Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-18
2001-12-11
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S188000, C546S152000, C546S153000, C546S290000, C546S292000
Reexamination Certificate
active
06329360
ABSTRACT:
The present invention relates to hetero-linked phenylglycinolamides, processes for their preparation and their use as medicaments, in particular as antiatherosclerotic medicaments.
It is known that raised 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 moreover exists 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 active medicaments for the control of atherosclerosis and coronary heart diseases.
The present invention relates to hetero-linked phenylglycinolamides of the general formula (I)
in which
A represents aryl having 6 to 10 carbon atoms, benzyl or an optionally benzo-fused 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the series S, N and/or O, the ringsystems optionally being substituted—also via the N function—up to 3 times identically or differently by halogen, trifluoromethyl, carboxyl, hydroxyl, nitro, cycloalkyl having 3 to 7 carbon atoms, benzyl, phenyl, benzyloxy or by straigt-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or
a radical of the formula R
5
R
4
N— or
in which
R
4
and R
5
are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
R
6
denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
D represents an oxygen atom or a radical of the formula —CO—, —(CO)
a
—NR
7
, —(CH
2
)
b
S—, —(CH
2
)
c
—NR
8
or —CH═CH—, in which
a, b and c are identical or different and denote a number 0 or 1,
R
7
and R
8
are identical or different and denote hydrogen, straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, phenyl or benzyl, the ring systems optionally being substituted up to 2 times identically or differently by nitro, halogen, trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
E and L are identical or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms, azido, hydroxyl, halogen, straight-chain or branched alkyl, alkoxy or alkenyl each having up to 6 carbon atoms,
R
1
represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 10 carbon atoms,
R
2
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R
3
represents a radical of the formula
in which
R
9
denotes hydrogen or a radical of the formula CH
2
—OH,
R
10
denotes phenyl which is optionally substituted up to 3 times identically or differently by hydroxyl, halogen or straight-chain or branched alkyl having up to 5 carbon atoms,
and their salts.
The hetero-linked phenylglycinolamides 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. 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.
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 and to the diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated in a manner known per se into the stereoisomerically uniform constituents.
In the context of the invention heterocycle, optionally benzo-fused, in general represents a saturated, partially unsaturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered, heterocycle which can contain up to 3 heteroatoms from the series 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, thiazolyt, oxazolyl, imidazolyl, morpholinyl or piperidyl. Quinolyl, furyl, pyridyl and thienyl are preferred.
Preferred compounds of the general formula (I) according to the invention are those in which
A represents naphthyl, phenyl, benzyl, pyridyl, imidazolyl, benzimidazolyl or quinolyl, each of which is optionally substituted—also via the N function—up to 3 times identically or differently by fluorine, chlorine, bromine, trifluoromethyl, carboxyl, hydroxyl, nitro, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, phenyl, benzyloxy or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or
a radical of the formula R
5
R
4
N— or
in which
R
4
and R
5
are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R
6
denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms,
D represents an oxygen atom or a radical of the formula —CO—, —(CO)
a
—NR
7
, —(CH
2
)
b
S—, —(CH
2
)
c
—NR
8
or —CH═CH—, in which
a, b and c are identical or different and denote a number 0 or 1,
R
7
and R
8
are identical or different and denote hydrogen, straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, phenyl or benzyl, the ring systems optionally being substituted up to 2 times identically or differently by nitro, fluorine, chlorine, bromine, trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
E and L are identical or different and represent hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, azido, hydroxyl, fluorine, chlorine, bromine, straight-chain or branched alkyl, alkoxy or alkenyl each having up to 3 carbon atoms,
R
1
represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or straight-chain or branched alkyl having up to 8 carbon atoms,
R
2
represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R
3
represents a radical of the formula,
in which
R
9
denotes hydrogen or a radical of the formula CH
2
—OH,
R
10
denotes phenyl which is optionally substituted up to 2 times identically or differently by hydroxyl, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 3 carbon atoms,
and their salts.
Particularly preferred compounds of the general formula (I) according to the invention are those in which
A represents naphthyl, phenyl, benzyl, pyridyl, imidazolyl, benzimidazolyl or quinolyl, each of which is optionally substituted—also via the N function—up to 2 times identically or differently by fluorine, chlorine, trifluoromethyl, carboxyl, hydroxyl, nitro, cyclohexyl, benzyl, phenyl, benzyloxy or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or a radical of the formula R
5
R
4
N— or
in which
R
4
Beuck Martin
Bischoff Hilmar
Connell Richard
Denzer Dirk
Goldmann Siegfried
Bayer Aktiengesellschaft
Norris & McLaughlin & Marcus
Qazi Sabiha
LandOfFree
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