Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-08
2001-05-22
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S415000, C548S492000, C548S503000
Reexamination Certificate
active
06235770
ABSTRACT:
The present invention relates to indolyl-substituted phenylacetic acid derivatives, processes for their preparation and their use as medicaments, in particular as antiatherosclerotic medicaments.
Phenylacetic acid derivatives with heterocyclic substituents and substituted imidazo[4,5-b]pyridines and benzimidazoles are known from the publications DOS 42 00 954 and DOS 43 02 956. Benzimidazole derivatives having a PAF-antagonistic action are furthermore described in the publication U.S. Pat. No. 5,314,880.
The compounds according to the invention are partly covered by the scope of meaning of these publications.
It is known that increased blood levels of triglycerides (hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) are associated with the origin of atherosclerotic changes to the vascular walls and coronary heart diseases.
A significantly increased risk of the development of coronary heart diseases furthermore 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 diseases.
The present invention relates to indolyl-substituted phenylacetic acid derivatives of the general formula (I)
in which
D represents a radical of the formula
wherein
T denotes a nitrogen atom or the —CH group,
R
6
, R
7
, R
10
and R
11
are identical or different and denote hydrogen, trifluoromethyl, halogen or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,
R
5
, R
8
and R
9
are identical or different and denote hydrogen, cycloalkyl having 3 to 6 carbon atoms, phenyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen,
or, in the case where T represents a nitrogen atom, R
5
can also denote benzyl,
E and L 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,
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, 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, each of which is 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
12
,
wherein
R
12
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 phenylacetic acid derivatives with heterocyclic substituents and substituted imidazo[4,5-b]pyridines and benzimidazoles 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 which, 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
D represents a radical of the formula
wherein
T denotes a nitrogen atom or the —CH group,
R
6
, R
7
, R
10
and R
11
are identical or different and denote hydrogen, trifluoromethyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms,
R
5
, R
8
and R
9
are identical or different and denote hydrogen, cyclpropyl, cyclopentyl, cyclohexyl, phenyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by fluorine, chlorine or bromine,
or, in the case where T represents a nitrogen atom, R
5
can also denote benzyl,
E and L are identical or different and represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl or straight chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
R
1
represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or represents straight-chain or branched alkyl having up to 7 carbon atoms, or represents phenyl, which is optionally substituted by fluorine, chlorine, bromine, cyano, hydroxyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,
R
2
denotes hydrogen or methyl,
R
3
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or represents phenyl, pyridyl, thienyl or furyl, each of which is optionally substituted up to twice in an identical or different manner by fluorine, chlorine, bromine, phenyl, nitro, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms,
R
4
represents hydrogen, or represents a group of the formula —CH
2
—OH or —CH
2
O—CO—R
12
,
wherein
R
12
denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, which is optionally substituted up to twice in an identical or different manner by fluorine, chlorine, bromine, cyano, hydroxyl or straight-chain or branched alkyl or alkoxy ha
Bischoff Hilmar
Connell Richard
Denzer Dirk
Goldmann Siegfried
Grutzmann Rudi
Bayer Aktiengesellschaft
Morris Patricia L.
Norris & McLaughlin & Marcus
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