Benzimidazole derivatives, preparation and therapeutic use...

Details Benzimidazole derivatives, preparation and therapeutic use... Benzimidazole derivatives, preparation and therapeutic use...

2003-01-30

2004-09-21

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S217050, C514S218000, C514S253030, C514S252110, C514S275000, C514S292000, C540S575000, C540S579000, C540S598000, C544S295000, C544S361000, C546S084000

Reexamination Certificate

active

06794382

ABSTRACT:

The present invention relates to benzimidazole derivatives, to their preparation and to their therapeutic application.
The present invention relates to compounds corresponding to formula (I):
in which:
R1 represents a hydrogen atom, a C1-C4 alkyl group, a halogen atom, a nitro group or a C1-C4 alkoxy group,
R2 and R2′ represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
X represents a nitrogen atom or a carbon atom,
n is equal to 1 or 2,
m is equal to 1 or 2,
and, when X represents a nitrogen atom:
R3 represents a hydrogen atom or a C1-C4 alkyl group, to give compounds of formula (I) comprising a quaternary ammonium, or alternatively does not exist, to give compounds of formula (I) comprising a secondary or tertiary amine,
R4 represents
a hydrogen atom,
a C1-C6 alkyl group,
a C3-C7 cycloalkyl group,
a C3-C7 heterocycloalkyl group optionally substituted with a C1-C4 alkyl group or a group —COOR, in which R represents a C1-C6 alkyl group,
a group —(CH
2
)
p
-heteroaryl, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from pyridyl, aminopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl and thienyl groups, the said heteroaryl group optionally being substituted with a C1-C4 alkyl group,
a heteroarylcarbonyl group, the heteroaryl group being chosen from furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and imidazolyl groups,
a phenylcarbonyl group, the phenyl group optionally being substituted with a halogen atom,
a (C1-C6)alkylcarbonyl group,
a group —(CH
2
)
p
COOR in which p may range from 0 to 4 and in which R represents a C1-C6 alkyl group,
a phenylsulphonyl group optionally substituted on the phenyl nucleus with a halogen atom, a trifluoromethyl group, a C1-C4 alkyl group, a nitro group or a C1-C4 alkoxy group, or alternatively
a —(CH
2
)
p
-phenyl group, in which p may range from 0 to 4 and in which the phenyl group is optionally substituted, in the ortho and/or meta and/or para position, with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a C1-C4 alkoxy group, a (C1-C4)alkoxyphenyl group, a C1-C4 alkylamino group, a C1-C4 dialkylamino group, an —NHCHO group or a group —NHCOR′, in which R′ represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group optionally being substituted with a dimethylamino group,
and, when X represents a carbon atom:
R3 represents a hydrogen atom, a group —NR5R6, a group —N(R5)
3
+
, a group —NHCOR7, a group —CONHR5, a group —COR7, an —NHCONH
2
group, an —OH group or a —CH
2
OH group,
R4 represents
a hydrogen atom,
a —(CH
2
)
p
-phenyl group, in which p may range from 0 to 4 and in which the phenyl group is optionally substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a halogen atom, a trifluoromethyl group or a C1-C4 alkoxy group,
a —(CH
2
)
p
-heteroaryl group, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from an imidazolyl group, optionally substituted with a C1-C4 alkyl group, a pyridyl group, an aminopyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group, or alternatively
a group —(CH
2
)
t
NR7R8, in which t is equal to 0 or 1,
with the proviso that when R4 represents a group —NR7R8, R3 is other than the groups —NR5R6, —NHCOR7, —NHCONH
2
and —OH,
R5 and R6 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
R7 and R8 represent, independently of each other, a C1-C4 alkyl or C1-C4 alkoxy group or together form a saturated 5- to 7-membered ring optionally comprising an additional nitrogen atom, to form, for example, a 1-piperidyl group, a 1-pyrrolidinyl group or a 1-piperazinyl group, this ring optionally being substituted, on a carbon atom or on a nitrogen atom, including the nitrogen atom to which the groups R7 and R8 are attached to form a quaternary ammonium, with a C1-C4 alkyl group or a group —COOR″, in which R″ represents a phenyl or (C1-C4)alkylphenyl group,
with the exclusion of the two compounds for which R1=R2=R2′=R3=H, X=C, n=m=1 and R4 represents either a 4-imidazolyl group or a 5-methyl-4-imidazolyl group.
These two compounds are disclosed in patent application EP 646 583, as compounds 16 and 17 in the table, as 5-HT
3
and 5-HT
4
type serotoninergic receptor ligands.
The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also the mixtures thereof, including racemic mixtures, form part of the invention.
The compounds of the invention may exist in the form of bases or of addition salts with pharmaceutically acceptable acids. Such addition salts also form part of the invention.
In the context of the present invention, the term:
“a (Cq-Cr)alkyl group” means a linear or branched saturated aliphatic group comprising from q to r carbon atoms, q and r being integers; mention may be made in particular of methyl, ethyl, propyl, isopropyl, n-propyl, butyl, isobutyl, tert-butyl, n-butyl, pentyl, etc. groups;
“a halogen atom” means a fluorine, a chlorine, a bromine or an iodine;
“a C3-C7 cycloalkyl group” means a cyclic alkyl group containing from 3 to 7 carbon atoms; mention may be made in particular of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups;
“a C3-C7 heterocycloalkyl group” means a cyclic alkyl group containing from 3 to 7 carbon atoms and also one or more hetero atoms, for example a nitrogen atom; mention may be made in particular of piperidyl groups;
“a (C1-C4)alkoxyphenyl group” means a group of formula —O—(CH
2
)
x
-phenyl, in which x may range from 1 to 4.
Among the compounds of formula (I) which are the subjects of the present invention, mention may be made of the preferred compounds for which:
R1 represents a hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group,
R2 represents a hydrogen atom or a C1-C4 alkyl group,
R2′ represents a hydrogen atom,
X represents a nitrogen atom,
n is equal to 1 or 2,
m is equal to 1 or 2,
R3 represents a hydrogen atom, to give compounds of formula (I) comprising a quaternary ammonium, or alternatively does not exist, to give compounds of formula (I) comprising a secondary or tertiary amine,
R4 represents
a hydrogen atom,
a C1-C6 alkyl group,
a C3-C7 cycloalkyl group,
a pyridyl, pyrimidinyl or pyrazinyl group, optionally substituted with a C1-C4 alkyl group,
a heteroarylcarbonyl group, the heteroaryl group being chosen from a furyl group and a pyridyl group,
a phenylcarbonyl group, the phenyl group optionally being substituted with a halogen atom,
a (C1-C6)alkylcarbonyl group,
a group —(CH
2
)
p
COOR in which p can range from 0 to 4 and in which R represents a C1-C6 alkyl group,
a phenylsulphonyl group,
a phenyl group substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a C1-C4 alkoxy group, a (C1-C4)alkoxyphenyl group, a (C1-C4)dialkylamino group, an —NHCHO group or a group —NHCOR′, in which R′ represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group optionally being substituted with a dimethylamino group,
a —(CH
2
)
p
-phenyl group, in which p can range from 0 to 4,
a —(CH
2
)
p
-pyridyl group, in which p can range from 0 to 4,
a —(CH
2
)
p
-thienyl group, in which p can range from 0 to 4,
a (C3-C7)heterocycloalkyl group optionally substituted with a C1-C4 alkyl group or a group —COOR, in which R represents a C1-C6 alkyl group,
or alternatively the preferred compounds for which:
R1 represents a hydrogen atom,
R2 and R2′ represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
X represents a carbon atom,
n is equal to 1 or 2,
m is equal to 1,
R3 represents a hydrogen atom, a

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