Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-20
2001-07-03
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...
C548S187000, C548S188000
Reexamination Certificate
active
06255330
ABSTRACT:
The present invention relates to heterocyclically substituted 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 wad 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 compounds according to the invention are partially covered by the widest scope of meaning of the publications DE 43 09 968, DE 43 02 956, DE 43 01 900, EP 565 086, EP 560 163, EP 560 162, EP 513 533 and DE 42 00 954, without a pharmacological representative of this type being mentioned there. The compounds mentioned here surprisingly show a decrease in or complete inhibition of the formation and/or the release of ApoB-100-associated lipoproteins from liver cells.
The present invention relates to heterocyclically substituted phenylglycinolamides of the general formula (I)
in which
A represents quinolyl or a radical of the formula
in which
R
3
, R
4
, R
6
and R
7
are identical or different and denote hydrogen, phenyl, halogen, formyl, carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl,
R
5
denotes phenyl, straight-chain or branched alkyl, acyl or alkylthio each having up to 6 carbon atoms or a group of the formula —CO—NR
10
R
11
,
in which
R
10
and R
11
are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms,
R
8
and R
9
are identical or different and denote hydrogen, straight-chain or branched alkyl or alkoxycarbonyl each having up to 6 carbon atoms or a radical of the formula —CO—R
2
,
in which
R
12
denotes morpholinyl or the radical of the formula
—NH—CH
2
—C
6
H
5
or
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 a radical of the formula
in which
R
13
denotes hydrogen or a radical of the formula CH
2
—OH,
R
14
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 heterocyclically substituted 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 known manner into the stereoisomerically uniform constituents.
Preferred compounds of the general formula (I) according to the invention are those
in which
A represents quinolyl or a radical of the formula
in which
R
3
, R
4
, R
6
and R
7
are identical or different and denote hydrogen, phenyl, fluorine, chlorine, bromine, formyl, straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl,
R
5
denotes phenyl, straight-chain or branched alkyl, acyl or alkylthio each having up to 5 carbon atoms or a group of the formula —CO—NR
10
R
11
,
in which
R
10
and R
11
are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms,
R
8
and R
9
are identical or different and denote hydrogen, straight-chain or branched alkyl or alkoxycarbonyl each having up to 5 carbon atoms or a radical of the formula —CO—R
12
,
in which
R
12
denotes morpholinyl or the radical of the formula
—NH—CH
2
—C
6
H
5
or
R
1
represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or represents straight-chain or branched alkyl having up to 8 carbon atoms,
R
3
represents a radical of the formula
in which
R
13
denotes hydrogen or a radical of the formula CH
2
—OH,
R
14
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 quinolyl or a radical of the formula
in which
R
3
, R
4
, R
6
and R
7
are identical or different and denote hydrogen, phenyl, chlorine, formyl, methoxycarbonyl, ethoxycarbonyl or methyl or ethyl, which is optionally substituted by hydroxyl,
R
5
denotes phenyl, methylthio, acetyl, ethylthio or straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula —CO—NR
10
R
11
,
in which
R
10
and R
11
are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R
8
denotes methyl, methoxycarbonyl, ethoxycarbonyl or the radical of the formula
—CO—NH—CH
2
—C
6
H
5
or
and
R
9
denotes hydrogen, methyl, propyl or butyl,
and their salts.
Very particularly preferred compounds of the general formula (I) are those which are listed in the following table.
A
R
1
R
2
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cPent
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cPent
(dia A) cPent
(dia B) cPent
(R&S) cPent
(R&S) cPent
(dia A) cPent
(dia B) cPent
(dia A) cPent
(dia B) cPent
(dia A) cHept
(dia B) cHept
(R&S) cPent
(R&S) cHept
(R&S) cPent
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cHept
(R&S) cHept
CH
2
—C
6
H
5
(R&S) cPent
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cHept
(R&S) cHept
CH
2
—C
6
H
5
(R&S) cPent
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cHept
(R&S) cHept
CH
2
—C
6
H
5
(R&S) cPent
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cHept
(R&S) cHept
CH
2
—C
6
H
5
(R&S) cPent
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cHept
(R&S) cHept
CH
2
—C
6
H
5
(R&S) cPent
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cHept
(R&S) cHept
CH
2
—C
6
H
5
(R&S) cPent
(R&S) cPent
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cHept
(R&S) cPent
CH
2
—C
6
H
5
(R&S) cHept
CH
2
—C
6
H
5
(dia A) cPent
(dia B) cPent
A process for the preparation of the compounds of the general formula (I) according to the invention has additionally been found, characterized in that carboxylic acids of the general formula (II)
in which
A and R
1
have the meaning indicated abo
Beuck Martin
Bischoff Hilmar
Connell Richard
Denzer Dirk
Goldmann Siegfried
Bayer Aktiengesellschaft
Morris Patricia L.
Norris & McLaughlin & Marcus
LandOfFree
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