Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-24
2001-06-19
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S210210, C514S234500, C514S252060, C514S269000, C514S274000, C514S332000, C514S338000, C514S369000, C514S370000, C514S394000, C544S116000, C544S238000, C544S298000, C544S315000, C544S316000, C544S317000, C544S318000, C544S319000, C544S320000, C544S370000, C546S199000, C546S256000, C546S273400, C548S143000, C548S245000, C548S253000, C548S304400, C548S304700, C548S309700, C548S310100
Reexamination Certificate
active
06248770
ABSTRACT:
DESCRIPTION OF THE INVENTION
The present invention relates to benzimidazoles of general formula
their tautomers, their stereoisomers, the mixtures thereof, their prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions instead of a carboxy group, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable properties.
The compounds of the above general formula I wherein R
c
denotes a cyano group are valuable intermediates for preparing the other compounds of general formula I, and the compounds of the above general formula I wherein R
c
denotes one of the following amidino groups, as well as their tautomers, their stereoisomers, the mixtures thereof, their prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions instead of a carboxy group, and their salts, particularly the physiologically acceptable salts thereof with
The present application thus relates to the new compounds of the above general formula I as well as the preparation thereof, the pharmaceutical compositions containing the pharmacologically active compounds, the preparation and use thereof.
In the above general formula
Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C
1-3
-alkyl or C
1-3
-alkoxy group,
a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C
1-3
-alkyl group,
A denotes a C
1-3
-alkylene group,
B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C
1-3
-alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group,
R
a
denotes an R
1
—CO—C
3-5
-cycloalkyl group wherein
R
1
denotes a C
1-3
-alkoxy, amino, C
1-4
-alkylamino or di-(C
1-4
-alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group,
a 4- to 7-memberecl cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by a hydroxy group or by one or two C
1-3
-alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C
1-3
-alkoxy, carboxy, carboxy-C
1-3
-alkoxy, carboxy-C
1-3
-alkylamino, N-(C
1-3
-alkyl)-N-(carboxy-C
1-3
-allyl)-amino, carboxy-C
1-3
-alkylaminocarbonyl, N-(C
1-3
-alkyl)-N-(carboxy-C
1-3
-alkyl)-aminocarbonyl, carboxy-C
1-3
-alkylaminocarbonylamino, 1-(C
1-3
-alkyl)-3-(carboxy-C
1-3
-alkyl)-aminocarbonylamino, 3-(C
1-3
-alkyl)-3-(carboxy-C
1-3
-alkyl)-aminocarbonylamino or 1,3-di-(C
1-3
-alkyl)-3-(carboxy-C
1-3
-alkyl)-aminocarbonylamino group,
a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C
1-3
-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms,
a morpholino, piperazino, N-(C
1-3
-alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group,
an R
2
-CX-C
3-5
-cycloalkyl group wherein
R
2
denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C
1-3
-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C
1-3
-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C
1-3
-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy-C
1-3
-alkoxy, carboxy-C
1-3
-alkylamino or N-(C
1-3
-alkyl)-carboxy-C
1-3
-alkylamino group, and
X denotes an oxygen atom, a C
1-3
-alkylimino, C
1-3
-alkoxyimino, C
1-3
-alkylhydrazino, di-(C
1-3
-alkyl)-hydrazino, C
2-4
-alkanoyl-hydrazino, N-(C
1-3
-alkyl)-C
2-4
-alkanoylhydrazino or C
1-3
-alkylidene group each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group,
a C
1-3
-alkyl or C
3-5
-cycloalkyl group substituted by an imidazole or imidazolone group wherein
the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C
1-3
-alkyl groups or by one, two or three C
1-3
-alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C
2-4
-alkanoylamino, C
1-3
-alkylamino, N-(C
2-4
-alkanoyl)-C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group, and
the imidazolone ring may be substituted by a C
1-3
-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an amino, C
2-4
-alkanoylamino, C
1-3
-alkylamino, N-(C
2-4
-alkanoyl)-C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group, and
additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms,
an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C
1-3
-alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy group,
a C
1-4
-alkyl group which is substituted
by a C
1-3
-alkyl-Y
1
-C
1-3
-alkyl, HOOC-C
1-3
-alkyl-Y
1
-C
1-3
-alkyl, tetrazolyl-C
1-3-
alkyl-Y
2
, R
3
NR
4
— or R
3
NR
4
-C
1-3
-alkyl group and
by an isoxazolidinylcarbonyl group optionally substituted by a C
1-3
-alkyl group, by a pyrrolino-carbonyl, 3,4-dehydropiperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C
1-3
-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the C
1-4
-alkyl group may be wholly or partially replaced by fluorine atoms wherein
R
3
denotes a hydrogen atom or a C
1-3
-alkyl group optionally substituted by a carboxy group and
R
4
denotes a hydrogen atom, a C
1-3
-alkyl-Y
1
-C
1-3
-alkyl-Y
2
, carboxy-C
1-3
-alkyl-Y
1
-C
1-3
-alkyl-Y
2
, C
1-3
-alkyl-Y
2
or carboxy-C
1-3
-alkyl-Y
2
group or
R
3
and R
4
together with the nitrogen atom between them denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C
1-3
-alkyl or carboxy-C
1-3
-alkyl group wherein
Y
1
denotes a carbon—carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, —NH—, —NH—CO— or —NH—CO—NH— group and
Y
2
denotes a carbon—nitrogen bond or a carbonyl, sulphonyl, imino or —NH—CO— group, wherein the carbonyl group of the —NH—CO— group is linked to the nitrogen atom of the R
3
NR
4
-group, and the imino groups occurring in the definition of the groups Y
1
and Y
2
may each additionally be substituted by a C
1-3
-alkyl or carboxy-C
1-3
-alkyl group,
a C
1-3
-alkyl or C
3-5
-cycloalkyl group substituted by a R
5
NR
6
-group wherein
R
5
denotes a hydrogen atom, a C
1-3
-alkyl, C
5-7
-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and
R
6
denotes a C
1-3
-alkyl, carboxy-C
1-3
-alkyl or carboxy-C
1-3
-alkylcarbonyl group,
a C
1-3
-alkyl group which is substituted by a C
2-4
-alkanoyl or C
5-7
-cycloalkanoyl group and by a C
1-3
-alkyl group substituted by a chlorine, bromine or iodine atom,
R
b
denotes a hydrogen atom or a C
1-3
-alkyl group and
R
c
denotes a cyano group or an amidino group optionally substituted by one or two C
1-3
-alkyl groups.
The carboxy groups mentioned in the definitions of the abovementioned groups may also be replaced by a group which can be converted in vivo into a carboxy group or by a group which is negatively charged under physiological conditions, or
the amino and imino groups me
Hauel Norbert
Kauffmann Iris
Nar Herbert
Priepke Henning
Ries Uwe
Boehringer Ingelheim Pharma KG
Raymond R. P.
Schroeder Ben
Shah Mukund J.
Stempel A. R.
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