NL8502010A - Naphthylanalogalonolactone and its derivatives, processes for their preparation and pharmaceutical compositions containing them. - Google Patents

Description

- 1 - »', *

Naphthyl analogues of mevalonolactone and derivatives thereof, processes for their preparation and pharmaceutical preparations containing them.

This invention relates to compounds of formula 1, wherein

Rj represents an alkyl group of 1-3 carbon atoms and Z represents a group of formula la or lb, wherein R ^ represents a hydrogen atom, Rg or M, wherein R is a physiologically acceptable and hydrolysable ester-forming group and M is a cation proposes, methods for and intermediates in their synthesis and pharmaceutical preparations containing one or a number of compounds of the formula 1 and, on the use of the compounds of the formula 1 to inhibit the cholesterol biosynthesis and to lower the blood cholesterol mirror and therefore for the treatment of hyperlipoproteinemia and athero sclerosis.

Published European patent application 0117228A1 (hereinafter EP 117228) discloses a wide variety of naphthyl analogues of mevalonolactone as hypolipoproteinemic and anti-atherosclerotic agents, but no mention is made of the compound type of the present invention.

By the term "physiologically acceptable and hydrolyzable ester-forming group" is meant a group which, together with the -COO group to which it is attached, forms an ester group which is physiologically acceptable and hydrolysable under physiological conditions, thereby providing a compound of formula 1 is obtained, wherein R 1 represents a hydrogen atom and a.-¾ f · 4 * Λ

Ij u. 4-2 alcohol which is itself physiologically acceptable, ie non-toxic in the desired dosage range.

As will be appreciated by those skilled in the art, each compound of formula 1 (and each component and 5 species thereof) has two asymmetry centers (the two carbon atoms representing the hydroxyl groups in the group of formula la and the carbon atom representing the hydroxy group and the carbon free-valence atom in the group of formula Ib and therefore there are two stereoisomeric forms 10 (enantiomers) of each compound (racemate) The two stereoisomers of the compounds in which Z represents a group of formula la are the 3R, 5S and 3S, 5R isomers and the two stereoisomers of the compounds wherein Z is a group of formula Ib are the 4R, 6S and 4S, 6R isomers, with both the individual stereoisomers and the racemates being within the scope of this invention. If R ^ contains one or more centers of asymmetry, then there are four or more stereoisomers, since it is recommended that R ^ has no asynimetry center and, for the sake of simplicity, no attention will be paid to bases on any additional stereoisomers resulting from the presence of one or more centers of asymmetry in R1 are assumed to have no asymmetry centers.

The recommended stereoisomer of any compound in which Z represents a group of formula la is the 3R, 5S isomer and the recommended stereoisomer of any compound in which Z represents a. group of formula lb represents the 4R, 6S isomer. These preferences also apply to the compounds of formula 1 having more than two asymmetry-30 centers and represent the recommended configurations in the indicated locations.

R 1 preferably represents a methyl or iso-propyl group.

R ^ is preferably R ^ ', where R?' a hydrogen atom, an alkyl group with 1-3 carbon atoms or M, especially R ^ ", where R ^" is a hydrogen atom, an alkyl group containing 1 or 2 carbon atoms, or M represents, and in particular M is, especially sodium. M preferably represents M ', especially sodium.

Rg preferably does not contain asymmetry centers, especially as Rg1, wherein Rg1 is an alkyl group of 1-3 carbon atoms, an n-butyl, i-butyl, t-butyl or benzyl group, especially an alkyl group of 1-3 carbon atoms and in particular an alkyl group with 1 or 2 carbon atoms.

M is preferably a pharmaceutically acceptable cation and further contains no asymmetry centers and in particular is M ', i.e. sodium, potassium or ammonium and especially sodium. For the sake of simplicity, each of the formulas in which M exists (in the description and in the claims) is indicated as whether M is monovalent and preferably this is also the case. However, it can also be bivalent or trivalent and, if so, balances the charge of two or three carboxyl groups, respectively. The recommended compounds of formula 1 wherein Z represents a group of formula la are those (i) wherein R ^ is R ^ *, (ii) of (i) wherein R_ is R ", / 7 (iii) of (ii ) where R ^ is M, (iv) from (iii) where R? is M ', (v) from (iv) where R? is sodium and (vi) - (x) from (i) - (v) wherein R 1 represents the methyl or isopropyl group.

Groups (i) - (x) include the 3R, 5S-3S, 5R 30 racemates and the 3R, 5S, and 3S, 5R enantiomers, of which the racemates and the 3R, 5s enantiomers are recommended.

The recommended compounds of formula 1 wherein Z represents a group of formula 1b are those wherein R 1 represents a methyl or isopropyl group. This group 35 includes the 4R, 6S-4S, 6R racemates and the 4R, 6S and 4S, 6R

enantiomers, of which the racemates and the 4R, 6S enantiomers r r r * λ λ λ ‘i <tJ O tL Ü i li * - - 4 - are preferred.

For example, the compounds of formula 1 can be prepared by a) stereoselective reduction of a compound of formula 1, wherein Z = Z ', wherein Z' represents a group of formula lc, wherein R is a group that represents a physi logically hydrolyzable and acceptable ester, b) hydrolysis of a compound of formula 1 in the form of a physiologically hydrolysable ester or a lactone, or c) esterification or lactonization of an acidic compound of formula 1 in free X form, and, if a free carboxyl group is present, recovery of the compound thus obtained in a free acid form or in the form of a salt. In process a), Rg is preferably an alkyl group with 1-3 carbon atoms, n-butyl, i-butyl, t-butyl or benzyl group, especially an alkyl group with 1-3 carbon atoms, in particular an alkyl group with 1 or 2 carbon atoms.

It will be clear that the different forms of the compounds of formula 1 can be converted into each other, as can be seen from b) and c) above.

In the same manner, the compounds obtained according to a) can be hydrolyzed to the free acid forms and the free acid forms can be esterified or lactonized to a desired end product.

Thus, the invention also provides a process for preparing a compound of formula 1 which comprises the hydrolysis of a compound of formula 1 in an ester or lactone form or esterification or lactonization of a compound of formula 1 in free acid form and, if a free carboxyl group is present, recovering the compound obtained in a free acid form or in the form of a salt.

The methods can be carried out in a conventional manner.

The finished products are supplied as racemates

i] j A V V L · v i V

5, which can be separated in a usual manner.

Insofar as the preparation of the starting materials has not been described, they are known, or may be obtained analogously to methods described herein or to known methods.

The reaction products, both intermediates and end products, can be separated and purified in a conventional manner.

As mentioned above, the processes for preparing the end products and intermediates, for separating the isomers, for separating and purifying as well as for forming the salts can be carried out in a conventional manner, such as for example, is described in, or analogous to, the following examples, or as described, for example, in EP 117228 or 114027, EP 117228 and 114027, in which other processes suitable for preparing intermediates and final products are also found.

Also within the scope of the invention are the intermediates of Example 1, steps 1-6 (compounds i) to vi) and those corresponding to Example I, steps 2-6, replacing the 3'-methyl group by a 3 '- (C 2-8) alkyl group, for example the compounds vii) and viii).

The compounds of formula 1 have a pharmacological action, especially as competitive inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HKG-CoA) reductase and are therefore inhibitors of cholesterol biosynthesis, such as from the following tests show:

Test A: The in vitro microsomal test of the inhibition of HMG-CoA reductase, as described in EP 114027 or 117228.

Test B: The in vitro cell culture cholesterol biosyrithesis study, as described in EP 114027 or 117228.

'350 2 ü ί ü 4 y - 6 -

Test C: The in vivo cholesterol biosynthesis inhibition: as described in EP 114027 or 117228.

Thus, the compounds are indicated for use as hypolipoproteinemic and anti-atherosclerotic agents.

An indicated, appropriate, daily dose for use in the treatment of hyperlipoproteinemia and atherosclerosis is between about 1 to 1000 mg, suitably 1 to 150 mg, suitably administered in divided doses 1 to 4 times daily or in a slow-release form . A typical dosage unit for oral administration may contain 0.5 to 500 mg.

They can be administered both in a free acid form and in the form of a physiologically hydrolyzable and acceptable ester or a lactone thereof, or in a pharmaceutically acceptable salt form.

Therefore, the invention also relates to a method of treating hyperlipoproteinemia or atherosclerosis by administering one or a number of compounds of formula 1 in free acid form and / or in the form of a physiologically hydrolysable and acceptable ester or a lactone thereof, and / or in a pharmaceutically acceptable salt form, and to such compounds for use as pharmaceuticals, for example, as hypo-lipoproteinemic and anti-atherosclerotic agents.

The compounds may be administered alone or in admixture with a pharmaceutically acceptable diluent and / or carrier and, if desired, other excipients, and may be presented orally in forms such as tablets, elixirs, capsules or suspensions or parenterally in forms such as injectable solutions or suspensions.

The recommended pharmaceutical preparations from the viewpoint of ease of preparation and administration are solid preparations, in particular tablets and hard-filled or liquid-filled capsules.

Such preparations are also part of 8502010.k-7 - of the invention.

Example I

Ethyl erythro- (E) -3,5-dihydroxy-7- / 1 - (3 ", 5" -dimethylphenyl) -5 3'-methylnaphtho-2'-yl7hept-6-encate (comp. No. 1, R ^ = CH ^, Z = a), R? = C2H5)

Step 1 4,4-Dimethyl-2- / 11- (3 ", 5" -dimethylphenyl) naphth-2'-yl7-2-oxazoline (Compound (i)) 10 (a) Preparation of the Grignard Reagent:

80 g (0.432 mol) of 1-bromo-3,5-dimethylbenzene were added over 1 hour to 10.8 g (0.44 mol) of magnesium shavings and a trace of iodine in 545 ml of dry tetrahydrofuran (distilled over sodium). is stirred in a nitrogen atmosphere, adding at such a rate that the reaction mixture flows gently. Before starting the reaction, the reaction mixture is heated to a temperature between 40 and 45 ° C.

After the reaction, the reaction mixture was refluxed in a nitrogen atmosphere for 2 hours and then cooled to a temperature of 20-25 ° C.

(b) The solution of the Grignard reagent of part (a) of this step was added slowly over 45 minutes, in a nitrogen atmosphere and with cooling (the reaction is exothermic), to 84.0 g (0.329 mol) 4 , 4-dimethyl-2- (1'-methoxynaphth-2'-yl) -2-oxazoline, which was stirred at 45 ° C, in 500 ml dry tetrahydrofuran. The reaction mixture was then stirred in a nitrogen atmosphere at a temperature between 20 and 25 ° C for 16 hours and the reaction was quenched by adding a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the ethyl acetate extract was dried over anhydrous sodium sulfate and evaporated to a small volume under reduced pressure. Diethyl ether and then petroleum ether were added with cooling and stirring of the mixture. The solid products obtained became SS 2 O 2

t L

- filtered off and dried under reduced pressure at 40 ° C, whereby the white, crystalline product with a melting point of 97-100 ° C was obtained.

5 Step 2 4,4-Dimethyl-2- / 1 '- (3 ", 5" - dimethylphenyl) -3' -methylnaphth-2'-yl7-2-oxazoline (compound ii)

236.1 ml of a 1.6 M solution of n-butyl lithium in n-hexane 10 (0.377 mol) was added over 30 minutes to 108 g (0.33 mol) of compound i) in 1.8 ml anhydrous diethyl ether, which was stirred at -5 ° C, after which the reaction mixture was stirred at -5 ° C for 1 hour, while stirring at -5 ° C 85.8 g (0.60 mol) of methyl iodide was added for 15 minutes and the temperature of the reaction mixture was allowed to rise to 20-25 ° C and stirred for 16 hours at a temperature between 20 and 25 ° C, the reaction mixture being kept in a nitrogen atmosphere at all times. The reaction mixture was poured carefully onto a mixture. of saturated sodium chloride solution and ice and filtered to remove some insoluble material.

The diethyl ether phase was separated, the aqueous phase extracted with diethyl ether and the diethyl ether phases were combined, dried over anhydrous sodium sulfate and evaporated to a small volume under reduced pressure. Petroleum ether was added and the crystalline product was dried and dried under reduced pressure, mp: 153-156 ° C.

Step 3 2- / 1- '- (3 ", 5" -dimethylphenyl) -31-methylnaphth-2'-yl7-3,4,4-trimethyl-2-oxazolinium iodide (compound iii).

220 ml (3.53 mol) of methyl iodide were added to 129 g (0.376 mol) of compound ii). in 600 ml nitro-methane and heated the reaction mixture in a nitrogen atmosphere at 60 ° C, stirred the mixture atmosphere at 60 ° C for 1 hour and cooled to 30 ° C, making 8502 0 1 0 «- * 9 - product started to crystallize. Then 1 liter of diethyl ether was added at 30 ° C, the mixture was stirred for 15-20 minutes and the solid products were filtered off, washed with diethyl ether and dried under reduced pressure at 45 ° C to melt the crystalline product.

> 290 ° C (dec.).

Step 4 1- (3 ', 5'-dimethylphenyl) -3-methyl-2-naphthaldehyde 10 (compound iv) (a) 37 g (1.7 mol) of lithium borohydride were added in portions to 150 g ( 0.3 mol) compound iii) in 1.8 liters of dry tetrahydrofuran (dried over molecular sieves) and 720 ml of absolute ethanol (dried over molecular sieves) in a nitrogen atmosphere at a temperature between -15 and -5 ° C was stirred. The reaction mixture was stirred in a nitrogen atmosphere at -10 ° C for 2 hours and a mixture of ice and a saturated sodium chloride solution was added. The mixture was extracted with ethyl acetate, the ethyl acetate extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to a small volume, to which crystalline oxazolidine was added by adding diethyl ether followed by petroleum ether, melting point: 151-156 ° C.

(b) 1.5 liters of 2 N hydrochloric acid (3 mol) were added dropwise over 15 minutes to 99 g (0.275 mol) of the product of part (a) of this step in 1.8 liters of ethanol and 600 ml of tetrahydrofuran, stirred at 15 ° C and 30 the reaction mixture was stirred at a temperature between 20 and 25 ° C for 4 hours. Water was then added and the mixture of diethyl ether extracted. The diethyl ether extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure, and the residue was treated with petroleum ether to give the product which was dried under high vacuum at a temperature of 8502010 ° C at 20 and 25 ° C. Melting point: 105-107 ° C.

Step 5 (E) -3- / Ï '- (3 ”, 5” -Dimethylphenyl) -3'-methylnaphth-2'-yl / prop-2-enal (compound v) 5 (a) Preparation of cis-1 ethoxy-2-tri-n-butyl stannylethylene.

7.0 g (0.1 mole) of ethoxyacetylene was added over 1 hour to 29.1 g (0.1 mole) of tri-n-butyltin hydride, which was stirred in a nitrogen atmosphere at 50 ° C and then heated the reaction mixture for 3 hours at a temperature between 50 and 55 ° C and 1 hour at a temperature between 60 and 70 ° C in a nitrogen atmosphere.

(b) Preparation of cis-1-lithium-2-ethoxyethylene.

50.14 ml of a 1.6 M solution of n-butyl lithium in n-hexane (0.082 mol) was added dropwise to 28.9 g (0.08 mol) cis-1-ethoxy-2-tri for 15 minutes -n-butyl stannous ethylene in 700 ml of dry tetrahydrofuran, which were stirred in a nitrogen atmosphere at -60 ° C and then stirred the reaction mixture obtained for 1 hour in a nitrogen atmosphere at -60 ° C to give a solution of cis- 1-lithium-2-ethoxyethylene was obtained.

(c) 20.0 g (0.073 mol) of compound iv) in 80 ml of dry tetrahydrofuran were added to the product of 25 part (b) of this step and then the reaction mixture was stirred in a nitrogen atmosphere at 60 ° C for 2 hours and gently quench the reaction with a saturated ammonium chloride solution. (During the addition, the temperature rose to 20-25 ° C). The mixture was extracted with ethyl acetate and the ethyl acetate extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was partitioned between acetonitrile and n-hexane and the acetonitrile layer was extracted again with n-hexane and evaporated to dryness under reduced pressure to obtain the crude enol ether intermediate.

Cd) 400 ml of tetrahydrofuran, 100 ml of 8502010 - 11-vater and 1 g of p-toluenesulfonic acid were added. Add HjO to 10 g of the enol ether product from part (c) of this step and stir the reaction mixture at a temperature between 20 and 25 ° C for 16 hours. Then 1.5 liters of water were added and the mixture was extracted 3 times with ethyl acetate. The ethyl acetate extracts were combined, washed with a saturated sodium chloride solution and washed with 50-60 ml of a 10% sodium too carbonate solution, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

The residue was dried under high vacuum at 40 ° C for 5 hours to give the crude product as a yellow oil.

Step 6 Ethyl (E) -7- / yl 7-5-hydroxy-3-oxohept-6-enoate (compound vi) (a) 82.9 ml of a 1.6 M solution of n-butyl lithium was instilled in n.hexane (0.133 mol) to 13.4 g (0.133 mol) dilsopropylamine in 360 ml dry

20 tetrahydrofuran which is in a nitrogen atmosphere at -5 ° C

were stirred and then the reaction mixture was stirred under the same conditions for 15 minutes to give a solution of lithium diisopropylamide.

(b) 8.6 g (0.066 mol) of ethyl acetoacetate was added dropwise to the product of part (a) of this step which was stirred at a temperature between -5 and 0 ° C, the mixture was stirred for 1 hour at temperature between -5 and 0 ° C and cooled to -60 ° C. Then a solution of 12 g of the crude compound v) in 100 ml of dry tetrahydrofuran was slowly added and the mixture was stirred at -60 ° C for 2 hours, the reaction mixture being kept in a nitrogen atmosphere. The reaction mixture was slowly added to a saturated ammonium chloride solution and the mixture was extracted with ethyl acetate.

The ethyl acetate extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure,

3 5 δ 2 0 5 C

- 12 - whereby the crude product is obtained as an oil.

The product is a racemate and can be cleaved into the 5R and 5S enantiomers.

5 Step 7

Ethyl erythro- (E) -3,5-dihydroxy-7- / 1 '- (3', 5'-dimethylphenyl) -31-methylnaphth-21-yl / hept-6-enoate (Compound No. 1).

(a) 42 d were dropped. 1M triethyl borane in tetrahydrofuran (42 mole) to 11.6 g (27 mole) of the crude compound vi) in 500 ml dry tetrahydrofuran

(distilled over sodium), which was stirred in a nitrogen atmosphere at a temperature between 20 and 25 ° C, bubbled in 200 ml of air (at 760 mm Hg and 25 ° C) and stirred the reaction mixture for 1 hour at a temperature between 20 and 25 ° C 15 and finally cooled to a temperature between -78 ° C

and -69 ° C. Then, 1.9 g (50 mole) of sodium borohydride were added and the reaction mixture was stirred in a nitrogen atmosphere at a temperature between -78 ° C and -69 ° C for 16 hours. The reaction mixture was heated to -20 ° C and 150 ml of 2N hydrochloric acid was added dropwise for 15 minutes with vigorous stirring. Water was added and the mixture was extracted with diethyl ether. The diethyl ether extract was dried over anhydrous sodium sulfate and under reduced pressure. evaporated to dryness, after which 50 ml of isopropanol (reagent-grade) was added. The mixture was heated in an oil bath (bath temperature 100 ° C) for about 1 minute, after which it was cooled and seeded with one crystal of the product (obtained from a previous batch) and cooled in a refrigerator for 16 hours. The precipitate was filtered off, washed with cold isopropanol and dried under high vacuum to give the cyclic ethyl boron ester, mp: 80-81 ° C.

(b) 4.49 g (9.5 mMol) of the cyclic ethyl boron ester product of part (a) of this step was stirred in 250 ml of methanol (reagent quality) for 5 hours at a temperature between 20 and 25 ° C. The reaction mixture was then evaporated to dryness under reduced pressure, the residue obtained was dissolved in diethyl ether. and the diethyl ether solution was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the product (compound 1) as an oil slightly yellow.

N.M.R. (CDCl3): 1.30 (t, 3H (J = 1.5 Hz)), 1.45 (m, 2H), 2.35 (s, 6H), 2.42 (m, 2H), 2, 50 (s, 3H), 3.65 (bm, 1H), 4.10 (bm, 1H), 4.15 (m, 1H), 10 4.20 (q, 2H (J = 1.5 Hz) ), 4.35 (m, 1H), 5.45 (dd, 1H (J - 1.5 Hz and 2 Hz)), 6.50 (d, 1H (J = 3.5 Hz)), 6, 85 (d, 2H), 7.0 (bs, 1H), 7.35 (m, 3H), 7.75 (m, 2H).

This compound can also be prepared by, for example, reaction of compound No. 4 with sodium or potassium ethoxide in, for example, ethanol.

Example II

Sodium erythro- (E) -3,5-dihydroxy-7 - / ”1 '- (3", 5 "-dimethyl-' 20 phenyl) -3 '-inethylnaphth-2' -yl_7hept-6-enoate (compound no. .

2, R ^ = CH ^, Z = a), R? = sodium).

9.0 ml of a 1N sodium hydroxide solution (9 mMol) was added dropwise over 15 minutes to 4.01 g (9.3 mMol) of compound No. 1 in 250 ml of absolute ethanol, stirred at a temperature between 0 and 5 ° C. The reaction mixture was then stirred for 2 hours, the temperature of the reaction mixture being allowed to rise to 20-25 ° C. The reaction mixture was evaporated to another vacuum and the residue was dried under high vacuum for 2 hours and dissolved in chloroform (spectral quality). The chloroform solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure to a volume of 50 ml, and anhydrous diethyl ether added under cooling and stirring. The precipitate was filtered off, dried in a nitrogen atmosphere, washed with anhydrous diethyl ether and dried under reduced pressure to give the following product, m.p. > 230 ° C (dec.).

N.M.R. (CDC13 + CD3OD): 1.3 (m, 2H), 2.25 (m, 2H), 2.35 (s, 6H), 2.52 (s, 3h), 4.01 (m, 1H ), 4.28 (m, 1H), 5.45 (dd, 1H (J1 = 1.25 Hz. And 2.0 Hz.)), 6.45 (d, 1H (J = 3.5 Hz.)), 6.85 (d, 2H), 7.0 (s, 1H), 7.34 (m, 3H), 7.70 (m, 2h). This compound can also be obtained by reaction of compound No. 4 with 1N sodium hydroxide.

Example III

Erythro- (E) -3,5-dihydroxy-7- / 1 '- (3 ", 5" -dimethylphenyl) -15 31-methylnaphth-21-yl 7bept-6-enoic acid (compound no. 3, R1 = CH3 , Z = a), R? = H).

For example, prepared from compound No. 1 by reaction with sodium hydroxide followed by HCl.

Example IV

(E) -Trans-6- (21- / 1 "- (31'1.51" - dimethylphenyl) -3 "-methyl-naphth-2" -yl-7ethenyl) -4-hydroxy-3,4,5, 6-tetrahydro-2H-pyran-2-one (compound No. 4, R 3 = CH 3, Z = b) prepared, for example, by lactonization of compound No. 3, melting point: 53-56 ° C, (trans-cis - mixture, 5.7: 1).

N.M.R. (CDCl3): 1.65 (m, 2H), 1.73 (m, 1H), 2.39 (s, 6H), 2.52 (s, 3H), 2.65 (m, 2H), 4 0.02 (m, 1H), 5.12 (m, 1H), 5.45 (dd, 1H (J = 1.25 Hz).

30 and 2 Hz.)), 6.55 (d, 1H (J = 3.25 Hz.)), 6.85 (m, 2H), 7.05 (s, 1H), 7.37 (m, 3H), 7.75 (m, 2H).

For example, the starting material for the compounds of formula 1, wherein R 1 represents the isopropyl group, may be prepared analogously to steps 7 and 8502010-15-8 of Example 10 of EP 117228.

Step 1 4.4-Dimethyl-1-2- / 1 '- (3 ", 5" -dimethylphenyl) -3'-methoxy-naphth-2'-yl 7-2-oxazoline (compound no. Vii).

Step 2 4.4-Dimethyl-2- / 1 (3 ", 5" -dimethylphenyl) -3 "- (1-methyl-ethyl) -naphth-21-yl / -2-oxazoline (Compound No. viii).

The compounds used in Examples I-IV

may contain a small amount of the corresponding threo (Z = a)) or cis (Z = b) racing water. This can vary, depending on the method used and the conditions used, for example from 15 to 15%. The two racemates can be separated by conventional methods and each can be split in a conventional manner. The erythro racemate provides the 3R, 5S and 3S, 5R enantiomers and the threo racemate provides the 3R, 5R and 3S, 5S enantiomers. In the examples, the term "reduced pressure" designates suction pressure. If no solvent is reported in connection with a solution, this is water and all solvent mixtures are by volume. When a reaction is carried out in a nitrogen atmosphere, dry nitrogen is used to maintain anhydrous conditions.

All nuclear magnetic resonance spectra were taken at room temperature with a 200 MHz spectrometer. All chemical shifts are expressed in ppm. (6) 30 relative to tetramethylsilane and if a single δ value for anything other than a sharp singlet is indicated it is the center point. In the N.M.R. values: bm = wide multiplet bs = wide singlet 35 d = doublet dd = doublet of a doublet 8502010 - 16 - m = multiplet q = quartet s = singlet t = triplet 5

The starting materials can be obtained, for example, in the manner described in EP 117228, in particular examples 14 and 10 thereof.

10 8502 O 1 0

Claims (9)

1. Compounds of formula 1, wherein R ^ represents an alkyl group of 1-3 carbon atoms and Z represents a group of formula la or 1b, wherein R ^ represents a hydrogen atom, Rg or M, wherein Rg represents a physiologically acceptable and hydrolysable ester-forming group and M represents a cation. Compounds according to claim 1, wherein if R ^ = Μ, M is a pharmaceutically acceptable cation. 3. Erythro (E) -3,5-dihydroxy-7- / 1- (3 ", 5" -15-dimethylphenyl) dimethylphenyl) -3'-methylnaphth-2'-yl / hept-6-enoate. Compounds according to claims 1, 2 or 3 in free form or in the form of the ethyl ester or the sodium salt thereof. 20 5s. Pharmaceutical composition containing one or more compounds according to claims 1 or 2, optionally together with a pharmaceutically acceptable diluent and / or carrier therefor. A compound according to any one of the preceding claims for use as a pharmaceutical. A method for inhibiting the biosynthesis of cholesterol and treating atherosclerosis, characterized in that a pharmaceutical preparation according to claim 5 is used for this. A process for preparing an aromatic compound, characterized in that a compound according to claim 1 is prepared by hydrolyzing a compound of formula 1 in ester or lactone form or esterifying or compounding a compound of formula 1 in free form Lactonize and, if a free carboxyl group is present, the compound obtained in a free acid form or in the form of a salt to be recovered. 9. Process for preparing an aromatic compound, characterized in that a compound according to claim 1 is prepared by a) a compound of formula 1, wherein Z = Z ', wherein Z' represents a group of formula 1c, wherein R is a group having a physiologically hydrolyzable and Y-acceptable ester. stereoselectively reducing, b) hydrolyzing a compound of formula 1 in the form of a physiologically hydrolysable ester or a lactone, or c) esterifying or lactonizing a compound of formula 1 in free acid form and, if a free carboxyl group is present, to recover the compound obtained in a free acid form or in the form of a salt. 10. The compounds designated (i) - (viii), as previously identified. 11. Methods as described in the description and / or examples. 5 03Ö2 010