3-demethylmevalonic acid derivatives, and pharmaceutical products based on these compounds

3-Demethylmevalonic acid derivatives of the formula I (.delta.-lactone) and II (corresponding dihydroxy carboxylic acid derivative) ##STR1## in which A--B, Z, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the indicated meanings, a process for the preparation of these compounds, their use as medicaments, and pharmaceutical products, are described. In addition, new intermediates for the preparation of the compounds of the formula I and formula II are described.

Derivatives of 3-hydroxy-3-methylglutaric acid (HMG) and of mevalonic acid 
have been described as inhibitors of cholesterol biosynthesis (M. T. Boots 
et al., J. Pharm. Sci. 69, 306 (1980), F. M. Singer et al., Proc. Soc. 
Exper. Biol. Med. 102, 270 (1959), H. Feres, Tetrahedron Lett. 24, 3769 
(1983)). 3-Hydroxy-3-methylglutaric acid itself shows a significant 
cholesterol-lowering action in the rat and in human experiments (Z. Beg, 
Experimentia 23, 380 (1967), ibid 24, 15 (1968), P. J. Lupien et al., 
Lancet 1978, 1, 283). 
Endo et al. (FEBS Letters 72, 323 (1976), J. Biol. Chem. 253, 1121 (1978)) 
reported the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase 
(HMG-CoA reductase), the rate-determining enzyme of cholesterol 
biosynthesis, by the fermentation product "compactin". 
Brown et al. (J. Chem. Soc. 1165 (1976) determined the chemical structure 
and the absolute configuration of "compactin" by a combination of 
chemical, spectroscopic and X-ray crystallographic methods and were able 
to show that "compactin" is a derivative of the lactone of 
3-demethylmevalonic acid. 
Compactin derivatives which inhibit the activity of HMG-CoA reductase have 
already been described (G. E. Stokker et al., J. Med. Chem. 28, 347-358 
(1985)). 
The present invention relates to new synthetic analogs of "compactin" in 
the form of the .delta.-lactone of the formula I or in the form of the 
dihydroxy acid derivative II 
##STR2## 
In the formulae 
A--B denotes a radical of the formula --CH.dbd.CH-- or --CH.sub.2 
--CH.sub.2 --, 
Z denotes a radical of the formula --CH or a nitrogen atom, 
R.sup.1, R.sup.2 and R.sup.3, independently of one another, denote 
hydrogen, a saturated or unsaturated, straight-chain or branched 
hydrocarbon radical which has up to 6 carbon atoms and can optionally be 
substituted on the terminal carbon by a saturated or unsaturated, cyclic 
hydrocarbon radical having 3-6 carbon atoms, a cyclic hydrocarbon radical 
which has 3-7 carbon atoms and is saturated or is unsaturated once or 
twice, an aromatic radical selected from the group comprising phenyl, 
furyl, thienyl or pyridinyl, which can optionally carry in the nucleus 1-3 
identical or different substituents from the following groups: halogen, 
trifluoromethyl, alkyl or alkenyl, each having up to 6 carbon atoms, 
hydroxyl, alkoxy having 1-6 carbon atoms, carboxyl, or carbalkoxy having 
1-6 carbon atoms in the alkoxy moiety, 
R.sup.4 denotes hydrogen, a straight-chain or branched, saturated or 
unsaturated hydrocarbon radical having up to 5 carbon atoms, a benzyl 
radical whose nucleus can be substituted 1-2 times by halogen or an alkyl 
radical having 1-4 carbon atoms, an alkali metal or an ammonium ion 
NR.sup.5 R.sup.6 R.sup.7 R.sup.8, where R.sup.R.sup.5, R.sup.6, R.sup.7 
and R.sup.8 are identical or different and denote hydrogen, alkyl having 
1-4 carbon atoms or hydroxyalkyl having 1-4 carbon atoms. 
The invention relates to the pure enantiomers having the absolute 
configuration 4R,6S indicated in the general formula I or the absolute 
configuration 3R,5S depicted in formula II. 
Preferred substituents R.sup.1 and R.sup.2 are a straight-chain or branched 
alkyl radical having 1-4 carbon atoms, a cycloalkyl radical having 3-6 
carbon atoms, a cycloalkylmethyl or cycloalkenylmethyl radical having a 
ring size of 5-6 carbon atoms, a phenyl radical which can optionally carry 
1-3 identical or different substituents from the following groups halogen, 
trifluoromethyl, alkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 
1-4 carbon atoms or carbalkoxy having 1-4 carbon atoms in the alkoxy 
moiety. 
The preferred meanings for R.sup.3 are hydrogen, a straight-chain or 
branched alkyl or alkenyl radical having up to 6 carbon atoms, a 
cycloalkyl or cycloalkenyl radical, each having 3-6 carbon atoms, a phenyl 
or pyridinyl radical, it being possible for the aromatic radicals 
optionally to carry 1-3 identical or different substituents from the 
following groups: halogen, alkyl having 1-4 carbon atoms, hydroxyl, alkoxy 
having 1-4 carbon atoms or carbalkoxy having 1-4 carbon atoms in the 
alkoxy moiety. 
The preferred radicals R.sup.4 are hydrogen, methyl, ethyl, isopropyl, 
isobutyl, benzyl, sodium, potassium, ammonium (NH.sub.4) or 
methyltris(hydroxymethyl)ammonium. 
Particularly preferred substituents R.sup.1 are: methyl, ethyl, isopropyl, 
sec.-butyl, tert.-butyl, cyclopropyl, cyclohexyl, phenyl, 4-chlorophenyl, 
4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluoro-3-methylphenyl, 
3,5-dimethylphenyl, cyclohexylmethyl and 4-trifluoromethylphenyl. 
Particularly preferred substituents R.sup.2 are methyl, ethyl, isopropyl, 
sec.-butyl, tert.-butyl, cyclopropyl, cyclohexyl, phenyl, 4-chlorophenyl, 
4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluoro-3-methylphenyl, 
3,5-dimethylphenyl, cyclohexylmethyl and 4-trifluoromethylphenyl. 
Particularly preferred substituents R.sup.3 are hydrogen, methyl, 
isopropyl, tert.-butyl, cyclohexyl, phenyl, 4-fluorophenyl, 
4-hydroxyphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl and 
4-trifluoromethylphenyl. 
Particularly preferred substituents R.sup.4 are hydrogen, methyl, ethyl, 
sodium and potassium. 
Very particular preference is given to compounds of the formula I in which 
Z denotes a radical of the formula --CH or N, R.sup.1 denotes ethyl, 
isopropyl, cyclopropyl, R.sup.2 denotes 4-fluorophenyl, 4-hydroxyphenyl 
and R.sup.3 denotes isopropyl, tert.-butyl, cyclohexyl, phenyl, 
4-hydroxyphenyl or 4-fluorophenyl, and to the sodium and potassium salts 
of the corresponding dihydroxy carboxylic acids of the formula II. 
The invention also relates to a process for the preparation of compounds of 
the formulae I and II, which comprises 
(a) reaction of the phosphonium salts of the formula III 
##STR3## 
in which R.sup.1, R.sup.2, R.sup.3 and Z have the meaning indicated for 
formula I, and X is Cl, Br or I, with the chiral aldehyde of the formula 
IV 
##STR4## 
in which R.sup.9 is a protective group which is stable to bases and weak 
acids, for example the t-C.sub.4 H.sub.9 (C.sub.6 H.sub.5).sub.2 Si group, 
to give a compound of the formula V 
##STR5## 
in which R.sup.1, R.sup.2, R.sup.3 and Z have the meaning given for 
formula I, R.sup.9 has the meaning given for formula IV, and A-B 
represents the (--CH.dbd.CH--) group, 
(b) acid hydrolysis of the methyl acetal group in a compound of the general 
formula V to give a lactol of the formula VI 
##STR6## 
in which R.sup.1, R.sup.2, R.sup.3 and Z have the meaning given for 
formula I, R.sup.9 has the meaning given for formula IV, and A-B 
represents the (--CH.dbd.CH--) group, 
(c) oxidation of the compound of the formula VI to give a lactone of the 
general formula VII 
##STR7## 
in which R.sup.1, R.sup.2, R.sup.3 and Z have the meaning given for 
formula I, R.sup.9 has the meaning given for formula IV, and A-B 
represents the (--CH.dbd.CH--) group, 
(d) elimination of the protective group R.sup.9 in a compound of the 
general formula VII to give a compound of the formula I in which R.sup.1, 
R.sup.2, R.sup.3 and Z have the meaning indicated for formula I, and A-B 
represents the (--CH.dbd.CH--) group, 
(e) where appropriate hydrogenation of a resulting compound of the general 
formula I in which A-B represents a (--CH.dbd.CH--) group to give a 
compound of the general formula I in which A-B represents a (--CH.sub.2 
--CH.sub.2 --) group, it also being possible for the hydrogenation to be 
carried out on the compounds of the formula V, VI or VII to give compounds 
in which A-B represents the (--CH.sub.2 --CH.sub.2 --) group, 
(f) where appropriate conversion of a hydroxylactone of the general formula 
I into the corresponding dihydroxy acid of the formula II, or its salts, 
or, where appropriate, preparation from the hydroxylactone I or the free 
hydroxy acid II of the corresponding esters. 
The phosphonium salts which are used as starting material in the process 
according to the invention and have the general formula III, in which 
R.sup.1, R.sup.2 and R.sup.3 have the meaning given for the general 
formula I, are obtained as depicted in scheme 1. 
Ketones of the general formula VIII, where R.sup.2 and R.sup.3 have the 
indicated meaning, are known from the literature or can be prepared by 
processes known from the literature (cf., for example, D. Vorlander and F. 
Kalkow, Berichte d. Dtsch. Chem. Ges. 30, 2268 (1897) or H. Stetter in 
Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic 
Chemistry) Vol. VII/26, 1449-1507, Thieme, Stuttgart 1976). Likewise known 
from the literature or amenable to preparation by processes known from the 
literature (for example in analogy to M. Jackman, M. Klenk, B. Fishburn, 
B. F. Tullar and S. Archer, J. Am. Chem. Soc. 70, 2884 (1948)) are the 
.beta.-keto esters of the general formula IX, where R.sup.1 has the 
abovementioned meaning, and R.sup.10 denotes a straight-chain or branched 
alkyl radical having up to 6 carbon atoms, preferably a methyl or ethyl 
radical. 
Compounds of the formula X in which R.sup.1, R.sup.2, R.sup.3 and R.sup.10 
have the indicated meaning are prepared in analogy to literature 
processes, for example according to R. Connor, D. B. Andrews, J. Am. Chem. 
Soc. 56 2713 (1943) and literature cited therein. An example of a process 
used to convert compounds of the type X into pyridines of the general 
formula XV (in this, R.sup.1, R.sup.2 and R.sup.3 have the abovementioned 
meaning, and Z denotes a CH group) is that described by F. Rehberg and F. 
Krohnke, Liebigs Ann. Chem. 717, 91 (1968). 
Dihydropyrimidines of the general formula XIV can be prepared, for example, 
in analogy to a literature process (E. F. Silversmith, J. Org. Chem. 27, 
4090 (1962)) or, for example, also by a synthesis shown in scheme 1, route 
A, by reacting a .beta.-keto ester of the general formula IX with an 
aldehyde of the type XI to give a compound of the general formula XII, and 
reacting the latter, without further purification, with an amidinium 
compound of the type XIII to give a dihydropyrimidinecarboxylic ester of 
the general formula XIV. The preparation of compounds of the type XIV from 
components of the general formulae IX, XI and XIII can likewise be carried 
out as a one-pot reaction (scheme 1, route B). 
The oxidation of compounds of the formula XIV to give pyrimidinecarboxylic 
esters of the general formula XV in which R.sup.1, R.sup.2, R.sup.3 and 
R.sup.10 have the abovementioned meaning, and Z denotes a nitrogen atom, 
is carried out in analogy to processes known from the literature, for 
example by dehydrogenation using chloroanil or 
2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) as described by E. A. 
Braude, J. Hannah, R. Linstead, J. Chem. Soc. 1960, 3257. 
Compounds of the general formula XV are reduced by reaction with complex 
metal hydrides such as, for example, lithium aluminum hydride or 
diisobutylaluminum hydride, in aprotic solvents, for example diethyl ether 
or tetrahydrofuran, at temperatures between -30.degree. C. and +50.degree. 
C. 
Alkyl halides of the general formula XVII, where R.sup.1, R.sup.2, R.sup.3 
and X have the abovementioned meaning, can be prepared from alcohols of 
the type XVI, for example by reaction with phosphorus halides in inert 
solvents such as, for example, dichloromethane or toluene, at temperatures 
between 0.degree. and 100.degree. C., or by reaction with hydrohalic 
acids. 
Phosphonium salts of the general formula III are obtained by, for example, 
reaction of the alkyl halides XVII with triphenylphosphine in inert 
solvents such as toluene, at temperatures between 20.degree. C. and 
120.degree. C. (cf. scheme 1). 
##STR8## 
The chiral aldehyde of the formula IV which is used as starting material in 
the process according to the invention is obtained by a process known from 
the literature (Yuh Lin, J. R. Falck, Tetrahedron Letters 23, 4305-4308 
(1982)) from the corresponding alcohol by oxidation with, for example, 
CrO.sub.3 or oxalyl chloride/dimethyl sulfoxide in the presence of 
triethylamine. 
Reaction of the chiral aldehyde of the formula IV with a phosphonium salt 
of the formula III by the Wittig method (for example Wittig, Haag, Chem. 
Ber. 88, 1654 (1955)) results in compounds of the formula V, a preferred 
embodiment comprising dissolution or suspension of phosphonium salts of 
the formula III in a solvent such as tetrahydrofuran, dimethyl sulfoxide 
or DME, liberation of the corresponding phosphoranes using a suitable 
strong base such as, for example, sodium hydride, potassium 
tert.-butylate, Li ethylate or butyllithium, and then addition of the 
aldehyde of the formula IV and allowing reaction to take place at 
-10.degree. C. to +50.degree. C. for 1-6 h. 
In this, the compounds of the formula V are mainly obtained in the form of 
mixtures of the E/Z olefins. Mixtures of E/Z olefins can, where 
appropriate, be fractionated by chromatography. The pure Z-olefins can 
also be obtained, as described by G. Drefahl Chem. Ber. 94, 907 (1961), by 
irradiation of the E/Z mixture in solutions, such as, for example, toluene 
or nitrobenzene. 
The corresponding pure E-olefins can be obtained, as described by De Tar et 
al. in J. Amer. Chem. Soc. 78, 474 (1955), by heating the E/Z mixtures in 
solution in the presence of iodine. 
The methyl acetal protective group in the compounds of the formula V can be 
selectively eliminated by acid hydrolysis in the generally customary 
manner, preferably using a mixture of glacial acetic acid, tetrahydrofuran 
and water in the ratio 3:2:2, at +20.degree. to +90.degree. C., within 
6-24 hours. 
Oxidation of the compounds of the formula VI to give a lactone of the 
formula VII can be carried out by oxidizing agents such CrO.sub.3 
.times.2Pyr, or pyridinium chlorochromate in inert solvents such as, for 
example, methylene chloride or chloroform. Further possibilities for the 
oxidation comprise reaction with thioanisole/Cl.sub.2 /NEt.sub.3 in carbon 
tetrachloride, reaction with DMSO/oxalyl chloride/NEt.sub.3 at -20.degree. 
C., or reaction with N-iodosuccinimide/tetrabutylammonium iodide in 
dichloromethane. 
To prepare the compounds of the formula I, the protective group R.sup.9 in 
the compounds of the formula VII is eliminated. This can take place with 
strong acids, such as 5-normal hydrochloric acid or sulfuric acid, at 
-10.degree. C. to +30.degree. C., or with fluoride ions, preferably by 
dissolving the compounds of the formula VII in tetrahydrofuran or diethyl 
ether, and adding a mixture of tetrabutylammonium fluoride and glacial 
acetic acid, followed by stirring at 0.degree. C. to 40.degree. C. for 
between 1 and 12 hours. 
Compounds of the formula I in which A-B represents a (CH.dbd.CH) group are 
hydrogenated by a generally customary method, expediently at a temperature 
between 20.degree. C. and 40.degree. C. using hydrogen in the presence of 
a metal catalyst, preferably palladium, platinum, PtO.sub.2 or PdO.sub.2, 
to give compounds of the formula I, in which A-B denotes a --CH.sub.2 
--CH.sub.2 -- group. This hydrogenation can be carried out under 
atmospheric pressure in customary solvents such as tetrahydrofuran, ethyl 
acetate, methanol, low molecular weight alcohols, glacial acetic acid or 
chloroform, or in autoclaves under elevated pressure (2-50 atm). The 
hydrogenation of the --CH.dbd.CH-- group can also be carried out on the 
compounds of the formulae V, VI or VII. 
The resulting compounds of the formula I can be isolated in a 
straightforward manner by evaporation of the solvent, where appropriate 
after purification by chromatography. 
The compounds of the formula I are obtained in optically pure form. 
Concerning the configuration of the double bond (A-B=--CH.dbd.CH--), E/Z 
mixtures are obtained, and these can, at all stages of the synthesis, be 
fractionated by chromatography or isomerized to give the E form (cf. in 
this context, De Tar et al., J. Amer. Chem. Soc. 78 475 (1955)). 
Compounds of the formula I in the form of the .delta.-lactone can be 
hydrolyzed in alkaline medium to give the corresponding salts of the 
dihydroxy acids, for example using NaOH or KOH in a low molecular weight 
alcohol such as methanol, or in ethers such as dimethoxyethane or THF, 
where appropriate in the presence of water. The alkali metal cation in the 
resulting salts of the dihydroxy acids can, after acidification, be 
exchanged by any desired cations in ion exchangers in the customary 
manner. For this purpose, for example, the dihydroxy acids are allowed to 
run through a column packed with a cation exchanger, such as, for example, 
based on polystyrene/divinylbenzene (.RTM.AMBERLITE CG-150 or .RTM.DOWEX 
CCR-2). The cation exchanger is loaded with the desired cation, for 
example with ammonium ions derived from a primary, secondary or tertiary 
amine. The desired salt is obtained by evaporation of the eluate. 
Ammonium salts of the dihydroxy acids, which are derived from a primary, 
secondary or tertiary amine, can also be prepared by mixing the free 
dihydroxy acids in an alcohol solution with an equimolar amount of the 
appropriate amine, and evaporating the solvent. 
The free dihydroxy acids II of the .delta.-lactones I can be esterified by 
customary methods, for example using a diazoalkane. Thus, for example, 
compounds of the formula I can be esterified with a diazoalkane at 
temperatures between -40.degree. C. and +20.degree. C., it being possible 
to use the customary solvents such as, for example, diethyl ether, 
tetrahydrofuran, chloroform or low molecular weight alcohols such as 
methanol. The resulting esters can be isolated in a straightforward manner 
by evaporation of the solvent and, where appropriate, purified by 
chromatography. Another esterification method comprises reaction of salts 
of the dihydroxy acids II with an alkylating agent in the presence of a 
base such as, for example, a metal alcoholate or metal carbonate in a 
suitable solvent. An example of a suitable metal alcoholate is sodium 
ethylate or potassium tertiarybutylate. Suitable solvents are alcohols 
such as, for example, methanol or tert.-butanol, ethers such as 
tetrahydrofuran or 1,2-dimethoxyethane and, in particular, dipolar aprotic 
solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile or 
N-methylpyrrolidone. Another suitable method for the preparation of esters 
of the dihydroxy acids is transesterification with an excess of alcohols, 
such as, for example, methanol, ethanol or isopropanol. 
Where the individual reaction products do not result in a form which is 
sufficiently pure for them to be used in the subsequent reaction step, it 
is advisable to purify by crystallization, or column, thin-layer or 
high-pressure liquid chromatography. 
If the aldehyde of the formula IV is not in the form of the pure 
enantiomer, it is also possible for mixtures of the enantiomeric final 
products to be produced, and these can be fractionated by generally 
customary processes. 
It is expedient in the synthesis of compounds of the general formulae I and 
II in which R.sup.1, R.sup.2 and R.sup.3, independently of one another, 
contain hydroxyl groups to use starting compounds of the general formulae 
VIII-XII in which the hydroxyl groups are protected in a suitable manner, 
for example as alkyl or silyl ethers. The compounds then obtained in the 
process according to the invention are of the general formulae I or II in 
which R.sup.1, R.sup.2 or R.sup.3 contain the correspondingly protected 
hydroxyl groups. The latter can be converted, by elimination of the 
protective groups by processes known from the literature, into compounds 
of the general formula I with hydroxyl-substituted radicals R.sup.1, 
R.sup.2 or R.sup.3. Suitable protective groups, as well as methods for the 
introduction and removal thereof, are known from the literature (cf. for 
example T. W. Greene, Protective Groups in Organic Synthesis, Wiley and 
Sons, N.Y., 1981). 
In more cases, where the intention is to prepare compounds of the general 
formulae I and II with acid-sensitive radicals R.sup.1, R.sup.2 or 
R.sup.3, this can also take place by the process described in patent 
application No. P37 22 807.2. 
Apart from the compounds described in the examples, the process according 
to the invention can be used to prepare the following compounds: 
E-6S-(2-(2-Cyclohexyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl)ethenyl)-4R-h 
ydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-Cyclohexyl-2-(4-fluorophenyl)-6-phenylpyridin-3-yl)ethenyl)-4R-h 
ydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-Cyclohexylmethyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethenyl 
)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-Cyclohexylmethyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethenyl 
)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(3,5-Dimethylphenyl)-2-(1-methylethyl-6-phenylpyridin-3-yl)ethen 
yl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(3,5-Dimethylphenyl)-2-(1-methylethyl-6-phenylpyridin-3-yl)ethen 
yl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4,6-Diphenyl-2-(1-methylethyl)pyridin-3-yl)ethenyl)-4R-hydroxy-3,4 
,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2,6-Diphenyl-2-(1-methylethyl)pyridin-3-yl)ethenyl)-4R-hydroxy-3,4 
,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(1-Methylethyl)-6-phenyl-4-(4-trifluoromethylphenyl)pyridin-3-yl 
)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(1-Methylethyl)-6-phenyl-4-(4-trifluoromethylphenyl)pyridin-3-yl 
)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl 
)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl 
)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(4-Fluorophenyl)-2-(1-methylethyl)-4-phenylpyridin-3-yl)ethenyl) 
-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(4-Fluorophenyl)-4-(1-methylethyl)-2-phenylpyridin-3-yl)ethenyl) 
-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(3,5-Dimethylphenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)pyridin 
-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(3,5-Dimethylphenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)pyridin 
-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4,6-Bis-(1-methylethyl)-2-(4-fluorophenyl)pyridin-3-yl)ethenyl)-4R 
-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2,6-Bis-(1-methylethyl)-4-(4-fluorophenyl)pyridin-3-yl)ethenyl)-4R 
-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(4-trifluoromethylphenyl)py 
ridin-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Fluorophenyl)-4-(1-methylethyl)-6-(4-trifluoromethylphenyl)py 
ridin-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(4-Fluorophenyl)-4-(4-methoxyphenyl)-2-(1-methylethyl)pyridin-3- 
yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(4-Fluorophenyl)-2-(4-methoxyphenyl)-2-(1-methylethyl)pyridin-3- 
yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2,6-Bis(1,1-dimethylethyl)-4-(4-fluorophenyl)pyridin-3-yl)ethenyl) 
-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4,6-Bis(1,1-dimethylethyl)-2-(4-fluorophenyl)pyridin-3-yl)ethenyl) 
-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4,6-Dimethyl-2-(4-fluorophenyl)pyridin-3-yl)ethenyl)-4R-hydroxy-3, 
4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-Chlorophenyl)-4,6-dimethylpyridin-3-yl)-ethenyl)-4R-hydroxy-3,4, 
5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Fluorophenyl)-4-methyl-6-phenylpyridin-3-yl)ethenyl)-4R-hydro 
xy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Fluorophenyl)-6-methyl-4-(1-methylethyl)pyridin-3-yl)ethenyl) 
-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(1,1-Dimethylethyl)-2-(4-fluorophenyl)-6-phenylpyridin-3-yl)ethe 
nyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2,6-Dimethyl-4-(4-methoxyphenyl)pyridin-3-yl)ethenyl)-4R-hydroxy-3 
,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4,6-Dimethyl-2-(4-methoxyphenyl)pyridin-3-yl)ethenyl)-4R-hydroxy-3 
,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(4-Methoxyphenyl)-6-methyl-2-(1-methylethyl)pyridin-3-yl)ethenyl 
)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Methoxyphenyl)-6-methyl-4-(1-methylethyl)pyridin-3-yl)ethenyl 
)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Methoxyphenyl)-4-(1-methylethyl)-6-phenylpyridin-3-yl)ethenyl 
)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(2,5-Dimethylphenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)pyridin 
-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2,4-Bis-(4-fluorophenyl)-4-(1-methylethyl)pyridin-3-yl)ethenyl)-4R 
-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)pyridin-3-yl)ethe 
nyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-Cyclohexyl-2-(4-fluorophenyl)-4-(1-methylethyl)pyridin-3-yl)ethe 
nyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(4-Fluorophenyl)-2-(1R-methylpropyl)-6-phenylpyridin-3-yl)etheny 
l)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(4-Fluorophenyl)-2-(1S-methylpropyl)-6-phenylpyridin-3-yl)etheny 
l)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Fluorophenyl)-4-(1R-methylpropyl)-6-phenylpyridin-3-yl)etheny 
l)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Fluorophenyl)-4-(1S-methylypropyl)-6-phenylpyridin-3-yl)ethen 
yl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2,6-Dimethyl-4-(4-fluorophenyl)pyridin-3-yl)ethyl)-4R-hydroxy-3,4, 
5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethyl)-4 
R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenylpyridin-3-yl)ethyl)-4 
R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-Cyclohexyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl)ethyl)-4R-hyd 
roxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-(4-Methoxyphenyl)-2-(1-methylethyl)-6-phenyl)ethyl)-4R-hydroxy-3 
,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(2,5-Dimethylphenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)pyridin 
-3-yl)ethyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(6-(3,5-Dimethylphenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)pyridin 
-3-yl)ethyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Phenyl-4-(4-fluorophenyl)-6-isopropyl)pyrimidinyl)ethenyl)-4R 
-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-(2-Methylphenyl)-4-(4-chlorophenyl)-6-isopropyl)pyrimidinyl)e 
thenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-(2,6-Dimethylphenyl)-4-(4-fluorophenyl)-6-isopropyl)pyrimidin 
yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-(2,6-Dichlorophenyl)-4-(4-fluorophenyl)-6-isopropyl)pyrimidin 
yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Phenyl-4-(4-chlorophenyl)-6-t-butyl)pyrimidinyl)ethenyl)-4R-h 
ydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Phenyl-4-(4-fluorophenyl)-6-t-butyl)pyrimidinyl)ethyl)-4R-hyd 
roxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Phenyl-4-(4-fluoro-3-methylphenyl)-6-isopropylpyrimidinyl)eth 
enyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Phenyl-4-(4-fluoro-3-methylphenyl)-6-isopropylpyrimidinyl)eth 
yl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2,6-Diisopropyl-4-(4-chlorophenyl)pyrimidinyl)ethenyl)-4R-hydro 
xy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2,6-Diisopropyl-4-(4-methoxyphenyl)pyrimidinyl)ethenyl)-4R-hydr 
oxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2,6-Dimethyl-4-cyclohexyl)pyrimidinyl)ethenyl)-4R-hydroxy-3,4,5 
,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2,6-Diisopropyl-4-cyclohexyl)pyrimidinyl)ethenyl)-4R-hydroxy-3, 
4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Phenyl-4-cyclohexyl-6-isopropyl)pyrimidinyl)ethenyl)-4R-hydro 
xy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2,6-Ditert.-butyl-4-(4-chlorophenyl)pyrimidinyl)ethenyl)-4R-hyd 
roxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2,6-Ditert.-butyl-4-(4-fluorophenyl)pyrimidinyl)ethenyl)-4R-hyd 
roxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Methyl-4(4-fluoro-3-methylphenyl)-6-isopropyl)pyrimidinyl)eth 
enyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Methyl-4(4-fluorophenyl)-6-isopropyl)pyrimidinyl)ethyl)-4R-hy 
droxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-(2,6-Dichlorophenyl)-4-(4-fluorophenyl)-6-isopropyl)pyrimidin 
yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-(2-Chloro-4-methylphenyl)-4-(4-chlorophenyl)-6-isopropyl)pyri 
midinyl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-(2,4-Dichlorophenyl)-4-(4-fluorophenyl)-6-methyl)pyrimidinyl) 
ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-(2,4-Dimethyl-phenyl)-4-(4-methoxyphenyl)-6-isopropyl)pyrimid 
inyl)ethyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-(2-Chloro-4-methyl-phenyl)-4-(4-fluoro-3-phenyl)-6-isopropyl) 
pyrimidinyl)ethyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Methyl-4-phenyl-6-tert.butyl)pyrimidinyl)ethenyl)-4R-hydroxy- 
3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Methyl-4-phenyl-6-tert.butyl)pyrimidinyl)ethyl)-4R-hydroxy-3, 
4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Phenyl-4-(4-fluorophenyl)-6-isopropyl)pyrimidinyl)ethyl)-4R-h 
ydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(5-(2-Phenyl-4-(4-fluoro-3-methyl-phenyl)-6-tert.butyl)pyrimidinyl) 
ethyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Fluorophenyl)-6-(4-hydroxyphenyl)-4-(1-methylethyl)pyridin-3- 
yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(2-(4-Hydroxyphenyl)-4-(1-methylethyl)-6-phenylpyridin-3-yl)ethenyl 
)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
E-6S-(2-(4-Cyclopropyl-2-(4-fluorphenyl)-6-phenylpyridin-3-yl)ethenyl)-4R-h 
ydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 
BIOLOGICAL ASSAY SYSTEMS 
1. HMG-CoA reductase activity in enzyme preparations 
The HMG-CoA reductase activity was measured on solubilized enzyme 
preparations from rat liver microsomes induced, after a changeover in the 
day/night rhythm, with cholestyramine (.RTM. CUEMID). The substrate used 
was (S,R)-.sup.14 C-HMG-CoA, and the NADPH concentration was maintained 
during the incubation by a regenerating system. .sup.14 C-Mevalonate was 
separated from the substrate and other products (for example .sup.14 
C-HMG) by column elution, the elution profile of each individual sample 
being determined. .sup.3 H-Mevalonate was not always included in the 
determination because relative data on the inhibitory effects were 
required. In each series of tests, the enzyme-free control, the 
enzyme-containing normal mixture (=100%) and those with additions of 
product, final concentration 10.sup.-5 to 10.sup.-9 M, were treated 
together. Each individual value was the mean formed from 3 parallel 
samples. The significance of the mean differences between product-free and 
product-containing samples was assessed using the t test. 
Using the method described above, the following values for the inhibition 
of HMG-CoA reductase was determined for the compounds according to the 
invention, for example [IC.sub.50 /mol/liter denotes the molar 
concentration of the compound required for 50% inhibition]: 
TABLE 1 
__________________________________________________________________________ 
Compound of IC.sub.50 /mol/ 
Example Z R.sup.1 
R.sup.2 
R.sup.3 A-B Liter 
__________________________________________________________________________ 
13a CH CH.sub.3 
4-FC.sub.6 H.sub.4 
CH.sub.3 
(E)--CH.tbd.CH 
2.6 .multidot. 10.sup.-7 
13b CH CH.sub.3 
4-ClC.sub.6 H.sub.4 
CH.sub.3 
(E)--CH.tbd.CH 
9.4 .multidot. 10.sup.-8 
13c CH CH.sub.3 
4-FC.sub.6 H.sub.4 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
3.8 .multidot. 10.sup.-8 
13d CH iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
CH.sub.3 
(E)--CH.tbd.CH 
9.1 .multidot. 10.sup.-9 
13e CH iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
2.9 .multidot. 10.sup.-9 
13f CH 4-FC.sub.6 H.sub.4 
iC.sub.3 H.sub.7 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
4.0 .multidot. 10.sup.-9 
13g CH tC.sub.4 H.sub.9 
4-FC.sub.6 H.sub.4 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
1.8 .multidot. 10.sup.-8 
13i CH iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
2.5-(CH.sub.3).sub.2 C.sub.6 H.sub.4 
(E)--CH.tbd. CH 
5.0 .multidot. 10.sup.-9 
13j CH iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 
(E)--CH.tbd.CH 
2.3 .multidot. 10.sup.-9 
13k N CH.sub.3 
4-FC.sub.6 H.sub.4 
CH.sub.3 
(E)--CH.tbd.CH 
5.0 .multidot. 10.sup.-7 
13l N CH.sub.3 
4-ClC.sub.6 H.sub.4 
CH.sub.3 
(E)--CH.tbd.CH 
6.0 .multidot. 10.sup.-7 
13o N iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
3.0 .multidot. 10.sup.-9 
13q CH iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
iC.sub.3 H.sub.7 
(E)--CH.tbd.CH 
2.5 .multidot. 10.sup.-9 
13r CH 1C.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
tC.sub.4 H.sub.9 
(E)--CH.tbd.CH 
1.2 .multidot. 10.sup.-9 
13s CH iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
cC.sub.6 H.sub.11 
(E)--CH.tbd.CH 
3.7 .multidot. 10.sup.-9 
missing 
missing 
13v N iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
iC.sub.3 H.sub.7 
(E)--CH.tbd.CH 
2.5 .multidot. 10.sup.-9 
13w N iC.sub. 3 H.sub.7 
4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 
(E)--CH.tbd.CH 
0.9 .multidot. 10.sup.-9 
13z N iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
C.sub.6 H.sub.5 
--CH.sub.2--CH.sub.2-- 
3.3 .multidot. 10.sup.-9 
13ab CH iC.sub.3 H.sub.7 
4-FC.sub.6 H.sub.4 
4-HOC.sub.6 H.sub.4 
(E)--CH.tbd.CH 
1.5 .multidot. 10.sup.-9 
13ac CH cC.sub.3 H.sub.5 
4-FC.sub.6 H.sub.4 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
1.0 .multidot.10.sup.-9 
__________________________________________________________________________ 
2. Suppression or inhibition of HMG-CoA reductase in cell cultures of 
HEP-G2 cells 
Monolayers of HEP-G2 cells in lipoprotein-free nutrient medium were 
preincubated with appropriate concentrations of the test substances for a 
defined time (for example 1 hour), the labeled precursor, for example 
sodium .sup.14 C-acetate was added and then the incubation was continued 
(for example for 3 hours). Addition of an internal standard (.sup.3 
H-cholesterol) was followed by alkaline hydrolysis of some of the cells. 
The lipids were extracted from the hydrolyzed cells using 
chloroform/methanol. Carrier cholesterol was added to this lipid mixture 
which was then subjected to preparative thin-layer chromatography, the 
cholesterol band was visualized with iodine vapor and then isolated, and 
the amount of .sup.14 C-cholesterol formed from the .sup.14 C-precursor 
was determined by scintigraphy. Cellular protein was determined in an 
aliquot of the cells, so that it is possible to calculate the amount of 
.sup.14 C-cholesterol formed per mg of cellular protein in unit time. 
Comparison of this figure with the amount of .sup.14 C-cholesterol formed 
per mg of cellular protein and unit time in a culture treated in the same 
way but containing no test substance revealed the inhibitory effect of the 
particular test product on the cholesterol biosynthesis of HEP-G2 cell 
cultures. 
______________________________________ 
Testing of substances for inhibition of cholesterol 
biosynthesis in cell cultures 
______________________________________ 
Confluent cell culture (monolayer) of HEP-G2 cells 
##STR9## 
##STR10## 
##STR11## 
##STR12## 
8. Result 
in nmol of .sup.14 C-cholesterol/mg of cell protein 
in comparison with the solvent control. 
______________________________________ 
Using the method described above, the following values for the inhibition 
of cholesterol biosynthesis (in HEP-G2 cells) were determined for the 
compounds according to the invention, for example (the IC.sub.50 
/mol/liter is the concentration of the compound which brings about 50% 
inhibition of cholesterol biosynthesis) (Tab. 2): 
TABLE 2 
__________________________________________________________________________ 
Compound of IC.sub.50 /mol/ 
Example Z R.sup.1 
R.sup.2 
R.sup.3 A-B liter 
__________________________________________________________________________ 
11c CH CH.sub.3 
4-F-C.sub.6 H.sub.4 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
9 .multidot. 10.sup.-8 
11d CH i-C.sub.3 H.sub.7 
4-F-C.sub.6 H.sub.4 
CH.sub.3 
(E)--CH.tbd.CH 
5 .multidot. 10.sup.-8 
11e CH i-C.sub.3 H.sub.7 
4-F-C.sub.6 H.sub.4 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
5 .multidot. 10.sup.-9 
11o N i-C.sub.3 H.sub.7 
4-F-C.sub.6 H.sub.4 
C.sub.6 H.sub.5 
(E)--CH.tbd.CH 
5 .multidot. 10.sup.-9 
__________________________________________________________________________ 
The compounds of the general formula I or II are distinguished by strong 
inhibition of HMG-CoA reductase, the rate-determining enzyme of 
cholesterol biosynthesis. 
The extent of inhibition which is characterized by IC.sub.50 values in the 
range 10.sup.-7 -10.sup.-9 mol per liter for compounds of the general 
formula I or II is distinctly higher than that for fully synthetic HMG-CoA 
reductase inhibitors known from the literature, such as, for example, 
those described by G. E. Stokker et al., J. Med. Chem. 29, 170 (1986). 
The enzyme HMG-CoA reductase is widespread in nature. It catalyzes the 
formation of mevalonic acid from HMG-CoA. This reaction is a central step 
in cholesterol biosynthesis (cf. J. R. Sabine in CRC Series in Enzyme 
Biology: 3-hydroxy-3-methylglutaryl Coenzyme A Reductase, CRS Press Inc. 
Boca Raten, Fla. 1983 (ISBN 0-8493-6551-1)). 
A connection is drawn between high cholesterol levels and a number of 
disorders such as, for example, coronary heart disease or 
arteriosclerosis. Hence the lowering of elevated cholesterol levels is an 
aim of therapy for the prevention and treatment of disorders of these 
types. One starting point for this is the inhibition or reduction of 
endogenous cholesterol biosynthesis. Inhibitors of HMG-CoA reductase block 
cholesterol biosynthesis at an early stage. 
Hence the compounds of the general formula I or II are suitable as 
hypolipidemics and for the treatment or prophylaxis of arteriosclerotic 
changes. 
Hence the invention also relates to pharmaceutical products based on these 
compounds and to their use as medicaments, in particular as hypolipodemics 
and for the prophylaxis of arteriosclerotic changes. 
The compounds of the formula I or II are used as hypolipidemics or 
anti-arteriosclerotics in oral doses of 3 to 2500 mg, but preferably in 
the dose range 10-500 mg. These daily doses can, where required, also be 
divided into two to four single doses or administered in sustained release 
form. The dosage regimen may depend on the type, age, weight, sex and 
medical condition of the patient. 
An additional cholesterol-lowering effect can be achieved by concurrent 
administration of the compounds according to the invention with substances 
which bind bile acids, such as, for example, anion exchanger resins. 
Excretion of bile acids results in an increase in neosynthesis and thus in 
an increase in cholesterol breakdown (cf. M. S. Brown, P. T. Koranen and 
J. C. Goldstein, Science 212, 628 (1981); M. S. Brown, J. C. Goldstein, 
Spektrum der Wissenschaft 1985, 1, 96). 
The compounds of the formula I or II, according to the invention, can be 
used in the form of the .delta.-lactones, as the free acids or in the form 
of their physiologically acceptable inorganic or organic salts or as 
esters. Acids and salts or esters can be used in the form of their aqueous 
solutions or suspensions, or dissolved or suspended in pharmacologically 
acceptable organic solvents such as monohydric or polyhydric alcohols such 
as, for example, ethanol, ethylene glycol or glycerol, in triacetin, in 
alcohol/acetaldehyde diacetal mixtures, oils such as, for example, 
sunflower oil or fish liver oil, ethers such as, for example, diethylene 
glycol dimethyl ether, or polyethers such as, for example, polyethylene 
glycol, or in the presence of other pharmacologically acceptable polymeric 
vehicles such as, for example, polyvinylpyrrolidone, or in solid 
formulations. 
The preferred pharmaceutical forms for the compounds of the formula I or II 
are solid, can be administered orally and may contain the customary 
auxiliaries. They are produced by customary methods. 
Particularly suitable formulations for oral use are tablets, coated tablets 
or capsules. One dosage unit preferably contains 10 to 500 mg of active 
substance. 
The compounds of the formula III, V, VI and VII are new and represent 
valuable intermediates for the preparation of compounds of the formula I. 
Hence the invention also relates to these compounds and to processes for 
their preparation. 
Preliminary note: Unless otherwise specified, NMR spectra were measured in 
CDCl.sub.3 with TMS as internal standard. The following abbreviations are 
used to classify NMR signals: s=singlet, brs=broad singlet, d=doublet, 
t=triplet, q=quartet, h=heptet, mc=multiplet center, m=multiplet. Melting 
points are uncorrected. The following abbreviations are used for 
substituents: i=iso, t=tertiary, c=cyclo.