Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-18
2001-03-13
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230500, C514S300000, C514S312000, C544S048000, C544S052000, C544S105000, C546S123000, C546S155000
Reexamination Certificate
active
06200971
ABSTRACT:
The present invention relates to bicyclic heterocyclic compounds, processes for their preparation and their use in medicaments, in particular as antiatherosclerotic medicaments.
It is known that increased blood levels of triglycerides (hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) are associated with the origin of atherosclerotic changes to the vascular wall and coronary heart disease.
Moreover, a significantly increased risk of developing coronary heart disease exists if these two risk factors occur in combination, which in turn is accompanied by excessive production of apolipoprotein B-100. There is therefore still a great need to provide active medicaments for combating atherosclerosis and coronary heart disease.
Benzimidazole derivatives having a PAF-antagonistic action furthermore are described in U.S. Pat. No. 5,314,880.
The present invention relates to bicyclic heterocyclic compounds of the general formula (I)
in which
A represents a radical of the formula
wherein
L and M are identical or different and denote hydrogen, halogen, trifluoromethyl, carboxyl, cycloalkyl having 3 to 6 carbon atoms, hydroxyl, phenyl, or straight-chain or branched alkyl, alkoxycarbonyl or alkoxy having in each case up to 6 carbon atoms,
Q denotes a nitrogen atom or the —CH group,
T denotes a group of the formula —SO
2
or —CO or an oxygen or sulphur atom,
V denotes an oxygen or sulphur atom,
R
5
, R
6
, R
7
and R
8
are identical or different and denote hydrogen, straight-chain or branched alkyl or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which are optionally substituted by halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,
R
9
denotes trifluoromethyl, benzyl or a 5- to 7-membered, optionally benzo-fused heterocyclic radical having up to 3 heteroatoms from the series consisting of S, N and/or O, which is optionally substituted up to 3 times in an identical or different manner by halogen, phenyl, hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, or denotes a group of the formula —S(O)
a
—R
10
, wherein
a denotes the number 0, 1 or 2,
R
10
denotes straight-chain or branched alkyl or alkenyl having in each case up to 8 carbon atoms, which are optionally substituted by straight-chain or branched acyl having up to 6 carbon atoms or by aryl or aroyl having in each case up to 10 carbon atoms, which in turn can be substituted up to twice in an identical or different manner by halogen, trifluoromethyl or by straight-chain or branched acyl having up to 5 carbon atoms, or denotes aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl trifluoromethyl or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms,
D and E are identical or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl or carboxyl, or represent straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms,
Z represents an oxygen or sulphur atom,
R
1
represents cycloalkyl having 3 to 10 carbon atoms, or represents straight-chain or branched alkyl having 1 to 10 carbon atoms, or represents phenyl, which is optionally substituted up to twice in an identical or different manner by halogen, nitro, cyano, hydroxyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
R
2
represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R
3
represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or represents cycloalkyl having 3 to 7 carbon atoms, or represents phenyl or represents a 5- to 7-membered aromatic heterocyclic radical having up to 3 heteroatoms from the series consisting of S, N and/or O, which are optionally substituted up to 3 times in an identical or different manner by halogen, nitro, phenyl, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,
R
4
represents hydrogen, or represents a group of the formula —CH
2
—OH or CH
2
O—CO—R
11
, wherein
R
11
denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, which is optionally substituted up to 3 times in an identical or different manner by halogen, hydroxyl, cyano or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
and salts thereof.
The bicyclic heterocyclic compounds according to the invention can also be in the form of their salts. Salts with organic or inorganic bases or acids may be mentioned in general here.
Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can likewise be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds according to the invention can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers and to the particular mixtures thereof. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
In the context of the invention, a heterocyclic radical, which is optionally benzo-fused, in general represents a saturated or unsaturated 5- to 7-membered, preferably 5- or 6-membered, heterocyclic radical which can contain up to 3 heteroatoms from the series consisting of S, N and/or O and, in the case of a nitrogen atom, can also be bonded via this. Examples which may be mentioned are: indolyl, quinolyl, benzo[b]thienyl, benzo[b]furyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Quinolyl, furyl, pyridyl and thienyl are preferred.
Preferred compounds of the general formula (I) are those in which
A represents a radical of the formula
wherein
L and M are identical or different and denote hydrogen, fluorine, chlorine, bromine, trifuoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, phenyl or straight-chain or branched alkyl, alkoxycarbonyl or alkoxy having in each case up to 5 carbon atoms,
Q denotes a nitrogen atom or the —CH group,
T denotes a group of the formula —SO
2
or —CO or an oxygen or sulphur atom,
V denotes an oxygen or sulphur atom,
R
5
, R
6
, R
7
and R
8
are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 5 carbon atoms, benzyl or phenyl, which are optionally substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl having up to 5 carbon atoms,
R
9
denotes trifluoromethyl, benzyl, benzothienyl, thienyl, pyridyl, quinolyl, imidazolyl, furyl, pyrryl, oxazolyl or thiazolyl, which are optionally substituted up to 3 times in an identical or different manner by fluorine, chlorine, bromine, phenyl, hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms, or denotes a group of the formula —S(O)
a
—R
10
, wherein
a denotes the number 0 or 1,
R
10
denotes straight-chain or branched alkyl or alkenyl having in each cas
Bischoff Hilmar
Connell Richard
Denzer Dirk
Goldmann Siegfried
Gr{umlaut over (u )}tzmann Rudi
Bayer Aktiengesellschaft
Coleman Brenda
Norris & McLaughlin & Marcus
Shah Mukund J.
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