Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-21
2002-11-12
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S085000, C546S087000
Reexamination Certificate
active
06479503
ABSTRACT:
The present invention relates to cycloalkano-indole and -azaindole derivatives, processes for their preparation and their use as medicaments, in particular as antiatherosclerotic medicarnents.
It is known that increased blood levels of triglycerides (hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) are associated with the genesis of atherosclerotic vessel wall changes and coronary heart diseases.
A distinctly increased risk of the development of coronary heart disease is moreover present if these two risk factors occur in combination, which is accompanied, in turn, with an overproduction of apolipoprotein B-100. There is therefore, as before, a great need to make available effective medicarnents for the control of atherosclerosis and coronary heart diseases.
The present invention relates to cycloalkano-indole and -azaindole derivatives of the general formula (I)
in which
R
1
and R
2
, including the double bond connecting them, together form a phenyl or pyridyl ring or a ring of the formula
wherein
R
8
denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R
3
and R
4
, including the double bond connecting them, together form a phenyl ring or a 4- to 8-membered cycloaukene or oxocycloalkene radical,
all ring systems mentioned under R
1
/R
2
and R
3
/R
4
optionally being substituted up to 3 times by identical or different halogen, trifluoromethyl, carboxyl or hydroxyl substituents, by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by straiht-chain or branched alkyl having up to 6 carbon atoms, which, for its part, can be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms,
D represents hydrogen, cycloalkyl having 4 to 12 carbon atoms or straight-chain or branched alkyl having up to 12 carbon atoms,
E represents the —CO— or —CS— group,
L represents an oxygen or sulphur atom or a group of the formula —NR
9
,
wherein
R
9
denotes hydrogen or straight-chain or branched alkyl having up to 6 catbon atoms, which is optionally substituted by hydroxyl or phenyl,
R
5
represents phenyl or a 5- to 7-membered sated or unsaturated heterocycle having up to 3 heteroatoms from the series consisting of S, N and/or O, the cycles optionally being substituted up to 3 times by identical or different nitro, carboxyl, halogen or cyano substituents or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by staight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and/or the cycles optionally being substituted by a group of the formula —OR
10
or —NR
11
R
12
,
wherein
R
10
denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms,
R
11
and R
12
are identical or different and denote phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or straight-chain or branched acyl having up to 8 carbon atoms, which is optionally substituted by a group of the formula —NR
13
R
14
,
wherein
R
13
and R
14
are identical or different and denote hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,
R
6
represents hydrogen, carboxyl or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or by a group of the formula —O—CO—R
15
,
wherein
R
15
denotes phenyl which is optionally substituted up to 3 times by identical or different halogen or hydroxyl substituents or by straight-chain or branched alkyl having up to 5 carbon atoms, or straight-chain or branched alkyl or alkenyl each having up to 22 carbon atoms, each of which is optionally substituted by a group of the formula —OR
6
,
wherein
R
16
is hydrogen, benzyl, triphenylmethyl or straight-chain or branched acyl having up to 6 carbon atoms,
R
7
represents hydrogen or
R
6
and R
7
together represent the group of the formula ═O,
if appropriate in an isomeric form and their salts.
The cycloalkan-indole and -azaindole derivatives according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. 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, hydrobrornic 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 also 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, and also 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.
Including the double bond of parent structure, the cycloalkene radical (R
3
/R
4
) in the context of the invention in general represents a 4 -to 8-membered hydrocarbon radical, preferably a 5- to 8-membered hydrocarbon radical, for example a cyclobutene, cyclopentene, cyclohexene, cycloheptene or cyclooctene radical. The cyclopentene, cyclohexene, cyclooctene or cycloheptene radicals are preferred
Heterocycle (R
5
) in the context of the invention in general represents a saturated or unsaturated 5- to 7-membered heterocycle, preferably a 5- to 6-membered heterocycle, which can contain up to 3 heteroatoms from the series consisting of S, N and/or O. Examples which may be mentioned are: pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Pyridyl and thienyl are preferred.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or do which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers and diastereomers and their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated in a known manner into the stereoisomerically uniform constituents.
Preferred compounds of the general formula (I) are those
in which
R
1
and R
2
, including the double bond connecting them, together form a phenyl or pyridyl ring or a ring of the formula
wherein
R
8
denotes hydrogen or stright-chain or branched alkyl having up to 3 carbon atoms,
R
3
and R
4
, including the double bond connecting them, together form a phenyl ring or a cyclopentene, cyclohexene, cycloheptene, cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene or oxocyclooctene radical,
all ring systems mentioned under R
1
/R
2
and R
3
/R
4
optionally being substituted up to 2 times by identical or different fluorine, chlorine, bromine, trifluoromethyl, carboxyl or hydroxyl substituents, by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or by straight-chain or branched alkyl having up to 4 carbon atoms, which, in turn, can be substituted by hydroxl or by straight-chain or branched alkoxy having up to 3 carbon atoms.
D represents hydrogen, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or straight-chain or branched alkyl having up to 10 carbon atoms,
E represents the —CO— or —CS— group,
L represents an oxygen or sulphur atom or represents a group of the formula —NR
9
,
wherein
R
9
denotes hydrogen or staight-chain or branched alkyl having
Beuck Martin
Bischoff Hilmar
Connell Richard
Denzer Dirk
Domdey-Bette Anke
Bayer Aktiengesellschaft
Desai Rita
Norris & McLaughlin & Marcus
Rotman Alan L.
LandOfFree
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