The heterocyclically substituted phenylglycinolamides are obtained by reaction of heterocyclically substituted phenylacetic acids with appropriate phenylglycinols. The heterocyclically substituted phenylglycinolamides are suitable as active compounds in medicaments, in particular in antiatherosclerotically active medicaments.

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 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 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) 
##STR1## 
in which A represents quinolyl or 
a radical of the formula 
##STR2## 
in which R.sup.3, R.sup.4, R.sup.6 and R.sup.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.sup.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.sup.10 
R.sup.11, 
in which 
R.sup.10 and R.sup.11 are identical or different and denote hydrogen or 
straight-chain or branched alkyl having up to 5 carbon atoms, 
R.sup.8 and R.sup.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.sup.2, 
in which 
R.sup.12 denotes morpholinyl or the radical of the formula 
##STR3## 
R.sup.1 represents cycloalkyl having 3 to 8 carbon atoms, or represents 
straight-chain or branched alkyl having up to 10 carbon atoms, 
R.sup.2 represents a radical of the formula 
##STR4## 
in which R.sup.13 denotes hydrogen or a radical of the formula CH.sub.2 
--OH, 
R.sup.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 
##STR5## 
in which R.sup.3, R.sup.4, R.sup.6 and R.sup.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.sup.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.sup.10 
R.sup.11, 
in which 
R.sup.10 and R.sup.11 are identical or different and denote hydrogen or 
straight-chain or branched alkyl having up to 5 carbon atoms, 
R.sup.8 and R.sup.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.sup.12, 
in which 
R.sup.12 denotes morpholinyl or the radical of the formula 
##STR6## 
R.sup.1 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 
cycloheptyl, or represents straight-chain or branched alkyl having up to 8 
carbon atoms, 
R.sup.3 represents a radical of the formula 
##STR7## 
in which R.sup.13 denotes hydrogen or a radical of the formula CH.sub.2 
--OH, 
R.sup.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 
##STR8## 
in which R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are identical or different 
and denote hydrogen, phenyl, chlorine, formyl, methoxycarbonyl, 
ethoxycarbonyl or methyl or ethyl, which is optionally substituted by 
hydroxyl, 
R.sup.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.sup.10 R.sup.11, 
in which 
R.sup.10 and R.sup.11 are identical or different and denote hydrogen or 
straight-chain or branched alkyl having up to 3 carbon atoms, 
R.sup.8 denotes methyl, methoxycarbonyl, ethoxycarbonyl or the radical of 
the formula 
##STR9## 
and R.sup.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. 
__________________________________________________________________________ 
1 #STR10## 
A R.sup.1 
R.sup.2 
__________________________________________________________________________ 
##STR11## 
2 (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
3 #STR12## (R&S) cPent 
5 #STR13## 
3 #STR14## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
4 #STR15## (R&S) cPent 
5 #STR16## 
4 #STR17## (dia A) cPent 
5 #STR18## 
4 #STR19## (dia B) cPent 
5 #STR20## 
6 #STR21## (R&S) cPent 
5 #STR22## 
7 #STR23## (R&S) cPent 
5 #STR24## 
7 #STR25## (dia A) cPent 
5 #STR26## 
7 #STR27## (dia B) cPent 
5 #STR28## 
8 #STR29## (dia A) cPent 
5 #STR30## 
8 #STR31## (dia B) cPent 
5 #STR32## 
8 #STR33## (dia A) cHept 
5 #STR34## 
8 #STR35## (dia B) cHept 
5 #STR36## 
9 #STR37## (R&S) cPent 
5 #STR38## 
9 #STR39## (R&S) cHept 
5 #STR40## 
0 #STR41## (R&S) cPent 
5 #STR42## 
0 #STR43## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
0 #STR44## (R&S) cHept 
5 #STR45## 
0 #STR46## (R&S) cHept 
CH.sub.2 --C.sub.6 H.sub.5 
1 #STR47## (R&S) cPent 
5 #STR48## 
1 #STR49## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
1 #STR50## (R&S) cHept 
5 #STR51## 
1 #STR52## (R&S) cHept 
CH.sub.2 --C.sub.6 H.sub.5 
2 #STR53## (R&S) cPent 
5 #STR54## 
2 #STR55## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
2 #STR56## (R&S) cHept 
5 #STR57## 
2 #STR58## (R&S) cHept 
CH.sub.2 --C.sub.6 H.sub.5 
3 #STR59## (R&S) cPent 
5 #STR60## 
4 #STR61## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
4 #STR62## (R&S) cHept 
5 #STR63## 
3 #STR64## (R&S) cHept 
CH.sub.2 --C.sub.6 H.sub.5 
5 #STR65## (R&S) cPent 
5 #STR66## 
5 #STR67## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
5 #STR68## (R&S) cHept 
5 #STR69## 
5 #STR70## (R&S) cHept 
CH.sub.2 --C.sub.6 H.sub.5 
6 #STR71## (R&S) cPent 
5 #STR72## 
6 #STR73## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
6 #STR74## (R&S) cHept 
5 #STR75## 
6 #STR76## (R&S) cHept 
CH.sub.2 --C.sub.6 H.sub.5 
7 #STR77## (R&S) cPent 
5 #STR78## 
8 #STR79## (R&S) cPent 
5 #STR80## 
8 #STR81## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
8 #STR82## (R&S) cHept 
5 #STR83## 
9 #STR84## (R&S) cPent 
CH.sub.2 --C.sub.6 H.sub.5 
9 #STR85## (R&S) cHept 
CH.sub.2 --C.sub.6 H.sub.5 
0 #STR86## (dia A) cPent 
0 #STR87## (dia B) cPent 
5 #STR88## 
__________________________________________________________________________ 
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) 
##STR89## 
in which A and R.sup.1 have the meaning indicated above, 
are reacted with amines of the general formula (III) 
EQU H.sub.2 N--R.sup.2 (III) 
in which 
R.sup.2 has the meaning indicated above, 
in inert solvents and in the presence of bases and/or auxiliaries. 
The process according to the invention can be illustrated by way of example 
by the following equation: 
##STR90## 
Suitable solvents for the amidation here are inert organic solvents which 
do not change under the reaction conditions. These include ethers, such as 
diethyl ether or tetrahydrofuran, halogenohydrocarbons such as 
dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, 
trichloroethane, tetrachloroethane, 1,2-dichloroethylene or 
trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, 
cyclohexane or petroleum fractions, nitromethane, dimethylformamide, 
acetone, acetonitrile or hexamethylphosphoramide. It is also possible to 
employ mixtures of the solvents. Dichloromethane, tetrahydrofuran, acetone 
and dimethylformamide are particularly preferred. 
In general, bases which can be employed for the process according to the 
invention are inorganic or organic bases. These preferably include alkali 
metal hydroxides such as, for example, sodium hydroxide or potassium 
hydroxide, alkaline earth metal hydroxides 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 
alkali metal or alkaline earth metal alkoxides such as sodium or potassium 
methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or 
organic amines (trialkyl(C.sub.1 -C.sub.6)amines) such as triethylamine or 
heterocycles such as 1,4-diazabicyclo2.2.2!octane (DABCO), 
1,8-diazabicyclo5.4.0!undec-7-ene (DBU), pyridine, diaminopyridine, 
methylpiperidine or morpholine. It is also possible to employ as bases 
alkali metals such as sodium and their hydrides such as sodium hydride. 
Sodium and potassium carbonate and triethylamine are preferred. 
The base is employed in an amount from 1 mol to 5 mol, preferably from 1 
mol to 3 mol, relative to 1 mol 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 at normal, elevated or at reduced pressure 
(e.g. 0.5 to 5 bar). In general, it is carried out at normal pressure. 
The amidation can optionally also proceed via the activated stage 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 abovementioned bases can optionally also be employed as acid-binding 
auxiliaries for the amidation. 
Suitable auxiliaries are also dehydrating reagents. These include, for 
example, carbodiimides such as 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 propanephosphonic anhydride 
or isobutyl chloroformate or 
benzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate or 
diphenyl phosphoramidate 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 from 0.5 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 
mol of the corresponding carboxylic acids. 
The variation of functional groups such as, for example, hydrolysis, 
esterification and reduction, as well as separation of isomers and salt 
formation are carried out by customary methods. 
The carboxylic acids of the general formula (II) are in the main new and 
can be prepared by 
reacting compounds of the general formula (IV) 
##STR91## 
in which R.sup.1 has the meaning indicated above, 
T represents a typical leaving group such as, for example, chlorine, 
bromine, iodine, tosylate or mesylate, preferably bromine, 
and 
X represents (C.sub.1 -C.sub.4)-alkyl, 
with compounds of the general formula (V) 
EQU A--H (V) 
in which 
A has the meaning indicated 
in inert solvents, if appropriate in the presence of a base, and then 
hydrolysing the esters according to customary methods. 
Suitable solvents for the process are customary organic solvents which do 
not change under the reaction conditions. These preferably include ethers 
such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or 
hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or 
petroleum fractions, or halogenohydrocarbons such as dichloromethane, 
trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene 
or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethyl 
sulphoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile, 
acetone or nitromethane. It is also possible to use mixtures of the 
solvents mentioned. Dimethylformamide and tetrahydrofuran are preferred. 
In general, bases which can be employed for the process according to the 
invention are inorganic or organic bases. These preferably include alkali 
metal hydroxides such as, for example, sodium hydroxide or potassium 
hydroxide, alkaline earth metal hydroxides 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 
alkali metal or alkaline earth metal alkoxides such as sodium or potassium 
methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or 
organic amines (trialkyl(C.sub.1 -C.sub.6)amines) such as triethylamine, 
or heterocycles such as 1,4-diazabicyclo2.2.2!octane (DABCO), 
1,8-diazabicyclo5.4.0!undec-7-ene (DBU), pyridine, diaminopyridine, 
methylpiperidine or morpholine. It is also possible to employ as bases 
alkali metals such as sodium or their hydrides such as sodium hydride. 
Sodium hydride, potassium carbonate, triethylamine, pyridine and potassium 
tert-butoxide, DBU or DABCO are preferred. 
In general, the base is employed in an amount from 0.05 mol to 10 mol, 
preferably from 1 mol to 2 mol, relative to 1 mol of the compound of the 
formula (IV). 
The process according to the invention is in general carried out in a 
temperature range from -30.degree. C. to +100.degree. C., preferably from 
-10.degree. C. to +60.degree. C. 
The process according to the invention is in general carried out at normal 
pressure. However, it is also possible to carry out the process at 
elevated pressure or at reduced pressure (e.g. in a range from 0.5 to 5 
bar). 
The compounds of the general formula (III) are known per se. 
The compounds of the general formula (IV) are known or can be prepared in 
analogy to known methods. 
The compounds of the general formula (V) are known or can be prepared in 
analogy to known methods. 
The compounds of the general formula (I) according to the invention have an 
unforeseeable spectrum of pharmacological action. 
They can be used as active compounds in medicaments for the reduction of 
changes to vascular walls and for the treatment of coronary heart 
diseases, cardiac insufficiency, brain function disorders, ischaemic 
cerebral disorders, apoplexy, circulatory disorders, disorders of the 
microcirculation and thromboses. 
The proliferation of smooth muscle cells furthermore plays a decisive part 
in the occlusion of vessels. The compounds according to the invention are 
suitable for inhibiting this proliferation and thus preventing 
atherosclerotic processes. 
The compounds according to the invention are distinguished by a lowering of 
the ApoB-100-associated lipoproteins (VLDL and its degradation products, 
such as, for example, LDL), of ApoB-100, of triglycerides and of 
cholesterol. They thus have useful pharmacological properties which are 
superior compared with the prior art. 
Surprisingly, the action of the compounds according to the invention 
consists first in a decrease in or complete inhibition of the formation 
and/or the release of ApoB-100-associated lipoproteins from liver cells, 
which results in a lowering of the VLDL plasma level. This lowering of 
VLDL has to be accompanied by a lowering of the plasma levels of ApoB-100, 
LDL, triglycerides and of cholesterol; thus simultaneously several of the 
abovementioned risk factors which are involved in vascular wall changes 
are lowered. 
The compounds according to the invention can therefore be employed for the 
prevention and treatment of atherosclerosis, obesity, pancreatitis and 
constipation. 
1. Inhibition of the Release of ApoB-100-associated Lipoproteins 
The test for detecting the inhibition of the release of ApoB-100-associated 
lipoproteins from liver cells was carried out in vitro using cultured 
liver cells, preferably using cells of the human line HepG2. These cells 
were cultured under standard conditions in medium for the culture of 
eukaryotic cells, preferably in RPMI 1640 using 10% 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 using an immunoassay for human LDL. This 
immunoassay is carried out using antibodies which have been induced under 
standard conditions against human LDL in rabbits. The anti-LDL antibodies 
(rabbit anti-LDL ABs) were purified by affinity chromatography on an 
immunosorbent using human LDL. These purified rabbit anti-LDL ABs are 
adsorbed on the surface of plastic. Expediently, this adsorption is 
carried out on the plastic surface of microtitre plates having 96 wells, 
preferably on MaxiSorp plates. If ApoB-100-associated particles are 
present in the supernatant of HepG2 cells, then these can bind to the 
insolubilized rabbit anti-LDL ABs, and an immune complex results which is 
bound to the plastic surface. Non-bound proteins are removed by washing. 
The immune complex situated on the plastic surface is detected using 
monoclonal antibodies which have been induced against human LDL and 
purified under standard conditions. These antibodies were conjugated with 
the enzyme peroxidase. Peroxidase converts the colourless substrate TMB 
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 is determined, which is a measure of the amount 
of ApoB-100-associated particles which has been secreted into the culture 
supernatant by the HepG2 cells. 
Surprisingly, the compounds according to the invention inhibit the release 
of ApoB-100-associated particles. The IC.sub.50 indicates at which 
substance concentration the light adsorption is inhibited by 50% in 
comparison to the control (solvent control without substance). 
2. Determination of VLDL Secretion in vivo in the Hamster 
The effect of the test substances on VLDL secretion in vivo is investigated 
in the hamster. To do this, golden hamsters are anaesthetized with Ketavet 
(83 mg/kg s.c.) and Nembutal (50 mg/kg i.p.) after premedication with 
atropine (83 mg/kg s.c.). When the animals have become reflex-free, the 
jugular vein is exposed and cannulated. 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 a rise in the triglyceride level on account of an absent 
catabolism of secreted VLDL particles. This triglyceride rise can be used 
as a measure of the VLDL secretion rate. Blood is taken from the animals 
before and one and two hours after administration of the detergent by 
puncture of the retroorbital venous plexus. The blood is incubated for two 
hours at room temperature, then overnight at 4.degree. C. in order to 
finish clotting completely. It is then centrifuged at 10,000 g for 5 
minutes. In the serum thus obtained, the triglyceride concentration is 
determined with the aid of a modified commercially available enzyme test 
(Merckotest.RTM. triglyceride No. 14354). 100 .mu.l of serum are treated 
with 100 .mu.l of test reagent in 96-hole plates and incubated at room 
temperature for 10 minutes. The optical density is then determined at a 
wavelength of 492 nm in an automatic plate-reading apparatus (SLT 
spectra). Serum samples having 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 
intravenously either immediately before administration of the detergent or 
orally or subcutaneously before initiation of anaesthesia. 
3. Inhibition of Intestinal Triglyceride Absorption 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 substance and the feed is then withdrawn from them. 
Drinking water is available to the animals ad libitum. The animals of the 
control groups receive an aqueous tragacanth suspension or a tragacanth 
suspension which contains olive oil. The tragacanth-olive oil suspension 
is prepared using the Ultra-Turrax. The substances to be investigated are 
suspended in an appropriate tragacanth-olive oil suspension, likewise 
using the Ultra-Turrax, directly before substance administration. 
Blood is taken from each rat by puncture of the retroorbital venous plexus 
before stomach tube application to determine the basal serum triglyceride 
content. The tragacanth suspension, the tragacanth-olive oil suspensions 
without substance (control animals), or the substances suspended in an 
appropriate tragacanth-olive oil suspension are then administered to the 
fasting animals using a stomach tube. Further taking of blood to determine 
the postprandial serum triglyceride rise is generally carried out 1, 2 and 
3 hours after stomach tube application. 
The blood samples are centrifuged and, after recovering the serum, the 
triglycerides are determined photometrically using an EPOS analyser 5060 
(Eppendorf Geratebau, Netheler & Hinz GmbH, Hamburg). The determination of 
the triglycerides is carried out completely enzymatically using a 
commercially available UV test. 
The postprandial serum triglyceride rise is determined by subtraction of 
the triglyceride preliminary value of each animal from its corresponding 
postprandial triglyceride concentrations (1, 2 and 3 hours after 
administration). 
The differences (in mmol/l) at each time (1, 2 and 3 hours) are averaged in 
the groups, and the average values of the serum triglyceride rise 
(.DELTA.TG) of the substance-treated animals are compared with the animals 
which only received the tragacanth-oil suspension. 
The serum triglyceride course of the control animals which only received 
tragacanth is likewise calculated. The substance effect at each time (1, 2 
or 3 hours) is determined as follows and indicated in .DELTA.% of the 
oil-loaded control. 
##EQU1## 
Effect of 10 mg of test substance/kg of body weight p.o. on the 
triglyceride rise (.DELTA.%) 2 h after a triglyceride loading in the serum 
of fasting rats. The serum triglyceride rise of fat-loaded control animals 
relative to the serum triglyceride level of tragacanth control animals 
corresponds to 100%. n=6 animals per group. 
Statistical analysis is carried out using Student's t-test after prior 
checking of the variances for homogeneity. 
Substances which at one time statistically significantly (p&lt;0.05) decrease 
the postprandial serum triglyceride rise by at least 30%, compared with 
the untreated control group, are regarded as pharmacologically active. 
4. Inhibition of VLDL Secretion in vivo (Rat) 
The action of the test substances on VLDL secretion is likewise 
investigated in the rat. To do this, Triton WR-1339 (2.5 mg/kg), dissolved 
in physiological saline solution, is administered intravenously into the 
tail vein of rats of 500 mg/kg body weight. Triton WR-1339 inhibits 
lipoprotein lipase and thus leads by inhibition of VLDL catabolism to a 
rise in the triglyceride and cholesterol level. These rises can be used as 
a measure of the VLDL secretion rate. 
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 1 h for clothing and the 
serum is recovered by centrifugation at 10,000 g for 20 s. The 
triglycerides are then determined photometrically at a wavelength of 540 
nm by means of a commercially available coupled enzyme test (Sigma 
Diagnostics.RTM., No. 339). Measurement is carried out with the aid of a 
likewise coupled enzyme test (Boehringer Mannheim.RTM., No. 1442350) at a 
wavelength of 546 nm. Samples having triglyceride or cholesterol 
concentrations which exceed the measuring range of the methods are diluted 
with physiological saline solution. The determination of the respective 
serum concentrations is carried out with the aid of standard series 
measured in parallel. Test substances are administered orally, 
intravenously or subcutaneously immediately after Triton injection. 
The invention additionally relates to the combination of heterocyclically 
substituted phenylglycinolamides of the general formula (I) with a 
glucosidase and/or amylase inhibitor for the treatment of familiar 
hyperlipidaemias, of obesity (adiposity) and of diabetes mellitus. 
Glucosidase and/or amylase inhibitors in the context of the invention are, 
for example, acarbose, adiposine, voglibose, miglitol, emiglitate, 
MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, trestatin, 
pradimicin-Q and salbostatin. 
The combination of acarbose, miglitol, emiglitate or voglibose with one of 
the abovementioned compounds of the general formula (I) according to the 
invention is preferred. 
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. In this 
connection, the therapeutically active compound should in each case be 
present in a concentration of approximately 0.5 to 90% by weight of the 
total mixture, i.e. in amounts which are sufficient in order to achieve 
the dosage range indicated. 
The formulations are prepared, for example, by extending the active 
compounds with solvents and/or excipients, if appropriate using 
emulsifiers and/or dispersants, it being possible, for example, if water 
is used as a diluent optionally to use organic solvents as auxiliary 
solvents. 
Administration is carried out in a customary manner, preferably orally or 
parenterally, in particular perlingually or intravenously. 
In the case of parenteral administration, solutions of the active compound 
can be employed using suitable liquid excipient materials. 
In general, it has proved advantageous in the case of intravenous 
administration to administer amounts of approximately 0.001 to 1 mg/kg, 
preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieve 
effective results, and in the case of oral administration the dose is 
approximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, of body 
weight. 
In spite of this, it may, if appropriate, be necessary to depart from the 
amounts mentioned, namely depending on the body weight or on the type of 
administration route, on individual behaviour towards the medicament, the 
manner of its formulation and the time or interval at which administration 
takes place. Thus, in some cases it may be adequate to manage with less 
than the abovementioned minimum amount, while in other cases the upper 
limit mentioned has to be exceeded. In the case of the administration of 
larger amounts, it may be advisable to divide these into several 
individual doses over the course of the day. 
Abbreviations used: 
Ph=phenyl 
Me=methyl 
Et=ethyl 
cHex=cyclohexyl 
Bn=CH.sub.2 --C.sub.6 H.sub.5 
Gly= 
##STR92## 
C=cyclohexane EA=ethyl acetate 
P=petroleum ether