DE3823045A1 - 3-Desmethylmevalonic acid derivatives, process for their preparation, pharmaceutical preparations based on these compounds, their use and intermediates - Google Patents

Abstract

3-Desmethylmevalonic acid derivatives of the formula I ( delta -lactone) or II (corresponding dihydroxycarboxylic acid derivative) <IMAGE> in which A-B, Z, R<1>, R<2>, R<3> and R<4> have the meanings indicated, processes for the preparation of these compounds and their use as medicaments and pharmaceutical preparations are described. Novel intermediates for the preparation of the compounds of the formula I or II are additionally described.

Description

Derivatives of 3-hydroxy-3-methyl-glutaric acid (HMG) and Mevalonic acid are 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-methyl-glutaric acid itself indicates the rat and significant in human experiments cholesterol-lowering effect (Z. Beg, Experimentia 23, 380 (1967), ibid. 24, 15 (1968), P.J. Lupien et al., Lancet 1978, 1, 283)).

Endo et al. (Feb. Letter 72, 323 (1976), J. Biol. Chem. 253, 1121 (1978)) reported inhibition of 3- Hydroxy-3-methyl-glutaryl-coenzyme-A reductase (HMG-CoA- Reductase), the rate-limiting enzyme of Cholesterol biosynthesis, through the fermentation product "Compactin".

Brown et al. (J. Chem. Soc. 1165 (1976)) determined the chemical structure and the absolute configuration of the "Compactins" through a combination of chemical, spectroscopic and radiocrystallographic methods and were able to show that "Compactin" is a derivative of 3-desmethyl-mevalonic acid lactone.

Compactin derivatives, the activity of HMG-CoA reductase inhibit 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 δ- lactone of the formula I or in the form of the dihydroxy acid derivative II

Mean in the formulas

A-legs radical of the formula -CH = CH- or -CH₂-CH₂- Zeinen radical of the formula -CH or a nitrogen atom R¹, R², R³ independently of one another hydrogen,
a saturated or unsaturated, straight-chain or branched hydrocarbon radical with up to 6 C atoms, which can optionally be substituted at the terminal carbon by a saturated or unsaturated, cyclic hydrocarbon radical with 3-6 C atoms,
a cyclic saturated or up to double unsaturated hydrocarbon radical with 3-7 C atoms, an aromatic radical selected from the group phenyl, furyl, thienyl, pyridinyl, which may optionally carry 1-3 identical or different substituents from the following groups:
Halogen, trifluoromethyl, alkyl or alkenyl, each with up to 6 C atoms, hydroxy, alkoxy with 1-6 carboxy, carbalkoxy with 1-6 C atoms in the alkoxy part R⁴hydrogen, a straight-chain or branched, saturated or unsaturated hydrocarbon radical with up to 5 C atoms, a benzyl radical, the core of which can be substituted 1-2 times with halogen or an alkyl radical with 1-4 C atoms, alkali metal or an ammonium ion NR⁵R⁶R⁷R⁸, where R⁵, R⁶, R⁷ and R⁸ are the same or different and hydrogen, alkyl with 1-4 carbon atoms, hydroxyalkyl with 1-4 carbon atoms.

The invention relates to the pure enantiomers with the in of the general formula I given absolute Configuration 4 R, 6 S or that shown in Formula II absolute configuration 3 R, 5 S.

Among the substituents R¹ and R² are preferred
a straight-chain or branched alkyl radical with 1-4 C atoms,
a cycloalkyl radical with 3-6 C atoms,
a cycloalkylmethyl or cycloalkenylmethyl radical with a ring size of 5-6 carbon atoms,
a phenyl radical which may optionally carry 1-3 identical or different substituents from the following groups
Halogen, trifluoromethyl, alkyl with 1-4 C atoms, hydroxy, alkoxy with 1-4 C atoms or carbalkoxy with 1-4 C atoms in the alkoxy part.

Among the meanings for R³ are preferably hydrogen,
a straight-chain or branched alkyl or alkenyl radical with up to 6 C atoms,
a cycloalkyl or cycloalkenyl radical each having 3-6 C atoms,
a phenyl or pyridinyl radical, where the aromatic radicals can optionally carry 1-3 identical or different substituents from the following groups:
Halogen, alkyl with 1-4 C atoms, hydroxy, alkoxy with 1-4 C atoms or carbalkoxy with 1-4 C atoms in the alkoxy part.

Among the radicals R⁴ are preferred
Hydrogen, methyl, ethyl, isopropyl, isobutyl, benzyl, sodium, potassium, ammonium (NH₄) or methyltris (hydroxymethyl) ammonium.

Among the substituents R 1 are particularly preferred
Methyl, ethyl, isopropyl, sec-butyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-flurophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluoro-3-methylphenyl, 3,5- Dimethylphenyl, cyclohexylmethyl, 4-trifluoromethylphenyl.

Among the substituents R² are particularly preferred 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, 4-trifluoromethylphenyl.

Among the substituents R³ are particularly preferred Hydrogen, methyl, isopropyl, tert-butyl, cyclohexyl, Phenyl, 4-flurophenyl, 4-hydroxyphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl, 4-trifluoromethylphenyl.

Among the substituents R⁴ are particularly preferred Hydrogen, methyl, ethyl, sodium, potassium.

Compounds of the formula I are very particularly preferred wherein Z is a radical of the formula -CH or N, R¹ ethyl, Isopropyl, cyclopropyl, R² 4-fluorophenyl, 4-hydroxyphenyl, R³ isopropyl, tert-butyl, cyclohexyl, phenyl, 4-Hydroxyphenyl or 4-fluorophenyl as well as the Sodium and potassium salts of the corresponding Dihydroxycarboxylic acids of formula II.

The invention further relates to a method of manufacture of compounds of the formulas I and II, which thereby is characterized in that one

• a) the phosphonium salts of the formula III, wherein R1, R2, R3 and Z have the meaning given for the formula I and X = Cl, Br, I, with the chiral aldehyde of the formula IV, wherein R⁹ is a protective group stable against bases and weak acids, e.g. B. the t-C₄Hg (C₆H₅) ₂ Si group, to a compound of formula V. wherein R¹, R², R³ and Z have the meaning given for formula I, R⁹ the meaning given for formula IV and AB represents the (-CH = CH -) group,
• b) in a compound of the general formula V, the methyl acetal acid hydrolyzes to a lactol of the formula VI wherein R¹, R², R³ and Z have the meaning given for formula I, R⁹ the meaning given for formula IV and AB represents the (-CH = CH -) group,
• c) the compound of the formula VI oxidizes to a lactone of the general formula VII, wherein R¹, R², R³ and Z have the meaning given for formula I, R⁹ the meaning given for formula IV and AB represents the (-CH = CH -) group,
• d) in a compound of general formula VII Protecting group R⁹ splits off to a compound of formula I, wherein R¹, R², R³ and Z are those given for formula I. Have meaning and A-B represents the (-CH = CH -) group,
• e) optionally a compound of the general obtained Formula I, in which A-B represents a (-CH = CH -) group, hydrogenated to a compound of general formula I, in the A-B represents a (-CH₂-CH₂ -) - group, the Hydrogenation also in the compounds of formula V, VI or VII can take place to compounds in which A-B is the Represents (-CH₂-CH₂ -) - group,
• f) optionally a hydroxylactone of the general formula I. into the corresponding dihydroxy acid of formula II, or  their salts transferred or, if appropriate, from the Hydroxylacton I or the free hydroxy acid II the represents corresponding ester.

The starting material in the process according to the invention related phosphonium salts of the general formula III, wherein R¹, R² and R³ are those given for general formula I. Have meaning, you get as shown in Scheme 1.

Ketones of the general formula VIII, where R² and R³ have the meaning given, are known from the literature or can be prepared by processes known from the literature (see, for example, BD Vorländer and F. Kalkow, reports from Dtsch. Chem. Ges. 30, 2268 (1897 ) or H. Stetter in Houben-Weyl, Methods of Organic Chemistry Vol. VII / 26, 1449-1507, Thieme, Stuttgart 1976). The β are also known from the literature or can be prepared by methods known from the literature (for example analogously to M. Jackman, M. Klenk, B. Fishburn, BF Tullar and S. Archer, J. Am. Chem. Soc. 70, 2884 (1948)) Keto esters of the general formula IX, where R¹ has the meaning given above and R¹⁰ is a straight-chain or branched alkyl radical having up to 6 carbon atoms, preferably a methyl or ethyl radical.

The preparation of compounds of the formula X in which R 1, R², R³ and R¹⁰ have the meaning given analogous to literature processes, e.g. B. after R. Connor, D. B. Andrews, J. Am. Chem. Soc. 56 2713 (1943) and cited there Literature. For the transfer of connections of type X in Pyridines of the general formula XV (R¹, R², R³ have here has the meaning given above and Z means a CH group) B. by a method by F. Rehberg and F. Kröhnke, Liebigs Ann. Chem. 717, 91 (1968) has been described.

Dihydropyrimidines of the general formula XIV are e.g. B. analogous to a literature method (EF Silversmith, J. Org. Chem. 27, 4090 (1962)), or z. B. also by a synthesis according to Scheme 1, route A, by using a β- ketoester of the general formula IX with an aldehyde of type XI to a compound of general formula XII and this without further purification with an amidinium compound of type XIII to a dihydropyrimidinecarboxylic acid ester of the general formula XIV. The preparation of compounds of the type XIV from components of the general formulas IX, XI and XIII can also be carried out as a one-pot reaction (Scheme 1, route B).

The oxidation of compounds of formula XIV too Pyrimidine carboxylic acid esters of the general formula XV, wherein R¹, R², R³ and R¹⁰ have the meaning given above and Z represents a nitrogen atom, is carried out analogously methods known from the literature, e.g. B. by dehydration with Chloranil or 2,3-dichloro-5,6-dicyan-p-benzoquinone (DDQ), as described by E. A. Braude, J. Hannah, R. Linstead, J. Chem. Soc. 1960, 3257.

The reduction of compounds of the general formula XV is done by reaction with complex metal hydrides, such as e.g. B. lithium aluminum hydride or diisobutyl aluminum hydride in aprotic solvents, e.g. B. diethyl ether or Tetrahydrofuran, at temperatures between -30 ° C and + 50 ° C.

Alkyl halides of the general formula XVII, where R¹, R², R³ and X have the meaning given above, can be from alcohols of the type XVI z. B. by implementation with Phosphorus halides in inert solvents such as. B. Dichloromethane or toluene at temperatures between 0 and 100 ° C or by reaction with hydrohalic acids represent.

Phosphonium salts of the general formula III are obtained, for. B. by reaction of the alkyl halides XVII with Triphenylphosphine in inert solvents such as toluene Temperatures between 20 ° C and 120 ° C (see Scheme I).  

Scheme 1

The starting material in the process according to the invention related chiral aldehyde of formula IV is obtained after a method known from the literature (Yuh Lin, J.R. Falck, Tetrahedron Letters 23, 4305-4308 (1982) from corresponding alcohol by oxidation with z. B. CrO₃ or Oxal chloride / dimethyl sulfoxide in the presence of triethylamine.

The reaction of the chiral aldehyde of the formula IV with a Phosphonium salt of formula III according to Wittig (e.g. Wittig, Haag, Chem. Ber. 88, 1654 (1955) gives the connections of formula V, with a preferred embodiment therein consists in that the phosphonium salts of the formula III in a solvent such as tetrahydrofuran, dimethyl sulfoxide, DME, dissolves or suspended and with a suitable strong Base such as B. sodium hydride, potassium tert. butylate, Li-ethylate or butyllithium the corresponding phosphorane releases and then adds the aldehyde of formula IV and can react at -10 ° C to + 50 ° C for 1-6 hours.

The compounds of formula V are predominantly in Obtained form of the mixture of the E / Z olefins. Mixtures of E / Z olefins can optionally be chromatographed be separated. The pure Z-olefins can also, like with G. Drefahl Chem. Ber. 94, 907 (1961) Expose the E / Z mixture in solutions, such as. B. toluene, Nitrobenzene.

The corresponding pure E-olefins can 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 be obtained from iodine.

In the compounds of formula V, the Methyl acetal protecting group in the usual way selectively split off by acid hydrolysis, preferably with a mixture of glacial acetic acid, tetrahydrofuran, water in Ratio 3: 2: 2 at +20 to + 90 ° C within 6-24 hours.  

The oxidation of the compounds of formula VI to a lactone of formula VII can by oxidizing agents such as CrO₃ × 2 Pyr, Pyridium chlorochromate in inert solvents, such as. B. Methylene chloride or chloroform. Further Oxidation is possible in the reaction with Thioanisole / Cl₂ / NEt₃ in carbon tetrachloride, in the Reaction with DMSO / oxalyl chloride / NEt₃ at -20 ° C or in the reaction with N-iodosuccinimide / tetrabutylammonium iodide in dichloromethane.

To represent the compounds of formula I, the Protecting group R⁹ in the compounds of formula VII cleaved. This can be normal with strong acids like 5 Hydrochloric acid or sulfuric acid at -10 ° C to + 30 ° C, or with fluoride ions, preferably by dissolving the Compounds of formula VII in tetrahydrofuran or Diethyl ether and addition of a mixture of Tetrabutylammonium fluoride and glacial acetic acid followed by Stir at 0 ° C to 40 ° C for 1 to 12 hours.

Compounds of the formula I in which A-B is a (CH = CH) - Group represents, according to the generally accepted method, useful at temperatures between 20 ° C and 40 ° C with Hydrogen in the presence of a metal catalyst, preferably palladium, platinum, PtO₂ or PdO₂ to compounds of the formula I in which A-B represents a -CH₂-CH₂ group, hydrated. This can be done at normal pressure in usual Solvents such as tetrahydrofuran, ethyl acetate, methanol, low molecular weight alcohols, glacial acetic acid, chloroform hydrogenated or in autoclaves at elevated pressure (2-50 atm). The Hydrogenation of the -CH = CH group can also occur in the compounds of formulas B, VI or VII.

The resulting compounds of formula I can in simply by evaporating the solvent be isolated, if necessary by chromatographic Cleaning.  

The compounds of formula I fall in optically pure form at. Regarding the configuration of the double bond (A-B) = -CH = CH- you get E / Z mixtures, these can be broken down separate all stages of synthesis by chromatography, or Isomerize to the E form (see De Tar et al. J. Amer. Chem. Soc. 78 475 (1955)).

Compounds of formula I, in the form of the δ- lactone, can be saponified in an alkaline medium to give the corresponding salts of the dihydroxy acids, e.g. B. with NaOH or KOH in a low molecular weight alcohol such as methanol or in ethers such as dimethoxyethane or THF, optionally in the presence of water. In the salts of dihydroxy acids obtained, the alkalization after acidification in ion exchangers can be exchanged in the usual way for any cations. To do this, z. B. the dihydroxy acids by a with a cation exchanger, such as. B. based on polystyrene / divinylbenzene (®Amberlite CG-150 or ®Dowex-CCR-2) filled column. The cation exchanger is loaded with the desired cation, e.g. B. with ammonium ions derived from a primary, secondary or tertiary amine. The desired salt is obtained by evaporating the eluate.

Ammonium salts of the dihydroxy acids which differ from one derive primary, secondary or tertiary amine, one can also by making the free dihydroxy acids in an alcoholic solution with an equimolar amount of appropriate amine and the solvent evaporates.

The free dihydroxy acids II of the δ- lactones I can be z. B. esterify with a diazoalkane. So you can z. B. esterify compounds of formula I at temperatures between -40 ° C and + 20 ° C with a diazoalkane, the usual solvents such as. B. diethyl ether, tetrahydrofuran, chloroform or low molecular weight alcohols such as methanol can be used. The resulting esters can be isolated in a simple manner by evaporating the solvent and, if necessary, purified by chromatography. Another esterification method is that salts of dihydroxy acids II in the presence of a base such as. B. a metal alcoholate or metal carbonate in a suitable solvent with an alkylating agent. As a metal alcoholate such. B. sodium ethylate or potassium tert-butylate into consideration. Suitable solvents are alcohols such as. B. methanol or tert. Butanol, ethers such as tetrahydrofuran or 1,2-dimethoxyethane and in particular dipolar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, or N-methylpyrrolidone into consideration. The method of transesterification with excess alcohols, such as, for example, is also suitable for preparing esters of dihydroxy acids. B. methanol, ethanol, isopropanol.

If the individual reaction products are not already in enough pure form are obtained so that they can be used for the following Reaction step can be used is recommended cleaning by crystallization, columnar, Thin layer or high pressure liquid chromatography.

If the aldehyde of formula IV is not as pure Enantiomer is present, mixtures of the enantiomeric end products arise, which according to general usual procedures can be separated.

In the synthesis of compounds of general formulas I and II, wherein R¹, R² and R³ are independent of each other Contain hydroxyl groups, it is expedient Starting compounds of the general formulas VIII-XII use, in which the hydroxy groups in a suitable manner  are protected, e.g. B. as alkyl or silyl ether. in the Compounds according to the invention are then obtained of the general formulas I or II, in which R¹, R² or R³ the correspondingly protected hydroxy functions contain. By splitting off the protective groups after methods known from the literature can be found in Compounds of general formula I with Transfer hydroxy-substituted residues R¹, R² or R³. Suitable protective groups and methods for their introduction and distance are known from the literature (see e.g. T. W. Greene, Protective Groups in Organic Synthesis, Wiley and Sons, New York, 1981) -

In rare cases where compounds of general Formulas I and II with acid-sensitive radicals R¹, R² or R³ are to be produced, this can also be done after in the patent application P 37 22 807.2 described method happen.

Except for the compounds described in the examples can be according to the inventive method establish the following connections:

E-6S- (2- (2-cyclohexyl-4- (4-fluorophenyl) -6-phenylpyridin-3-yl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (4-cyclohexyl-2- (4-fluorophenyl) -6-phenylpyridin-3-yl) ethenyl) -
4R-hydroxy-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) ethenyl) -
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) ethenyl) -
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- on
E-6S- (2- (2, 6-diphenyl-2- (1-methylethyl) pyridin-3-yl) ethenyl) -4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2- on
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-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-2-yl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (2,6-bis (1-ethylethyl) -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) pyridin-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) pyridin-3-yl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (6- (4-fluorophenyl) -4- (4methoxyphenyl) -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- on
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-hydroxy-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) ethenyl) -
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- on
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, 6-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) ethenyl) -
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) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (4- (4-fluorophenyl) -2- (1R-methylpropyl) -6-phenylpyridin-3-yl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (4- (4-fluorophenyl) -2- (1S-methylpropyl) -6-phenylpyridin-3-yl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (2- (4-fluorophenyl) -4- (1R-methylpropyl) -6-phenylpyridin-3-yl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (2- (4-fluorophenyl) -4- (1S-methylpropyl) -6-phenylpyridin-3-yl) ethenyl) -
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- on
E-6S- (2- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyridin-3-yl) ethyl-
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (2- (4-fluorophenyl) -4- (1-methylethyl) -6-phenylpyridin-3-yl) ethyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (2-cyclohexyl-4- (4-fluorophenyl) -6-phenylpyridin-3-yl) ethyl) -
4R-hydroxy-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 -on
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) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2- (2,6-dimethylphenyl) -4- (4-fluorophenyl) -6-isopropyl) pyrimidinyl) 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) pyrimidinyl) 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-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2-phenyl-4- (4-fluorophenyl) -6-6-butyl) pyrimidinyl) ethyl -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2-phenyl-4- (4-fluoro-3-methylphenyl) -6-isopropylpyrimidinyl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2-phenyl-4- (4-fluoro-3-methylphenyl) -6-isopropylpyrimidinyl) ethyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2,6-diisopropyl-4- (4-chlorophenyl) pyrimidinyl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2,6-diisopropyl-4- (4-methoxyphenyl) pyrimidinyl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran
2-on
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-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2,6-di-tert-butyl-4- (4-chlorophenyl) pyrimidinyl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2,6-di-tert-butyl-4- (4-fluorophenyl) pyrimidinyl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2-methyl-4 (4-fluoro-3-methylphenyl) -6-isopropyl) pyrimidinyl) ethenyl) -
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-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2- (2,6-dichlorophenyl) -4- (4-fluorophenyl) -6- isopropyl) pyrimidinyl) 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) pyrimidinyl) 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-dimethylphenyl) -4- (4-methoxyphenyl) -6-isopropyl) pyrimidinyl) ethyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2- (2-chloro-4-methylphenyl) -4- (4-fluoro-3-phenyl) - 6-isoproyl) 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- on
E-6S- (2- (5- (2-methyl-4-phenyl-6-tert-butyl) pyrimidinyl) ethyl) -4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2 -on
E-6S- (2- (5- (2-phenyl-4- (4-fluorophenyl) -6-isopropyl) pyrimidinyl) ethyl)
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one
E-6S- (2- (5- (2-phenyl-4- (4-fluro-3-methylphenyl) -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-fluorophenyl) -6-phenylpyridin-3-yl) ethenyl) -
4R-hydroxy-3, 4, 5, 6-tetrahydro-2H-pyran-2-one

Biological test systems HMG-COA reductase activity in enzyme preparations

The HMG-COA reductase activity was measured on solubilized enzyme preparations from liver microsomes of rats, which were induced with cholestyramine (®Cuemid) after switching in a day-night rhythm. (S, R) ¹⁴C-HMG-COA served as the substrate, the concentration of NADPH was maintained during the incubation by a regenerating system. ¹⁴C-Mevalonate was separated from the substrate and other products (e.g. ¹⁴C-HMG) by column elution, whereby the elution profile of each individual sample was determined. The ³H-Mevalonate was not carried on a permanent basis because the determination is a relative statement of the inhibitory effect. In a series of experiments, the enzyme-free control, the enzyme-containing normal batch (= 100%) and those with preparation additives, final concentration 10 ^-5 to 10 ^-9 M, were treated together. Each individual value was averaged from 3 parallel samples. The significance of the differences in mean values between specimen-free and specimen-containing samples was assessed according to the t-test.

According to the method described above, the compounds of the invention z. B. the following inhibitory values determined on the HMG-COA reductase [IC₅₀ / mol / liter means the molar concentration of the compound per Liters required for 50% inhibition]:

Table 1

2. Suppression or inhibition of HMG-COA reductase in Cell cultures of HEP-G2 cells

Monolayers of HEP-G2 cells in lipoprotein-free Culture media were mixed with appropriate concentrations of   Test substances for a certain time (e.g. 1 hour) pre-incubated, after adding the marked precursor, e.g. B. 14 C sodium acetate, the incubation was continued (e.g. 3 hours). After adding an internal standard (3 H-cholesterol) some of the cells became alkaline saponified. The lipids of the saponified cells were included Chloroform / methanol extracted. This lipid mixture became preparative after the addition of carrier cholesterol separated by thin layer chromatography Cholesterol band after visualization with iodine steam isolated and the amount formed from the ¹⁴C precursor ¹⁴C-Cholesterol determined by scintigraphy. In one aliquot of the cells, cell protein was determined, so that the formed in the unit of time per mg of cell protein Amount of C cholesterol can be calculated. By Comparison of this value with the amount of ¹⁴C-cholesterol, that per mg of cell protein and unit of time in one culture treated equally, but without test substance was formed, the inhibitory effect of respective investigational drug for cholesterol biosynthesis of HEP-G2 cell cultures.  

Testing substances for inhibition of cholesterol biosynthesis in cell cultures

confluent cell culture (monolayer) of HEP-G2 cells

According to the method described above, the compounds of the invention z. B. the following inhibitory values of Cholesterol biosynthesis (in HEP-G2 cells) determined (the IC₅₀ / mol is the concentration of the compound that causes a 50% inhibition of cholesterol biosynthesis) (Tab. 2):  

Table 2

Draw the compounds of general formula I or II by strong inhibition of HMG-CoA reductase, the rate-determining enzyme of the Cholesterol biosynthesis.

The extent of inhibition characterized by IC₅₀ values in the range of 10 ^-7 -10 ^-9 mol per liter is significantly higher for compounds of the general formula I or II than for fully synthetic HMG-CoA reductase inhibitors known from the literature, e.g. B. those described by GE 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 response is a key step in the Cholesterol biosynthesis (see J.R. Sabine in CRC Series in Enzyme Biology: 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase, CRC Press Inc. Boca Raten, Florida 1983 (ISBN 0-8493-6551-1)).

High cholesterol levels are associated with a number of Diseases such as B. coronary artery disease or Arteriosclerosis has been linked. Hence the Lowering elevated cholesterol levels for prevention and Treatment of such diseases is a therapeutic goal.  

One starting point for this is inhibition or reduction endogenous cholesterol biosynthesis. Inhibitors of HMG-CoA reductase block cholesterol biosynthesis an early stage.

The compounds of the general formula I or II are suitable therefore as hypolipidemics and for treatment or Prophylaxis of atherosclerotic changes.

The invention therefore also relates to pharmaceutical preparations based on these compounds as well as their use as Medicines, especially as hypolipidemics and Prophylaxis of atherosclerotic changes.

The application of the compounds of formula I or II as Hypolipidemics or anti-arteriosclerotics are done in oral doses of 3 to 2500 mg, but preferably in Dose range of 10-500 mg. These daily doses can after Can also be divided into two to four single doses as needed or administered in sustained release form. The dosing schedule can be of type, age, weight, gender and medical Depend on the patient's condition.

An additional cholesterol-lowering effect can be seen by simultaneous administration of the compounds according to the invention with bile acid binding substances, such as. B. Anion exchange resins. The Bile acid excretion leads to an increased New synthesis and thus an increased cholesterol reduction (see M. S. Brown, P. T. Koranen and J. C. Goldstein, Science 212: 628 (1981); M. S. Brown, J.C. Goldstein, Spectrum of Science 1985, 1, 96).

The compounds of the formula I or II according to the invention can be used in the form of the δ- lactones, as free acids or in the form of their physiologically acceptable inorganic or organic salts or as esters. Acids and salts or esters can be in the form of their aqueous solutions or suspensions or dissolved or suspended in pharmacologically acceptable organic solvents such as mono- or polyhydric alcohols such as. As ethanol, ethylene glycol or glycerol, in triacetin, in alcohol-acetaldehyde diacetal mixtures, oils such as. B. sunflower oil or cod liver oil, ethers, such as. B. diethylene glycol dimethyl ether, or polyethers, such as. B. polyethylene glycol, or in the presence of other pharmacologically acceptable polymer carriers such. B. polyvinyl pyrrolidone or in solid preparations.

For the compounds of formula I or II are solid, oral administrable preparation forms preferred, the can contain customary auxiliaries. You will after usual methods.

Are suitable as preparations for oral use in particular tablets, coated tablets or capsules. A Dosage unit preferably contains 10 to 500 mg Active ingredient.

The compounds of formula III, V, VI and VII are new and provide valuable intermediates for the production of Compounds of formula I. The invention therefore relates these compounds as well as processes for their preparation.

Preliminary remark: Unless otherwise stated, NMR spectra were measured in CDCl₃ with an internal standard TMS. The following abbreviations apply to the classification of NMR signals:
s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, h = heptet, mc = centered multiplet, m = multiplet.
Melting points are uncorrected.
The following substituent abbreviations apply:
i = iso, t = tertiary, c = cyclo.

Example 1 General instructions for the preparation of the connections of the general formula X Example 1 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, R¹⁰ = CH₃) Methyl 2- (1-oxoethyl) -3- (4-fluorophenyl) -5-oxohexanoate X a

A solution of 1.2 g of potassium hydroxide in 12 ml of ethanol was added to 58.1 g (0.50 mol) of methyl acetoacetate. A solution of 41.0 g (0.25 mol) of 4- (e-fluorophenyl) but-3-en-2-one in 600 ml of ether was then added dropwise so slowly that the temperature of the reaction mixture did not exceed 30 ° C. After standing at room temperature for three hours, the mixture was diluted with 1 liter of ether and brought to a pH of 5 by adding acetic acid. It was shaken successively with water and saturated NaHCO₃ solution, dried over MgSO₄ and evaporated.
Yield: 50.6 g (72%)
Mp .: oil
1 H-NMR: δ /ppm=0.8-1.0 (m, 6 H), 1.9 (S, 3 H), 2.2-2.9 (m, 2 H), 3.1-4.1 (m, 7 H), 7.0-7.8 ( m, 4 H).

Example 1 b-1 o

The compounds X bX j and X qX u were prepared in a manner analogous to that described in Example 1a (see Table 3)

Example 2 General regulation for the representation of the connections of the general formula XV (Z = CH) (see F. Rehberg, F. Kröhnke, Liebigs Ann. Chem. 717, 91 (1968)) Example 2a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, R¹⁰ = CH₃) 2,6-dimethyl-4- (4-fluorophenyl) pyridine-3-carboxylic acid methyl ester XV a

A suspension of 28.0 g (100 mmol) of 3- (4-fluorophenyl) -2- (1-oxoethyl-5-oxohexanoic acid methyl ester (= X a from Example 1), 120 g of ammonium acetate and 120 g of iron (III) chloride hexahydrate in 1000 ml of glacial acetic acid was refluxed with stirring until starting material could no longer be detected by thin layer chromatography (4 h). After cooling, the mixture was filtered, the solid residue was washed with ethanol and toluene. After evaporation of the filtrate, the residue was suspended in water by adding solid sodium bicarbonate brought to pH 8-9 and extracted several times with ether. The combined extracts were washed with saturated sodium chloride solution, dried over MgSO₄ and evaporated. Purification by column chromatography of the crude product (silica gel, cyclohexane / ethyl acetate 2: 1) yielded 23.6 g (91% ) XV a in the form of white crystals.
Mp 89-90 ° C
1 H-NMR (CDCl₃; 60 MHz): δ = 2.60 (s, 6 H), 3.66 (s, 3 H), 6.95-7.50 (m, 5 H) ppm.
MS: m / e = 259 (M⁺)

Example 2 b-2 o

The compounds XV b-XV j and XV q-XV u were prepared in an analogous manner to that described in Example 2 a (see Table 4)

Example 3 General regulation for the production of connections of the general formula XIV Example 3a (R¹ = iC₃H₇, R² = 4-FC₆H₄, R³ = C₆H₅, R¹⁰ = C₂H₅) 1,4-dihydro-4- (4-fluorophenyl) -2- (1-methylethyl) -6- phenylpyrimidine-3-carboxylic acid ethyl ester XIV o Path A

98.6 g (0.62 mol) of methyl 4-methyl-3-oxopentanoate (corresponds to the general formula IX, Scheme 1) were in 400 ml Toluene dissolved and with 77.0 g of 4-fluorobenzaldehyde XI a, 6.8 g Piperazine and 7.3 g of caproic acid are added. The The reaction mixture was kept on the water separator for so long Boiled reflux until no more water of reaction formed (24 h) and then three times with saturated Sodium bicarbonate solution, three times with 5% acetic acid and shaken out once with water. After drying over Magnesium sulfate, the organic phase was evaporated. This left 150 g (<0.58 mol) of the crude XII a, which in 1700 ml of toluene dissolved and successively with 102.2 g (0.85 mol) Benzamidine · HCl · H₂O XIII a and 90.7 g (0.94 mol) of potassium acetate was transferred. This mixture was used until the end of Water of reaction on the water separator under reflux boiled (24 h), then with sodium bicarbonate solution, 5% acetic acid and water washed over magnesium sulfate dried and evaporated.

The crude product obtained (78 g) was filtered through silica gel (mobile phase cyclohexane / ethyl acetate 4: 1).
Yield: 72.6 (63%) XIV o as a yellow oil
Rf (cyclohexane / ethyl acetate 2: 1): 0.31
1 H-NMR: δ /ppm=1.2 (t, J = 7 Hz, 3 H), 1.3 (d, J = 7 Hz, 6 H), 4.0-4.5 (m, 3 H), 5.8 (s, 1 H) ), 7.0-7.9 (m, 10 H).

Path B

98.6 g (0.62 mol) of 4-methyl-3-oxopentanoic acid ethyl ester (IX a), 77.0 g (0.62 mol) of 4-fluorobenzaldehyde XI a, 102 g (0.85 mol) of benzamidine · H₂O · HCl (XIII a) and 90.7 (0.94 mol ) Potassium acetate were dissolved in 1500 ml of toluene and refluxed for 24 hours on a water separator. Working up and cleaning as described in route A gave XIV o as a yellow oil.
Yield: 110 g (55%)
Rf value: cf. Path A
1 H-NMR: cf. Path A

Example 3 b-3 h

The compounds XIV k-XIV n, XIV p, XIV v and XIV w were prepared in an analogous manner to that described in Example 3a (see Table 5).

Example 4 General regulation for the production of connections of the general formula XV (Z = N) Example 4 a (R¹ = iC₃H₇, R² = 4-FC₆H₄, R³ = C₆H₅, R¹⁰ = C₂H₅) (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyrimidine-3- carboxylic acid ethyl ester XV o

24.2 g (66.0 mmol) 1,4-dihydro-4- (4-fluorophenyl) -2- (1- methylethyl) 6-phenylpyrimidine-3-carboxylic acid ethyl ester XIV o (from Example 3a) were dissolved in 300 ml of toluene, with 18.0 g (790 mmol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (= DDQ) added and heated to 50 ° C. with stirring.

After 3 h the solvent was removed in vacuo, the residue was extracted several times with a 4: 1 mixture of cyclohexane and ethyl acetate. The organic extracts were evaporated again. The residue was purified by filtration over silica gel (cyclohexane / ethyl acetate 4: 1).
Yield: 19.95 g XV o (82%) as white crystals
Rf (cyclohexane / ethyl acetate 4: 1) 0.73
Mp: 105 ° C
1 H-NMR: δ /ppm=1.1 (t, J = 7 Hz, 3 H), 1.4 (d, J = 7 Hz, 6 H), 3.2 (h, J = 7 Hz, 1 H), 4.2 (q , J = 7 Hz, 2 H), 7.0-8.0 (m, 7 H), 8.5-8.8 (m, 2 H).

Examples 4 b-4 h

The compounds XV k-XV n, XV p, XV v and XV w were prepared in an analogous manner to that described in Example 4 a (see Table 6).

Example 5 General instructions for the preparation of the connections of the general formula XVI Example 5 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, Z = CH) 2,6-Dimethyl-4- (4-fluorophenyl) pyridin-3-yl-methanol XVI a

A solution of 7.8 g (30.1 mmol) of 2,6-dimethyl-4- (4-fluorophenyl) pyridine-3-carboxylic acid methyl ester XV a (from Example 2) in 40 ml of tetrahydrofuran was added dropwise with 30 ml (30 mmol) with the exclusion of moisture. a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran. After stirring for 1.5 hours, the mixture was poured into water, extracted several times with ether, washed with water, dried over MgSO₄ and evaporated. The remaining, crude XVI a was washed with a 1: 1 mixture of cyclohexane and ethyl acetate.
Yield: 6.5 g (93%)
Mp .: 124 ° C
1 H-NMR (CDCl₃; 60 MHz) δ = 2.0 (s, 1 H); 2.5 (s, 3H); 2.7 (s, 3H); 4.6 (s, 2H); 6.9 (s, 1H); 7.0-7.5 (m, 4H) ppm
MS: m / e = 231 (M⁺)

Example 5 b-5 w

The compounds XVI b-XVI w were prepared in a manner analogous to that described in Example 5 a (see Table 7)

Example 6 General instructions for making the connections of the general formula XVII Example 6 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, Z = CH, X-Br) 2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-yl) methylene bromide XVII a

A solution of 6.4 g (27.7 mmol) of 2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-ylmethanol XVI a in a Sovens mixture of 50 ml of toluene and 25 ml of dichloromethane was added dropwise with 5.3 ml (54.4 mmol) of phosphorus tribromide added and stirred for 1 h at room temperature. The mixture was added to saturated NaHCO₃ solution and shaken out several times with ether. The combined organic extracts were washed with water, dried over MgSO₄ and evaporated. This left 6.4 g (79%) XVII a, which could be reacted further without purification.
Mp .: 86-87 ° C
1 H-NMR (CDCl₃; 60 MHz): δ = 2.5 (s, 3 H); 2.7 (s, 3H); 4.4 (s, 2H); 6.9 (s, 1H); 7.0-7.5 (m, 4H) ppm.
MS: m / e = 295.293 (M⁺)

Example 6 b-6 w

The compounds XVII b-XVII w were prepared in a manner analogous to that described in Example 6 (cf. Table 8)

Example 7 General instructions for the preparation of the connections of the general formula III Example 7 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, Z = CH, X = Br) 2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-yl) methyltriphenyl- phosphonium bromide III a

A solution of 6.4 g (22.5 mmol) of 2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-yl-methylene bromide XVII a and 6.2 g (23 mmol) of triphenylphosphine in 200 ml of toluene was refluxed for 5 hours under TLC control . When the reaction solution was cooled, the phosphonium salt formed precipitated out in the form of white crystals. These were filtered off, washed with ether and dried in vacuo. The yield of III a was 11.2 g (89%).
Mp .: 218-220 ° C
1 H-NMR (CDCl₃; 60 MHz): δ = 2.3 (d, J = 2 Hz, 3 H); 2.5 (d, J = 3 Hz, 3 H); 6.5 (d, J = 16 Hz, 2H); 6.8-7.9 (m, 20H) ppm.
MS: 476 (M⁺ cation)

Example 7 b-7 w

The compounds III b-III w were prepared in an analogous manner to that described in Example 7 a (cf. Table 9).

Example 8 General instructions for the preparation of the connections of the general formula V Example 8 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, A-B =, -CH = CH-) (4R, 6S) -4- (tert-butyldiphenylsilyloxy) 6- (2- (2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-yl) ethenyl) -2-methoxy-3,4,5,6- tetrahydropyranone Z-V a and E-V a

12.0 ml (19.2 mmol) of a 1.6 molar solution were added to a solution of 9.70 g (17.5 mmol) of 2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-yl) methyltriphenylphosphonium bromide III a in 100 ml of THF at 0 ° C. Drop of solution of n-butyllithium in hexane. The mixture was stirred at room temperature for 30 min and then a solution of 7.29 g (18.4 mmol) of the aldehyde IV in 40 ml of THF was added dropwise. After stirring for one hour, the mixture was quenched by adding water, brought to pH between 5 and 6 with acetic acid and extracted several times with ether. The combined organic extracts were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. The crude diastereomer mixture which remained was separated by column chromatography (silica gel, cyclohexane / ethyl acetate 2: 1).
Yield: 2.36 g ZV a and 4.99 g EV a, corresponding to 70% with a Z: E ratio of 32:68 (approx. 1: 2).
ZV a: mp: 111-113 ° C
1 H-NMR: δ /ppm=0.9 (s, 9 H), 1.0-1.8 (m, 4 H), 2.6 (s, 6 H), 3.3 (s, 3 H), 4.2 (mc, 1 H), 4.3 (mc, 1 H), 5.5 (mc, 1 H), 6.3 (d, J = 10 Hz, 1 H), 6.9-7.8 (m, 15 H).
MS: m / e = 596 (M⁺ + H)
EV a: Fp: oil
1 H-NMR: δ /ppm=1.1 (s, 9 H), 1.1-1.9 (m, 4 H), 2.5 (s, 3 H), 2.6 (s, 3 H), 3.5 (s, 3 H), 4.2 (mc, 1 H), 4.5 (mc, 1 H), 4.9 (mc, 1 H), 5.5 (dd, J = 16 Hz, 6 Hz, 1 H), 6.43 (d, J = 16 Hz, 1 H), 6.9-7.7 (m, 15 H).
MS: m / e = 596 (M⁺ + H)

Example 8 a-8 w

The compounds V bV w were prepared in a manner analogous to that described in Example 8 a (cf. Table 10)

Example 9 General instructions for the preparation of the connections of the general formula VI Example 9 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, A-B = -CH = CH-) (4R, 6S) -4- (tert-butyldiphenylsilyloxy) 6- (2- (2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-yl) ethenyl) -2-hydroxy-3,4,5,6- tetrahydro-2H-pyrans Z-VI a and E-VI a

7.25 g (12 mmol) of a 32:68 mixture of the compounds ZV a and EV a were boiled under reflux in a solvent mixture of 85 ml of THF, 85 ml of water and 140 ml of glacial acetic acid for 48 h. After adding 200 ml of toluene, the reaction solution was evaporated. The residue was freed of acetic acid residues by repeated evaporation with the addition of toluene, then taken up in ether, shaken with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated again. Subsequent chromatographic purification gave 1.35 g of Z-VI a and 3.14 g of E-VI a, corresponding to a yield of 63% and a Z: E ratio of 30:70.
Z-VI a: mp: 147-149 ° C
1 H-NMR: δ /ppm=0.9 (s, 9 H), 1.0-1.9 (m, 4 H), 2.5 (s, 6 H), 4.0-4.4 (m, 2 H), 4.8-6.5 (m, 3 H), 6.9-7.6 (m, 15 H).
MS: m / e = 581 (M⁺)
E-VI a: mp: 119 ° C
1 H-NMR: δ /ppm=1.1 (s, 9 H), 1.2-2.0 (m, 4 H), 2.5 (s, 3 H), 2.6 (s, 3 H), 3.9-5.0 (m, 3 H) ), 5.1-5.6 (m, 2 H), 6.4 (d, J = 16 Hz, 1 H), 6.9-7.8 (m, 15 H).
MS: m / e = 581 (M⁺)

Example 9 b-9 w

The compounds VI b-VI w were prepared in a manner analogous to that described in Example 9 a (cf. Table 11)

Example 10 General regulation for the production of the general Formula VII Example 10 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, A-B =, -CH = CH-) (4R, 6S) -4- (tert-butyldiphenylsilyloxy) 6- (2- (2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-yl) ethenyl) -3,4,5,6-tetrahydro- 2H-pyran-2-one Z-VII a and E-VII a

A solution of 8.32 g (37.0 mmol) of N-iodosuccinimide and 2.73 g (7.4 mmol) of tetra-n-butylammonium iodide in 100 ml of dichloromethane was added dropwise with 4.30 g (7.4 mmol) of a 30:70 mixture of the compounds Z-VI a and E-VI a, dissolved in 20 ml dichloromethane, added. The mixture was stirred at room temperature for 2 h, then poured onto water and etherified several times. The combined extracts were decolorized with sodium thiosulfate solution, washed with water, dried over magnesium sulfate and evaporated. The residue was taken up in diisopropyl ether, filtered and the filtrate evaporated again. Purification of the remaining oil by column chromatography (silica gel, deactivated with 10% water, cyclohexane / ethyl acetate 1: 1) gave 0.82 g of Z-VII a and 2.45 g of E-VII a. This corresponds to a yield of 76% with a Z: E ratio of 25:75. Z-VII a: mp: 188 ° C.
1 H-NMR: δ /ppm=0.9 (s, 9 H), 1.3-1.7 (m, 4 H), 2.4 (mc, 2 H), 2.6 (s, 6 H), 4.2 (mc, 1 H), 5 (mc, 1 H), 5.6 (mc, 1 H), 6.5 (d, J = 11 Hz, 1 H), 6.9-7.5 (m, 15 H).
MS: m / e = 580 (M⁺ + H)
E-VII a: Mp: oil
1 H-NMR: δ /ppm=1.1 (s, 9 H), 1.3-1.7 (m, 2 H), 2.4-2.6 (m, 8 H), 4.2 (mc, 1 H), 5.2 (mc, 1 H ), 6.5 (d, J = 16 Hz, 1 H), 6.9-7.7 (m, 15 H).
MS: m / e = 580 (M⁺ + H)

Example 10 b-10 w

The compounds VII b-VII w were prepared in an analogous manner to that described in Example 10 a (cf. Table 12)

Example 11 General instructions for the preparation of the connections of the general formula I. Example 11 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, A-B =, -CH = CH-) (4R, 6S) -6- (2- (2,6-dimethyl-4- (4-fluorophenyl) pyridin-3-yl) ethenyl) - 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one Z-I a and E-I a

A solution of 3.00 g (5.2 mmol) of a mixture of the compounds Z-VII a and E-VII a, 4.90 g (15.5 mmol) of tetra-n-butylamonium fluoride trihydrate and 11.8 ml of 20.7 mmol) of acetic acid in 50 ml of tetrahydrofuran was at room temperature for 15 h touched. The mixture was then added to saturated sodium bicarbonate solution and etherified several times. The combined organic extracts were washed with saturated saline, dried over magnesium sulfate and evaporated. The remaining product was chromatographed (silica gel, deactivated with 10% water, cyclohexane / methanol 10: 1). 0.29 g of the Z isomer ZI a and 0.97 g of EI a were obtained, equivalent to a yield of 71% with a diastereomer ratio (Z: E) of 23:77.
ZI a: mp: 188 ° C
1 H-NMR: δ /ppm=1.5 (mc, 1 H), 1.8-2.2 (m, 2 H), 2.4-2.6 (m, 8 H), 4.2 (mc, 1 H), 4.8 (mc, 1 H) ), 5.6 (mc, 1 H), 6.5 (mc, 1 H), 6.9 (s, 1 H), 7.0-7.4 (m, 4 H),
MS: m / e = 341 (M⁺)
EI a: mp: 205 ° C
1 H-NMR: δ /ppm=1.6-1.9 (m, 3 H), 2.5 (s, 3 H), 2.6 (s, 3 H), 2.6-2.8 (m, 2 H), 4.3 (mc, 1 H ), 5.3 (mc, 1 H), 5.5 (mc, 1 H), 6.6 (d, J = 16 Hz, 1 H), 6.9 (s, 1 H), 7.0-7.3 (m, 4 H).
MS: m / e = 341 (M⁺)

Example 11 b-11 w

The compounds I bI w were prepared in a manner analogous to that described in Example 11 a (see Table 13)

Example 12 Hydrogenation of compounds of the general formula I with A-B = -CH = CH- to compounds of the formula I with A-B = -CH₂-CH₂- Example 12 a (4R, 6S) - (6- (2- (2,6-Dimethyl-4- (4-fluorophenyl) pyrimidin-3-yl) ethyl) - 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (I x) (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, Z = N, A-B =, -CH₂-CH₂-)

4.00 g (11.7 mmol) of the compound E-Ik were dissolved in a mixture of 50 ml of methanol and 50 ml of ethyl acetate and, after adding 50 mg of palladium on carbon / 10%, and 50 μl of triethylamine, shaken in a hydrogen atmosphere until no H₂ more was recorded. The reaction solution was filtered through kieselguhr and evaporated. I x remained in the form of white crystals.
Yield: 3.93 g (98%)
Mp: 170-172 ° C
(CH₃OH): + 13 °
1 H-NMR: δ / ppm = 1.5-1.9 (m, 2 H), 1.9 (brs, 1 H), 2.6 (s, 3 H), 2.7 (s, 3 H), 2.6-3.0 (m, 2 H) ), 4.3 (m, 1 H), 4.5-4.6 (m, 1 H), 7.1-7.2 (m, 2 H), 7.4-7.5 (m, 2 H).

Example 12 b

Under the conditions given in Example 12 a, 1.0 g of the compound EI e (Example 11 e) was converted into the hydrogenation product I y (R¹ = iC₃H₇, R² = 4-FC₆H₄, R³ = C₆H₅, Z = CH, AB = -CH₂- CH₂) implemented.
Yield: 0.91 g (91%)
Mp: oil
(CH₃OH): + 26 °
1 H-NMR: δ / ppm = 1.3-1.8 (m, 11 H), 2.3-2.8 (m, 7 H), 3.4 (h, J = 7 Hz, 1 H), 4.2 (mc, 1 H), 4.5 (mc, 1 H), 7.1 (mc, 2 H), 7.3-7.5 (m, 6 H), 8.1 (mc, 2 H)
MS: m / e = 433 (M⁺)

Example 12 c

Under the conditions given in Example 12 a, 1.0 g of the compound EI t was reacted to the hydrogenation product I z (R¹ = C₂H₅, R² = 4-FC₆H₄, R³ = C₆H₅, Z = CH, AB = -CH₂-CH₂).
Yield: 0.93 g (93%)
Mp: 53-55 ° C
1 H-NMR: δ / ppm = 1.4 (mc, 6 H), 1.5-1.9 (m, 4 H), 2.5-2.9 (m, 4 H), 4.3 (mc, 1 H), 4.5 (mc, 1 H ), 7.1 (mc, 2 H), 7.3-7.5 (m, 6 H), 8.01 (mc, 2 H)
MS: m / e = 429 (M⁺)

In a manner analogous to that described in Example 12 the compounds of general formula I with A-B = CH = CH- Compounds of the general formula I with A-B = CH₂-CH₂- be hydrogenated.

Example 13

Preparation of the salts of the free dihydroxy acids general formula II  

Example 13 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, R⁴ = K, Z = CH, A-B = (E) -CH = CH-) (E) - and (Z) - (3R, 5S) -3,5-dihydroxy-7- (2,6-dimethyl-4- (4- fluorophenyl) pyridin-3-yl) -hept-6-enoic acid potassium salts E-II a and Z-II a (as a 30:70 mixture of Z and E isomer)

0.10 g (0.29 mmol) of compound I a was dissolved in 5 ml of ethanol. 2.9 ml (0.29 mmol) of a 0.1 molar solution of potassium hydroxide in ethanol were added to this solution at room temperature. The progress of the reaction was monitored by thin layer chromatography (mobile phase ethyl acetate / methanol 10: 1). After 3 hours there was no longer any starting material. The reaction solution was concentrated in vacuo. The potassium salt II a remained in the form of white crystals.
Yield: 0.11 g (96%) (30:70 mixture of Z-II a and E-II a)

The isomers were then separated by medium pressure liquid chromatography.
Z-II a: R _f value (ethyl acetate / methanol 2: 1): 0.23, IR: 1605/1575 cm ^-1 (C = O band)
E-II a: R _f value (ethyl acetate / methanol 2: 1): 0.19, IR: 1610/1580 cm ^-1 (C = O band)

Example 13 b-13 z

The compounds II b-II z were prepared in an analogous manner to that described in Example 13 a (cf. Table 14).

Example 14 General instructions for the preparation of carboxylic acid esters the free dihydroxy acids of the general formula II Example 14 a (R¹ = CH₃, R² = 4-FC₆H₄, R³ = CH₃, R⁴ = CH₃, Z = CH A-B = (E) -CH = CH-) E- (3R, 5S) -3,5-dihydroxy-7- (2,6-dimethyl-4- (4-fluorophenyl) pyridine- 3-yl) -hept-6-enoic acid methyl ester E-II ad

0.40 g (1.17 mmol) of the compound EI a (Example 11) were dissolved in 10 ml of methanol and 1.3 ml (0.13 mmol) of a 0.1 molar solution of sodium methanol in methanol were added at room temperature. After stirring for one hour - the conversion of the reaction was monitored by thin layer chromatography (mobile solvent: ethyl acetate) - the solvent was removed in vacuo. The residue was taken up in water, neutralized with acetic acid and etherified. The organic extracts were dried over magnesium sulfate and evaporated. This left 0.39 g (94%) of the title compound E-II ad.
1 H-NMR (extract): δ / ppm = 3.6 (s, 3 H)

In an analogous manner, as described in Example 14 a, can the methyl esters of the free dihydroxy acids of the general Formula II can be produced. If you replace methanol other alcohols (R⁴OH) are also corresponding other esters II (R⁴ = ethyl, iso-propyl, benzyl etc.) can be easily represented.

Claims (10)

1. 3-desmethyl-mevalonic acid derivatives of the formula I ( δ- lactone) or II (corresponding dihydroxycarboxylic acid derivative) in which A-legs are the radical of the formula -CH = CH- or -CH₂-CH₂- the radical of the formula -CH or a nitrogen atom R¹, R², R³ independently of one another are hydrogen
a saturated or unsaturated, straight-chain or branched hydrocarbon radical with up to 6 C atoms, which can optionally be substituted at the terminal carbon by a saturated or unsaturated, cyclic hydrocarbon radical with 3-6 C atoms,
a cyclic saturated or up to double unsaturated hydrocarbon radical with 3-7 C atoms, an aromatic radical selected from the group phenyl, furyl, thienyl, pyridinyl, which may optionally carry 1-3 identical or different substituents from the following groups:
Halogen, trifluoromethyl, alkyl or alkenyl, each with up to 6 carbon atoms, hydroxy, alkoxy with 1-6 carbon atoms, carboxy, carbalkoxy with 1-6 carbon atoms in the alkoxy part R⁴hydrogen, a straight-chain or branched, saturated or unsaturated hydrocarbon radical up to 5 carbon atoms, a benzyl radical, the core of which can be substituted 1-2 times with halogen or an alkyl radical with 1-4 carbon atoms, alkali metal or an ammonium ion NR⁵R⁶R⁷R⁸, where R⁵, R⁶, R⁷ and R⁸ are also different and mean :
Hydrogen, alkyl with 1-4 C atoms, hydroxyalkyl with 1-4 C atoms. 2. Compounds according to claim 1, characterized in that in formula I or formula II R¹ and R² independently of one another
a straight-chain or branched alkyl radical with 1-4 C atoms, a cycloalkyl radical with 3-6 C atoms, a cycloalkylmethyl or cycloalkenylmethyl radical with a ring size of 5-6 C atoms,
a phenyl radical which optionally carries 1-3 identical or different substituents from the groups halogen, trifluoromethyl, alkyl with 1-4 C atoms, hydroxy, alkoxy with 1-4 C atoms, carbalkoxy with 1-4 C atoms in the alkoxy part, mean R³hydrogen,
a straight-chain or branched alkyl or alkenyl radical with up to 6 C atoms, a cycloalkyl or alkenyl radical with 3-6 C atoms each,
a phenyl or pyridinyl radical, the aromatic radicals optionally 1-3 identical or different substituents from the groups halogen, alkyl with 1-4 C atoms, hydroxy, alkoxy with 1-4 C atoms or carbalkoxy with 1-4 C atoms wear in the alkoxyl part, represents R⁴hydrogen, methyl, ethyl, isopropyl, isobutyl, benzyl, sodium, potassium, ammonium (NH₄) or methyltris (hydroxymethyl) ammonium. 3. Compounds according to claim 1, characterized in that that in formula I or formula II R1 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, 4-trifluoromethyl R²methyl, 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, 4-trifluoromethyl R³hydrogen, methyl, isopropyl, tert-butyl, Cyclohexyl, phenyl, 4-fluorophenyl, 4-hydroxyphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl, 4-trifluoromethylphenyl R⁴hydrogen, methyl, ethyl, sodium, potassium, represents. 4. Compounds according to claim 1, characterized in that in Formula 1 or Formula II Zthe CH group or N R1 ethyl, isoprophyl, cyclopropyl R²4-fluorophenyl, 4-hydroxyphenyl  R³isopropyl, tert-butyl, cyclohexyl, phenyl, 4-fluorophenyl or 4-hydroxyphenyl and R represents sodium or potassium. 5. A process for the preparation of compounds of formula I and II, characterized in that

• a) the phosphonium salts of formula III wherein R1, R2, R3 and Z have the meaning given for the formula I and X = Cl, Br, I, with the chiral aldehyde of the formula IV, wherein R⁹ is a protective group stable against bases and weak acids, to a compound of formula V. wherein R¹, R², R³ and Z have the meaning given for formula I, R⁹ the meaning given for formula IV (and AB represents the (-CH = CH -) group),
• b) in a compound of the general formula V, the methyl acetal acid hydrolyzes to a lactol of the formula VI, wherein R¹, R², R³ and Z have the meaning given for formula I, R⁹ the meaning given for formula IV and AB represents the (-CH = CH -) group),
• c) the compound of the general formula VI oxidizes to a lactone of the formula VII, wherein R¹, R², R³ and Z to formula I, R⁹ have the meaning given for formula IV and AB represents the (-CH = CH -) group and
• d) in a compound of the general formula VII the protective group R⁹ splits off to a compound of the formula I in which R¹, R², R³ and Z have the meanings given for the formula I and AB represents the (-CH = CH -) group and
• e) optionally containing a compound of the general formula I in which AB represents a (-CH = CH -) group, hydrogenated to a compound of general formula I in which AB represents a (-CH₂-CH₂ -) group, wherein the hydrogenation can also take place in the compounds of the formula V, VI or VII to give corresponding compounds in which AB represents the (-CH = CH₂ -) group, and
• f) optionally converting a hydroxylactone of the formula I into the corresponding dihydroxy acid II or its salts or optionally representing the corresponding esters from the hydroxylactone I or the free hydroxy acid II.

6. Pharmaceutical preparation, characterized in that it contains a compound according to claim 1. 7. Use of compounds according to claim 1 for Prophylaxis and therapy of atherosclerosis and Hypercholesterolemia. 8. Compounds of formula V wherein R¹, R², R³, AB and Z have the meaning given for formula I, R⁹ for formula IV. 9. Compounds of formula VI wherein R¹, R², R³, AB and Z have the meaning given for formula I, R⁹ for formula IV. 10. Compounds of formula VII wherein R¹, R², R³, AB and Z have the meaning given for formula I, R⁹ for formula IV.