
of the title compound as a colourless solid (m.p. 303-305 C).
1. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylidene-amino)-2,3-
dimethyl-3H-
benzimidazole
A suspension of 0.8 g (3.4 mmol)1,2-dimethyl-7-nitro-1 H-benzimidazole-5-
carboxylic acid in 10 ml
methanol and I ml acetic acid was hydrogenated over palladium on charcoal (3
h, 80 C). The reac-
tion mixture was neutralized with 40% aqueous sodium hydroxide and the
catalyst was filtered off. The
filtrate was evaporated and the residue was redissolved in 15 ml methanol and
10 ml acetic acid and
treated with 2,6-dimethylbenzaidehyd to yield the corresponding imine, which
was dissolved in 10 ml
dimethylformamide and 10 ml dichloromethane. To this solution were added 1.5 g
(4.7 mmol) O-(1H-
benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and
the mixture was heated
to 50 C. After 20 min, 5 ml (10 mmol) dimethylamine (2M in tetrahydrofuran)
were added at ambient
temperature. After 30 min, the reaction mixture was partitioned between
saturated aqueous sodium
hydrogen carbonate and dichloromethane. The organic layer was separated, dried
over anhydrous
magnesium sulphate and evaporated. Purification of the residue by column
chromatography on silica
gel using dichloromethane:methanol (10:1) and crystallization from ethyl
acetate/n-heptane yielded
0.6 g (51 %) of the title compound as a light yellow solid (m.p. 165-166 C).
J. 4-Methylam ino-3,5-d initro-N-pyrrolidinyl-benzamide
To a suspension of 2.0 g (8.3 mmol) 4-methylamino-3,5-dinitrobenzene-
carboxylic acid and 4.0 g
(12.4 mmol) O-(1F!-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium
tetrafluoroborate (TBTU) in 25 ml
chloroform were added 2.5 ml (30 mmol) pyrrolidine at 45 C. After 30 min, a
further amount of 4.0 g
TBTU and 2.5 ml pyrrolidine were added and stirring was continued for 45 min.
The reaction mixture

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was partitioned between saturated aqueous sodium hydrogen carbonate and
dichloromethane. The
organic layer was separated, dried over anhydrous magnesium sulphate and
evaporated. Purification
of the residue by column chromatography on silica gel using
dichloromethane:methanol (100:1) and
crystallization from ethyl acetate/n-heptane yielded 1.72 g (70 %) of the
title compound as an orange
solid (m.p. 148-150 C).
K. 2,3-Dimethyl-4-n itro-6-(N-pyrrol id inocarbonyl)-3H-benzi m idazole
To a mixture of 1.65 g (5.6 mmol) 4-methylamino-3,5-dinitro-N-pyrrolidinyl-
benzamide and 330 mg
ruthenium on charcoal (5 %) in 30 ml ethanol were slowly added 0.55 ml (11.2
mmol) hydrazine hy-
drate at 75 C. After 1.5 h, the catalyst was filtered off and the filtrate
was evaporated to dryness. The
residue was purified by column chromatography on silica gel using
dichloromethane:methanol (20:1).
The intermediate product was suspended in 25 ml methanol and 5 ml 5N
hydrochloric acid. To this
suspension were added 1.15 ml (11.2 mmol) 2,4-pentanedione at 80 C. After 30
min, the reaction
mixture was cooled down, neutralized with 40% aqueous sodium hydroxide and
extracted with di-
chloromethane. The organic layer was separated, dried over anhydrous magnesium
sulphate and
evaporated. Purification of the residue by column chromatography on silica gel
using dichloro-
methane:methanol (20:1) and crystallization from ethyl acetate/n-heptane
yielded 0.91 g (56 %) of the
title compound as an orange solid (m.p. 114-117 C).
L. 4-Amino-2,3-dimethyl-6-(N-pyrrolidinocarbonyl)-3H-benzimidazole ~t.
A solution of 0.82 g (2.84 mmol) 2,3-dimethyl-4-nitro-6-(N-
pyrrolidinocarbonyl)-3H-benzimidazole in 20
ml methanol and I ml acetic acid was hydrogenated over 300 mg palladium on
charcoal (10 %, 2.5 h,
50 C). The catalyst was filtered off and the reaction mixture was evaporated
to dryness. The residue
was crystallized with ethyl acetate/n-heptane to give 0.61 g (83 %) of a beige
solid (m.p. 250-251 C).

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Industrial applicability
The compounds of the formula I and their salts have valuable pharmacological
properties which
make them commercially utilizable. In particular, they exhibit marked
inhibition of gastric acid se-
cretion and an excellent gastric and intestinal protective action in warm-
blooded animals, in par-
ticular humans. In this connection, the compounds according to the invention
are distinguished by a
high selectivity of action, an advantageous duration of action, a par6cularly
good enteral activity,
the absence of significant side effects and a large therapeutic range.
"Gastric and intestinal protection" in this connection is understood as
meaning the prevention and
treatment of gastrointestinal diseases, in particular of gastrointestinal
inflammatory diseases and
lesions (such as, for example, gastric ulcer, peptic ulcer, including peptic
ulcer bleeding, duodenal
ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia),
which can be caused, for
example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins,
medicaments (e.g. certain
antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors),
chemicals (e.g. etha-
nol), gastric acid or stress situations. "Gastric and intestinal protection"
is understood to include,
according to general knowledge, gastroesophageal reflux disease (GERD), the
symptoms of which
include, but are not limited to, heartbum and/or acid regurgitation.
In their excellent properties, the compounds according to the invention
surprisingly prove to be
clearly superior to the compounds known from the prior art in various models
in which the antiul-
cerogenic and the antisecretory properties are determined. On account of these
properties, the
compounds of the formula 1 and their pharmacologically acceptable salts are
outstandingly suitable
for use in human and veterinary medicine, where they are used, in par6cular,
for the treatment
and/or prophylaxis of disorders of the stomach and/or intestine.
A further subject of the invention are therefore the compounds according to
the invention for use in
the treatment and/or prophylaxis of the abovementioned diseases.
The invention likewise includes the use of the compounds according to the
invention for the pro-
duction of medicaments which are employed for the treatment and/or prophylaxis
of the above-
mentioned diseases.
The invention furthermore includes the use of the compounds according to the
invention for the
treatment and/or prophylaxis of the abovementioned diseases.
A further subject of the invention are medicaments which comprise one or more
compounds of the
formula 1 and/or their pharmacologically acceptable salts.

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The medicaments are prepared by processes which are known per se and familiar
to the person
skilled in the art. As medicaments, the pharmacologically active compounds
according to the in-
vention (= active compounds) are either employed as such, or preferably in
combination with suit-
able pharmaceutical auxiliaries or excipients in the form of tablets, coated
tablets, capsules, sup-
positories, patches (e.g. as TTS), emulsions, suspensions or solutions, the
active compound con-
tent advantageously being between 0.1 and 95% and it being possible to obtain
a pharmaceutical
administration form exactly adapted to the active compound and/or to the
desired onset and/or du-
ration of action (e.g. a sustained-release form or an enteric form) by means
of the appropriate se-
lection of the auxiliaries and excipients.
The auxiliaries and excipients which are suitable for the desired
pharmaceutical formulations are
known to the person skilled in the art on the basis of his/her expert
knowledge. In addition to sol-
vents, gel-forming agents, suppository bases, tablet auxiliaries and other
active compound excipi-
ents, it is possible to use, for example, antioxidants, dispersants,
emulsifiers, antifoams, flavor cor-
rigents, preservatives, solubilizers, colorants or, in particular, permeation
promoters and complex-
ing agents (e.g. cyclodextrins).
The active compounds can be administered orally, parenterally or
percutaneously.
In general, it has proven advantageous in human medicine to administer the
active compound(s) in
the case of oral administration in a daily dose of approximately 0.01 to
approximately 20, prefera-
bly 0.05 to 5, in particular 0.1 to 1.5, mg/kg of body weight, if appropriate
in the form of several,
preferably I to 4, individual doses to achieve the de,sired result. In the
case of a parenteral treat-
ment, similar or (in particular in the case of the intravenous administration
of the active com-
pounds), as a rule, lower doses can be used. The establishment of the optimal
dose and manner of
administration of the active compounds necessary in each case can easily be
carried out by any
person skilled in the art on the basis of his/her expert knowledge.
If the compounds according to the invention and/or their salts are to be used
for the treatment of
the abovementioned diseases, the pharmaceutical preparations can also contain
one or more
pharmacologically active constituents of other groups of medicaments, for
example: tranquillizers
(for example from the group of the benzodiazepines, for example diazepam),
spasmolytics (for ex-
ample, bietamiverine or camylofine), anticholinergics (for example,
oxyphencyclimine or phencar-
bamide), local anesthetics, (for example, tetracaine or procaine), and, if
appropriate, also enzymes,
vitamins or amino acids.
To be emphasized in this connection is in particular the combination of the
compounds according
to the invention with pharmaceuticals which inhibit acid secretion, such as,
for example, H2 block-
ers (e.g. cimetidine, ranitidine), H+/K' ATPase inhibitors (e.g. omeprazole,
pantoprazole), or further
with so-called peripheral anticholinergics (e.g. pirenzepine, telenzepine) and
with gastrin antago-

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nists with the aim of increasing the principal action in an additive or super-
additive sense and/or of
eliminating or of decreasing the side effects, or further the combination with
antibacterially active
substances (such as, for example, cephalosporins, tetracyclines, penicillins,
macrolides, nitroimi-
dazoles or altematively bismuth salts) for the control of Helicobacter pylori.
Suitable antibacterial
co-components which may be mentioned are, for example, mezlocillin,
ampicillin, amoxicillin, cefa-
lothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin, erythromycin,
ciprofloxacin, met-
ronidazole, clarithromycin, azithromycin and combinations thereof (for example
clarithromycin +
metronidazole).
In view of their excellent gastric and intestinal protection action, the
compounds of formula 1 are
suited for a free or fixed combination with those medicaments (e.g. certain
antiinflammatories and
antirheumatics, such as NSAIDs), which are known to have a certain ulcerogenic
potency. In addi-
tion, the compounds of formula 1 are suited for a free or fixed combination
with motility-modifying
drugs.

Representative Drawing