Arylacetamides and their use as medicaments

The new arylacetamides are obtained by first converting appropriately substituted arylacetic acids into the acetyl chlorides and then converting these into the amides using the appropriate amines. The new arylacetamides can be used as active compounds in medicaments, in particular in antiatherosclerotic medicaments.

The present invention relates to new arylacetamides, processes for their
 preparation and their use as medicaments, in particular as
 antiatherosclerotic medicaments.
 It is known that increased blood levels of triglycerides
 (hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) are
 associated with the genesis of atherosclerotic vascular wall changes and
 coronary heart diseases.
 A distinctly increased risk of the development of coronary heart diseases
 is moreover present if these two risk factors occur in combination, which
 in turn is accompanied by an overproduction of apoliprotein B-100. There
 is therefore still a great need to make available effective medicaments
 for the control of atherosclerosis and of coronary heart diseases.
 The present invention relates to new arylacetamides of the general formula
 (I)
 ##STR1##
 in which
 R.sup.1 and R.sup.2, including the double bond connecting them, together
 form a phenyl
 ##STR2##
 in which
 R.sup.7 denotes hydrogen or straight-chain or branched alkyl having up to 4
 carbon atoms,
 R.sup.3 and R.sup.4, including the double bond connecting them, together
 form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene
 ring,
 where all ring systems mentioned under R.sup.1 /R.sup.2 and R.sup.3
 /R.sup.4 are optionally substituted up to 3 times in an identical or
 different manner by halogen, trifluoromethyl, carboxyl, hydroxyl, by
 straight- chain or branched alkoxy or alkoxycarbonyl each having up to 6
 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon
 atoms, which for its part can be substituted by hydroxyl or by
 straight-chain or branched alkoxy having up to 4 carbon atoms,
 D and E are identical or different and represent hydrogen, cycloalkyl
 having 3 to 8 carbon atoms or straight-chain or branched alkyl having up
 to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3
 to 6 carbon atoms, or represent phenyl which is optionally substituted by
 halogen or trifluoromethyl,
 or
 D and E together, including the CH group, form a 4- to 8-membered
 carbocyclic system,
 R.sup.5 represents hydrogen, straight-chain or branched alkyl having up to
 12 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
 R.sup.6 represents cycloalkyl having 3 to 8 carbon atoms or phenyl, or
 represents straight- chain or branched alkyl having up to 9 carbon atoms,
 which is optionally substituted by hydroxyl, naphthyl, trifluoromethyl or
 by a radical of the formula
 ##STR3##
 in which
 a denotes a number 1 or 2
 or
 R.sup.6 represents a radical of the formula --(CH.sub.2).sub.n --R.sup.8,
 in which
 n denotes a number 2, 3, 4 or 5,
 R.sup.8 denotes naphthyl or phenyl, each of which is optionally substituted
 by carboxyl, trifluoromethyl, halogen, hydroxyl, trifluoromethoxy or by
 straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each
 having up to 6 carbon atoms,
 or
 represents a radical of the formula
 ##STR4##
 R.sup.5 and R.sup.6, together with the nitrogen atom, form a heterocyclic
 radical of the formula --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2,
 --CH.sub.2 --(CH.sub.2).sub.p --CH.sub.2 --,
 ##STR5##
 in which
 p denotes a number 2, 3, 4, 5, 6, 7, 8 or 9,
 if appropriate in an isomeric form, and their salts.
 The new acrylacetamides according to the invention can also be present in
 the form of their salts. In general, salts with organic or inorganic bases
 or acids may be mentioned here.
 In the context of the present invention, physiologically acceptable salts
 are preferred. Physiologically acceptable salts of the compounds according
 to the invention can be salts of the substances according to the invention
 with mineral acids, carboxylic acids or sulphonic acids. Particularly
 preferred salts are, for example, those with hydrochloric acid,
 hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid,
 ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,
 naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid,
 tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
 Physiologically acceptable salts can also be metal or ammonium salts of the
 compounds according to the invention which have a free carboxyl group.
 Those particularly preferred are, for example, sodium, potassium,
 magnesium or calcium salts, as well as ammonium salts which are derived
 from ammonia, or organic amines, such as, for example, ethylamine, di- or
 triethylamine, di- or triethanolamine, dicyclohexylamine,
 dimethylaminoethanol, arginine, lysine, ethylenediamine or
 2-phenylethylamine.
 The cycloalkene radical (R.sup.3 /R.sup.4), including the double bond of
 the parent structure, in the context of the invention in general
 represents a 4- to 8-membered, preferably 5- to 8-membered, hydrocarbon
 radical such as, for example, a cyclobutene, cyclopentene, cyclohexene,
 cycloheptene or cyclooctene radical. The cyclopentene, cyclohexene,
 cyclooctene and cycloheptene radicals are preferred.
 The compounds according to the invention can exist in stereoisomeric forms
 which either behave as image and mirror image (enantiomers), or which do
 not behave as image and mirror image (diastereomers). The invention
 relates both to the enantiomers or diastereomers and to their respective
 mixtures. These mixtures of the enantiomers and diastereomers can be
 separated into the stereoisomerically uniform constituents in a known
 manner.
 Preferred compounds of the general formula (I) are those
 in which
 R.sup.1 and R.sup.2, including the double bond connecting them, together
 form a phenyl or pyridyl ring or a ring of the formula
 ##STR6##
 in which
 R.sup.7 denotes hydrogen or straight-chain or branched alkyl having up to 3
 carbon atoms,
 R.sup.3 and R.sup.4, including the double bond connecting them, together
 form a phenyl ring or a cyclopentene, cyclohexene, cycloheptene,
 cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene or
 oxocyclooctene radical,
 where all ring systems mentioned under R.sup.1 /R.sup.2 and R.sup.3
 /R.sup.4 are optionally substituted up to 2 times in an identical or
 different manner by fluorine, chlorine, bromine, trifluoromethyl,
 carboxyl, hydroxyl, by straight-chain or branched alkoxy or alkoxycarbonyl
 each having up to 4 carbon atoms or by straight-chain or branched alkyl
 having up to 4 carbon atoms, which for its part can be substituted by
 hydroxyl or by straight-chain or branched alkoxy having up to 3 carbon
 atoms,
 D and E are identical or different and represent hydrogen, cyclopropyl,
 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or
 straight-chain or branched alkyl having up to 8 carbon atoms, which is
 optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl, or
 represent phenyl which is optionally substituted by fluorine, chlorine or
 bromine,
 or
 D and E together, including the CH group, form a cyclobutyl, cyclopentyl,
 cyclohexyl, cycloheptyl or cyclooctyl ring,
 R.sup.5 represents hydrogen, straight-chain or branched alkyl having up to
 10 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
 cycloheptyl or cyclooctyl,
 R.sup.6 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
 cycloheptyl, cyclooctyl or phenyl, or represents straight-chain or
 branched alkyl having up to 7 carbon atoms, which is optionally
 substituted by hydroxyl, naphthyl, trifluoromethyl or by a radical of the
 formula
 ##STR7##
 in which
 a denotes a number 1 or 2
 or
 R.sup.6 represents a radical of the formula --(CH.sub.2).sub.n --R.sup.8,
 in which
 n denotes a number 2, 3 or 4,
 R.sup.8 denotes naphthyl or phenyl, each of which is optionally substituted
 by trifluoromethyl, fluorine, chlorine, bromine, hydroxyl,
 trifluoromethoxy or by straight-chain or branched alkyl, alkoxy or
 alkoxycarbonyl each having up to 5 carbon atoms,
 or
 represents a radical of the formula
 ##STR8##
 or
 R.sup.5 and R.sup.6, together with the nitrogen atom, form a heterocyclic
 radical of the formula --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2,
 --CH.sub.2 --(CH.sub.2).sub.p --CH.sub.2 --,
 ##STR9##
 in which
 p denotes a number 2, 3, 4, 5, 6, 7 or 8,
 if appropriate in an isomeric form, and their salts.
 Particularly preferred compounds of the general formula (I) are those
 in which
 R.sup.1 and R.sup.2, including the double bond connecting them, together
 form a phenyl or pyridyl ring or a ring of the formula
 ##STR10##
 in which
 R.sup.7 denotes hydrogen or methyl,
 R.sup.3 and R.sup.4, including the double bond connecting them, together
 form a phenyl ring or a cyclopentene, cyclohexene, cycloheptene,
 cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene or
 oxocyclooctene radical,
 where all ring systems mentioned under R.sup.1 /R.sup.2 and R.sup.3
 /R.sup.4 are optionally substituted up to 2 times in an identical or
 different manner by fluorine, chlorine, bromine, trifluoromethyl,
 carboxyl, hydroxyl, by straight-chain or branched alkoxy or alkoxycarbonyl
 each having up to 3 carbon atoms or by straight-chain or branched alkyl
 having up to 3 carbon atoms, which for its part can be substituted by
 hydroxyl, methoxy or ethoxy,
 D and E are identical or different and represent hydrogen, cyclopropyl,
 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or
 straight-chain or branched alkyl having up to 6 carbon atoms, which is
 optionally substituted by cyclopentyl or cyclohexyl, or represent phenyl
 which is optionally substituted by fluorine, chlorine or bromine,
 or
 D and E together, including the CH group, form a cyclopentyl, cyclohexyl or
 cycloheptyl ring,
 R.sup.5 represents hydrogen, straight-chain or branched alkyl having up to
 8 carbon atoms, cyclopentyl, cyclohexyl or cycloheptyl,
 R.sup.6 represents cyclopentyl, cyclooctyl or phenyl, or represents
 straight-chain or branched alkyl having up to 6 carbon atoms, which is
 optionally substituted by hydroxyl, naphthyl, trifluoromethyl or by a
 radical of the formula
 ##STR11##
 in which
 a denotes a number 1 or 2
 or
 R.sup.6 represents a radical of the formula --(CH.sub.2).sub.n --R.sup.8,
 in which
 n denotes a number 2 or 3,
 R.sup.8 denotes naphthyl or phenyl, each of which is optionally substituted
 by trifluoromethyl, fluorine, chlorine, hydroxyl, trifluoromethoxy or by
 straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up
 to 3 carbon atoms,
 or
 represents a radical of the formula
 ##STR12##
 or
 R.sup.5 and R.sup.6, together with the nitrogen atom, form a heterocyclic
 radical of the formula --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2,
 --CH.sub.2 --(CH.sub.2).sub.p --CH.sub.2 --,
 ##STR13##
 in which
 p denotes a number 2, 3, 4, 5, 6 or 7,
 if appropriate in an isomeric form, and their salts.
 A process was additionally found, characterized in that starting from the
 (racemic or enantiomerically pure) carboxylic acids of the general formula
 (II)
 ##STR14##
 in which
 D, E, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the meaning indicated,
 the corresponding (racemic or enantiomerically pure) acid chlorides of the
 general formula (III)
 ##STR15##
 in which
 D, E, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the meaning indicated,
 are first prepared
 and finally reacted with amines of the general formula (IV)
EQU HNR.sup.5 R.sup.6 (IV)
 in which
 R.sup.5 and R.sup.6 have the meaning indicated,
 in inert solvents, if appropriate 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:
 ##STR16##
 Suitable solvents here are inert organic solvents which do not change under
 the reaction conditions. These include ethers, such as diethyl ether or
 tetrahydrofuran, halo genohydrocarbons 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, ditnethylformamide, acetonitrile or
 hexamethylphosphoramide. It is also possible to employ mixtures of the
 solvents. Dichloromethane, tetrahydrofiran and dimethylformamide are
 particularly preferred.
 Bases which can be employed for the process according to the invention are
 in general organic amines (trialkyl(C.sub.1 -C.sub.6)amines) such as
 triethylamine, or heterocycles such as 1,4-diazabicyclo[2.2.2]octane
 (DABCO), 1,8-diazabicyclo[5.4.0]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. Pyridine 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
 (III).
 The reaction is in general carried out in a temperature range from
 0.degree. C. to 150.degree. C., preferably from 0.degree. C. to
 +25.degree. C.
 The reaction can be carried out at normal, elevated or reduced pressure
 (e.g. 0.5 to 5 bar). In general it is carried out at normal pressure.
 The variation of functional groups such as, for example, hydrolysis,
 esterification and reduction, as well as isomer separation and salt
 formation is carried out according to customary methods.
 The racemic carboxylic acids of the general formula (II) are new and can be
 prepared by a process in which
 first, by reaction of compounds of the general formula (V) T-C
 ##STR17##
 in which
 D and E have the meaning indicated,
 T represents a typical leaving group such as, for example, chlorine,
 bromine, iodine, tosylate or mesylate, preferably bromine,
 and
 R.sup.9 represents (C.sub.1 -C.sub.4)-alkyl,
 with compounds of the general formula (VI)
 ##STR18##
 in which
 R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the meaning indicated,
 the compounds of the general formula (VII)
 ##STR19##
 in which
 D, E, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.9 have the meaning
 indicated,
 are prepared in inert solvents, if appropriate in the presence of bases and
 then the esters are hydrolysed according to customary methods.
 The enantiomerically pure acids, i.e. compounds of the formula (II) in
 which D and E must be different, are moreover obtained by a process in
 which, starting first from the D- or L-menthyl esters of the general
 formula (VIII)
 ##STR20##
 in which
 R.sup.10 represents D- or L-menthyl,
 by reaction with compounds of the general formulae (IXa) and (IXb)
EQU D-Z (lXa)
EQU E-Z (IXb)
 in which
 D and E are different and otherwise have the meaning indicated,
 and
 Z represents halogen, preferably bromine,
 the enantiomerically pure menthyl esters of the general formulae (Xa) and
 (Xb)
 ##STR21##
 in which
 D, E and R.sup.10 have the meaning indicated,
 are prepared,
 these are converted in a next step by halogenation into the compounds of
 the general formulae (XIa) and (XIb)
 ##STR22##
 in which
 D, E, T and R.sup.10 have the meaning indicated,
 from which then, by reaction with the compounds of the general formula (V),
 the enantiomerically pure compounds of the general formulae (XIIa) and
 (XlIb)
 ##STR23##
 in which
 D, E, R.sup.1,R.sup.2,R.sup.3,R.sup.4 and R.sup.10 have the meaning
 indicated,
 are prepared,
 and these are then converted by hydrolysis into the enantiomerically pure
 acids of the general formula (II).
 Additionally, the enantiomerically pure acids of the formula (II) can be
 prepared by a process in which first racemic carboxylic acids of the
 general formula (XIII)
 ##STR24##
 in which
 D and E have the meaning indicated above,
 are converted by reaction with (R)- or (S)-phenylethylamine in inert
 solvents and subsequent crystallization of the phenethylammonium salts and
 subsequent hydrolysis of the salts into the enantiomerically pure
 compounds of the general formula (XIVa,b)
 ##STR25##
 in which
 D and E have the meaning indicated above,
 in a further step with isobutene, in inert solvents and in the presence of
 acids, the enantiomerically pure esters of the general formula (XVa,b)
 ##STR26##
 in which
 D and E have the meaning indicated above,
 are prepared,
 converted as described above by halogenation into the enantiomerically pure
 compounds of the general formula (XVIa,b)
 ##STR27##
 in which
 D and E have the meaning indicated above,
 and
 T' has the meaning of T indicated above and is identical to or different
 from this,
 and converted by reaction with the compounds of the general formula (VI)
 into the enantiomerically pure esters of the general formula (XVIIa,b)
 ##STR28##
 in which
 D, E, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the meaning indicated
 above,
 and in the last steps, as described above, corresponding enantiomerically
 pure acids and their derivatives are prepared.
 Suitable solvents for the processes 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, toluene and tetrahydrofuran are
 preferred.
 Bases which can be employed for the processes according to the invention
 are in general 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 and hydrogen carbonates such as sodium
 carbonate, sodium hydrogen 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-diazabicyclo[2.2.2]octane (DABCO),
 1,8-diazabicyclo[5.4.0]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 hydrogen carbonate, potassium carbonate and potassium
 tert-butoxide, DBU or DABCO are preferred.
 Suitable solvents for the hydrolysis are water or the organic solvents
 customary for hydrolysis. These preferably include 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 using acids such as,
 for example, trifluoroacetic acid, acetic acid, hydrochloric acid,
 hydrobromic acid, methanesulphonic acid, sulphuric acid or perchloric
 acid, preferably using 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.
 In general, the hydrolysis is carried out at normal pressure. However, it
 is also possible to work at elevated pressure or at reduced pressure (e.g.
 from 0. 5 to 5 bar).
 When carrying out the hydrolysis, the base is in general employed in an
 amount from 1 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of
 the ester. Molar amounts of the reactants are particularly preferably
 used.
 The hydrolysis of tert-butyl esters is in general carried out using acids
 such as, for example, hydrochloric acid or trifluoroacetic acid, in the
 presence of one of the solvents indicated above and/or water or mixtures
 thereof, preferably using dioxane or tetrahydrofuran.
 The preparation of the compounds of the general formulae (Xa) and (Xb) is
 preferably carried out in dimethylformamide and potassium tert-butoxide in
 a temperature range from -10.degree. C. to +10.degree. C.
 The halogenation of the compounds of the general formulae (XIa) and (XIb)
 is carried out in chlorobenzene using 1,3-dibromo-5,5-dimethylhydantoin in
 the presence of azobisisobutyronitrile in a temperature range from
 0.degree. C. to 110.degree. C.
 The reaction to give the compounds of the general formulae (XIIa) and
 (XIIb) is carried out under a protective gas atmosphere in
 dimethylformamide and potassium tert-butoxide in a temperature range from
 0.degree. C. to 30.degree. C.
 The hydrolysis of the compounds of the general formulae (XIIa) an& (XIIb)
 can be carried out as described above, the system HBr/formic acid being
 particularly preferred. The hydrolysis is carried out in a temperature
 range from 20.degree. C. to 100.degree. C.
 In the first step, the reaction to give the compounds of the general
 formulae (XIIla) and (XIIb) is preferably carried out in tetrahydrofuran
 and triethylamine and, in the second step, in the system
 water/hydrochloric acid. The reaction is carried out in a temperature
 range from 30.degree. C. to 70.degree. C.
 The acid employed for the preparation of the compounds of the general
 formulae (XVIa) and (XVIb) according to the invention is particularly
 preferably concentrated sulphuric acid. The preparation is carried out
 using methylene chloride.
 In a further working-up step, potassium carbonate is employed as the base.
 The reaction is carried out in a temperature range from 0.degree. C. to
 +20.degree. C., particularly preferably at 10.degree. C.
 The halogenation of the compounds of the general formulae (XVIa) and (XVIb)
 is carried out using N-bromosuccinimide in carbon tetrachloride in the
 presence of azobisisobutyronitrile.
 In general, the base is employed in an amount from 0.05 mol to 10 mol,
 preferably from 1 mol to 2 mol, in each case relative to 1 mol of the
 compounds of the general formulae (V), (IXa), (IXb), (XIIa), (XIIb),
 (XIIa) and (XlIIb).
 The processes according to the invention are 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 new and can be prepared as
 described above.
 The compounds of the general formulae (IV), (IXa) and (IXb) are known or
 can be prepared in analogy to known methods.
 The compounds of the general formula (VI) are known in some cases or are
 new and can then be prepared, however, in analogy to published methods.
 The compounds of the general formula (VIII) are new as a species and are
 prepared from the corresponding acid.
 With the exception of D/E=CH-isopropyl, the enantiomerically pure compounds
 of the general formulae (Xa) and (Xb) are new and can be prepared as
 described above.
 The compounds of the general formulae (XIa), (XIb), (XlIa), (XIIb) are new
 and can be prepared as described above.
 The compounds of the general formula (IV) are known per se.
 The compounds of the general formulae (XIVa) and (XIVb) are known in some
 cases or can be prepared by customary methods.
 The enantiomerically pure compounds of the general formulae (XVIa), (XVIb),
 (XVIIa) and (XVIIb) are new and can be prepared as described above.
 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 brain
 disorders, apoplexy, circulatory disorders, microcirculation disorders and
 thromboses.
 Furthermore, the proliferation of smooth muscle cells 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 in comparison with those of the prior art.
 Surprisingly, the action of the compounds according to the invention
 consists first in a decrease 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 must be accompanied by a lowering of the plasma levels of ApoB-100,
 LDL, triglycerides and of cholesterol; several of the abovementioned risk
 factors which are involved in vascular wall changes are thus
 simultaneously lowered.
 The compounds according to the invention can therefore be employed for the
 prevention and treatment of atherosclerosis, of obesity, pancreatitis and
 of constipation.
 1. 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
 using cultured liver cells, preferably using cells of the human line
 HepG2. These cells are cultured under standard conditions in medium for
 the culture of eucaryotic 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 of similar construction to the VLDL or 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 in the rabbit to human LDL. The anti-LDL antibodies
 (rabbit anti-LDL-Ab) were purified by affinity chromatography on an
 immunosorbent using human LDL. These purified rabbit anti-LDL-Ab are
 adsorbed onto the surface of plastic. Expediently, this adsorption takes
 place onto the plastic surface of microtitre plates having 96 depressions,
 preferably onto MaxiSorp plates. If ApoB-100-associated particles are
 present in the supernatant of Hep-G2 cells, these can bind to the
 insolubilized rabbit anti-LDL-Ab, and an immune complex is formed which is
 bound to the plastic surface. Unbound proteins are removed by washing. The
 immune complex on the plastic surface is detected using monoclonal
 antibodies which have been induced against human LDL and purified
 according to 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 absorption at 450 nm is determined, which is a measure of the amount
 of ApoB-100-associated particles which have 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 lC.sub.50 value indicates at which
 substance concentration the light absorption is inhibited by 50% in
 comparison with the control (solvent control without substance).

Apo B
 Ex. No. IC.sub.50 [nM]
 2 8.2
 20 12.5
 2. Determination of the 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 as a result of a lack of
 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 end
 coagulation 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.TM. triglyceride No. 14354). 100 .mu.l of serum are mixed with
 100 .mu.l of test reagent in 96-hole plates and the mixture is 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 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 either
 administered intravenously immediately before administration of the
 detergent or orally or subcutaneously before initiation of anaesthesia.
 3. Inhibition of the intestinal triglycende 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
 substance administration 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 an Ultra-Turrax The substances to be investigated are
 likewise suspended in a corresponding tragacanth-olive oil suspension
 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 itragacanth 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 as a rule takes place 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
 (EppendorfGeratebau, 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 meaned 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 also 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 1, 3 or 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.

Serum triglyceride rise
 in % (2 h pp)
 Triglyceride loading 100
 Tragacanth control 0
 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
 by at least 30% the postprandial serum triglyceride rise, 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 also 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 g 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.
 Before and two hours after administration of the detergent, blood is taken
 from the animals by puncture of the retroorbital venous plexus. The blood
 is incubated at room temperature for 1 h for coagulation 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 the Triton injection.
 The invention additionally relates to the combination of new arylacetamides
 of the general formula (I) with a glucosidase and/or amylase inhibitor for
 the treatment of familial hyperlipidaemias, of obesity (adiposity) and of
 diabetes mellitus. G lucosidase 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. The
 therapeutically active compound here 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 adequate 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 from 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, if appropriate it may be necessary to deviate 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 must be exceeded. In the case of the administration of
 relatively large amounts, it may be advisable to divide these into several
 individual doses over the course of the day.

EXAMPLE I
 6-Chloro-2,4-lutidine

##STR29##
 For the preparation of the title compound [U.S. Pat. No. 36 32 807], 600 g
 (4.91 mol) of 6-amino-2,4-lutidine are dissolved in 2 l of methanol and
 the solution is saturated at 0.degree. C. with hydrogen chloride gas.
 1.307 l (9.82 mol) of isopentyl nitrite are added dropwise at an internal
 temperature below 10.degree. C. (about 2.5 h) and the mixture is then left
 for 15 h while warming to room temperature (about 25.degree. C.). The
 solution is largely freed from the solvent in vacuo, mixed with 3 l of
 dichloromethane and 1.5 l of water and adjusted to pH=9.5 using
 concentrated aqueous ammonia solution with cooling (&lt;20.degree. C.). The
 organic phase removed is dried with sodium sulphate, first concentrated in
 vacuo on a rotary evaporator and then distilled through a Vigreux column:
 Fraction 1) b.p.=47-49.degree. C. (12 mm Hg), 603 g
 Fraction 2) b.p.=82-85.degree. C. (12 mm Hg), 612 g (about 88% crude)
 R.sub.f =0.39 (petroleum ether:ethyl acetate=10:1)
 .sup.1 H-NMR (CDCl.sub.3, 200 MHz, TMS): .delta.=2.28 (s, 3H), 2.47 (s,
 3H), 6.88 (s, 1H), 6.96 (s, 1H) ppm.
 The crude product, which may contain small amounts of
 6-methoxy-2,4-lutidine, is reacted further without further purification.
 EXAMPLE II
 6-Hydrazino-2,4- lutidine (4,6- dimethyl-2-hydrazino-pyridine)

##STR30##
 580 g (4.10 mol) of the compound from Example II are dissolved in 800 ml of
 diethylene glycol and stirred with 1050 ml of hydrazine hydrate for 48 h
 at a bath temperature of about 140.degree. C. The cooled mixture is poured
 onto 4.5 l of ether and 4.5 l of water and the organic phase is extracted
 twice using 2.3 l of dichloromethane each time. The combined organic
 phases are dried using sodium sulphate and evaporated in vacuo. 784 g of
 solvent-containing crude product are obtained, which is reacted further
 without working up.
 R.sub.f.apprxeq.0.37 (dichloromethane:methanol=10:1)
 .sup.1 H-NMR (d.sub.6 -DMSO, 250 MHz, TMS): .delta.=2.13 (s, 3H), 2.22 (s,
 3H), 4.02 10 (s, 2H), 6.26 (s, 1H), 6.35 (s, 1H), 7.11 (s, 1H) ppm.
 EXAMPLE III
 2,4-Dimethyl-5,6,7,8-tetrahydro-.alpha.-carboline

##STR44##
 100 g (499 mmol) of the compound from Example III are reacted under reflux
 in 700 ml of diethylene glycol with 164 ml (1 mol) of diethyl fumarate on
 52 g of palladium (5% on carbon). At the high internal temperature, a
 small amount of ethanol distils off (if appropriate use a water
 separator). After about 8 h the starting material has disappeared (TLC
 checking, petroleum ether:ethyl acetate=1:1, detection in the iodine
 chamber). The cooled mixture is treated with 3 l of acetone, boiled, and
 solid is filtered off hot with suction through a clarifying filter (Seitz)
 and washed with 1 l of hot acetone. On cooling, a precipitate is obtained
 which, after filtering off with suction, rinsing with cold acetone and
 drying in vacuo, yields 58.3 g of product. The mother liquor is largely
 freed from acetone in vacuo, the precipitae which is deposited being
 worked up as above (9.4 g). The filtrate is in turn freed from acetone;
 after addition of n-pentane product precipitates a further time (3.1
 g/working-up see above); total yield: 72%.
 M.p.: 220-221.degree. C. (uncorrected)
 R.sub.f =0.47 (petroleum ether:ethyl acetate=1:1)
 .sup.1 H-NMR (d.sub.6 -DMSO, 200 MHz, TMS): .delta.=2.54 (s, 3H), 2.75 (s,
 3H), 6.89 (s, 1H), 7.20 (m, 1H), 7.40 (m, 1H), 7.48 (dd, 1H), 8.05 (dd,
 1H), 11.61 (s, 1H) ppm.
 EXAMPLE XVII
 tert-Butyl 2(R,S)-2-cyclopentyl-2-
 [4-(2,4-dimethyl-.alpha.-carbolin-9-yl)methyl]-phenyl-acetate

##STR93##
 300 g (1.998 mol) of 4-tolyl-acetic acid are dissolved in 2.5 l of
 methanol, and the solution is stirred with 100 ml of concentrated
 sulphuric acid and refluxed for 2.5 hours. A total of 430 g (5.1 mol) of
 sodium hydrogen carbonate are gradually stirred into this mixture
 (evolution of carbon dioxide !), the methanol is largely evaporated in
 vacuo, the residue is partitioned between water and dichloromethane and
 the aqueous phase is reextracted with dichloromethane. The combined
 organic phases are dried using sodium sulphate and freed from the solvent
 in vacuo. The residue is distilled in a high vacuum.
 Yield: 336 g
 Boiling temperature=65.degree. C. (0.5 mbar)
 R.sub.f =0.81 (toluene:ethyl acetate=2:1)
 EXAMPLE LXIV
 Ethyl 4-tolyl-acetate

##STR94##
 Starting from 4-tolyl-acetic acid, ethyl 4-tolyl-acetate is prepared
 analogously to the procedure of Example LXIII.
 R.sub.f =0.43 (N)
 EXAMPLE LXV
 tert-Butyl 4-methylphenylacetate

##STR95##
 450 g (3 mol) of 4-methylphenylacetic acid, 1.13 l (12 mol) of tert-butanol
 and 90 g (0.74 mol) of dimethylaminopyridine are dissolved in 2 l of
 dichloromethane. After addition of 680 g (3.3 mol) of
 dicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, the
 mixture is stirred at 25.degree. C. for 20 h, the precipitated urea is
 filtered off with suction and washed with 200 ml of dichloromethane, and
 the organic phase is washed twice each with 500 ml of 2M hydrochloric acid
 and water. The organic phase is dried using sodium sulphate, concentrated
 and distilled.
 Yield: 408 g (66%)
 Boiling point: 73-78.degree. C. (0.2 mm Hg)
 EXAMPLE LXVI
 tert-Butyl 2-cyclopentyl-2-(4-methylphenyl)acetate

##STR149##
 The reaction is carried out under a nitrogen atmosphere. 480 g (2.44 mol)
 of carboline are suspended in 4.13 l of dimethylformamide and treated with
 reaction with 287.7 g of potassium tert-butoxide dissolved in 1 l of
 dimethylformamide. The reaction solution warms to 30.degree. C. After 30
 min, the mixture is cooled to 20.degree. C. 1.707 kg (2.69 mol) of 69%
 strength menthyl ester bromide (CXXXV), dissolved in 1.56 l of
 dimethylformamide, are then added dropwise such that the internal
 temperature does not rise above 35.degree. C. After a reaction time of a
 further 15 min, the reaction solution is poured into a mixture of 1.8 l of
 10% strength sodium chloride solution and 13 l of ethyl acetate. After
 stirring for 20 min, the ethyl acetate phase is separated off and
 extracted twice with 3 l of 10% strength sodium chloride solution each
 time. After drying the organic phase over sodium sulphate, ethyl acetate
 is distilled off in vacuo at about 40.degree. C. The syrupy residue is
 taken up in 4.4 l of methanol and stirred under reflux for 30 min and at
 room temperature for 12 h. The precipitated crystals are filtered off with
 suction, washed with methanol and dried in vacuo at 400.degree. C.
 Yield: 947 g (70.6% of theory)
 Melting point: 142.degree. C.
 EXAMPLE CXXV
 2-(S)-2-Cyclopentyl-2-[4-(2,4-dimethyl-.alpha.-carbolin-9-yl)-methyl]phenyl
 acetic acid

##STR150##
 947 g (1.72 mol) of the compound from Example CXXIV are treated with 2.4 l
 of formic acid. 1.21 l of aqueous hydrobromic acid (48% strength) are
 added dropwise with stirring The suspension obtained is stirred at
 95-98.degree. C. for 6 hours and then cooled to room temperature. The
 reaction solution is treated with stirring with 1.6 l of isopropanol and
 3.2 l of water. A pH of 5 is established with slight cooling using 45%
 strength sodium hydroxide solution (consumption of sodium hydroxide
 solution: 5.2 kg). The precipitate is filtered off with suction, washed
 twice with 5.7 l of water and sucked dry. The water-moist product is then
 extracted by stirring at room temperature for 2 hours in 2.6 l of
 isopropanol. The crystallizate is filtered off with suction, washed with
 2.8 l of isopropanol and dried in vacuo at 60.degree. C.
 Yield: 574 g (81% of theory)
 Melting point: 197-199.degree. C.
 EXAMPLE CXXVI
 2-(S)-2-Cyclopentyl-2-[4-(2,4-dimethyl-.alpha.-carbolin-9-yl)-methyl]phenyl
 acetyl chloride

##STR151##
 A suspension of 350 g (0.85 mol) of the compound from Example CXXV in 3 l
 of methylene chloride is heated to reflux with stirring. In the course of
 1 h, 95 ml (155 g, 1.3 mol) of thionyl chloride are added dropwise and the
 mixture is stirred at reflux temperature for a further 2 h. The reaction
 solution is then cooled to room temperature, concentrated in vacuo at
 25-30.degree. C. until crystallization begins and treated with 2.5 1 of
 toluene. A further 2.3 l of solvent are distilled off in vacuo at a
 temperature of 30-40.degree. C. After cooling to about 20.degree. C., 1.2
 l of toluene are added to the mixture. The suspension is cooled to
 0-50.degree. C., stirred at this temperature for 1 h and filtered off with
 suction, and the solid is washed with 1.4 l of toluene and sucked dry. The
 toluene- moist product is reacted without further characterization.
 EXAMPLE CXXVII
 Methyl 2-cyclopentyl-2-(3-tolyl)-acetate

##STR152##
 The title compound is prepared from methyl 2-(3-tolyl)-acetate analogously
 to the procedure of Example LXIII.
 R.sub.f =0.56 (P)
 EXAMPLE CXXVIII
 Methyl 2-(3-bromomethyl-phenyl)-2-cyclopentyl-acetate

##STR153##
 The title compound is prepared from the compound of Example CXXVII
 analogously to the procedure for Example XCIV.
 R.sub.f =0.40 (P)
 EXAMPLE CXXIX
 2(R/S)-2-Cyclopentyl-2-(4-methylpheny)-acetic acid

##STR154##
 2.0 kg (7.2 mol) of the compound from Example LXV are dissolved in 4 1 of
 dioxane in a 40 l stirring vessel with an attached scrubber. After
 addition of 4.5 l of concentrated hydrochloric acid, the mixture is
 stirred at 50.degree. C. until conversion is complete (3 h). The reaction
 mixture is treated with ice and adjusted to pH=12 with concentrated sodium
 hydroxide solution. After addition of water until the solids are
 completely dissolved, the mixture is washed with acetic acid, the organic
 phase is washed with dilute sodium hydroxide solution and the combined
 aqueous phases are adjusted to pH=1 with concentrated hydrochloric acid
 with cooling. The mixture is washed twice with ethyl acetate, dried over
 sodium sulphate and concentrated.
 Yield: 1.27 kg, 81% of theory
 Melting point: 92.degree. C.
 R.sub.f =0.20 (petroleum ether:ethyl acetate=4:1)
 .sup.1 H-NMR (CDCl.sub.3, 200 MHz, TMS): .delta.=0.98 (m, 1H); 1.20-1.71
 (m, 6H); 1.82-2.05 (m, 1H); 2.31 (s, 3H); 2.52 (m, 1H); 3.21 (d, 1H); 7.10
 (m, 2H); 7.21 (m, 2H); 11.90 (br, s, 1H) ppm.
 EXAMPLE CXXX
 (S)-(+)-2-Cyclopentyl-2-(4-methylphenyl)-acetic acid

##STR155##
 2.4 l of THF and 129.7 g (1.28 mol) of triethylamine are added with
 stirring to a suspension of 560 g (2.57 mol) of the compound from Example
 CXXIX in 4.8 l of water. The resulting solution is warmed to 60.degree.
 C., 155.4 g (1.28 mmol) of (S)-(-)-phenethylamine are added and the
 suspension obtained is stirred at 60.degree. C. for 2 h. The reaction
 mixture is cooled to 20.degree. C., and the precipitate is filtered off
 with suction, washed with 2.4 l of water/THF (2:1) and dried in vacuo.
 Yield: 360 g of phenethylammonium salt; 41.3% of theory based on racemate
 Ex. No. CXXIX
 745 g (2.2 mol) of phenethylammonium salt are suspended in 3 l of water,
 acidified (pH=1) with dilute hydrochloric acid (1:1) and stirred for 30
 minutes. The oily suspension is washed three times with 1 l of
 dichloromethane each time, and the combined organic phases are washed with
 water, dried over sodium sulphate and concentrated, whereupon the residue
 crystallizes.
 Yield: 475 g, 37.3% of theory based on racemate Ex. No. CXXIX
 ee: 96.3% (HPLC)
 Melting point: 66.degree. C.
 By crystallization of the phenethylammonium salt from THF and liberation of
 Example No. CXXX, the pure enantiomer is obtained as described above: ee:
 &gt;99.5% (HPLC)
 Specific rotation: [.alpha.].sub.D.sup.20 =+59.55 (ethanol/c=0.85)
 The HPLC method for the determination of the ee value is as follows (the
 racemic compound from Example CXXIX serves as a comparison):

##STR156##
 6 ml of concentrated sulphuric acid are added to a solution of 465 g (2.13
 mol) of the compound from Example CXXX in 1.4 l of dichloromethane, a
 temperature of about 10.degree. C. being established. 550 ml (5 mol) of
 isobutene are condensed into a Dewar vessel and added to the starting
 material solution in one portion. The reaction mixture is stirred
 overnight. To complete the conversion, a further 6 ml of concentrated
 sulphuric acid and 500 ml of isobutene are added and the mixture is
 stirred overnight. After addition of 40 g of potassium carbonate, the
 mixture is stirred for 3 h and 2 l of water are added to it, a vigorous
 evolution of gas initially occurring. The mixture is washed three times
 using 2 l of dichloromethane each time, and the combined organic phases
 are washed with 5 l of sodium chloride solution, dried over sodium
 sulphate and concentrated to give an oil, which slowly crystallizes.
 Yield: 480 g, 82% of theory
 Melting point: 45.degree. C.
 R.sub.f =0.90 (toluene:ethyl acetate=8:2)
 EXAMPLE CXXXII
 tert-Butyl (S)-(+)-2-(4-bromomethylphenyl)-2-cyclopentyl-acetate

##STR157##
 480 g (1.75 mol) of the compound from Example CXXXI are dissolved in 3.4 l
 of tetrachloromethane under reflux in a 10 l flask and the mixture is
 treated with 70 g of a total amount of 311 g (1.75 mol) of NBS and 14 g
 (0.085 mol) of AIBN. The reaction commences after refluxing for about 1 h;
 after it subsides further NBS is added in 50 g portions. After refluxing
 for 5 h and subsequently standing at room temperature overnight, for
 working up the mixture is cooled to 0.degree. C., and the succinimide is
 filtered off with suction and washed with 600 ml of tetrachloromethane.
 The combined filtrates are concentrated and residual solvent is removed in
 vacuo to constant weight.
 Crude yield: 570 g, about 100% of theory
 HPLC: 68.8% (15.5% starting material, 10.1% dibromo compound)
 The pure substance is obtained by column chromatography
 R.sub.f =0.42 (Q)
 .sup.1 H-NMR (CDCl.sub.3, 200 MHz, TMS): .delta.=0.98 (m, 1H); 1.22-1.71
 (m, 6H); 1.40 (s, 9H); 1.90 (m, 1H); 2.47 (m, 1H); 3.16 (d, 1H); 4.49 (s,
 2H); 7.32 (m, 4H) ppm.
 EXAMPLE CXXXIlI
 (L)-Menthyl 2-(4-tolyl)-acetate

##STR158##
 3.15 kg of p-tolylacetic acid and 9.45 l of toluene are initially
 introduced. 3.115 kg of L-menthol and 21.4 ml of methanesulphonic acid are
 added with stirring and cooling. The mixture is then heated to reflux
 temperature and the corresponding amount of water is removed by means of a
 water separator in the course of 16 to 20 hours. After cooling to room
 temperature, the mixture is extracted once by stirring with 4.41 l of
 saturated sodium hydrogen carbonate solution and twice with 4.41 l of
 water each time. The organic phase is freed from the solvent and affords
 5.725 kg of desired compound (GC 99.9%, retention time 19.49 min).
 .sup.1 H-NMR (CDCl.sub.3, ppm): 7.05-7.15 (4H, m); 4.55 (1H, txd); 3.5 (2H,
 s); 2.8 (3H, s); 0.65 (3H, s).
 EXAMPLE CXXXIV
 (L)-Menthyl 2-(S)-2-cyclopentyl-2-(4-tolyl)-acetate

##STR159##
 1.575 kg of potassium tert-butoxide are dissolved in 3.75 l of DMF at room
 temperature. The mixture is cooled to 10.degree. C. and 2.678 kg of the
 compound from Example CXXXIII are allowed to run in at this temperature in
 the course of 45 minutes and are rinsed in with 0.375 l of DMF. 1.658 kg
 of cyclopentyl bromide are then pumped in in the course of 1 to 2 hours
 with full cooling. The suspension is stirred for a further hour without
 cooling and then cooled to -70.degree. C. On reaching -10.degree. C., the
 mixture is seeded with the correct diastereomer and then further cooled to
 -70.degree. C. After reaching -70.degree. C., the mixture is stirred at
 this temperature for 3 to 4 hours. Working up is carried out by
 introducing the reaction suspension into a mixture of 1.5 kg of ice and 6
 kg of water. The mixture is then stirred overnight at 0 to 2.degree. C.
 Working up is carried out by filtering off the suspension with suction and
 washing the crystals with a total of 2.5 l of water. The crystals are
 dried at 45.degree. C. in a vacuum drying oven. 3.289 kg of an 85 to 15
 diastereomer mixture are obtained. 4.345 kg of a mixture prepared as
 described above are dissolved in 21.75 l of DMF at 30 to 35.degree. C.
 After seeding with the correct diastereomer and cooling to room
 temperature, the mixture is stirred overnight and cooled to 0 to 5.degree.
 C. the next morning. After 1 to 2 hours at this temperature, the crystals
 are filtered off with suction and dried or recrystallized again. By
 repeating the methanol crystallization one or two times, material having a
 diastereomer purity of .gtoreq.99.5% can be prepared (GC retention time
 22.61 min).
 The yield of diastereomerically pure title compound over the stages
 cyclopentylation and crystallization in pure form is 65-70% and can be
 raised to 75-80% by recrystallization or by epimerization of the mother
 liquors with potassium tert-butoxide in DMF and crystallization of the
 crude diastereomer mixture again.
 .sup.13 C-NMR (CDCl.sub.3, CH signals, ppm) 128.90; 128.92; 73.96; 57.85;
 46.92; 43.13; 31.28; 25.96.
 EXAMPLE CXXXV
 (L)-Menthyl 2-(S)-2-(4-bromomethyl-phenyl)-2-cyclopentyl-acetate

##STR160##
 1.40 kg of the compound from Example CXXXIV are warmed to 80.degree. C. in
 13.74 l of chlorobenzene. 0.618 kg of 1,3-dibromo-5,5-dimethylhydantoin is
 then added and the mixture is warmed further to 85.degree. C. At this
 temperature, 20.4 g of AIBN are then added to start the reaction. The
 temperature rises after the start of the reaction to 90 to 105.degree. C.,
 but then falls again to approximately 85.degree. C. Reaction is carried
 out for a total of 2 hours. The vessel contents are then cooled to room
 temperature and the mixture is stirred for one hour. The precipitated
 crystals are filtered off with suction and the filtrate is freed from the
 solvent. The residual oil is 61.2% strength according to HPLC analysis
 (retention time 14.68 min.). 1.69 kg are obtained. The mixture can be
 employed in crude form in the following alkylations. Chromatography and
 subsequent crystallization yield a white powder of melting point
 57-58.degree. C., with the correct CH analysis.
 .sup.1 H-NMR (CDCl.sub.3, ppm): 7.3 (4H, s); 4.65 (1H, txd); 4.45 (2H, s);
 3.35 (1H, d); 0.65 (3H, d).
 EXAMPLE CXXXVI
 Methyl 2-(R/S)-2-phenyl-2-(4-methyl)phenylacetate

##STR161##
 21.0 g (100 mmol) of 2-phenyl-1-(4-methyl)phenyl-1-oxoethane and 38.8 g
 (120 mmol) of iodobenzene diacetate are dissolved in 300 ml of trimethyl
 orthoformate. 19.6 g of concentrated sulphuric acid are added to this
 solution, and the solution is stirred at 60.degree. C. for 6 h. The
 solution is cooled to room temperature, diluted with water and extracted
 with diethyl ether. The combined organic phases are dried over sodium
 sulphate and concentrated in a rotary evaporator. The residue is purified
 by column chromatography.
 Yield: 13.1 g(55%)
 R.sub.f =0.33 (Q)
 MS (FAB): 241 (25%), 181 (100%).
 .sup.1 H-NMR (200 MHz, CDCl.sub.3, TMS): .delta.=7.3-7.10 (m, 9H); 4.99 (s,
 1H); 3.73 (s, 3H); 2.31 (s, 3H) ppm.
 EXAMPLE CXXXVII
 Methyl 2-(R/S)-2-(4-chlorophenyl)-2-(4-tolyl)-acetate

##STR162##
 The title compound is prepared in analogy to the procedure of Example
 CXXXVI.
 PREATION EXAMPLES
 Example 1
 2-(S)-2-Cyclopentyl-2-[4-(2,4-dimethyl-.alpha.-carbolin-9-yl)-
 methyl]phenylacetic acid N-propylamide

##STR177##
 2.00 g (3.76 mmol) of
 2-(S)-2-cyclopentyl-2-[4-(2,4-dimethyl-.alpha.-carbolin-9-yl)methylphenyl]
 -acetic acid N-((1R)-1-phenyl-2-hydroxy)-ethanamide are dissolved in 20 ml
 of anhydrous DMF, and the solution is treated with 0.52 ml (3.76 mmol) of
 triethylamine and stirred with mesyl chloride at -30.degree. C. After 2
 hours, the mixture is warmed to 20.degree. C., treated with a further 1.04
 ml (7.52 mmol) of triethylamine and stirred for 20 hours. The reaction
 mixture is diluted with diethyl ether and an aqueous buffer of pH=2
 (Merck), the phases are separated and the organic phase is evaporated in
 vacuo. The residue is recrystallized in methanol, and the crystals are
 filtered off with suction after cooling washed with cold methanol and
 dried in vacuo over phosphorus pentoxide.
 Yield: 0.81 g (42% of theory)
 R.sub.f =0.60 (G)
 .sup.1 H-NMR (d.sub.6 -DMSO, 200 MHz, TMS): .delta.=3.84 (dd, 1H); 4.53
 (dd, 1H); 5.08 (dd, 1H) ppm.
 MS (ES): m/z=514 ([M+H].sup.+, 100%).
 Example 29
 2-(S)-2-cyclohexyl-2-[4-{(2,4-dimethyl-.alpha.-carbolin-9-yl)-methyl}phenyl
 ]acetic acid n-(1-phenyl-ethen-1-yl)amide

##STR178##
 In analogy to the procedure of Example 24, the title compound is prepared
 from
 2-(S)-2-cyclohexyl-2-[4-(2,4-dimethyl-.alpha.-carbolin-9-yl)-methylphenyl]
 -acetic acid N-((1R)-1-phenyl-2-hydroxy)-ethanamide
 R.sub.f =0.63 (g)
 MS (ES): m/z=528 ([M+H].sup.+, 100%).