LU86012A1 - NOVEL NAPHTHALENIC COMPOUNDS, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS - Google Patents

Description

ß c i? - 1 -

The subject of the present invention is new naphthalene compounds and their preparation. The invention also includes the application of these compounds to inhibit cholesterol biosynthesis and lower blood cholesterol levels and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis, as well as pharmaceutical compositions containing these compounds.

The invention relates in particular to

compounds of formula I

^ / CH1

Xj \ / z T \ / (ï>.

i. ~ Jb 1 mrXa 3 1 in which R-j represents a C1_C3 alkyl group and Z Z represents a group of formula (a) or (b) CH-

V V

1 —ch-ch2-ch-ch2-coor7 Γ 1 ’\ /" 2 OH OH (a) \ c /

where Ry represents hydrogen, Rg or Μ, O

Rg signifying a residue forming an ester group: p h y s i o'Jticuement acceptable and hydrolysable and M s i g n i * 3 ° t a cation.

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The European patent application. No. Q117228A1 describes a broad class of mevalonolactone naphthalene analogs which can be used as lipid-lowering and anti-atherosclerotic agents. This document, however, makes no mention of the type of compounds of the present invention.

The expression "residue forming a physiologically acceptable and hydrolyzable ester group" means a residue which, with the group -C00-10 to which it is attached, forms an ester group which is physiologically acceptable and hydrolyzable under physiological conditions to give a compound of formula I in which Ry signifies hydrogen, and an alcohol which is itself physiologically acceptable, that is to say non-toxic at the doses administered.

It will be noted that each compound of formula I has two centers of asymmetry, namely in formula ^ i) the two carbon atoms substituted by a hydroxy group and in formula (b) 1 1 atom

of carbon substituted by the hydroxy group and the carbon atom having the free valence. There are therefore two stereoisomeric forms (enantiomers) of each compound (a racemic). The two stereo-25 isomers of the compounds of formula I in which Z

represents a group of formula (a), are the isomers 3R, 5S and 3S, 5R, and the two stereoisomers of the compounds of formula I in which Z represents a group of formula (b), are the isomers 4R, 6S and 30S , 6R. The invention includes both individual stereoisomers and racemates. When Ry contains one or more centers of asymmetry, there are four or more stereoisomers. Preferably - 3 -

Ry contains no center of asymmetry.

The preferred steroisomer of each compound of formula I in which Z signifies a group of formula (a) is the 3R, 5S isomer and the preferred stereoisomer 5 of each compound of formula I in which Z signifies a group of formula (b ) is the 4R, 6S isomer. These preferences also apply to compounds of formula I having more than two centers of asymmetry and represent the preferred configurations of the positions shown.

R.j preferably means a methyl or isopropyl group.

Ry preferably means Rÿ, that is to say hydrogen, a C 3 or M alkyl group, more particularly Rÿ, that is to say hydrogen, a C 1 - alkyl group C2 or M, and more particularly M, especially sodium. M preferably means M 'and more particularly sodium. Rg is preferably free of center of asymmetry and especially signifies Rg, that is to say a C alk | -Cg alkyl group, n-butyl, isobutyl, tert.-butyl or benzyl, more particularly a group C 1 -C 6 alkyl and very particularly a methyl or ethyl group.

M preferably means a pharmaceutically acceptable cation and in addition free of center of asymmetry, and more particularly M ', that is to say sodium, potassium or an ammonium group, and more especially sodium. For reasons of simplicity, M has been indicated as being mono valent.

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However, it can also be divalent or trivalent and, in this case, it compensates for the charge of two or three carboxy groups respectively.

M is preferably monovalent.

The preferred compounds of formula I in which Z signifies a group of formula fe) are those i) in which R ^ signifies Rÿ, ii) those of i) in which R ^ signifies Rÿ, iii) those of ii) in which R ^ signifies M, iv) those of iii) in which R ^ signifies M1, v) those of iv) in which R ^ signifies sodium, vi) - x) those of i) to v) in which R. | means a methyl or isopropyl group.

Groups i) - x) include the 3R, 5S-3S, 5R racemics and the 3R, 5S and 3S, 5R enantiomers, with the racemates and 3R, 5S enantiomers being preferred.

The preferred compounds of formula I in which Z signifies a group of formula (b) are those in which R-j signifies a methyl or isopropyl group. This group includes the racemates 4R, 6S-4S, 6R and the enantiomers 4R, 6S and 4S, 6R, the racemates and the enantiomers 4R, 6S being preferred.

According to the invention, the compounds of formula I can be prepared for example a) by stereoselective reduction of a compound of formula I in which Z signifies Z 'where Z1 signifies - 5 - in which Rg represents an ester-forming residue physiologically hydrolyzable and acceptable, b) by hydrolysis of a compound of formula I in the form of a physiologically hydrolysable ester or of lactone, or c) by esterification or lactonization of a compound of formula I in the form of free acid , and when a free carboxy group is present, recovery of the compound obtained in the form of free acid or in the form of a salt.

In process a), Rg preferably signifies a C 1 -C 4 alkyl, n-butyl, isobutyl, tert.-butyl or benzyl group, in particular a C 1 -C 4 alkyl group and more particularly a methyl or ethyl group.

It will be noted that the different forms of the compounds of formula I can be transformed into one another as indicated under b) and c) above. Likewise, the compounds obtained according to a) can be hydrolyzed to free acids and the free acids can be esterified or lactonized to give a desired final product. The invention therefore also relates to a process for the preparation of a compound of formula I, process according to which a compound of formula I is hydrolyzed in the form of an ester or lactone or a compound of formula is esterified or lactonized I in the form of free acid, and, when a free carboxy group is present, the compound obtained is recovered in the form of free acid or in the form of salt.

The methods can be carried out according to conventional methods.

- 6-- * ï

The fine products are obtained in the form of racemes which can be split in accordance with conventional methods.

When the preparation of the starting products is not described, these are known or can be obtained according to known methods or in a similar manner to the methods described in the present application.

Intermediate products and final products can be isolated and purified according to known methods.

The processes for the preparation of the intermediate and final products, separation of the isomers, isolation and purification as well as formation of the salts are carried out according to known methods, for example as described in the examples below or from in a manner analogous to the examples described below, or as described for example in European patent applications No. 0117228 or 0114027. These patent applications also describe other processes suitable for the preparation of intermediate products and end products.

The invention also includes the intermediates of Example 1 described below, steps! to 6 (compounds i) to vi)), and those corresponding to example 1 steps 2 to 6 having a 3'-C 1 alkyl group, - ^ instead of a 3'-methyl group, for example the compounds vii) and viii).

The -inooses of formula I have pharmacological activity and can therefore be used therapeutically as medicaments.

'S

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In particular, the compounds of formula I are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl “coenzyme A reductase (HMG-CoA reductase) and are therefore inhibitors of the bio-synthesis of cholesterol. The pharmacological activity of the compounds of formula I was demonstrated in the following tests:

Test A: In Vitro: Test on microsomes of T inhibition of HMG-CoA reductase, 1Q as described in European patent applications No. 0114027 or 0117228.

Test B: In Vitro: Test for biosynthesis of cholesterol in cell culture, as described in European patent applications 15 n 0 01 1 4027 or 01 1 7228.

Test C: In Vivo: Inhibition of the biosynthesis of cholesterol, as described in European patent applications No. 0114027 or 0117228.

Thanks to its properties, the compounds of formula I can therefore be used in therapy as lipid-lowering and anti-atherosclerotic agents.

For use in the treatment of hyperlipoproteinemia and atherosclerosis, the compounds of formula I will be administered at a daily dose of between about 1 and 1000 mg, preferably 1 to 150 mg, advantageously administered in divided doses a four times a day in unit doses, or in an extended-release form. For oral administration, unit doses may contain from 0.5 to 500 ng of active ingredient.

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The compounds of formula I can be administered in the form of free acid or in the form of a physiologically hydrolyzable and acceptable ester or of lactone, or of a pharmaceutically acceptable salt.

The present invention therefore therefore also relates to a compound of formula I in the form of free acid or in the form of a physiologically hydrolysable and acceptable ester or of a lactone, or of a pharmaceutically acceptable salt, for use as a medicament , for example as a lipid-lowering and anti-atherosclerotic agent.

The invention also includes a medicament comprising, as active principle, a compound of formula I in the form of free acid or in the form of a physiologically hydrolysable and acceptable ester or of lactone, or of a pharmaceutically acceptable salt .

As medicaments, the compounds of formula I are advantageously administered in the form of a pharmaceutical composition comprising a compound of formula I in the form of free acid or in the form of a physiologically hydrolyzable and acceptable ester or of lactone, or d 'a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent or vehicle and, optionally, other excipients. Such compositions, which are also part of the present invention, may be in the form of tablets, elixirs, capsules or suspensions intended for oral administration or in the form of solutions or injectable suspensions intended for parenteral administration. The preferred pharmaceutical compositions from the point of view of preparation and administration are solid compositions, in particular tablets and capsules with liquid or solid filling.

The following examples illustrate the present invention without in any way limiting its scope. The temperatures are indicated in degrees 10 Celsius.

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Example 1

Erythro- (E) -3,5-di hydroxy-7- [l'- (3 ", 5" -dimethylphenyl} -3'-methylnaphthyl-2 '] -6- ethyl heptenoate (compound n ° 1, R1 = CH3, Z = a, R? = C2H5)

Step 1 4,4-dimethyl-2- [1 '- (3 ", 5" -dimethylphenyl) naphthyl-2'] - 2-oxazoline (compound (i)) (a) Preparation of Grignard reagent: 10 SO g of 1-bromo-3,5-dimethylbenzene are added over the course of an hour, at a speed suitable for maintaining a moderate reflux, to 10.8 g of magnesium turnings and a trace of iodine in 545 ml of anhydrous tetra-bydrofuran (distilled over sodium) with stirring and under a nitrogen atmosphere, the reaction mixture being heated at the start to 40-45 ° to initiate the reaction. When the reaction is complete, the reaction mixture is heated at reflux for two hours under nitrogen and is then cooled to 20-25 °.

(B) The Grignard reagent solution obtained under (a) is added slowly over 45 minutes to 84.0 g of 4,4-dimethyl-2- (1'-methoxynaphthyl -2 ') - 2 -oxozoline in 500 ml of anhydrous tetrahydrofuran, with stirring at 45 °, under nitrogen and under cooling (the reaction being exothermic), The reaction mixture is stirred at 20-25 ° under nitrogen for sixteen hours and the reaction is stopped by adding a saturated solution of ammonium chloride. The mixture is extracted with ethyl acetate, the ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated under reduced pressure to a small volume. While stirring and cooling, diethyl ether and then petroleum ether are added. The resulting solid product is collected by filtration and dried under vacuum at 40 °, which gives a white crystalline product, melting at 97-100 °.

5 Step 2 4,4-dimethyl-2- [11 - (3 ", 5" -dimethylphenyl) -3'-methyl-naphthyl-2 '] - 2-oxazoline (compound ii)

To 108 g of compound i) in 1.8 liters of anhydrous diethyl ether with stirring at -5 °, 236.1 ml of 1.6M solution are added within 30 minutes.

of n-butyl 1ithium in hexane, the reaction mixture is stirred at -5 ° for one hour, added dropwise over 15 minutes with stirring at -5 ° 85.8 g of methyl iodide , the mixture is allowed to return to 20-25 ° and it is stirred for sixteen hours at 20-25 °, the reaction mixture being maintained under a nitrogen atmosphere throughout the operations. The reaction mixture is carefully poured into a mixture of a saturated solution of sodium chloride and ice and filtered to remove the insoluble products. The ethereal phase is separated, the aqueous phase is extracted with diethyl ether, the ethereal phases are combined, the overall solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure to a small volume. Petroleum ether is then added, the crystalline product is collected and dried under vacuum. The product melts at 153-156 °.

Step 3 2- 2- [r-f3 ", 5" -dimethylphenyl) -3'-methyl-naphthyl-2 '] - 3,4,4-trimethyl-2-oxazolini um (compound iii) to 129 g of compound ii) in 600 ml of nitromethane, 220 ml of methyl iodide are added, the reaction mixture is heated to 60 ° under a nitrogen atmosphere, it is stirred at 60 ° under a nitrogen atmosphere for hour and cooled to 30 °, period during which the product begins to cris-5 talliser. 1 liter of diethyl ether is added at 30 °, the mixture is stirred for 15-20 minutes, the product is collected by filtration, washed with diethyl ether and dried under vacuum at 45 °, which gives a crystalline product melting above 10 290 ° (with decomposition).

Step 4 1 - (3 i 5'-dimethylphenyl) -3-methyl-2-naphthaldehyde (compound iv) (a) At 150 g of compound iii) in 1.8 liters of anhydrous tetrahydrofuran (dried on molecular sieve) and 720 ml of absolute ethanol (dried on molecular sieve) 37 g of li-20 thium borohydride are added in portions over three hours with stirring between -15 and -5 ° and under a nitrogen atmosphere. The reaction mixture is stirred for two hours at -10 ° under a nitrogen atmosphere and a mixture of ice and saturated sodium chloride solution is added. The mixture is extracted with ethyl acetate, the ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated under reduced pressure to a small volume. By addition of diethyl ether and then petroleum ether, the oxazolidine is obtained in the form of a crystalline product melting at 151-155 °.

(B) 99 g of the product obtained under (a) in 1.8 liters of ethanol and 600 ml of tetrahydrofuran are added dropwise over 15 minutes, with stirring and at 15 °, 1, 5 liters of hydrochloric acid - 13 - at 9 2N and the reaction mixture is stirred for four hours at 20-25 °. Water is then added, the mixture is extracted with diethyl ether, the ethereal extract is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with petroleum ether and the product is dried under high vacuum at 20-25 °; M = 105-107 °.

Step 5 (E) -3- [l '- (3 ", 5" -dimethylphenyl) -3'-methylnaphthyl- 10 2'] - 2-propenal (compound v) (a) Preparation of cis-1-ethoxy- 2-tri-n-butyl-stannylethylene: 29.1 g of tri-n-butyltin hydride are added over the course of an hour, with stirring at 50 ° and under a nitrogen atmosphere, 7 g of ethoxyacetylene and the reaction mixture is heated for three hours at 50-55 ° under a nitrogen atmosphere and for one hour at 60-70 °.

(b) Preparation of cis-1-1ithium-2-ethoxy-ethylene: To 28.9 g of cis-1-ethoxy-2-tri-n-butylstanylethylene in 700 ml of anhydrous tetrahydrofuran, dropwise added drop in the course of 15 minutes, with stirring at -60 ° and under a nitrogen atmosphere, 50.14 ml of 1.6M solution of n-butyl lithium in hexane and the reaction mixture is stirred for one hour at 25 -60 ° under a nitrogen atmosphere, which gives a solution of ci s-1 -1ithium-2-ethoxyethylene.

(c) To the product obtained under (b), 20 g of compound iv) are added to 80 ml of anhydrous tetrahydrofuran and the reaction mixture is stirred for two hours at -60 ° under a nitrogen atmosphere. The reaction is stopped by carefully adding a saturated solution of ammonium chloride, the temperature of the mixture rising to 20-25 ° during the addition. The mixture is then extracted with ethyl acetate, the ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is distributed between 5 of acetonitrile and n-hexane, the acetonitrile phase is again extracted with n-hexane and evaporated to dryness under reduced pressure, which gives the intermediate enolic ether to raw.

(d) To 10 g of the enolic ether obtained under 10 (c), 400 ml of tetrahydrofuran, 100 ml of water and 1 g of p-thuene sulfonic acid monohydrate are added and the reaction mixture is stirred for sixteen hours at 20-25 °. 1.5 liters of water are then added and the mixture is extracted three times with ethyl acetate. The ethyl acetate extracts are combined, the overall solution is washed with a saturated sodium chloride solution, it is washed with 50 to 60 ml of a 10% sodium bicarbonate solution, it is washed with a saturated 2o sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is dried for five hours at 40 ° under high vacuum, which gives the product in the raw state in the form of a yellow oil.

25 Step 6 (Ε) -7- [Γ- (3 ", 5” -dimethylphenyl) -3'-methylnaphthyl-2 '] - 5-hydroxy-3-oxo-6-heptenoate (compound vi) ( a) To 13.4 g of diisopropylami ne in 360 ml of anhydrous tetrahydrofuran, 82.9 ml of 1.6M solution of n-butylithithium are added dropwise, with stirring at -5 ° and under a nitrogen atmosphere. in hexane and the reaction mixture is stirred for 15 minutes under the same conditions, giving a solution of the lithium salt of diisopropylamine.

(b) To the product obtained under (a), 8.6 g of ethyl acetoacetate is added dropwise, with stirring between -5 and 0 °, the reaction mixture is stirred for 1 hour between -5 and 0 °, it is cooled to -60 °, a solution of 12 g of the crude product v) is slowly added in 100 ml of anhydrous tetrahydrofuran, and the reaction mixture is stirred for two hours at -60 °, the reaction mixture being 10 maintained under a nitrogen atmosphere throughout the operations. The reaction mixture is slowly added to a saturated ammonium chloride solution and the mixture is extracted with ethyl acetate.

The ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give the crude product as an oil.

The product is a racemic which can be split into its 5R and 5S enantiomers.

20 Step 7

Erythro- (E) -3,5-dihydroxy-7- [l '- (3 ", 5" -dimethylphenyl) -3'-methylnaphthyl-2'] 6-ethyl heptenoate (compound 1) (a ) To 11.6 g of crude product vi) in 500 ml of anhydrous tetrahydrofuran (distilled over sodium) are added dropwise, with stirring at 20-25 ° and under a nitrogen atmosphere, 42 ml of IM solution of trië-thylborane in tetrahydrofuran. 200 ml of air are bubbled into the reaction mixture (at 760 mm Hg and at 25 °), the reaction mixture is stirred for one hour at 20-25 ° and cooled between -78 and -69 °. . 1.9 g of sodium borohydride are then added and the reaction mixture is stirred for sixteen hours under a nitrogen atmosphere and between -78 and -69 °. The mixture is heated to -20 ° and 150 ml of 2N hydrochloric acid are added dropwise over 15 minutes and with rapid stirring.

Water is then added, the mixture is extracted with ethyl ether, the ether extract 5 is dried over anhydrous sodium sulfate, it is evaporated to dryness under reduced pressure and 50 ml of isopropanol are added ( of reactive quality). The mixture is heated in an oil bath for about one minute (bath temperature = 100 °), it is allowed to cool, it is seeded with a crystal of product from a previous operation and it is left for sixteen hours in the refrigerator . The precipitate is collected by filtration, washed with cold isopropanol and dried under high vacuum, which gives 1 ‘cyclic boron ester, mp 80-81 °.

(b) Agitation is carried out for five hours at 20-25 ° 4.49 g of the cyclic boron ester obtained under (a) in 250 ml of methanol (of reagent quality).

The reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in ethyl ether, the ethereal solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the product (compound no. 1) as a light yellow oil.

NMR spectrum (CDCl ^): 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 (bn, 1H), 4.10 (bm, 1H), 4.15 (m, 1H), 4.20 (q, 2H (J = 1.5 Hz)), 30 4.35 (m, 1H), 5.45 (dd, 1H (J = 1.5 Hz and 2 Hz)), 6.50 (d, 1H (J = 3.5 Hz)), 6.35 (d, 2H), 7.0 (bs, 1H), 7.35 (m, 3H), 7.75 (m, 2H) - 17 -

This compound can also be prepared for example by reaction of compound n ° 4 with sodium or potassium ethylate for example in ethanol.

Example 2 5. Erythro- (E) -3,5-dihydroxy-7- [l '- (3 ", 5" -dimethylphenyl) - 3'-methylnaphthyl-2'1-6-heptenoate (compound n ° 2 R] = CH3, Z = a), R? = Na).

10 To 4.01 g of compound n ° 1 in 250 ml of absolute ethanol, dropwise is added over 15 minutes with stirring and at 0-5 °, 9.0 ml of IN hydroxide solution sodium. The reaction mixture is stirred for two hours, during which time the mixture is allowed to return to 20-25 °. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dried for two hours under high vacuum and dissolved in chloroform (of spectral quality).

The chloroform solution is dried over anhydrous sodium sulfate, concentrated under reduced pressure to a volume of 50 ml and, with cooling and stirring, anhydrous diethyl ether is added, the precipitate is collected by filtration, dried under nitrogen, washed with anhydrous diethyl ether and dried in vacuo to give the product; it melts above 230 ° (with decomposition). NHN spectrum (CDC13 + CD30D): 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 (J = 1.25 Hz 30 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) - 18 -

This compound can also be prepared by reaction of compound n ° 4 with NaOH IN,

Example 3

Aciderythro- (E) -3,5-di hydroxy-7- [1- (3 ", 5" -dimethyl -5 phenyl -3 '-methylnaphthyl-2') - 6-heptenoic Compound No. 3,

Rj = CH3, Z = a), Ry = H)

The product is prepared for example from compound No. 1 by reaction with NaOH then HCl.

Example 4 (E) -trans-6 - (21 - [1 "- (3" 1.5 "1-dimethyl phenyl) -3" -methylnaphthyl-2 "lethenyl) -4-hydroxy-3,4,5 , 6-tetra-hydro-2H-pyran-2-one (compound n ° 4, = CH ^, Z = b) The product is prepared for example by lactonization of compound n ° 3; F = 53-56 ° ( Cis / trans mixture 1: 5.7).

NMR spectrum (CDCl 4): 1.65 (m, 2H), 1.73 (m, 1H), 2.39 (s, 6H), 2.52 (s, 3H), 2.65 (m, 2H ),

4.02 (m, 1H), 5.12 (m, 1H), 5.45 (dd, 1H 20 (J = 1.25 Hz 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)

The starting material for the compounds of formula I in which R-j signifies an isopropyl group, can be prepared in a similar manner to steps 7 and 8 of Example 10 of European patent application No. 0117228.

Step 1 4,4-dimethyl-2- [1 1 - (3 ", 5" -dimethyl phenyl) - 3 '-methoxy-30 naphth, yl-2'] - 2-oxazol ine (compound no. Vii).

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Step 2 4,4-dimethyl -2-Π '- (3 ", 5" -dimethylphenyl) -3' - (1 "-methyl-ethyl) -naphthyl-2 '] -2-oxazoline (compound no. Viii) .

The compounds obtained in examples 1 to 4 5 may contain a small amount of threemic corresponding threo (Z = a)) or cis (Z = b)). This quantity can vary for example between 5 and 15% depending on the process used and the conditions under which it is operated. The two racemates can be separated from each other by conventional methods, and each can be split by conventional methods. The racemical ërythro gives the enantiomers 3R, 5S and 3S, 5R, and the racemical thrëo gives the enantiomers 3R, 5R and 3S, 5S.

In the examples, the expression "reduced pressure" indicates the pressure of the water pump. When no solvent is specified for a solution, the solvent is water and all mixtures of solvents are by volume. When a reaction is carried out under a nitrogen atmosphere, dry nitrogen was used to maintain the anhydrous conditions.

All NMR spectra were taken at room temperature on a 200 MHz spectrometer. All chemical shifts are given in p.p.m.

(£) relative to tettramethylsi 1ane and when a simple S value is given for something other than a narrow singlet, this is the central point. In the spectra R M N, the following abbreviations have been used: bm = large multiplet bs = large singlet 30 d = doublet dd = doublet of a doublet m = multiplet q = quartet s = singlet 35 t = triplet - 20 -

The starting materials can be obtained, for example, as described in European patent application No. 0117228, in particular examples 10 and 14 of this application.

Claims (9)

1. The compounds corresponding to the formula I 5 ÇH3 yCH3 / T \ / <i> ". it .C = C 10 1 in which R1 represents a C 1 -C 3 alkyl group and Z represents a group of formula (a) or (b) ch, 6 * "—CH-CH2-CH-CH2-COOR7 1 r, , \ / · * Oa oh (a), V '20 rt 1 (W, where R- represents hydrogen, Rg or M, "Rg signifying a residue forming a physiologically acceptable and hydrolysable ester group 25 and M signifying a cation. 2. Erythro- (E) -3,5-dihydroxy-7- [V- (3 ", 5" -dimethyl phenyl) -31-methyl naphthyl-2 ‘] - 6-heptenoic acid. 3. Jn compound according to claim 1 30 or 2, characterized in that it is in free form or in the form of ethyl ester or sodium salt. fat 1 - 22 -! 4. Process for the preparation of the compounds specified in claim 1, characterized in that a compound of formula I, as defined in claim 1, is hydrolyzed in the form of an ester or of lactone or an esterified or a lactonized com posed of formula I in the form of free acid, and, when a free carboxy group is present, the compound obtained is recovered in the form of free acid or in the form of salt. 5. Process for the preparation of the compounds specified in claim 1, characterized in that it comprises a) the stereoselective reduction of a compound of formula I in which Z signifies Z 'where 15. s 1 9n 1 f 1 e - CH-ChL-C-CFLCOORq, I 2 „2 9 c) OH 0 in which Rg represents a residue forming a physiologically hydrolysable and acceptable ester, b) hydrolysis of a compound of formula I in the form of physiologically hydrolyzable or lactone ester, or c) esterification or lactonization of a compound of formula I in the form of free acid, and when a free carboxy group is present, recovery of the compound obtained in the form of acid - free or salt. 6. A compound according to any one of claims 1 to 3, in the form of free acid or in the form of a physiologically hydrolyzable and acceptable ester or of lactone or of a pharmaceutically salt. t - 23 - acceptable, for use as a medicament. 7. A medicament, characterized in that it comprises, as active principle, a compound according to any one of claims 1 to 3, in the form of free acid or in the form of a physiologically hydrolyzable and acceptable ester or of lactone "Or a pharmaceutically acceptable salt. 8. A pharmaceutical composition, characterized in 1.0 that it comprises a compound according to any one of claims 1 to 3, in the form of free acid or in the form of a physiologically hydrolysable and acceptable ester or of lactone, or a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent or vehicle. 9. 4,4-Dimethyl-2- [l '- (3 ", 5" -dimethyl-phenyl) naphthyl-2'] - 2-oxazoline, 4,4-dimethyl-2- [1 '- ( 3 ", 5" -dimethylphenyl) -3'-methylnaphthyl -2 '] - 20 2-oxazoline, 2-C1' iodide - (3 ", 5" -dimethyl-phenyl) -3'-methyl-naphthyl-2 '] -3,4,4-trin] ethyl-2-oxazolinium, 1 - (3', 5'-dimethylphenyl) -3-methyl-2-naphthaldehyde, (E) -3-CT- (3 " , 5 "-dimethylphenyl) -3 '- methyl naphthyl- 2'] - 2-propenal, (E) -7- [V-25 (3", 5 "-dimethylphenyl) -3'-methylnaphthyl-2 '] -5-hydroxy-ethyl-3-oxo-6-heptenoate, 4,4-dimethyl-2- [1 '- (3 ", 5" -dimethylphenyl) -31-methoxynaphthyl-2'] - 2-oxazoline and 4,4-dimethyl-2- [Γ- (3 ", 5" -dimethyl-phenyl) -3 '- (1 "-methylethyl) -naphthyl-2'] - 2-oxazoline.