4-(Quinolin-2-yl-methoxy)-phenyl-acetic acid derivatives are prepared by reacting quinoline-methoxy-phenyl-acetic acids with the corresponding glycinol derivatives, if appropriate with activation of the carboxylic acid function. The new compounds are suitable as active compounds in medicaments, in particular in antiatherosclerotic medicaments.

The present invention relates to 4-(quinolin-2-yl-methoxy)-phenyl-acetic 
acid derivatives, to processes for their preparation and to 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 origin of atherosclerotic changes to the vascular 
walls and coronary heart diseases. 
There is also a significantly increased risk of the development of coronary 
heart diseases if these two risk factors occur in combination, which in 
turn is accompanied by an over-production of apolipoprotein B-100. There 
is therefore still a great need to provide effective medicaments for 
combating atherosclerosis and coronary heart diseases. 
The compounds 2(R*)- and 
2(S*)-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentylacetic acid 
(S)-phenylglycinolamide are known from the publication EP-344 519. 
The present invention relates to 4-(quinolin-2-yl-methoxy)-phenyl-acetic 
acid amides of the general formula (I), 
##STR1## 
in which A and D 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 having in 
each case up to 6 carbon atoms, or a 5- to 6-membered unsaturated or 
saturated heterocyclic radical having up to 3 heteroatoms from the series 
consisting of S, N and/or O, 
R.sup.1 represents hydrogen or hydroxyl, or represents straight-chain or 
branched alkyl having up to 4 carbon atoms, 
R.sup.2 represents hydrogen, hydroxyl, halogen, straight-chain or branched 
alkenyl or alkoxy having in each case up to 8 carbon atoms or cycloalkyl 
having 3 to 14 carbon atoms, or 
represents straight-chain or branched alkyl having up to 8 carbon atoms, 
which is optionally substituted by cycloalkyl having 3 to 14 carbon atoms, 
phenyl or tetrahydropyranyl, which in their turn can be substituted by 
halogen, or represents the indanyl radical, 
or 
R.sup.1 and R.sup.2 together with the carbon atom form a saturated 
carbocyclic ring having 5 to 7 carbon atoms, 
or 
R.sup.1 and R.sup.2 together represent a double bond radical of the formula 
##STR2## 
wherein a denotes the number 2, 3, 4, 5, or 6, 
E represents a radical of the formula 
##STR3## 
in which R.sup.3 denotes phenyl, methyl or a typical amino-protective 
group, 
R.sup.4 and R.sup.4' are identical or different and have the abovementioned 
meaning of R.sup.3 or denote hydrogen, 
R.sup.5 denotes straight-chain or branched acyl or alkyl having in each 
case up to 4 carbon atoms, 
L denotes phenyl, benzyl or naphthyl, which is optionally substituted up to 
twice in an identical or different manner by halogen, hydroxyl, 
pyrrolidinyl, morpholino, amino, trifluoromethyl, trifluoromethoxy, 
cycloalkyl having 3 to 6 carbon atoms or straight-chain or branched alkyl 
or alkoxy having in each case up to 6 carbon atoms, which in their turn 
can be substituted by hydroxyl, or are optionally substituted by phenyl or 
phenoxy, which in their turn can be substituted up to twice in an 
identical or different manner by halogen or by straight-chain or branched 
alkyl having up to 4 carbon atoms, and/or are optionally substituted by a 
group of the formula --(O).sub.c --SO.sub.2 R.sup.12, 
wherein 
c denotes the number 0 or 1 and 
R.sup.12 denotes straight-chain or branched alkyl having up to 4 carbon 
atoms or phenyl, 
b denotes the number 0, 1 or 2. 
T denotes a 5- to 7-membered optionally benzo-fused, saturated, partially 
unsaturated or unsaturated heterocyclic radical having up to 3 heteroatoms 
from the series consisting of S, N and/or O, wherein both rings are 
optionally substituted up to three times in an identical or different 
manner by halogen, hydroxyl, morpholino, amino, cycloalkyl having 3 to 6 
carbon atoms, straight-chain or branched alkyl or alkoxy having in each 
cage up to 6 carbon atoms or phenyl, 
V has the abovementioned meaning of L or T or denotes a radical of the 
formula 
##STR4## 
wherein d denotes the number 1, 2 or 3, 
R.sup.6 denotes a radical of the formula --(CH.sub.2).sub.e --R.sup.13, 
wherein 
e denotes the number 0 or 1, 
R.sup.13 denotes hydroxyl, carboxyl or straight-chain or branched 
alkoxycarbonyl having up to 4 carbon atoms, 
R.sup.7 denotes hydrogen, cyano, trifluoromethyl or straight-chain or 
branched alkenyl or alkyl having up to 7 carbon atoms, which is optionally 
substituted up to twice in an identical or different manner by 
straight-chain or branched alkoxy having up to 4 carbon atoms, or denotes 
alkoxy having up to 6 carbon atoms, or denotes a group of the formula 
--CO--NH--(CH.sub.2).sub.f --NR.sup.14 R.sup.15 
wherein 
f denotes the number 1, 2 or 3, 
R.sup.14 and R.sup.15 are identical or different and 
denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 
carbon atoms, 
R.sup.8 denotes hydrogen, carboxyl, straight-chain or branched 
alkoxycarbonyl having up to 4 carbon atoms or straight-chain or branched 
alkyl having up to 5 carbon atoms, which is optionally Substituted by 
hydroxyl, carboxyl or by straight-chain or branched alkoxycarbonyl having 
in each case up to 4 carbon atoms or phenyl, 
R.sup.9 and R.sup.10 are identical or different and 
denote hydrogen, cycloalkyl having 3 to 6 carbon atoms or phenyl, or denote 
straight-chain or branched alkyl having up to 6 carbon atoms, which is 
optionally substituted by phenyl, cycloalkyl having 3 to 6 carbon atoms, 
hydroxyl, carboxyl, by straight-chain or branched alkoxy or alkoxycarbonyl 
having in each case up to 4 carbon atoms or by a group of the formula 
--NR.sup.16 R.sup.17 
wherein 
R.sup.16 and R.sup.17 are identical or different and denote hydrogen, 
phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, 
or 
R.sup.9 and R.sup.10 together with the nitrogen atom form a heterocyclic 
radical of the formula 
##STR5## 
wherein Z denotes an oxygen atom or the group --NR.sup.18 or --CH, 
wherein 
R.sup.18 denotes hydrogen, acetyl, a typical amino-protective group or a 
radical of the formula --SO.sub.2 R.sup.19. 
wherein 
R.sup.19 denotes straight-chain or branched alkyl having up to 4 carbon 
atoms, benzyl or phenyl, which is optionally substituted by phenyl or 
tolyl, 
W denotes straight-chain or branched alkyl having 2 to 7 carbon atoms, 
which is substituted one to three tunes in an identical or different 
manner by hydroxyl, pyridyl, norbornyl or phenyl, which in its turn can be 
substituted by hydroxyl or benzyloxy, 
or is substituted by a group of the formula --OR.sup.20 or --NR.sup.21 
R.sup.22, 
wherein 
R.sup.20 denotes straight-chain or branched alkyl having up to 6 carbon 
atoms and 
R.sup.21 and R.sup.22 are identical or different and have the 
abovementioned meaning of R.sup.16 and R.sup.17, 
X denotes an oxygen or sulphur atom, 
Y denotes formyl or the group --CHR.sup.23 R.sup.24, 
wherein 
R.sup.23 denotes hydrogen and 
R.sup.24 denotes hydroxyl or straight-chain or branched alkoxy or acyl 
having in each case up to 4 carbon atoms, 
or 
R.sup.23 and R.sup.24 are identical or different and denote straight-chain 
or branched alkoxy having up to 4 carbon atoms, 
R.sup.11 denotes a radical of the formula 
##STR6## 
phenyl which is optionally substituted up to twice in an identical or 
different manner by halogen, carboxyl or straight-chain or branched 
alkoxycarbonyl having up to 5 carbon atoms, 
or 
denotes straight-chain or branched alkyl having up to 6 carbon atoms, 
which is optionally substituted up to twice in an identical or different 
manner by hydroxyl, carboxyl, halogen or by straight-chain or branched 
alkoxycarbonyl having up to 5 carbon atoms, 
and salts thereof, 
2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid 
metahyloxycarbonylmethylamide, 
2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid 
carboxymethylamide, 
N-methyl-2-3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl!-2-cycloheptylacetam 
ide, 
N-methyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cycloheptyl-acetic acid 
amide, 
N-ethyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid amide 
and 
N-ethyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclohexyl-acetic acid amide 
being excluded. 
The substituted 4-(quinolin-2-yl-methoxy-phenyl)-acetic acid derivatives 
according to the invention can also be in the form of their salts. Salts 
with organic or inorganic bases or acids may in general be mentioned 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 also be metal salts or ammonium salts 
of the compounds according to the invention which have a free carboxyl 
group or a tetrazolyl radical. Particularly preferred salts are, for 
example sodium potassium, magnesium or calcium salts, as well as 
ammunonium 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. 
A heterocyclic radical in general is a 5- to 6-membered, saturated, 
partially unsaturated or unsaturated ring which can contain up to 3 
oxygen, sulphur and/or nitrogen atoms as heteroatoms. Preferred rings are 
5and 6-membered rings with one oxygen, sulphur and/or up to 2 nitrogen 
atoms. Rings which are mentioned as preferred are: thienyl, furyl, 
pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 
thiazolyl, oxazolyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl. 
A 5- to 6-membered saturated heterocyclic radical which can also contain up 
to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms is in general 
piperidyl, morpholinyl, piperazinyl or pyrrolidyl. Morpholinyl is 
preferred. 
A carbocyclic radical in general is a 3- to 7-membered, preferably 5- to 
7-membered, saturated hydrocarbon ring. Cyclopentyl, cyclohexyl or 
cycloheptyl are mentioned as preferred. 
A hydroxy-protective group in the context of the abovementioned definition 
is in general a protective group from the series consisting of: 
tert-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, 
triisopropylsilyl, tert-butyl-dimethylsilyl, tert-butyl-diphenylsilyl, 
triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, benzyloxycarbonyl, 
2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 
4-nitrobenzyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, 
4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl, 
trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxymethyl, 
2,4-dimethoxybenzyloxycarbonyl, methylthiomethyl, methoxyethoxymethyl, 
2-(trimethylsilyl)ethoxy!methyl, 2-(methylthiomethoxy)ethoxycarbonyl, 
benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl 
or 4-methoxybenzoyl. Acetyl, benzoyl, benzoyl, or methylbenzyl are 
preferred. 
Amino-protective groups in the context of the invention are the customary 
amino-protective groups used in peptide chemistry. 
These include, preferably: benzyloxycarbonyl, 
3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 
4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 
2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, 
tert-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 
2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxylbenzyloxycarbonyl, 
cyclohexoxycarbonyl, 1,1-dimethylethoxycarbonyl, adamantylcarbonyl, 
phthaloyl, 2,2,2-trichloroethoxycarbonyl, 
2,,2,2-trichloro-tert-butoxycarbonyl, methyloxycarbonyl, phenoxycarbonyl, 
4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, 
propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl, 
2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 
4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 
4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl. 
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 to both the 
enantiomers or diastereomers or the particular mixtures thereof. These 
mixtures of the enantiomers and diastereomers can be separated into the 
stereoisomerically uniform constituents in a known manner. 
Diastereomers can be represented, for example, by the following formulae: 
##STR7## 
Preferred compounds of the general formula (I) 
are those in which 
A and D are identical or different and represent hydrogen, cyclopropyl, 
cyclopentyl, cyclohexyl, azido, hydroxyl, fluorine, chlorine, bromine, 
straight-chain or branched alkyl, alkoxy or alkenyl having in each case up 
to 5 carbon atoms, pyrryl or imidazolyl, 
R.sup.1 represents hydrogen or hydroxyl or represents straight-chain or 
branched alkyl having up to 3 carbon atoms, 
R.sup.2 represents hydrogen, hydroxyl, fluorine, chlorine, bromine, 
straight-chain or branched alkenyl or alkoxy having in each case up to 7 
carbon atoms, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 
cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl, or 
represents straight-chain or branched alkyl having up to 7 carbon atoms, 
which is optionally substituted by cyclopentyl, cyclohexyl, cycloheptyl, 
cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cycloclodecyl, phenyl 
or tetrahydropyranyl, which in their turn can be substituted by fluorine, 
chlorine or bromine, or represents the indanyl radical, 
or 
R.sup.1 and R.sup.2 together with the carbon atom form a cyclopentyl, 
cyclohexyl or cycloheptyl ring, 
or 
R.sup.1 and R.sup. 2 together represent a double bond radical of the 
formula 
##STR8## 
wherein a denotes the number 2, 3, 4 or 5, 
E represents a radical of the formula 
##STR9## 
in which R.sup.3 denotes phenyl, methyl, acetyl or tert-butoxycarbonyl 
(Boc), 
R.sup.4 and R.sup.4' are identical or different and have the 
abovementioned meaning of R.sup.3 or denote hydrogen. 
R.sup.5 denotes straight-chain or branched acyl or alkyl having in each 
case up to 3 carbon atoms, 
L denotes phenyl, benzyl or naphthyl, which are optionally substituted up 
to twice in an identical or different manner by fluorine, chlorine, 
bromine, iodine, hydroxyl, pyrrolidinyl, morpholino, amino, 
trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclohexyl or 
straight-chain or branched alkyl or alkoxy having in each case up to 6 
carbon atoms, which in their turn can be substituted by hydroxyl or are 
optionally substituted by phenyl or phenoxy, which in their turn can be 
substituted up to twice in an identical or different manner by fluorine, 
chlorine, bromine or by straight-chain or branched alkyl having up to 3 
carbon atoms, 
and/or are optionally substituted by a group of the formula --(O).sub.c 
SO.sub.2 --R.sup.12, 
wherein 
c denotes the number 0 or 1, 
and 
R.sup.12 denotes straight-chain or branched alkyl having up to 4 carbon 
atoms or phenyl, 
b denotes the number 0 or 1, 
T denotes a heterocyclic radical of the formula 
##STR10## 
wherein R.sup.25 and R.sup.26 are identical or different and denote 
hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or 
amino, 
V has the abovementioned meaning of L or T or denotes a radical of the 
formula 
##STR11## 
wherein d denotes the number 1 or 2, 
R.sup.6 denotes a radical of the formula --(CH.sub.2).sub.d --R.sup.13, 
wherein 
e denotes the number 0 or 1, 
R.sup.13 denotes hydroxyl, carboxyl or straight-chain or branched 
alkoxycarbonyl having up to 3 carbon atoms, 
R.sup.7 denotes hydrogen, cyano, trifluoromethyl, vinyl or straight-chain 
or branched alkyl having up to 6 carbon atoms, which is optionally 
substituted up to twice in an identical or different manner by 
straight-chain or branched alkoxy having up to 3 carbon atoms, or denotes 
alkoxy having up to 5 carbon atoms, or denotes a group of the formula 
--CO--NH--(CH.sub.2).sub.f --NR.sup.14 R.sup.15 
wherein 
f denotes the number 1, 2 or 3, 
R.sup.14 and R.sup.15 are identical or different and denote hydrogen, 
phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, 
R.sup.8 denotes hydrogen, carboxyl, straight-chain or branched 
alkoxycarbonyl having up to 3 carbon atoms or straight-chain or branched 
alkyl having up to 5 carbon atoms, which is optionally substituted by 
hydroxyl, carboxyl or by straight-chain or branched alkoxycarbonyl having 
in each case up to 3 carbon atoms or phenyl, 
R.sup.9 and R.sup.10 are identical or different and 
denote hydrogen, cyclopropyl, cyclopentyl cyclohexyl or phenyl, or denote 
straight-chain or branched alkyl having up to 5 carbon atoms, which is 
optionally substituted by phenyl, cyclopropyl, cyclopentyl, cyclohexyl, 
hydroxyl, carboxyl, by straight-chain or branched alkoxy or alkoxycarbonyl 
having in each case up to 3 carbon atoms or by a group of the formula 
--NR.sup.16 R.sup.17, 
wherein 
R.sup.16 and R.sup.17 identical or different and denote hydrogen, phenyl or 
straight-chain or branched alkyl having up to 3 carbon atoms, 
or 
R.sup.9 and R.sup.10 together with the nitrogen atom form a heterocyclic 
radical of the formula 
##STR12## 
wherein Z denotes an oxygen atom or the group --NR.sup.18 or --CH, 
wherein 
R.sup.18 denotes hydrogen, acetyl, tert-butoxycarbonyl or a radical of the 
formula --SO.sub.2 R.sup.19, 
wherein 
R.sup.19 denotes straight-chain or branched alkyl having up to 3 carbon 
atoms, benzyl or phenyl, which is optionally substituted by phenyl or 
tolyl, 
W denotes straight-chain or branch alkyl having 2 to 7 carbon atoms, which 
is substituted 1 to 3 times in an identical or different manner by _ 
hydroxyl, pyridyl, norbornyl or phenyl, which in its turn can be 
substituted by hydroxyl or benzyloxy, or is substituted by a group of the 
formula --OR.sup.20 or --NR.sup.21 R.sup.22, 
wherein 
R.sup.20 denotes straight-chain or branched alkyl having up to 5 carbon 
atoms and 
R.sup.21 and R.sup.22 are identical or different and have the 
abovementioned meaning of R.sup.16 and R.sup.17, 
X denotes an oxygen or sulphur atom, 
Y denotes formyl or the group --CHR.sup.23 R.sup.24, 
wherein 
R.sup.23 denotes hydrogen, 
R.sup.24 denotes hydroxyl or straight-chain or branched alkoxy or acyl 
having in each case up to 3 carbon atoms, 
or 
R.sup.23 and R.sup.24 are identical or different and denote straight-chain 
or branched alkoxy having up to 3 carbon atoms, 
R.sup.11 denotes a radical of the formula 
##STR13## 
phenyl, which is optionally substituted up to twice in an identical or 
different manner by fluorine, chlorine, bromine, carboxyl or 
straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, 
or 
denotes straight-chain or branched alkyl having up to 5 carbon atoms, 
which is optionally substituted up to twice in an identical or different 
manner by hydroxyl, carboxyl, fluorine, chlorine, bromine or by 
straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, 
and salts thereof, 
2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid 
methyloxycarbonyl-methylamide, 
2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid 
carboxymethylamide, 
N-methyl-2-3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl!-2-cycloheptylacetam 
ide, 
N-methyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cycloheptyl-acetic acid 
amide, 
N-ethyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid amide 
and 
N-ethyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclohexyl-acetic acid amide 
being excluded. 
Particularly preferred compounds of the general formula (I) are those 
in which 
A and D are identical or different and 
represent hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, azido, hydroxyl, 
fluorine, chlorine, bromine, straight-chain or branched alkyl, alkoxy or 
alkenyl having in each case up to 4 carbon atoms, imidazolyl or pyrryl, 
R.sup.1 represents hydrogen, hydroxyl or straight-chain or branched alkyl 
having up to 3 carbon atoms, 
R.sup.2 represents hydrogen, hydroxyl, fluorine, chlorine, straight-chain 
or branched alkenyl or alkoxy having in each case up to 5 carbon atoms, 
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl 
or cycloundecyl or represents straight-chain or branched alkyl having up 
to 6 carbon atoms, which is optionally substituted by cyclopentyl, 
cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cycloundecyl, phenyl or 
tetrahydropyranyl, which in their turn can be substituted by fluorine, 
chlorine or bromine, or represents the indanyl radical, 
R.sup.1 and R.sup.2 together with the carbon atom form a cyclopentyl, 
cyclohexyl or cycloheptyl ring, 
E represents a radical of the formula 
##STR14## 
in which R.sup.3 denotes phenyl, methyl, acetyl or tert-butoxycarbonyl 
(Boc), 
R.sup.4 and R.sup.4' are identical or different and have the 
abovementioned meaning of R.sup.3 or denote hydrogen, 
R.sup.5 denotes straight-chain or branched acyl or alkyl having in each 
case up to 3 carbon atoms, 
L denotes phenyl, benzyl or naphthyl, which are optionally substituted up 
to twice in an identical or different manner by fluorine, chlorine, 
bromine, iodine, hydroxyl, pyrrolidinyl, morpholino, trifluoromethoxy, 
trifluoromethyl, amino, cyclopropyl, cyclopentyl, cyclohexyl or 
straight-chain or branched alkyl or alkoxy having in each case up to 6 
carbon atoms, which in their turn can be substituted by hydroxyl, or are 
optionally substituted by phenyl or phenoxy, which in their turn can be 
substituted up to twice in an identical or different manner by fluorine, 
chlorine or by straight-chain or branched alkyl having up to 3 carbon 
atoms, 
and/or are optionally substituted by a group of the formula --(O).sub.c 
SO.sub.2 --R.sup.12, 
wherein 
c denotes the number 0 or 1, 
and 
R.sup.12 denotes straight-chain or branched alkyl having up to 3 carbon 
atoms or phenyl, 
b denotes the number 0 or 1, 
T denotes a heterocyclic radical of the formula 
##STR15## 
wherein R.sup.25 and R.sup.26 are identical or different and denote 
hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or 
amino, 
V has the abovementioned meaning of L or T or denotes a radical of the 
formula 
##STR16## 
wherein d denotes the number 1 or 2, 
R.sup.6 denotes a radical of the formula --(CH.sub.2).sub.d --R.sup.13, 
wherein 
e denotes the number 0 or 1, 
R.sup.13 denotes hydroxyl, carboxyl or straight-chain or branched 
alkoxycarbonyl having up to 3 carbon atoms, 
wherein 
R.sup.7 denotes hydrogen, cyano, trifluoromethyl, vinyl or straight-chain 
or branched alkyl having up to 5 carbon atoms, which is optionally 
substituted up to twice in an identical or different manner by 
straight-chain or branched alkoxy having up to 3 carbon atoms, or denotes 
alkoxy having up to 3 carbon atoms, or denotes a group of the formula 
--CO--NH--(CH.sub.2).sub.f --NR.sup.14 R.sup.15, 
wherein 
f denotes the number 1, 2 or 3, 
R.sup.14 and R.sup.15 are identical or different and 
denote hydrogen, phenyl or straight-chain or branched alkyl having up to 3 
carbon atom 
R.sup.8 denotes hydrogen, carboxyl, straight-chain or branched 
alkoxycarbonyl having up to 3 carbon atoms or straight-chain or branched 
alkyl having up to 4 carbon atoms, which is optionally substituted by 
hydroxyl, carboxyl or by straight-chain or branched alkoxycarbonyl having 
in each case up to 3 carbon atoms or phenyl, 
R.sup.9 and R.sup.10 are identical or different and 
denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl or phenyl, or denote 
straight-chain or branched alkyl having up to 5 carbon atoms, which is 
optionally substituted by phenyl, cyclopropyl, cyclopentyl cyclohexyl, 
hydroxyl, carboxyl, by straight-chain or branched alkoxy or alkoxycarbonyl 
having in each case up to 3 carbon atoms or by a group of the formula 
--NR.sup.16 R.sup.17, 
wherein 
R.sup.16 and R.sup.17 are identical or different and denote hydrogen, 
phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, 
or 
R.sup.9 and R.sup.10 together with the nitrogen atom form a heterocyclic 
radical of the formula 
##STR17## 
wherein Z denotes an oxygen atom or the group --NR.sup.18 or --CH, 
wherein 
R.sup.18 denotes hydrogen, acetyl, tert-butoxycarbonyl or a radical of the 
formula --SO.sub.2 R.sup.19, 
w.herein 
R.sup.19 denotes straight-chain or branched alkyl having up to 3 carbon 
atoms, benzyl or phenyl, which is optionally substituted by phenyl or 
tolyl, 
W denotes straight-chain or branched alkyl having 2 to 7 carbon atoms, 
which is substituted 1 to 3 times in an identical or different manner by 
hydroxyl, pyridyl, norbornyl or phenyl, which in its turn can be 
substituted by hydroxyl or benzyloxy, or is substituted by a group of the 
formula --OR.sup.20 or --NR.sup.21 R.sup.22, 
wherein 
R.sup.20 denotes straight-chain or branched alkyl having up to 4 carbon 
atoms and 
R.sup.21 and R.sup.22 are identical or different and have the 
abovementioned meaning of R.sup.16 and R.sup.17, 
X denotes an oxygen or sulphur atom, 
Y denotes formyl or the group --CHR.sup.23 R.sup.24, 
wherein 
R.sup.23 denotes hydrogen, 
R.sup.24 denotes hydroxyl or straight-chain or branched alkoxy or acyl 
having in each case up to 3 carbon atoms, 
or 
R.sup.23 and R.sup.24 are identical or different and denote straight-chain 
or branched alkoxy having up to 3 carbon atoms, 
R.sup.11 denotes a radical of the formula 
##STR18## 
phenyl, which is optionally substituted up to twice in an identical or 
different manner by fluorine, chlorine, bromine, carboxyl or 
straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, 
or 
denotes straight-chain or branched alkyl having up to 5 carbon atoms, 
which is optionally substituted up to twice in an identical or different 
manner by hydroxyl, carboxyl, fluorine, chlorine, bromine or by 
straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms. 
and salts thereof, 
2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid 
methyloxycarbonylmethylamide, 
2-4(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid 
carboxymethylamide, 
N-methyl-2-3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl!-2-cycloheptylacetam 
ide, 
N-methyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cycloheptyl-acetic acid 
amide, 
N-ethyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl-acetic acid amide 
and 
N-ethyl-2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclohexyl-acetic acid amide 
being excluded. 
Processes have also been found for the preparation of the compounds of the 
general formula (I) according to the invention, characterized in that 
A! in the case where E does not represent the radical of the formula 
##STR19## 
carboxylic acids of the general formula (II) 
##STR20## 
in which A, D, R.sup.1 and R.sup.2 have the meaning given, 
if appropriate with prior activation of the carboxylic acid function, are 
reacted with glycinols or esters thereof of the general formula (III) 
##STR21## 
in which R.sup.27 has the abovementioned scope of meaning of L, V, W and 
R.sup.8 
and 
R.sup.28 represents --CH.sub.2 --OH or represents (C.sub.1 
-C.sub.8)-alkoxycarbonyl 
in inert solvents, in the presence of a base and if appropriate of an 
auxiliary, 
and 
B! in the case where E represents the radical of the group 
##STR22## 
the carboxylic acids of the general formula (II), after prior activation 
of the carboxylic acid function, are reacted with compounds of the general 
formula (IV) 
##STR23## 
in which X and L have the abovementioned meaning and 
R.sup.29 and R.sup.30 are identical or different and denote C.sub.1 
-C.sub.6 -alkyl, 
in inert solvents, if appropriate in the presence of a base and/or 
auxiliary, 
and in the case where Y.dbd.CHO, oxidation follows, 
and, depending on the particular definition of the abovementioned 
substituent E, if appropriate an acylation, reduction, hydrolysis, 
amidation, alkylation, sulphoamidation and/or elimination is carried out 
by customary methods. 
The process according to the invention can be illustrated by way of example 
by the following equation: 
##STR24## 
Suitable solvents here are inert organic solvents which do not change under 
the reaction conditions. These include ethers, such as diethyl ether or 
tetrahydrofuran, halogenated hydrocarbons, such as methylene chloride, 
chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, 
tetachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, 
such as benzene, xylene, toluene, hexane, cyclohexane or petroleum 
fractions, nitromethane, dimethylformamide, acetone, acetonitrile or 
hexamethylphosphoric acid triamide. It is also possible to employ mixtures 
of the solvents. Methylene chloride, tetrahydrofuran, acetone or 
dimethylformamide are particularly preferred. 
Suitable bases are the customary inorganic or organic bases. These include, 
preferably, alkali metal hydroxides, such as, for example, sodium 
hydroxide or potassium hydroxide, or alkali metal carbonates, such as 
sodium carbonate or potassium carbonate, or alkali metal alcoholates such 
as, for example, sodium ethanolate or potassium ethanolate or sodium 
methanolate or potassium methanolate, or organic amines, such as 
triethylamine, picoline or N-methylpiperidine, or amides, such as sodium 
amide or lithium diisopropylamide, or organometallic compounds, such as 
butyllithium or phenyllithium. Sodium carbonate and potassium carbonate 
and triethylamine are preferred. 
The base is employed in an amount of 0.6 mol to 5 mol, preferably 0.7 mol 
to 2 mol, per mole of the compound of the general formula (II). 
The reaction is in general carried out in a temperature range from 
0.degree. C. to 150.degree. C., preferably from +20.degree. C. to 
+110.degree. C. 
The reaction can be carried out under normal, increased or reduced pressure 
(for example 0.5 to 5 bar). It is in general carried out under normal 
pressure. 
Compounds which are suitable for activation of the carboxylic acid function 
are in general bases and/or dehydrating reagents, such as, for example, 
diisopropylcarbodiimide, dicyclohexylcarbodiimide or 
N-(3-dimethylammopropyl)-N'-ethylcarbodiimide hydrochloride, or carbonyl 
compounds, such as carbonyldiimidazole, or 1,2-oxazolium compounds, such 
as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphonate, or propanephosphoric acid 
anhydride or isobutyl chloroformate or 
benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or 
phosphonic acid diphenyl ester amide or methanesulphonyl chloride, if 
appropriate in the presence of bases, such as triethylamine or 
N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and 
N-hydroxysuccinimide. 
The acid-binding agents and dehydrating reagents are in general employed in 
an amount of 0.5 to 3 mol, preferably 1 to 1.5 mol, per mole of the 
corresponding carboxylic acids. 
The carboxylic acid function is in general activated in a temperature range 
from 0.degree. C. to 150.degree. C., preferably from 0.degree. C. to 
80.degree. C., end if appropriate under an inert gas atmosphere. 
The alkylation is in general carried out with alkylating agents, such as, 
for example, (C.sub.1 -C.sub.8)-alkyl halides, sulphonic acid esters or 
substituted or unsubstituted (C.sub.1 -C.sub.8)-dialkyl- or (C.sub.1 
-C.sub.8)-diarylsulphonates, preferably methyl iodide or dimethyl 
sulphate. 
The alkylation is in general carried out in one of the abovementioned 
solvents, preferably in dimethylformamide, in a temperature range from 
0.degree. C. to +70.degree. C., preferably from 0.degree. C. to 
+30.degree. C., under normal pressure. 
Suitable bases for the hydrolysis are the customary inorganic bases. These 
include, preferably, alkali metal hydroxides or alkaline earth metal 
hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or 
barium hydroxide, or alkali metal carbonates, such as sodium carbonate or 
potassium carbonate or sodium bicarbonate, or alkali metal alcoholates, 
such as sodium methanolate, sodium ethanolate, potassium methanolate, 
potassium ethanolate or potassium tert-butanolate. Sodium hydroxide or 
potassium hydroxide are particularly preferably employed. 
Suitable solvents for the hydrolysis are water or the organic solvents 
customary for a hydrolysis. These include, preferably, alcohols, such as 
methanol, ethanol, propanol, isopropanol or butanol, or ethers, such as 
tetrahydrofuran or dioxane, or dimethylformamide, or dimethyl sulphoxide. 
Alcohols, such as methanol, ethanol, propanol or isopropanol, are 
particularly preferably used. It is also possible to employ mixtures of 
the solvents mentioned. 
If appropriate, the hydrolysis can also be carried out with acids, such as, 
for example, trifluoroacetic acid, acetic acid, hydrochloric acid, 
hydrobromic acid, methanesulphonic acid, sulphuric acid or perchloric 
acid, preferably with trifluoroacetic acid. 
The hydrolysis is in general carried out in a temperature range from 
0.degree. C. to +100.degree. C., preferably from +20.degree. C. to 
+80.degree. C. 
The hydrolysis is in general carried out under normal pressure. However, it 
is also possible to carry out the hydrolysis under reduced pressure or 
finder increased pressure (for example from 0.5 to 5 bar). 
In carrying out the hydrolysis, the base is in general employed in an 
amount of 1 to 3 mol, preferably 1 to 1.5 mol, per mole of the ester. 
Molar amounts of the reactants are particularly preferably used. 
The hydrolysis of tert-butyl esters is in general carried out with acids, 
such as, for example, hydrochloric acid or trifluoroacetic acid, in the 
presence of one of the abovementioned solvents and/or water or mixtures 
thereof, preferably with dioxane or tetrahydrofuran. 
The oxidation in the case where Y.dbd.CHO is in general carried out in one 
of the abovementioned ethers, preferably dioxane, and in the presence of 
an acid. Acids include, preferably, inorganic acids, such as, for example, 
hydrochloric acid or sulphuric acid, or organic carboxylic acids having 
1-6 C atoms, optionally substituted by fluorine, chlorine and/or bromine, 
such as, for example, acetic acid, trifluoroacetic acid, trichloroacetic 
acid or propionic acid, or sulphonic acids with C.sub.1 -C.sub.4 -alkyl 
radicals or aryl radicals, such as, for example, methanesulphonic acid, 
ethanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid. 
Hydrochloric acid is preferred. 
The oxidation is in general carried out in a temperature range from 
0.degree. C. to +100.degree. C., preferably from +20.degree. C. to 
+80.degree. C. 
The oxidation is in general carried out under normal pressure. However, it 
is also possible to carry out the oxidation under reduced pressure or 
under increased pressure (for example from 0.5 to 5 bar). 
The amidation and the sulphonamidation are in general carried out in one of 
the abovementioned solvents, preferably in tetrahydrofuran or methylene 
chloride. 
If appropriate, the amidation and the sulphonamidation can proceed via the 
activated state of the acid halides, which can be prepared from the 
corresponding acids by reaction with thionyl chloride, phosphorus 
trichloride, phosphorus pentachloride, phosphorus tribromide or oxalyl 
chloride. 
The amidation and the sulphonamidation are in general carried out in a 
temperature range from -20.degree. C. to +80.degree. C., preferably from 
-10.degree. C. to +30.degree. C., under normal pressure. 
Suitable bases for this are, in addition to the abovementioned bases, 
preferably triethylamine and/or dimethylaminopyridine, DBU or DABCO. 
The base is employed in an amount of 0.5 mol to 10 mol, preferably 1 mol to 
2 mol, per mole of the corresponding acid or ester. 
Acid-binding agents which can be employed for the sulphonamidation are 
alkali metal or alkaline earth metal carbonates, such as sodium carbonate 
or potassium carbonate, alkali metal or alkaline earth metal hydroxides, 
such as, for example, sodium hydroxide or potassium hydroxide, or organic 
bases, such as pyridine, triethylamine, N-methylpiperidine or bicyclic 
amidines, such as 1,5-diazabicyclo3.4.0!-non-5-ene (DBN) or 
1,5-diazabicyclo3.4.0!-undec-5-ene (DBU). Potassium carbonate is 
preferred. 
Suitable dehydrating reagents are carbodiimides, such as, for example, 
diisopropylcarbodiimide, dicyclohexylcarbodiimide or 
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or carbonyl 
compounds, such as carbonyldiimidazole, or 1,2-oxazolium compounds, such 
as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propanephosphoric acid 
anhydride or isobutylchloroformate or 
benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or 
phosphonic acid diphenyl ester-amide or methanesulphonyl chloride, if 
appropriate in the presence of bases, such as triethylamine or 
N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide or 
N-hydroxysuccinimide. 
The acid-binding agents and dehydrating reagents are in general employed in 
an amount of 0.5 to 3 mol, preferably 1 to 1.5 mol, per mole of the 
corresponding carboxylic acids. 
Suitable solvents here are all the inert solvents which do not change under 
the reaction conditions. These include, preferably, alcohols, such as 
methanol, ethanol, propanol or isopropanol, or ethers, such as diethylene 
glycol dimethyl ether, or amides, such as hexamethylphosphoric acid 
triamide or dimethylformamide, or acetic acid. It is also possible to use 
mixtures of the solvents mentioned. 
The reductions can in general be carried out by hydrogen in water or in 
inert organic solvents, such as alcohols, ethers or halogenated 
hydrocarbons, or mixtures thereof, with catalysts, such as Raney nickel, 
palladium, palladium-on-animal charcoal or platinum, or with hydrides or 
boranes in inert solvents, if appropriate in the presence of a catalyst. 
The reaction is preferably carried out with hydrides, such as complex 
borohydrides or aluminium hydrides. Sodium borohydride, lithium aluminium 
hydride or sodium cyanoborohydride are particularly preferably employed 
here. 
The reaction is in general carried out in a temperature range from 
0.degree. C. to 150.degree. C., preferably from +20.degree. C. to 
+110.degree. C. 
The reaction can be carried out under normal, increased or reduced pressure 
(for example 0.5 to 5 bar). The reaction is in general carried out under 
normal pressure. 
The acylation is in general carried out in one of the abovementioned 
solvents, preferably methylene chloride, and in the presence of a typical 
acylating agent such as, for example, acetyl chloride. 
The acylation is in general carried out in a temperature range from 
0.degree. C. to 150.degree. C., preferably from +20.degree. C. to 
+110.degree. C. 
The acylation can be carried out under normal, increased or reduced 
pressure (for example 0.5 to 5 bar). It is in general carried out under 
normal pressure. 
The elimination is in general carried out in one of the abovementioned 
solvents, in the presence of a base and an auxiliary. Diethylformamide, 
methyl chloride and triethylamine are preferred. 
The elimination is in general carried out in a temperature range from 
0.degree. C. to 150.degree. C., preferably from +20.degree. C. to 
+110.degree. C. 
The elimination can be carried out under normal, increased or reduced 
pressure (for example 0.5 to 5 bar). The elimination is in general carried 
out under normal pressure. 
The compounds of the general formula (II) are known (cf. U.S. Pat. Nos. 
4,929,629, 4,970,215, 5,091,392, 5,126,354, EP 414 078, 529 450) or they 
can be prepared by a process in which 
compounds of the general formula (V) 
##STR25## 
in which A, D, R.sup.1 and R.sup.2 have the abovementioned meaning 
R.sup.31 represents a typical hydroxy-protective group, preferably benzyl 
or tert-butyl, 
and 
R.sup.32 represents hydrogen or represents (C.sub.1 -C.sub.4)-alkyl, 
after this protective group has been split off by customary methods, are 
reacted with compounds of the general formula (VI) 
##STR26## 
in which R.sup.33 represents halogen, preferably bromine, 
in inert solvents, if appropriate in the presence of a base, 
and in the case of the acids the esters are hydrolysed. 
Solvents for the etherification can be inert organic solvents which do not 
change under the reaction conditions. These include, preferably, ethers, 
such as, for example, dioxane, tetrahydrofuran or diethyl ether, 
halogenated hydrocarbons, such as methylene chloride, chloroform, carbon 
tetrachloride, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such 
as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, 
nitromethane, dimethylformamide, acetonitrile, acetone or 
hexamethylphosphoric acid triamide. It is also possible to employ mixtures 
of these solvents. 
Bases which can be employed for the etherification are inorganic or organic 
bases. These include, preferably, alkali metal hydroxides, such as, for 
example, sodium hydroxide or potassium hydroxide, alkaline earth metal 
hydroxide, such as, for example, barium hydroxide, alkali metal 
carbonates, such as sodium carbonate or potassium carbonate, alkaline 
earth metal carbonates, such as calcium carbonate, or organic amines 
(trialkyl(C.sub.1 -C.sub.6)-amines), such as triethylamine, or 
heterocyclic bases, such as pyridine, methylpiperidine, piperidine or 
morpholine. 
It is also possible to employ alkali metals, such as sodium, and hydrides 
thereof, such as sodium hydride, as bases. 
The etherification is in general carried out in a temperature range from 
0.degree. C. to +150.degree. C., preferably from +10.degree. C. to 
+100.degree. C. 
The etherification is in general carried out under normal pressure. 
However, it is also possible to carry out the process under reduced 
pressure or increased pressure (for example in a range from 0.5 to 5 bar). 
In general, 0.5 to 5, preferably 1 to 2, mol of halide are employed per 
mole of the reaction partner. The base is in general employed in an amount 
of 0.5 to 5 mol, preferably 1 to 3 mol, based on the halide. 
The hydrolysis of the carboxylic acid esters is carried out by customary 
methods, by treating the esters with customary bases in inert solvents. 
Suitable bases for the hydrolysis are the customary inorganic bases. These 
include, preferably, alkali metal hydroxides or alkaline earth metal 
hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or 
barium hydroxide, or alkali metal carbonates, such as sodium carbonate or 
potassium carbonate or sodium bicarbonate. Sodium hydroxide or potassium 
hydroxide are particularly preferably employed. 
Suitable solvents for the hydrolysis are water or the organic solvents 
customary for a hydrolysis. They include, preferably, alcohols, such as 
methanol, ethanol, propanol, isopropanol or butanol, or ethers, such as 
tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide. 
Alcohols, such as methanol, ethanol, propanol or isopropanol, are 
particularly preferably used. It is also possible to employ mixtures of 
the solvents mentioned. 
In general the hydrolysis is carried out in a temperature range from 
0.degree. C. to +100.degree. C., preferably from +20.degree. C. to 
+80.degree. C. 
The hydrolysis is in general carried out under normal pressure. However, it 
is also possible to carry out the hydrolysis under reduced pressure or 
under increased pressure (for example from 0.5 to 5 bar). 
In carrying out the hydrolysis, the base is in general employed in an 
amount of 1 to 3 mol, preferably 1 to 1.5 mol, per mole of the ester. 
Molar amounts of the reactants are particularly preferably used. 
The compounds of the general formula (III) and (IV) are known. 
The compounds of the general formulae (V) and (VI) are known. 
The compounds of the general formula (I) according to the invention have an 
unforeseeable pharmacological action spectrum. 
They can be used as active compounds in medicaments for reducing changes to 
vascular walls and for treatment of coronary heart diseases, cardiac 
insufficiency, disturbances in cerebral performance, ischaemic cerebral 
diseases, apoplexy, circulatory disturbances, disturbances in 
microcirculation and thromboses. 
The proliferation of smooth muscle cells also plays a decisive role in the 
occlusion of vessels. The compounds according to the invention are capable 
of inhibiting this proliferation and therefore of preventing 
atherosclerotic processes. 
The compounds according to the invention are distinguished by a reduction 
in the ApoB-100 associated lipoproteins (VLDL and its breakdown products, 
such as, for example, LDL), of ApoB-100 of triglycerides and of 
cholesterol. They therefore have valuable pharmacological properties which 
are superior compared with the prior art. 
Surprisingly, the action of the compounds according to the invention 
comprises initially a reduction or complete inhibition of the formation 
and/or release of ApoB-100-associated lipoproteins from liver cells, which 
results in a reduction of the plasma VLDL level. This action in VLDL must 
be accompanied by a reduction in the plasma level of ApoB-100, LDL, 
triglycerides and cholesterol; several of the abovementioned risk factors 
which participate in changes to vascular walls are thus reduced at the 
same time. 
The compounds according to the invention can therefore be employed for 
prevention and treatment of atherosclerosis, obesity, pancreatitis and 
constipation. 
The invention also relates to a combination of oxyphenyl (phenyl)glycinol 
amides containing heterocyclic substituents of the general formula (I) 
with a glucosidase and/or amylase inhibitor for the treatment of familial 
hyperlipidemia, obesity (adipositas) and diabetes mellitus. Glucosidase 
and/or amylase inhibitors in the context of the invention are for example 
Acarbose, Adiposine, Voglibose (AQ-128), Miglitol, Emiglitate, MDL-25637, 
Camiglibose (MDL-73945), Tendamistate, A1-3688, Treslatin, Pradimicin-Q 
and Salboslatin. A combination of Acarbose, Miglitol, Emiglitate or 
Voglibose with one of the abovementioned compounds of the general formula 
(I) is preferred. 
I. Inhibition of the release of ApoB-100-associated lipoproteins 
The test for detection of the inhibition of the release of 
ApoB-100-associated lipoproteins from liver cells was carried out in vitro 
with cultured liver cells, preferably with cells of the human line HepG2. 
These cells are grown under standard conditions in a medium for culture of 
eukaryotic cells, preferably in RPMI 1640, with 10% of foetal calf serum. 
HepG2 cells synthesize and secrete into the culture supernatant 
ApoB-100-associated lipoprotein particles, which in principle are built up 
in a similar manner to the VLDL and LDL particles which are to be found in 
the plasma. 
These particles can be detected with an immunoassay for human LDL. This 
immunoassay is carried out with antibodies which have been induced against 
human LDL in the rabbit under standard conditions. The anti-LDL antibodies 
(rab-anti-LDL-ab) were purified by affinity chromatography on an 
immunosorbent with human LDL. These purified rab-anti-LDL-ab are adsorbed 
onto the surface of plastic. This adsorption is expediently carried out on 
the plastic surface of microtiter plates having 96 wells, preferably on 
MaxiSorp plates (Nunc). If ApoB-100-associated particles are present in 
the supernatant of HepG2 cells, these can bind to the insolubilized 
rab-anti-LDL-ab, and an immune complex which is bonded to the plastic 
surface is formed. Non-bonded proteins are removed by washing. The immune 
complex on the plastic surface is detected with monoclonal antibodies, 
which had been induced against human LDL according to standard conditions 
and purified. These antibodies were conjugated with the enzyme peroxidase 
(Boehringer, Mannheim). Peroxidase converts the colourless substrate TMB 
(Kirkegaard and Perry) into a coloured product in the presence of H.sub.2 
O.sub.2. After acidification of the reaction mixture with H.sub.2 
SO.sub.4, the specific light adsorption at 450 nm, which is a measure of 
the amount of ApoB-100-associated particles which had been secreted into 
the culture supernatant by the HepG2 cells, is determined. 
Surprisingly, the compounds according to the invention inhibit the release 
of ApoB-100-associated particles. The IC.sub.50 value indicates the 
concentration of substance at which the light adsorption is inhibited by 
50% in comparison with the control (solvent control without substance). 
TABLE 
______________________________________ 
Example No. 
IC.sub.50 nM! 
______________________________________ 
15 500 
53 250 
127 130 
141 20 
______________________________________ 
2. Investigation of the inhibition of the proliferation of smooth muscle 
cells 
The antiproliferative action of the compounds is determined using smooth 
muscle cells which are obtained from the aortas of rats by the media 
explant technique R. Ross, J. Cell. Biol. 50, 172, 1971!. The cells are 
sown in suitable culture dishes, generally 96-well plates, and are 
cultured for 2-3 days in medium 199 with 7.5% of FCS and 7.5% of NCS, 2 mM 
L-glutamine and 15 mM HEPES, pH 7.4, in 5% of CO.sub.2 at 37.degree. C. 
Thereafter, the cells are synchronized by withdrawal of serum for 2-3 days 
and are then stimulated to growth with serum or other factors. At the same 
time, test compounds are added. After 16-20 hours, 1 .mu.Ci of .sup.3 
H-thymidine is added, and after a further 4 hours the incorporation of 
this substance into the DNA of the cells which can be precipitated with 
TCA is determined. To determine the IC.sub.50 values, the active compound 
concentration which, on sequential diluent of the active compound, causes 
half the maximum inhibition of the thymidine incorporation caused by 10% 
of FCS. 
3. Determination of VLDL secretion in vivo on the hamster 
The effect of the test substances on VLDL secretion in vivo is investigated 
on the hamster. For this purpose, golden hamsters are premedicated with 
atropine (83 mg/kg s.c.) and anaesthetized with Ketavet (83 mg/kg s.c.) 
and Nembutal (50 mg/kg i.p.). When the animals have become free tom 
reflexes, the v. jugularis is exposed and a cannula is inserted. 0.25 
ml/kg of a 20% strength solution of Triton WR-1339 in physiological saline 
solution is then administered. This detergent inhibits the lipoprotein 
lipase and thus leads to an increase in the triglyceride level because of 
an absence of catabolism of secreted VLDL particles. This increase in 
triglycerides can be used as a measure of the rate of VLDL secretion. 
Blood is taken from the animals by puncture of the retroorbital venous 
plexus before and one and two hours after administration of the detergent. 
The blood is incubated at room temperature for two hours and then at 
4.degree. C. overnight in order to conclude the coagulation completely. 
Thereafter, it is centrifuged at 10,000 g for 5 minutes. The triglyceride 
concentration in the serum thus obtained is determined with the aid of a 
modified commercially obtainable enzyme test (Merckotest.RTM. Triglyceride 
No. 14354). 100 .mu.l of test reagent are added to 100 .mu.l of serum in 
96-well plates and the mixtures are incubated at room temperature for 10 
minutes. The optical density is then determined at a wavelength of 492 nm 
in an automatic plate reader (SLT-Spectra). Serum samples with too high a 
triglyceride concentration are diluted with physiological saline solution. 
The triglyceride concentration contained in the samples is determined with 
the aid of a standard curve measured in parallel. In this model test 
substances are administered either intravenously, immediately before 
administration of the detergent or orally or subcutaneously before 
initiation of the anaesthesia. 
4. Inhibition of the intestinal absorption of triglycerides in vivo (rats) 
The substances which are to be investigated for their triglyceride 
absorption-inhibiting action in vivo are administered orally to male 
Wistar rats having a body weight of between 170 and 230 g. For this 
purpose, the animals are divided into groups of 6 animals 18 hours before 
administration of the substance, and their food is then withdrawn. 
Drinking water is available to the animals ad libitum. The animals of the 
control group are given an aqueous tragacanth suspension or a tragacanth 
suspension which contains olive oil. The tragacanth-olive oil suspension 
is prepared with an Ultra-Turrax. The substances to be investigated are 
suspended in a corresponding tragacanth-olive oil suspension, likewise 
with the Ultra-Turrax, directly before administration of the substance. 
Blood is taken from each rat by puncture of the retroorbital venous plexus 
before application of the stomach tube in order to determine basal serum 
triglyceride content. The tragacanth suspensions, tragacanth-olive oil 
suspensions without a substance (control animals) and the substances 
suspended in a corresponding tragacanth-olive oil suspension, are then 
administered to the fasting animals with a stomach tube. Further blood is 
taken for determination of the postprandial increase in serum 
triglycerides as a rule 1, 2 and 3 hours after application of the stomach 
tube. 
The blood samples are centrifuged and, after isolation of the serum, the 
triglycerides are determined photometrically with an EPOS analyser 5060 
(Eppendorf Geratebau, Netlacier & Hinz GmbH, Hamburg). The triglycerides 
are determined completely enzymatically with a commercially available UV 
test. 
The postprandial increase in serum triglycerides is determined by 
subtraction of the triglyceride pre-value of each animal from its 
corresponding postprandial triglyceride concentrations (1, 2 and 3 hours 
after administration). 
The differences (in mmol/l) at each point in time (1, 2 and 3 hours) are 
averaged in the groups, and the means of the increase in serum 
triglycerides (.DELTA.TG) of the animals treated with the substances are 
compared with those of the animals which were given only the 
tragacanth-oil suspension. 
The course of the serum triglycerides of the control animals which were 
given only tragacanth is also calculated. The effect of the substance at 
each point in time (1, 2 or 3 hours) is determined as follows and stated 
in .DELTA.% of the oil-loaded control. 
##EQU1## 
Effect of 10 mg of test substance/kg of body weight p.o. on the increase in 
triglycerides (.DELTA.%) 2 h after a triglyceride loading in the serum of 
fasting rats. The increase in serum triglycerides of fat-loaded control 
animals based on the serum triglyceride level of tragacanth control 
animals corresponds to 100%. n=6 animals per group. 
Statistical analysis is by the Student t-test after first checking the 
variances for homogeneity. 
Substances which statistically significantly (p &lt;0.05) reduce the 
postprandial increase in serum triglycerides by at least 30% at a point in 
time, compared with that of the untreated control group, are regarded as 
pharmacologically active. 
5. Inhibition of VLDL secretion in vivo (rat) 
The action of the test substances on VLDL secretion is also investigated in 
the rat. For this, 500 mg/kg of body weight (2.5 mg/kg) of Triton WR-1339, 
dissolved in physiological saline solution, are administered intravenously 
into the tail vein of rats. Triton WR-1339 inhibits the lipoprotein lipase 
and thus leads to an increase in the triglyceride and cholesterol level by 
inhibition of VLDL catabolism. These increases can be used as a measure of 
the rate of VLDL secretion. 
Blood is taken from the animals by puncture of the retroorbital venus 
plexus before and one and two hours after administration of the detergent. 
The blood is incubated at room temperature for 1 h for coagulation and the 
serum is isolated by centrifugation at 10,000 g for 20 s. The 
triglycerides are then determined photometrically at a wavelength of 540 
nm with a commercially available coupled enzyme test (Sigma 
Diagnostics.RTM., No. 339). The measurement is made at a wavelength of 546 
nm with the aid of an enzyme test which is likewise coupled (Boehringer 
Mannhelm.RTM., No. 1442350). Samples with triglyceride or cholesterol 
concentrations which exceed the measurement range of the methods are 
diluted with physiological saline solution. The particular serum 
concentrations are determined with the aid of standard series measured in 
parallel. The test substances are administered orally, intravenously or 
subcutaneously immediately after the Triton injection. 
The new active compounds can be converted in a known manner into the 
customary formulations, such as tablets, coated tablets, pills, granules, 
aerosols, syrups, emulsions, suspensions and solutions, using inert, 
non-toxic, pharmaceutically suitable excipients or solvents. The 
therapeutically active compound should in each case be present here in a 
concentration of about 0.5 to 90% by weight of the total mixture, i.e. in 
amounts which are sufficient to achieve the stated dosage range. 
The formulations are prepared, for example, by extending the active 
compounds with solvents and/or excipients, if appropriate using 
emulsifying agents and/or dispersing agents, and in the case of the use of 
water as a diluent, for example, organic solvents can be used as auxiliary 
solvents if appropriate. 
The administration is carried out in the customary manner, preferably 
orally or parenterally, in particular perlingually or intravenously. 
In the case of parenteral use, solutions of the active compound can be 
employed, using suitable liquid carrier materials. 
In general, it has proved advantageous in the case of intravenous 
administration to administer amounts of about 0.001 to 1 mg/kg, preferably 
about 0.01 to 0.5 mg/kg of body weight, in order to achieve effective 
results, and in the case of oral administration the dosage is about 0.01 
to 20 mg/kg preferably 0.1 to 10 mg/kg of body weight. 
Nevertheless, it may be necessary to deviate from the amounts mentioned, 
and in particular as a function of the body weight or the nature of the 
administration route, of the behaviour of the individual towards the 
medicament, the nature of the formulation thereof and the time or interval 
at which administration takes place. Thus, in some cases it may be 
sufficient to manage with less than the abovementioned minimum amount, 
while in other cases the upper limit mentioned must be exceeded. In the 
event of administration of relatively large amounts, it may be advisable 
to distribute these into several individual doses over the day. 
Definition of the isomer types: 
4 dia=mixture of the four possible diastereomers with two centres of 
asymmetry in the molecule 
dia A=diastereomer having the higher R.sub.f value 
dia B=diastereomer having the lower R.sub.f value 
ent=enantiomer p1 2 ent dia=mixture of two enantiomerically pure 
diastereomers 
ent dia A=enantiomerically pure diastereomer having the higher R.sub.f 
value 
ent dia B=enantiomerically pure diastereomer having the lower R.sub.f value 
R=R enantiomer 
rac=racemate 
rac dia A=racemic diastereomer having the higher R.sub.f value 
rac dia B=racemic diastereomer having the lower R.sub.f value 
S=S enantiomer 
Abbreviations used: 
Ac=acetyl 
Bn=benzyl 
Bz=benzoyl 
iBu=iso-butyl 
nBu=normal butyl 
sBu=secondary butyl 
tBu=tertiary butyl 
cDec=cyclo decyl 
DMF=N,N,-dimethylformamide 
DMSO=dimethyl sulphoxide 
cDodec=cyclo-dodecyl 
Et=ethyl 
cHept=cyclo-heptyl 
cHex=cyclo-hexyl 
HOBT=1-hydroxy-1H-benzotriazole 
Me=methyl 
Mes=mesyl 
cNon=cyclo-nonyl 
cOct=cyclo-octyl 
cPent=cyclo-pentyl 
nPent=normal pentyl 
Ph=phenyl 
cPr=cyclo-propyl 
nPr=normal propyl 
iPr=iso-propyl 
THF=tetrahydrofuran 
TMS=tetramethylsilane 
pTol=para-tolyl 
pTos=para-tosyl 
cUndec=cyclo-undecyl 
______________________________________ 
Solvent mixtures used 
Designation 
Mobile phase Ratio 
______________________________________ 
A methylene chloride:ethyl acetate 
1:1 
B methylene chloride:methanol 
10:1 
C methylene chloride:methanol 
20:1 
D methylene chloride:methanol 
50:1 
E methylene chloride:methanol 
25:1 
F methylene chloride:ethanol 
20:1 
G methylene chloride:methanol 
100:1 
H petroleum ether:ethyl acetate 
2:1 
I toluene:ethyl acetate 
4:1 
J petroleum ether:acetone 
2:1 
K methylene chloride:ethyl acetate 
5:1 
L petroleum ether:acetone 
1:1 
M methylene chloride:ethyl acetate 
4:1 
N toluene:ethyl acetate 
1:1 
O petroleum ether:ethyl acetate 
1:1 
P petroleum ether:acetone 
3:1 
Q toluene:ethyl acetate 
2:3 
R toluene:ethyl acetate 
2:1 
S methylene chloride:ethyl acetate 
10:1 
T petroleum ether:ethyl acetate 
5:1 
U methylene chloride:methanol 
5:1 
V petroleum ether:ethyl acetate 
4:1 
W ethyl acetate 
X petroleum ether:ethyl acetate 
3:2 
Y methylene chloride:ethanol 
50:1 
Z methylene chloride:methanol 
19:1 
AA toluene:ethanol 30:1 
AB toluene:ethanol 15:1 
AC methylene chloride:methanol:ethyl 
90:10:1 
acetate 
AD methylene 90:10:1 
chloride:methanol:concentrated 
aqueous ammonia 
AE petroleum ether:ethyl acetate 
3:7 
AF petroleum ether:ethyl acetate 
7:3 
AG petroleum ether:ethyl acetate 
1:2 
AH petroleum ether:ethyl acetate 
2:3 
AI petroleum ether:ethyl acetate 
1:4 
AJ methylene chloride:methanol 
9:1 
AK toluene:acetone 10:1 
AL toluene:acetone 40:1 
______________________________________ 
Preparation instruction for the TLC mobile phase BABA 
87.9 ml of an aqueous 0.06667 molar potassium dihydrogen phosphate solution 
and 12.1 ml of an aqueous 0.06667 molar disodium hydrogen phosphate 
solution are mixed. 60 ml of the solution thus prepared are shaken with 
200 ml of n-butyl acetate, 36 ml of n-butanol and 100 ml of glacial acetic 
acid and the aqueous phase is removed. The organic phase is the mobile 
phase BABA. 
Starting compounds