FR2568248A1 - NOVEL NAPHTHALENIC COMPOUNDS, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES - Google Patents

Abstract

THE INVENTION CONCERNS COMPOUNDS RESPONDING TO FORMULA I: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS AN ALKYL IN CC AND Z REPRESENTS A GROUP OF FORMULA A OR B (CF DRAWING IN BOPI) OR R REPRESENTS HYDROGEN, R OR M, R MEANING A REMAINDER FORMING A PHYSIOLOGICALLY ACCEPTABLE AND HYDROLYSABLE ESTER GROUP AND M MEANING A CATION. THESE COMPOUNDS MAY BE USED AS MEDICINAL PRODUCTS, IN PARTICULAR FOR THE TREATMENT OF HYPERLIPOPROTEINEMIA AND ATHEROSCLEROSIS.

Description

The object of the present invention is to

  new naphthalenic compounds and their preparation

  tion. 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 the compounds of formula I CH3

H Z

  <15 ic = CX (I), wherein R1 represents a C1-C3 alkyl group and Z represents a group of formula (a) or (b)

-CH-CH2-CH-CH2-COOR7 / H2

  ## STR2 ## wherein R 7 represents hydrogen, R 8 or M, wherein R 8 signifies a radical forming a physiologically acceptable and hydrolysable ester group;

and M means (ends a cation.

  European Patent Application No. 0117228A1 discloses a broad class of naphthalenic analogs

  mevalonolactone, which can be used as hypo-

  lipoproteinemic and anti-atherosclerotic. This document

  However, no mention is made of the type of

of the present invention.

  By the expression "radical forming a physiologically acceptable and hydrolysable ester group",

  we mean a remnant which, together with the group -COO-

  to which it is attached forms an ester group which is physiologically acceptable and hydrolysable under

  physiological conditions to give a composition

  wherein R7 is hydrogen;

  gene, and an alcohol that is itself physiological-

  acceptable, that is to say non-toxic at the doses administered. It should be noted that each compound of formula I comprises two centers of asymmetry, namely in the formula) the two carbon atoms substituted by a hydroxyl group and in formula (b) the atom

  of carbon substituted by the hydroxy group and the ato-

  me of carbon having valence free. There are therefore two stereoisomeric forms (enantiomers)

  of each compound (a racemic). Both stereo-

  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

  compounds of formula I in which Z represents a group of formula O), are the 4R, 6S isomers and

  4S, 6R. The invention also includes the stereo-

  individual isomers than racemates. When R7 contains one or more centers of asymmetry, there are four or more stereoisomers. Preferably 3-

  R7 contains no center of asymmetry.

  The preferred stereoisomer of each compound of formula I wherein Z is a group of formula (a) is the 3R, 5S isomer and the preferred stereoisomer of each compound of formula I wherein Z is a group of formula (b) is isomer 4R, 6S. These preferences also apply to

  compounds of formula I having more than two

  very asymmetrical and represent the configurations

  preferred positions.

  R1 is preferably methyl or isopropyl.

  R7 preferably means R, i.e.

  gene, a C 1 -C 3 alkyl group or M, more particularly

  especially R7, that is to say hydrogen, a

  C 1 -C 2 alkyl group or M, and more particularly

  M, especially sodium. M means of

  preferably M 'and more particularly sodium.

  R8 is preferably asymmetrically free and especially R8, i.e., C1-C3 alkyl, n-butyl, isobutyl, tert-butyl or benzyl, more preferably C1-alkyl. -C3 and especially

a methyl or ethyl group.

  M preferably means a pharmaceutically acceptable cation and additionally free from asymmetric center, and more particularly M ', that is to say sodium, potassium or an ammonium group, and more especially sodium. For reasons of

  simplicity, M was indicated as mono-

  worth. 4 - However, it can also be divalent or trivalent and, in this case, it compensates the load

  respectively two or three carboxy groups.

M is preferably monovalent.

  Preferred compounds of formula I 'wherein Z is a group of formula O are those wherein R7 is R, ii) those of i) wherein R is R', R7 if iii) those of ii) in which R7 is M, iv) those of (iii) where R7 is M ', v) those of (iv) where R7 is sodium,

  vi) - x) those of i) to v) in which Rl signifies

  a methyl or isopropyl group.

  Groups i) - x) include racemes

  3R, 5S-3S, 5R and the enantiomers 3R, 5S and 3S, 5R, the racemates and enantiomers 3R, 5S

being preferred.

  The preferred compounds of formula I wherein Z is a group of formula ") are those wherein R 1 is methyl or isopropyl This group includes 4R, 6S-4S, 6R racemates and 4R, 6S and 4S, 6R enantiomers , the racemates and enantiomers 4R, 6S being

preferred.

  In accordance with the invention, the compounds of formula I can be prepared for example a) by stereoselective reduction of a compound of formula I wherein Z signifies Z 'o Z' signifies -5-

  in which Rg represents a strong remainder

  a physiologically hydrolysed ester

  and b) by hydrolysis of a compound of formula I as a physiologically hydrolysable ester or lactone, or

  (c) by esterification or lactonisation of a

  of formula I in free acid form, and when a free carboxy group is present, recovery of the compound obtained in the form of acid

free or in the form of a salt.

  In method a), R9 preferably means

  C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl or benzyl, especially C 1 -C 3 alkyl and more particularly

methyl or ethyl.

  It should be noted that the different forms of the compounds of formula I can be converted into one another as indicated under b) and c) above. Similarly, 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 relates to a method of pre-

  partion of a compound of formula I, wherein a compound of formula I is hydrolyzed to an ester or lactone form or esterified or

  lactonise a compound of formula I in the form of

  free, 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.

  Drocedés can be done according to

classical methods.

  - 6 - The final products are obtained in the form of

  which can be split according to the methods

classics.

  When the preparation of the products of

  are not known, these are known or can be obtained according to the known methods or in a similar way to the processes described in

this request.

  Intermediate products and products

  final products can be isolated and purified

known methods.

  Product preparation processes

  intermediates and final products, separa-

  isomers, isolation and purification as well as salt formation, are carried out

  according to known methods, for example as de-

  written in the following examples or analogously to the examples described below, or as described for example in European Patent Applications No. 0117228 or 0114027. These applications for

  patents also describe other methods

  proprieties for the preparation of intermediate products

products and final products.

  The invention also includes the intermediates of Example 1 described below,

  steps 1 to 6 (compounds i) to vi)), and those corresponding to

  in Example 1, Steps 2 to 6 having a 3'-C 1 -C 3 alkyl group in place of a 3'-methyl group,

  for example, compounds vii and viii).

  The compounds of formula I possess a phariacological activity and can therefore

  to be used therapeutically as drugs.

  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-

  cholesterol synthesis. The pharmacological activity of the compounds of formula I was demonstrated in the following tests: Test A: In Vitro: Microsomal Inhibition Test of HMG-CoA reductase, as described in the patent applications

No. 0114027 or 0117228.

  Test B: In Vitro: Biosynthesis Test of Choles-

  terol in cell culture, as described in European patent applications

0114027 or 0117228.

  Test C: In Vivo: Inhibition of cholesterol biosynthesis, as described in European Patent Applications No. 0114027

or 0117228.

  Thanks to its properties, the compounds of

  formula I can therefore be used in

  as hypolipoproteinemic and anti-

  atherosclerosis. For use in the treatment of

  hyperlipoproteinemia and atherosclerosis, it is recommended that

  The compounds of the formula I will be at a dose

  tidienne between about 1 and 1000 mg, preferably 1 to 150 mg, advantageously administered in divided doses one to four times daily as unit doses, or in an orolongated release form. For oral administration, unit doses may contain

from 0.5 to 500 mg of active ingredient.

  The compounds of formula I may be administered in free acid form or in the form of

  of a physiologically hydrolysable ester and

  table or lactone, or a pharmaceutically acceptable salt.

  The present invention therefore

  also a compound of Formula I in form

  of free acid or in the form of a physiological ester

  and a lactone, or a pharmaceutically acceptable salt, for use as a medicament, for example as a hypolipoproteinemic and anti-atherosclerotic agent.

  The invention also includes a medicament

  including, as an active ingredient, a compound

  of formula I in free acid form or in the form of a physiologically hydrolyzable ester and

  or lactone, or a pharmaceutically acceptable salt

just acceptable.

  As drugs, the compounds of

  Formula I are advantageously administered under

  of a pharmaceutical composition comprising a compound of formula I in the form of a free acid or in the form of a physiologically acceptable and hydrolysable ester or of a lactone, or of a pharmaceutically acceptable salt, in

  combination with a diluent or pharmaceutical vehicle

  acceptable, and possibly others

  excipients. Such compositions, which also make

  Part of the present invention may be in the form of tablets, elixirs,

  capsules or suspensions for the administration

  orally or in the form of solutions g-

  or injectable suspensions intended for administration

  parenteral administration. The preferred pharmaceutical compositions from the point of view of

  preparation and administration are the

  solid formulations, in particular tablets and

  capsules with liquid or solid filling.

  The following examples illustrate the

  invention without in any way limiting its

  ted. Temperatures are given in degrees

Celsius.

- 10 -

Example 1

  Erythro- (E) -3,5-dihydroxy-7- [1 '- (3 ", 5" -diméthylphénylY-

  Ethyl 3'-methylnaphthyl-2 '] - 6-heptenoate (Compound No. 1, R1 = CH3, Z = a, R7 = C2H5) Step 1

  4,4-dimethyl-2-El '- (3 ", 5" dimethylphenyl) naphthyl-2'] -

  2-oxazoline (Compound (i)) (a) Preparation of Grignard reagent: 80 g of 1-bromo-3,5-dimethylbenzene are added over one hour at a rate appropriate to maintain moderate reflux at 10.8 g turns of

  magnesium and a trace of iodine in 545 ml of tetra-

  anhydrous hydrofuran (distilled over sodium) with stirring under a nitrogen atmosphere, the reaction mixture being initially heated to 40 ° C. to initiate the reaction. The reaction

  the reaction mixture is heated with

  flow for two hours under nitrogen and is then

cooled to 20-25.

  (b) The solution of the Grignard reagent ob-

  clothes (a) is added slowly in the space of 45

  minutes to 84.0 g of 4,4-dimethyl-2- (1-methoxynaphthyl)

  2 ') - 2-oxozoline in 500 ml of tetrahydrofuranhydride,

  under stirring at 45, under nitrogen and under

  (The reaction being exothermic), the reaction mixture is stirred at 20-25 under nitrogen for sixteen hours and the reaction is interrupted by

  addition of a saturated solution of ammonium chloride

  minium. The mixture is extracted with ethyl acetate, the ethyl acetate extract is dried over anhydrous sodium sulphate and evaporated under reduced pressure.

  to a small volume. While waving and

  cooler, diethyl ether is added and then

- 1l -

  petroleum ether. The resulting solid product is collected by filtration and dried under vacuum at room temperature.

   , which gives a white crystalline product,

at 97-100 Step 2

  4,4-dimethyl-2- [l '- (3 ", 5" dimethylphenyl) -3'-methyl-

  naphthyl-2 '] - 2-oxazoline (compound ii) To 108 g of compound i) in 1.8 liter of anhydrous diethyl ether with stirring at -5, 236.1 ml of 1.6M solution

  of n-butyllithium in hexane, the mixture is stirred

  reaction at -5 for one hour, add

  dropwise in 15 minutes under stirring.

  At 85.8 g of methyl iodide, the mixture was allowed to warm to 2025 and stirred for 16 hours at 20-25, the reaction mixture being maintained under nitrogen from one end to the other. other operations. The reaction mixture is cautiously poured into a mixture of saturated sodium chloride and ice solution and filtered to remove insoluble products. The ether phase is separated off, the aqueous phase is extracted with diethyl ether, the ethereal phases are combined, the overall solution is dried over anhydrous sodium sulphate and evaporated under reduced pressure to a small volume. Petroleum ether is then added, the crystalline product is collected and dried in vacuo. The product melts at 153-156 Step 3

  2- [1 - <3 ", 5" -dimethylphenyl) -3'-methyl-iodide

  2-naphthyl-3,4,4-trimethyl-2-oxazolinium (compound iii) To 19 g of compound ii) in 600 ml of nitromethane is added 220 ml of methyl iodide,

- 12 -

  the reaction mixture is heated to 60 under atmospheric pressure.

  nitrogen, it is stirred at 60 under an atmosphere of

  zote for one hour and cool to 30,

  period during which the product begins to

  talliser. To 30 liters of diethyl ether is added, the mixture is stirred for 15-20 minutes, the product is collected by filtration, washed with diethyl ether and dried in vacuo at 45 to give a crystalline product. melting above

290 (with decomposition).

  Step 4 1- (3,5'-dimethylphenyl) -3-methyl-2-naphthaldehyde (compound iv) (a) To 150 g of compound iii) in 1.8 liter

  anhydrous tetrahydrofuran (dried over

  100 ml of absolute ethanol (dried over molecular sieves) is added in portions over a period of three hours with stirring between -15 and -5 and

  under a nitrogen atmosphere, 37 g of sodium borohydride

  thium. 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 sulphate and evaporated under

  reduced to a small volume. By addition of diethyl ether and then of petroleum ether, we obtain

  oxazolidine in the form of a crystalline product

at 151-155.

  (b) To 99 g of the product obtained under (a) in 1.8 liters of ethanol and 600 ml of tetrahydrofuran is added dropwise in the course of 15 minutes, under stirring and 150, 1.5 liter of 2N hydrochloric acid and the reaction mixture is stirred for four hours.

  hours to 20-25. Then we add water, we ex-

  The mixture is triturated with diethyl ether, the ether extract is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. We triturate

  residue with petroleum ether and dry the

  duit under high vacuum at 20-25; F = 105-107 Step 5

  (E) -3- [l '- (3 ", 5" dimethylphenyl) -3'-méthylnaphtyl-

2 '] - 2-propenal (compound v)

  (a) Preparation of cis-1-ethoxy-2-tri

  n-butyl-stannylethylene: 29.1 g of trisodium hydride

  n-butyltin, 7 g of ethoxyacetylene are added over one hour under stirring at 50 ° C. and under a nitrogen atmosphere, and the reaction mixture is heated for three hours at 50-55 under a nitrogen atmosphere and while

one hour at 60-70.

  (b) Preparation of cis-1-lithium-2-ethoxy-

  ethylene: 28.9 g of cis-1-ethoxy-2-tri-n-butyl

  In 60 ml of ethyl acetate in 700 ml of anhydrous tetrahydrofuran, 50.14 ml of a 1.6M solution of n-butyllithium in 50 ml of water are added dropwise over a period of 15 minutes under stirring at 50.degree. hexane and the reaction mixture is stirred for one hour at

  -60 under a nitrogen atmosphere, which gives a solution

  cis-1-lithium-2-ethoxyethylene.

  (c) To the product obtained under (b), compound iv) is added in 80 ml of anhydrous tetrahydrofuran and the reaction mixture is stirred for two hours at -60 under a nitrogen atmosphere. We stop the reaction by carefully adding

  a saturated solution of ammonium chloride, the temperature

  mixing temperature of 20-25 during ad-

- 14 -

  edition. The mixture is then extracted with acetylene

  The ethyl acetate extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is partitioned between acetonitrile and n-hexane, the acetonitrile phase is again extracted with n-hexane and evaporated to dryness under reduced pressure.

  gives the intermediate enol ether in the crude state.

  (d) To 10 g of the enol ether obtained under (c), 400 ml of tetrahydrofuran, ml of water and 1 g of p-toluenesulphonic acid are added.

  monohydrate and the reaction mixture was stirred

  16 hours to 20-25. 1.5 liters of water are then added and the mixture is extracted three times with

  ethyl acetate. The extracts of

  The total solution is washed with saturated sodium chloride solution, washed with 50 to 60 ml of 10% sodium bicarbonate solution and washed with saturated sodium chloride solution. it is dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is dried for five hours under high vacuum to give the product in the crude state.

in the form of a yellow oil.

Step 6

  (E) -7- [l '- (3 ", 5" dimethylphenyl) -3'-méthylnaphtyl-

  2 '] - Ethyl 5-hydroxy-3-oxo-6-heptenoate (compound vi) (a) To 13.4 g of diisopropylamine in 360 ml of anhydrous tetrahydrofuran is added dropwise with stirring to -5 and under a nitrogen atmosphere, 82.9 ml of 1.6M solution of n-butyllithium in hexane and the reaction mixture was stirred for minutes under the same conditions to give

- 15 -

  lithium salt solution of diisopropylamine.

  (b) The product obtained under (a) is added dropwise, with stirring, between -5 and 0,

  8.6 g of ethyl acetoacetate are added and the reaction mixture is stirred.

  For one hour between -5 and 0, cooled to -60, a solution of 12 g of the crude product v) in 100 ml of anhydrous tetrahydrofuran was slowly added, and the reaction mixture was stirred for two hours at -3 ° C. 60, the reaction mixture being maintained under a nitrogen atmosphere from one end to the other

  operations. The reaction mixture is added slowly

  to a saturated solution of ammonium chloride

  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 in the form of

of an oil.

  The product is a racemic that can

  be split into its 5R and 5S enantiomers.

Step 7

  Erythro- (E) -3,5-dihydroxy-7- [l '- (3 ", 5" dimethylphenyl) -

  Ethyl 3'-methylnaphthyl-2 '] 6-heptenoate (compound No. 1) (a) To 11.6 g of crude product vi) in 500 ml of anhydrous tetrahydrofuran (distilled over sodium) is added dropwise, under stirring at 20-25 and

  under a nitrogen atmosphere, 42 ml of a 1M solution of

  thylborane in tetrahydrofuran. Ml of air was bubbled into the reaction mixture (760 mm

* Hg and 25), the reaction mixture is stirred

  one hour at 20-25 and cool 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 added

- 16 -

  drop by drop, within 15 minutes and under

  stirring rapidly, 150 ml of 2N hydrochloric acid.

  Water is then added, the mixture is extracted with diethyl ether, the ethereal extract is dried over anhydrous sodium sulphate, evaporated to dryness under reduced pressure and 50 ml of isopropanol (from reactive quality). The mixture is heated in an oil bath for about one minute (bath temperature = 100), allowed to cool, seeded with a product crystal from a previous operation, and left for sixteen hours.

  in the refrigerator. The precipitate is collected by

  It is washed with cold isopropanol and dried under high vacuum to give the ester.

cyclic boron, F = 80-81.

  (b) The cyclic boron ester obtained is stirred for 5 hours at 4.49 g.

  under (a) in 250 ml of methanol (reagent grade).

  The reaction mixture is evaporated to dryness under pressure

  reduced, the residue is dissolved in diethyl ether.

  that the ether solution is washed with a solution

  saturated with sodium chloride, it is dried over

  of anhydrous sodium and evaporated under reduced pressure to give the product (compound no.

form of a clear yellow oil.

  NMR Spectrum (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), 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, for example, by reaction of compound 4 with ethylate

  sodium or potassium for example in ethanol.

Example 2

  Sodium Erythro- (E) -3,5-dihydroxy-7- [1 '- (3 ", 5" -dimethylphenyl) -3'-methylnaphthyl] - 6-heptenoate (compound

n 2 R 1 = CH 3, Z = a), R 7 = Na).

  To 4.01 g of the compound n 1 in 250 ml of ethanol

  Absolute mixture is added dropwise over a period of minutes with stirring and 0-5, 9.0 ml of 1N solution of sodium hydroxide. The reaction mixture is stirred for two hours, during which time the mixture is allowed to warm to 20-25. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dried for two hours under high vacuum and

  dissolve in chloroform (spectral quality).

  The chloroform solution is dried over anhydrous sodium sulfate, concentrated under reduced pressure to a volume of 50 ml and, under 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).

  NMR Spectrum (CDCl3 + 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 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 prepared

  by reaction of compound 4 with 1N NaOH.

Example 3

  Acideérythro- (E) -3,5-dihydroxy-7-El- (3 ", 5" -dimethyl

  pihenyl-3'-methylnaphthyl-2 '] - 6-heptenoic (compound 3, R1 = CH3, Z = a), R7 = H). The product is prepared, for example, from the compound

  by reaction with NaOH and then HCl.

Example 4

  (E) -trans-6- (2 '- [1l "- (3"', 5 " '- dimethylphenyl) -3" -

  methylnaphthyl-2 "] ethenyl) -4-hydroxy-3,4,5,6-tetra-

  hydro-2H-pyran-2-one (Compound No. 4, R1 = CH3, Z = b) The product is prepared for example by lactonization of

  RinD3 compound; F = 53-56 (cis / trans 1: 5.7).

  NMR Spectrum (CDCl3): 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 (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 compounds of the formula Wherein R 1 is an isopropyl group, may be prepared analogously to steps 7 and 8 of Example 10 of the European patent application.

n 0117228.

Step 1

  4,4-dimethyl-2- [1 '- (3 ", 5" dimethylphenyl) -3'-methoxy-

  2-naphthyl-2-oxazoline (compound n vii).

- 19- Step 2

  4,4-dimethyl-2- [1 '- (3 ", 5" -dimethylphenyl) -3' - (1 "-methyl);

  ethyl) -naphthyl-2 '] - 2-oxazoline (compound n viii).

  The compounds obtained in Examples 1 to 4 may contain a small amount of corresponding racemic threo (Z = a) or cis (Z = b)). Cettequantité

  for example between 5% and 15% depending on the procedure

  used and the conditions under which one operates.

  Both racemates can be separated from each other

  0l according to conventional methods, and each can be de-

  doubled according to conventional methods. The racemic erythro gives the enantiomers 3R, 5S and 3S, 5R, and the

  racemic threo 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 solvent mixtures are in volume. When a reaction is carried out subatmosphere of nitrogen, dry nitrogen was used

  to maintain the anhydrous conditions.

  All the spectra R M N have been taken

  at room temperature on a 200 MHz spectrometer.

  All chemical shifts are given in p.p.m.

  (6) with respect to tetramethylsilane, and when a simple value S is given for something other than a narrow singlet, it is the central point. In the R M N spectra, the following abbreviations have been used: bm = large multiplet bs = large singlet d = doublet dd = doublet of a doublet m = multiplet q = quartet s = singlet t: triplet

- 20 -

  Starting materials can be obtained

  for example as described in European Patent Application No. 0117228, in particular Examples 10 and

14 of this application.

- 21 -

Claims (8)

  1. Compounds of formula I CH3 3? 3 H Z 1   in which R1 represents a C1-C3 alkyl group and Z represents a group of formula (a) or (b) H -C H-CH'-CH-C H-COOR7 1   OH OH (a), C 2 (b), wherein R 7 is hydrogen, R 8 or M, where R 8 is for a radical forming a physiologically acceptable and hydrolysable ester group and M meaning a cation.   2. Erythro- (E) -3,5-dihydroxy-7-   El [1 '- (3 ", 5" dimethylphenyl) -3'-methylnaphthyl-2'] - 6-   hepténoTique. 3. Compound according to claim 1 or 2, characterized in that it is in free form or in the form of an ethyl ester or sodium salt. - 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 hydrolysed in ester or lactone form or esterified or lactonized. posed of formula I in the form of free acid, and   when a free carboxy group is present,   father the compound obtained as free acid or in the form of salt.   5. Process for the preparation of the specific compounds   Claim 1, characterized in that it comprises a) the stereoselective reduction of a compound of formula I wherein Z is Z 'o VZ is -CH-CH2-C-CH2COOR9 c) OH O   in which R9 represents a residue forming a   physiologically hydrolysable ester and   (b) the hydrolysis of a compound of formula I in the form of   of a physiologically hydrolysable ester or lac-   or (c) the esterification or lactonization of a compound of formula I as a free acid, and when a free carboxy group is present, recovering the compound obtained as an acid free or salt.   6. A compound according to any one of the   1 to 3, as a free acid or in the form of a physiologically and hydrolysable ester acceptable or lactone or a pharmaceutically acceptable salt - 23 -   acceptable, for use as a medicine. 7. A medicament, characterized in that it comprises, as active ingredient, a compound according to one of   any of claims 1 to 3, in the form of   of free acid or in the form of a physiological ester   hydrolysable and acceptable form or lactone,   or a pharmaceutically acceptable salt.   8. A pharmaceutical composition,   1.0 per se, in that it includes a.   any of claims 1 to 3, in the form of   of free acid or in the form of a physiological ester   hydrolysable and acceptable form or lactone, or a pharmaceutically acceptable salt   acceptable, in combination with a thinner or vehicle pharmaceutically acceptable.   9. 4,4-Dimethyl-2- [1 '- (3 ", 5" -dimethyl)   phenyl) naphthyl-2 '] - 2-oxazoline, 4,4-dimethyl-2-   [1 '- (3 ", 5" -dimethylphenyl) -3'-methylnaphthyl -2'] -   2-oxazoline, the iodide of 2- [1 '- (3 ", 5" -dimethyl)   phenyl) -3'-methylnaphthyl-2 '] - 3,4,4-trimethyl-2   oxazolinium, 1- (3 ', 5'-dimethylphenyl) -3-methyl-   2-Naphthaldehyde, (E) -3- [1 '- (3 ", 5" -dimethylphenyl) -   3'-methylnaphthyl-2 '] - 2-propenal, the (E) -7- [1'-   (3 ", 5" dimethylphenyl) -3'-methylnaphthyl-2 '] - 5-hydroxy-   Ethyl 3-oxo-6-heptenoate, 4,4-dimethyl-2-   El '- (3 ", 5" dimethylphenyl) -3'-methoxynaphthyl-2'] -   2-oxazoline and 4,4-dimethyl-2- [1 '- (3 ", 5" -dimethyl)   phenyl) -3 '- (l' -methylethyl) naphthyl-2 '] - 2-oxazoline.