Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-04-10
2001-02-27
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S087000
Reexamination Certificate
active
06194424
ABSTRACT:
The present invention relates to new arylacetamides, processes for their preparation and their use as medicaments, in particular as antiatherosclerotic medicaments.
It is known that increased blood levels of triglycerides (hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) are associated with the genesis of atherosclerotic vascular wall changes and coronary heart diseases.
A distinctly increased risk of the development of coronary heart diseases is moreover present if these two risk factors occur in combination, which in turn is accompanied by an overproduction of apoliprotein B-100. There is therefore still a great need to make available effective medicaments for the control of atherosclerosis and of coronary heart diseases.
The present invention relates to new arylacetamides of the general formula (I)
in which
R
1
and R
2
, including the double bond connecting them, together form a phenyl
in which
R
7
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 cycloalkene or oxocycloalkene ring,
where all ring systems mentioned under R
1
/R
2
and R
3
/R
4
are optionally substituted up to 3 times in an identical or different manner by halogen, trifluoromethyl, carboxyl, hydroxyl, by straight- chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by straight-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 and E are identical or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or represent phenyl which is optionally substituted by halogen or trifluoromethyl,
or
D and E together, including the CH group, form a 4- to 8-membered carbocyclic system,
R
5
represents hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
R
6
represents cycloalkyl having 3 to 8 carbon atoms or phenyl, or represents straight- chain or branched alkyl having up to 9 carbon atoms, which is optionally substituted by hydroxyl, naphthyl, trifluoromethyl or by a radical of the formula
in which
a denotes a number 1 or 2
or
R
6
represents a radical of the formula —(CH
2
)
n
—R
8
,
in which
n denotes a number 2, 3, 4 or 5,
R
8
denotes naphthyl or phenyl, each of which is optionally substituted by carboxyl, trifluoromethyl, halogen, hydroxyl, trifluoromethoxy or by straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,
or
represents a radical of the formula
R
5
and R
6
, together with the nitrogen atom, form a heterocyclic radical of the formula —(CH
2
)
2
—O—(CH
2
)
2
, —CH
2
—(CH
2
)
p
—CH
2
—,
in which
p denotes a number 2, 3, 4, 5, 6, 7, 8 or 9,
if appropriate in an isomeric form, and their salts.
The new acrylacetamides 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, 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 also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Those particularly preferred 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 cycloalkene radical (R
3
/R
4
), including the double bond of the parent structure, in the context of the invention in general represents a 4- to 8-membered, preferably 5- to 8-membered, hydrocarbon radical such as, for example, a cyclobutene, cyclopentene, cyclohexene, cycloheptene or cyclooctene radical. The cyclopentene, cyclohexene, cyclooctene and cycloheptene radicals are preferred.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
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
in which
R
7
denotes hydrogen or straight-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,
where all ring systems mentioned under R
1
/R
2
and R
3
/R
4
are optionally substituted up to 2 times in an identical or different manner by fluorine, chlorine, bromine, trifluoromethyl, carboxyl, hydroxyl, 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 for its part can be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 3 carbon atoms,
D and E are identical or different and represent hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl, or represent phenyl which is optionally substituted by fluorine, chlorine or bromine,
or
D and E together, including the CH group, form a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring,
R
5
represents hydrogen, straight-chain or branched alkyl having up to 10 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
R
6
represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl, or represents straight-chain or branched alkyl having up to 7 carbon atoms, which is optionally substituted by hydroxyl, naphthyl, trifluoromethyl or by a radical of the formula
in which
a denotes a number 1 or 2
or
R
6
represents a radical of the formula —(CH
2
)
n
—R
8
,
in which
n denotes a number 2, 3 or 4,
R
8
denotes naphthyl or phenyl, each of which is optionally substituted by trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethoxy or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,
or
represents a radical of the formula
or
R
5
and R
6
, together with the nitrogen atom, form a heterocyclic radical of the formula —(CH
2
)
2
—O—(CH
2
)
2
, —CH
2
—(CH
2
)
p
—CH
2
—,
in which
p denotes a number 2, 3, 4, 5, 6, 7 or 8,
if appropriate in an isomeric form, and their salts.
Particularly 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
in which
R
7
denotes hydrogen or methyl,
R
3
and R
4
, including the double bond connecting them, together
Bischoff Hilmar
Denzer Dirk
Eckenberg Peter
Grutzmann Rudi
Muller Ulrich
Bayer Aktiengesellschaft
Morris Patricia L.
Norris & McLaughlin & Marcus
LandOfFree
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