Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-29
2001-03-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S353000, C544S354000
Reexamination Certificate
active
06200976
ABSTRACT:
DESCRIPTION OF THE INVENTION
The present invention relates to bicyclic compounds of general formula
R
a
—Het—A—Ar—R
b
, (I)
their tautomers, stereoisomers, mixtures thereof 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
b
denotes a cyano group, are useful intermediates for preparing the other compounds of general formula I, and the compounds of the above general formula I, wherein R
b
denotes one of the following amidino groups, and the tautomers and stereoisomers thereof, have valuable pharmacological properties, particularly an antithrombotic activity.
The present application thus relates to the new compounds of the above general formula I and the preparation thereof, pharmaceutical compositions containing the pharmacologically actve compounds and their use.
In the above general formula
A denotes an oxygen or sulphur atom, a difluoromethylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C
1-3
-alkyl group, a methylene group optionally mono- or disubstituted by a carboxy-C
1-3
-alkyl group,
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 structure by a C
1-3
-alkyl group,
Het denotes a 1-(C
1-3
-alkyl)-2-oxo-1,2-dihydro-thieno[2,3-b]-pyrazinyl group,
a quinolinylene, isoquinolinylene, quinazolinylene, phthalazinylene, cinnolinylene or quinoxazolinylene ring, which may be substituted in the aromatic heterocyclic moiety by a C
1-3
-alkyl, amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)amino group,
a quinolinylene, isoquinolinylene, quinazolinylene or quinoxazolinylene ring, which are di- or tetrahydrogenated in the heterocyclic moiety, whilst in one of the abovementioned dihydrogenated rings, which may additionally be substituted by a C
1-3
-alkyl group, a methylene group adjacent to a nitrogen atom is replaced by a carbonyl or thiocarbonyl group, or in one of the abovementioned tetrahydrogenated rings, which may additionally be substituted by one or two C
1-3
-alkyl groups, two methylene groups adjacent to a nitrogen atom are each replaced by a carbonyl group, and the phenyl moiety of the abovementioned bicyclic rings, wherein additionally a methine group may be replaced by a nitrogen atom, is linked to the group R
a
,
R
a
denotes a hydrogen, fluorine, chlorine or bromine atom,
a C
1-3
-alkyl, C
1-3
-alkoxy, C
2-3
-alkenyl or C
2-3
-alkynyl group, which may be substituted by a hydroxymethyl or carboxy group,
a C
1-3
-alkyl group, which is substituted by a C
1-3
-alkanoylamino or carboxy-C
1-3
-alkylcarbonylamino group,
a R
1
—CO—CH
2
group which may be substituted in the methylene moiety by one or two C
1-3
-alkyl groups, or
a C
3-6
-cycloalkylene group which is substituted in the 1 position by an R
1
—CO group, whilst
R
1
is a hydroxy, C
1-3
-alkoxy, amino, C
1-3
-alkylamino, pyrrolidino, piperidino, morpholino, piperazino or N—(C
1-3
-alkyl)-piperazino group, whilst the abovementioned amino, C
1-3
-alkylamino, pyrrolidino and piperidino groups may additionally be substituted by a C
1-3
-alkyl, carboxy-C
1-3
-alkyl, carboxy-C
1-3
-alkylaminocarbonyl or di-(C
1-3
-alkyl)-amino-n-C
2-4
-alkyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms,
a phenyl, naphthyl or monocyclic 5 or 6 membered heteroaryl group optionally substituted by a C
1-3
-alkyl group, whereby a 6 membered heteroaryl group contains one, two or three nitrogen atoms and a 5 membered heteroaryl group contains an imino group optionally substituted by a C
1-3
-alkyl group, an oxygen or sulphur atom group 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 before mentioned 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,
a C
1-4
-alkyl group which is substituted by one or two carboxy groups,
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, tetrazoly-C
1-3
-alkyl-Y
2
—, R
2
NR
3
— or R
2
NR
3
—C
1-3
-alkyl group and
by a carboxy, aminocarbonyl, C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl or C
5-7
-cycloalkyleniminocarbonyl group, whereby the C
5-7
-cycloalkylenimino moiety in the before mentioned groups may be substituted by one or two C
1-3
-alkyl groups and at the same time additionally one alkyl moiety or alkyl substituent of the before mentioned C
1-3
-alkylaminocarbonyl, di-(C
1-3
-alkyl)-aminocarbonyl or C
5-7
-cycloalkyleniminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of a C
1-4
-alkyl group may be totally or partly replaced by fluorine atoms, wherein
R
2
denotes a hydrogen atom or a C
1-3
-alkyl group optionally substituted by a carboxy group and
R
3
denotes 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
2
and R
3
together with the attached nitrogen atom denotes a C
3-7
-cycloalkylenimino group optionaylly 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 or —NH—CO— group, whereby the carbonyl group of the —NH—CO— group is attached to the nitrogen atom of the R
2
NR
3
group, and the imino groups mentioned at the definition of the radicals Y
1
and Y
2
may be additionally substituted by a C
1-3
-alkyl or carboxy-C
1-3
-alkyl group,
a nitro group or an amino group optionally substituted by a C
1-3
-alkanoyl or carboxy-C
1-4
-alkyl group,
a hydroxyimino-C
1-3
-alkylene group which may be substituted at the oxygen atom by a carboxy-C
1-3
-alkyl group,
a C
3-7
-cycloalkyl or C
5-6
-cycloalkenyl group,
a phenyl group which may be substituted by a C
1-3
-alkyl, C
2-3
-alkenyl, carboxy, nitro or amino group, whilst the amino group may additionally be substituted by a C
1-3
-alkanoyl, carboxy-C
1-3
-alkyl, carboxy-C
1-3
-alkylcarbonyl or carboxy-C
1-3
-alkylamino-carbonyl group,
a phenyl group which is substituted by a C
1-3
-alkyl group and by a carboxy or carboxy-C
1-3
-alkylaminocarbonyl group,
a carbonyl group which is substituted by a C
1-6
-alkyl, C
5-7
-cycloalkyl, C
1-6
-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionally be substituted by a C
1-3
-alkyl group and the hydrogen atom of the abovementioned amino groups is replaced by a carboxy-C
1-3
-alkyl or tetrazolyl-C
1-3
-alkyl group,
a carboxy-C
1-3
-alkylsulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substituted by a carboxy-C
1-3
-alkyl, amino-C
1-3
-alkyl, C
1-3
-alkylamino-C
1-3
-alkyl or di-(C
1-3
-alkyl)-amino-C
1-3
-alkyl group,
a C
1-6
-alkylamino or C
3-7
-cycloalkylamino group, wherein the hydrogen atom of the amino group is replaced by a carboxy-C
1-3
-alkylcarbonyl, carboxy-C
1-3
-alkylsulphonyl, tetrazolyl-C
1-3
-alkylcarbonyl or carboxy-C
1-3
-alkylaminocarbonyl group,
a piperidino group, wherein a methylene group in the 2 position is replaced by a carbonyl or sulphonyl group,
a tetrazolyl group optionally substituted by a C
1-5
-alkyl group,
an imidazolyl group substituted in the 1 position by a carboxy-C
1-3
-alkyl group, which may additionally be substituted by a C
1-5
-alkyl group,
a phenylsulphonyl group or a C
1-5
-alkylsulphonyl group wherein the alkyl moiety may be substitut
Hauel Norbert
Nar Herbert
Priepke Henning
Ries Uwe
Stassen Jean Marie
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Raymond Richard L.
Raymond Robert P.
Stempel Alan R.
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