IE67059B1 - A process for the preparation of a 1,4-dihydropyridine derivative namely (-)-2-{[2-(aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxy-carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine and its salts - Google Patents

Abstract

(-)2{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-etho xycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine compound of formula I <IMAGE> and its addition salts with a pharmaceutically acceptable inorganic or organic acid. Medication.

Description

The present invention relates to a process for the preparation of a 1,4-dihydropyridine compound, (-)-2-((2(2-aminoethoxy) ethoxy]methyl )-4-(2,3-dichlorophenvl)-3ethoxycarbonyl-5-methoxycarbony 1-6-methyl-l, 4-dihydro- « pyridine, and its salts.

I Some 1,4-dihydropyridine compounds possessing valuable pharmacological properties have been described in European Patent Specification EP 259206. Among a large number of compounds, that patent describes and claims θ 2-((2-( 2-aminoethoxy) ethoxy ] methyl )-4- (2,3-dichlorophenyl ) ~3-ethoxycarbonyl"5-methoxycarfoonyl-6-methyl-i, 4dihvdropyridine. The process for preparing that compound in its racemic form is exemplified in that patent.

In view of the very valuable therapeutic results obtained 15 on that product, more detailed studies were undertaken in order to separate the optical isomers of that compound, and those studies have resulted in the process for the preparation of (-)-2-( (2-(2-aminoethoxy)ethoxy]methyl}-4( 2,3-dichlorophenyl) -3-ethoxycarbonvl-5-methoxycarbonyl20 6-methyl-l,4-dihydropyridine, to which process the present Application relates.

The various processes of isomer separation or of stereoselective synthesis described in the literature do not, in fact, allow the preparation of the isomers of 2-((225 ( 2-arainoethoxy)ethoxy]methyl )-4-( 2,3-dichlorophenyl)-3ethoxycarbonyl-5-inethoxycarbonyl-0-inethyl-l, 4-dihydropyridine. It has therefore been necessary to invent a naw process .

That process, to which the present invention relates, * does not fall within the scope of the conventional processes previously known for preparing analogous * compounds. Moreover, if reference is made to the process described in J. Med. Chem,,, Vol. 29, Mo. 9, 1595-1702 (1986), which is considered to be the closest prior art, it will be seen that the products prepared in accordance with that prior art all contain, up to the final step, an azide (H3) function which is particularly known as a cause of explosions especially in the industrial field. There is no such risk in the process of the present invention (since none of the starting materials, end products or intermediates contains an azide function). (-)-2- { [ 2- (2-aminoethoxy)ethoxy]mathyl )-4-(2,3-dichlorophenyl ) -3-ethoxycarbonyl-5~methoxycarbonyl-6-methyl-l, 4dihydropyridine is a powerful inhibitor of intracellular influx of calcium.

In theory, the active isomer of a compound having 5 pharmacological properties possesses at most twice the activity as compared with the racemic compound. In the present case, pharmacological tests have shown that the activity of the compound prepared in accordance with the invention is very much greater.

The present invention relates more particularly to a process for the preparation of (-)-2-([2-(2-aminoethoxy)ethoxy ]methyl )-4-( 2,3-dichlorophenyl) -3-ethoxycarbonyl-5methoxycarbonyl-6-methyl-l, 4-dihydropyridine, the compound of formula I: CH2-O-CH2CH2-O-CH2CH2NH2 and its addition salts with a pharmaceutically acceptable mineral or organic acid.

Of the acids used there may be mentioned fumaric acid, tartaric acid, camphorsulphonic acid, hydrochloric acid, citric acid, methanesulphonic acid, benzenesulphonic acid, etc..

The present invention relates to a process for the preparation of the compound of formula I, characterised in that 2-[2-(2-chloroethoxy)ethoxy]ethanol is condensed with potassium phthalimide, in dimethyl10 formamide, with heating, to form 2-(2-(2-phthalimidoethoxy ) ethoxy ] ethanol , the compound of formula II: which is converted with the aid of Jones' reagent into 2-(2-(2-phthalimidoethoxy)ethoxy]acetic acid, the compound of formula III: which is treated with carbonyldiimidazole and Meldrum acid in the presence of pyridine in methylene chloride, to obtain the compound of formula IV: which is then reacted with (R)-2"phenyI~2-methoxyethanol, the compound of formula V: to obtain the β-keto ester of formula VI: which is condensed in the presence of ammonium formate in ethanol, with a benzvlidene of formula VII; (VII) to obtain (4R,4 {’R/4S, 4 'R)-4~( 2,3-dichlorophenyl)-5methoxycarbonyl-3- (2-methoxy~2-phenylethoxycarbony 1) -6methy1-2-([2-(2-phthalimidoethoxy)ethoxy]methyl}-l, 4dihydropyridine, the compound of formula vill: which is then either: subjected to the action of an aqueous solution of sodium hydrogen carbonate, in solution in acetonitrile, to obtain (4R,4'R/4S,4'R)-2-{[2-(2-(2-carboxyphenyIcarbox™ amido) ethoxy]ethoxy]methyl)-4-(2,3-dichlorophenyl)-5methoxycarbony1-3-(2-methoxy-2~phenylethoxycarbonyl)-6methyl-1,4-dihydropyridine, the compound of formula IX: which is treated, after separation by HPLC, with a mixture of glyme and sodium ethoxide to obtain a mixture containing ( -) -2- { [2-(2-( 2-carboxyph.enylcarboxamido) ethoxy]ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl~6-methyl~l,4-dihydropyridine, the compound of formula X: and its homologue substituted in the 5-position by an ethoxycarbonyl radical, or: separated by chromatography on a silica column using as eluant a mixture of methylene chloride and ethyl acetate (95:5 v/v) to obtain the least polar isomer of 4-(2,3dichlorophenyl)-5-methoxycarbonvl-3-( 2-raethoxy-2-phenyl~ ethoxycarbonyl) -6-methyl-2- ([ 2-(2-phthalimidoethoxy)10 ethoxy]methy1}-1,4-dihvdropyridine, which is then subjected to the action of sodium ethoxide in the presence of glyme in solution in ethanol, to obtain a mixture containing the compound of formula X and its homologue substituted in the 5-position by an ethoxy15 carbonyl radical, which is then-subjected to the action of carbonyldiimidazole in solution in a halogenated alkane at room temperature to obtain a mixture containing (-) -4- ( 2,3-dichlorophenyl) ~3-ethoxyca.rbonyl-5-methoxyca.rhonyl-S-methyl-2-{ [ 2-( 2-phthe.limidoethoxy) ethoxy ] methyl )20 1,4-dihydropyridine, the compound of formula XI: and its homologue substituted in the 5-position by an ethoxycarbonyl radical, which mixture is then separated by HPLC, to obtain pure (-)-4-(2,3-dichlorophenyl)-3ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(25 phthalimidoethoxv)ethoxy]methyl )-1,4-dihydropyridine, which is then refluxed in ethanol in the presence of hydrazine hydrate to give the compound of formula I, which may then be converted into a salt with a pharmaceutically compatible organic or mineral acid.

(R)-2-phenyl-2-methoxyethanol, the compound of formula V, is obtained by reduction of the corresponding, optically active, acid. The latter compound is prepared in accordance with the process described in J. Chem. Soc., 1962, p. 1519.

The methyl ester of 2-(2,3-dichlorobenzylidene)-3oxobutanoic acid, the compound of formula VII, is obtained by condensing 2,3-dichlorobenzaldehyde with methyl acetoacetate.

The compound of formula I is a markedly more powerful inhibitor of intracellular influx of calcium than is its corresponding racemic compound. Surprisingly, the results of the pharmacological tests have shown that the compound of formula I possesses an activity that is from 4 to 30 times greater than the activity of the racemic compound.

The intracellular calcium concentration acts as the messenger for many biological functions: contractions and secretions. That concentration depends to a large extent on the transmembrane influx of calcium, which is very concentrated in the extracellular media and passes through the calcium-selective channels located in the membrane.

Thus, inhibitors of those channels that restrict or suppress the influx of calcium can have valuable therapeutic effects in a number of pathologies, such as, for example, vasorelaxation, for the treatment of arterial hypertension and pulmonary hypertension, and of peripheral and coronary vascular diseases (Am. J. Card., 1980, 46 . Ρ» 1047-1058,- Burger's Medicinal Chemistry, 4th edition, Part Ill, p. 5456 - John Wiley and Sons Inc., USA, 1981; Life Sciences, 1983, 33., P- 2571-2581).

Induced beneficial effects are also noted for the treatment of cardiac insufficiency.

Moderation of myocardial contraction is of use also in situations of cardiac ischaemia (Medicine, 1985, 64, p. 61-73). Limiting the influx of calcium into the cells can also play an important part in preventing the accumulation of calcium that is characteristic of cell ageing and is associated with certain degenerative vascular - especially atheromatous - diseases (Medicinal Research Review, 1985, 5, p. 394-425).

Calcium modulation is also of value for the treatment of epilepsy and of vertigos having a central origin.

Limiting ionised calcium in the smooth fibres of the walls of the digestive tract also permits the alleviation of oesophageal spasms and, at the pulmonary level, of bronchial spasm (treatment of asthma). Calcium moderation can also be of use as an adjuvant in the treatment of cancer and hypercoagulation.

Moreover, the present description is not limiting; the fundamental works in fact emphasise the key role played by calcium in many physiological and physiopathological phenomena.

Pharmacological tests on rats have proved in vivo that the activity of the compound of the invention is greater than that of its racemic compound, and that the compound of the invention has a longer duration of action, and they confirm the value of its use in therapeutics.

The invention extends also to the preparation of pharmaceutical compositions comprising as active ingredient the compound of formula I or an addition salt thereof with a mineral or organic acid, together with one or more suitable inert, non-toxic excipients.

JO The pharmaceutical compositions so obtained are advantageously presented in various forms, such as, for example, tablets, dragees, gelatin capsules, glossettes or other suitable galenic preparations.

The pharmaceutical compositions may also comprise an active ingredient having a complementary or synergistic action.

The dose may vary widely in dependence on the age and weight of the patient and the nature and severity of the disorder, and also on whether administration is by the buccal or parenteral route. In general, the unit dose will range from 0.02 to 50 mg and the daily dose, administered by the oral route, that can be used in human or animal therapeutics will range from 0.02 to 100 mg.

The following Examples, which are non-limiting, illus25 trate the invention.

The melting points indicated were measured in accordance with the micro-Kofler technique.

The proton nuclear magnetic resonance spectra (NMR) were recorded at 200 MHz.

EXAMPLE 1 2Γ2-Υ 2-phthalxmxdoethoxy) ethoxy.1 acetic acid STEP A 2-[2-(2-phthalimidoethoxy)ethoxy]ethanol 5 188 g of 2-[2-(2-chloroethoxy) ethoxy]ethanol and 146 g of potassium phthalimide in 700 ml of dimethylformamide are heated at 95*C for 17 hours.

The mixture is diluted with methylene chloride, washed with a saturated sodium chloride solution, dried and 10 evaporated. Distillation is carried out using a bulb tube; b.p.0e05 mmHg: 180-185’C.

Yield: 90% Proton nuclear magnetic resonance spectrum (solvent CPC131: 4H(m) 7.5 to 8 ppm; 12H(m) 3.4 to 4 ppm; IH (unresolved peak exchangeable with D2O) 2.5 to 3 ppm STEP B g of the alcohol obtained in the preceding step are dissolved in 150 ml of acetone. Jonese reagent is 20 added, with the temperature being maintained at between and 25’C. The mixture is allowed to stand for one hour at room temperature. The mixture is concentrated, then diluted with methylene chloride and washed with water. The product is dried and the solvent is evapora25 ted off, yielding the desired compound.

Melting point: 88-90°C Yield: 90% Proton nuclear magnetic resonance spectrum (solvent COCI3): IH (exchangeable unresolved peak) 8.8 to 9.5 ppm; 4H(m) 7.6 to 8.1 ppm; 2H(s) 4.1 ppm; 8H(m) 3.6 to 4 ppm EXAMPLE 2 (R )~2-phenvi~2-methoxy,ethanol g of (R)~2"phenyl~2-methoxyacetic acid (prepared in accordance with the method described in J. Chem. Soc., 1962, p, 1519) are reduced with 16,5 g of lithium aluminium hydride in 300 ml of tetrahydrofuran.

The mixture is hydrolysed and the mineral salts are filtered off, and then the residual oil is distilled using a bulb tube; b.p-15 mmiig - 105*C.

Yield: 76% Proton nuclear magnetic resonance spectrum (solvent CDCI3 ): 5H(m) 7.35 ppm; IH(d) 4.35 ppm; 2H(m) 3.65 ppm; 3H(s) 3.3 ppm; IH (exchangeable d) 2.35 ppm Rotatory power in a 1% solution in ethanol: i ii(nns) j (GpVC 589 1 - 122° 578 - 127® 5«6 - 1«5° «36 ~ 2«9e 365 - 396® EXAMPLE 3 (R)-2-phenyl-2-methoxvethvl ester of 5,8-dioxa~3-oxo-lQphthalimidodecanoic acid g of carbonyIdiimidazole are added in a single batch to a suspension containing 34.7 g of the compound of Example 1 in 210 ml of methylene chloride.

The mixture is stirred until the evolution of gas has ceased. A mixture consisting of 17.7 g of Meldrum acid and 9.2 g of pyridine in 70 ml of methylene chloride is then rapidly added dropwise. The mixture is stirred under nitrogen overnight.

The mixture is transferred into a separating funnel, is washed with N sulphuric acid until the pH is acid and then once with water, and is dried, and the solvent is evaporated off. The oil is placed in a water bath with 25 g of the alcohol obtained in Example 2, until evolution has ceased.

The reaction mixture is subjected to chromatography on a column (flash chromatography) containing 1.8 kg of silica, using a mixture of cyclohexane and ethyl acetate (1:1 v/v) as eluant, yielding the desired compound.

Yield: 70% Proton nuclear magnetic resonance spectrum (solvent CPC13 ) : 4H(m) 7.6 to 8.1 ppm; 5H(s) 7.35 ppm; 3H(m) 4 to 4.6 ppm; 2H(s) 4.1 ppm; 10H(ra) 3.5 to 4 ppm; 3H(s) 3.3 ppm - 13 " Rotatory power in a 1¾ solution in ethanol: A(nja) (ai2l’C 589 - 35.1’ 578 - 36.5° 546 H 1 h & «-> «· 1 _ ** • · ff 436 - 69.8" 365 - 107.2® EXAMPLE 4 2-(2«3-dichlorobenzylidene)-3-Oxobutagioic acid nethvl ester A mixture containing 8.7 g of 2, 3-dichlorobenzaldehyde, 5.8 g of methyl acetoacetate, 28 drops of pyridine and 38 drops of hexanoic acid in 280 ml of benzene is refluxed for 4 hours, with stirring. The mixture is *5 transferred into a separating funnel and is washed with a 10% sodium hydrogen carbonate solution and then with an N hydrochloric acid solution, and then with water. The mixture is dried and evaporated. The crystals obtained are washed with diisopropyl ether, Yield: 65% Proton nuclear magnetic resonance spectrum (solvent CPC13): lH(2s) 8 and 8.05 ppm; 3H(m) 7.1 to 7,8 ppm; 3H(2s) 3.9 and 3.75 ppm; 3H(2s) 2.45 and 2.2 ppm te EXAMPLE 5 (4R 4 «· R/4S,4g R)~4~ ί 2 , 3-dichloroohenvl) -5-mefchoxvcarbonvl3— f 2-methoxy-2-phenylethoxvcarbonyl ΐ -6-methvI-2- (f 2-(2phthalimidoethoxy) ethoxylmethyl) -1,4-dihydroovridine A mixture containing 22.2 g of the compound described in Example 4, 38 g of the compound described in Example 3 and 6.3 g of ammonium formate in 200 ml of ethanol is stirred under nitrogen at 40 G for 48 hours. The residual mixture is evaporated and purified on a column containing 4 kg of silica, using a mixture of methylene chloride and ethyl acetate (9:1 v/v) as eluant.

Proton nuclear magnetic resonance spectrum (solvent CDC13): 2H(m) 7.8 ppm; 2H(m) 7.7 ppm; 7H(m) 7.3 to 7.1 ppm; lH(t) 7.05 ppm; IH(s) 5.45 ppm; 2H(ra) 4.6 ppm; llH(m) 3.6 to 4.4 ppm; 3H(2s) 3.6 ppm; 3H(2s) 3.2 and 3.05 ppm; 3H(s) 2.3 ppm? lH(s) not exchangeable with D2O, 7.4 ppm Rotatory power in a 1¾ solution in chloroform: λ(ΠΕΒ> (flJ2rc 589 - 13.3° 578 ] - 13.86 546 j - 15.1° EXAMPLE 6 (4R, 4 *R/4S4 ‘''Rli - 2- (Γ 2 - Γ 2 - (2-carboxyphenvlcarboxamido)ethoxv '< ethoxy >ethyl} -4- (2 ;f 3-dichloroohenvl) -5-methoxycarbonyl-3- if 2-roethoxv2-phenylethoxycarfc>onvl) -6-methyi1,4-dihvdropyridine A mixture containing 16.5 g of the compound of Example 5, 100 ml of a 10% aqueous sodium hydrogen carbonate solution and 230 ml of acetonitrile is refluxed for hours, with stirring. The solvent is evaporated off, the residue is taken up in water and acidified with N hydrochloric acid, and extraction is carried out, yielding the desired compound.

Yield: 87% Proton nuclear magnetic resonance spectrum (solvent CDC13); IH(m) 7.9 ppm; 3H(m) 7.5 ppm; 7H(m) 7.4 to 7.15 ppm; IH(t) 7.05 ppm; lH(2s) 5.45 ppm; 2H(m) 4.8 ppm; 2H(m) 4.4 to 4.1 ppm; IH(m) 3.9 ppm; 8H(m) 3.8 to 3.5 ppm; 3H(2s) 3.6 ppm; 3H(2s) 3.2 and 3.05 ppm; 3H(s) 2.3 ppm; lH(t) 6.55 ppm; IH (masked signal exchanged with D2O) 7-45 ppm; IH (flat signal) 7 to 5 ppm exchanged with D20 Rotatory power in a 1% solution in chloroform: X(rua) [a]21eC 589 I - 14.2° 573 - 14,8® 546 | - 1630 EXAMPLE 7 20 Mixture of ()-2-(Γ 2τ Γ 2~( 2-carboxvohenyIcarboxamidoJ ~ ethoxy 1ethoxylmethy13 -4- (2,3-dichlorophenyJ.) -3-ethoxycarbonyl-5-methoxycagbonyl-e-methvl-l, 4-dxhvdropvridxne and its homolocme substituted in the 5-oosition by an ethoxycarbonyl radical 25 * * * * 30 * First process The compound of Example 6 is separated into its two isomers by HPLC using as the column a 50 cm long Lichroprep RP18 and as eluant a mixture of methanol and 0.025M disodium phosphate (55:45 v/v), flow rate ml/minute. Ιό g of the second compound obtained in the separation are refluxed with 30 ml of glyme and 28.6 ml of a 0.26M solution of sodium ethoxide. The mixture is evaporated, the residue is taken up in water and acidified, and extraction is carried out with ethyl acetate, yielding the desired compounds.

Overall yield: 10% * Second process.

STEP A o The compound of Example 5 is chromatographed on a preparative column containing 4 kg of silica, using a mixture of methylene chloride and ethyl acetate (95:5) as eluant. The first compound obtained in the separation, which is the least polar, is isolated.

Yield: 20% Proton nuclear magnetic resonance spectrum is.Qlyent. CQCl 31; 2H(m) 7.8 ppm? 2H(m) 7.7 ppm; 7H(m) 7.4 to 7.1 ppm; IH(t) 7.05 ppm; IH(s) 5.45 ppm; 2H(m) 4.4 ppm; HH(m) 4 to 3.7 ppm; 3H(s) 3.6 ppm; 3H(s) 3.05 ppm; 3H(s) 2.3 ppm; IH(s) 7.45 ppm (exchangeable with D2O with difficulty) Rotatory power in a 1% solution in chloroform: A(nm) [cj2rc 589 . 9« 578 - 546 - 10.«- STEP B g of the compound obtained in the preceding step are refluxed with 30 ml of glyme and 28.5 ml of an ethanolic solution of 0..26H sodium ethoxide. The mixture is evaporated, the residue is taken up in water and acidified, and extraction is carried out with ethyl acetate, yielding the desired compounds.

Yield: 65% EXAMPLE 8 Mixture of (-) -4- (2 -. 3-dichloroohenyl )-3-ethoxvcarbonvl-5~ methoxv-carlooD:jd^6--me-trn.vl-2-( [ 2-phthalimxdoethQxy)~ ethoxy!methyl>~l,4~dihydropvridiirae and its homologue io substituted in the 5-posifcion by, an ethoses,rbonyl radical 1.9 g of the mixture obtained in Example 7 are dissolved in 30 ml of methylene chloride, and 0.9 g of carbonyldiimidazole is added in a single batch. The mixture is stirred overnight.

The reaction mixture is transferred into a separating funnel and is washed with 10% sodium hydrogen carbonate and then with N hydrochloric acid and with water. The mixture is dried and evaporated, yielding the desired compounds.

Yield: 65% EXAMPLE 9 (~) —4— ( 2,3~dichlorophenylJ -3-ethoxvcarbonyl-5-methoxyr2 carbonyl-6-methyl-2-( f 2-( 2-ohthaliraidoethoxy) ethoxy. L·: methyl I -1,4-dihydropyrid3uae The mixture obtained in Example 8 is separated by preparative HPLC using a 50 cm long Lichroprep RP 18 column and a mixture of ethanol, water and TFA (500:500:1) as eluant. The desired compound is isolated first.

Yield: 30% Rotatory sower in a 1% solution 1ώ__Ώ££5Ω: X(ns) [a)20*C . 589 - 34.6° 578 - 36.5 546 - 43.,9° 436 - 119,051 EXAMPLE 10 (-)-2-( f 2-(2-aminoethoxy)ethoxvlmethyl s-4~f 2., 3-dichlorophenyl) —S-ethoxycagbomyl-S-meOioxycarboniyl-e—raethyl-1.41 g of the compound prepared in Example 9 is refluxed for 4 hours with 10 ml of ethanol and 0.25 ml of hydrazine hydrate. The solvent is evaporated off, the residue is taken up in diethyl ether and washed with 5 ml of normal sodium hydroxide, and the ethereal phase is exhaustively extracted with N hydrochloric acid. The aqueous phases are then rendered basic and extracted with diethyl ether, yielding the desired compound.

Yield: 60% Melting point: 69-71*C Proton nuclear magnetic resonance spectrum (solvent CDCl3): lH(m) 7.3 to 7.7 ppm exchangeable with 020; 3H(m) 7.6 to 6.9 ppm; IH(s) 5.5 ppm; 2H(s) 4.8 ppm; 2H(q) 4 ppm; 4H(s) 3.7 ppm; 2H(m) 3.4 to 3.7 ppm; 3H(s) 3.6 ppm; 2H(t) 2.9 ppm; 3H(s) 2.3 ppm; 2H(m) exchangeable with D20 1.4 to 1.8 ppm; 3H(t) 1.2 ppm Rotatory power in a 1% solution in chloroform: A(nes) (g]20.,5*C 589 - 36,5® 578 - 38.7® 546 | - 46.0" 436 - 133* ETfAHBLff 11 2WIabf. AA lU’sb Arf'rfWI Λ. «3» (-)-2-( Γ 2- (2-aminoethoxy) ethoxy laae thyl )-4-(2,3-dxchloroohenvl )-3-ethoxycarB3onyi-5—isaethoxycarb-onyl—S-methvl-1, 4dihydropyridine fumarate (-)-2-( [ 2-( 2-aminoethoxv) ethoxy]methyl )-4-( 2,3-dichlorophenyl )"3-ethoxycarbonyl-5-methoxycarbonyl6-methyl-l, 4dihydropyridine fumarate is obtained after dissolving 4.2 g of base in 50 ml of an ethanolic solution of 0.172M fumaric acid and recrystallising from acetonitrile.

Yield: 92% Melting point: 115°C Proton nuclear magnetic resonance spectrum (solvent CDCI3 and DMSO-d^): 2H(2dd) 7.3 ppm; lH(t) 7.1 ppm; 2H(s) 6.7 ppm; IH(s) .45 ppm; 2H(m) 4.7 ppm; 2H(q) 4 ppm; 6H(m) 5.7 ppm; 3H(S) 3.6 ppm; 2H(m) 3.1 ppm; 3H(s) 2.3 ppm; 3H(t) 1.3 ppm; lH(s exchanged with D2O) 7,7 ppm; 4H(s exchanged with D2O) 5.7 ppm Rotatory power in a 1% solution in DHSQ; A(ms) [g]20.5’C 589 - 33J0 578 - 35.26 546 - 43..0" 436 - 134.6 EXAMPLE 12 (-)-2-( Γ 2--( 2-aMirtoethoxy) ethoxy ] methyl 2,»3-dichloro phenyl) -3-ethoxycarlxsnvl~5~met,hoxvear!bonyI-0-,>aethvl-l „ 4. 10 dihydropyridine (4-) -tartrate 0.2 g of the compound of Example 10 is dissolved in 3.1 ml of an ethanolic solution of 0.133M (+)-tartaric evaporation of the solvent, 0.24 g of the is obtained. acid. Aftex desired salt Melting point: 150’c Rotatory power in a 1% solution in DMSO: 1 A (nas) I ia)21.5»C 589 I „ 9G QO «-» S B ✓ 578 ί - 32.5’ 546 I - 40.5s’ 436 s - 133.9° - 21 EXAMPLE 13 (- l-2rJ r 2- ί 2-aminoethoxv) ethoxy Imethyl) -4- (2,3-dichloro Phenyl) ~3--ethoxycarbonyl-5-methQxycarbppyJ^6^methyl-l, 4 dihydropyridine ί-)-tartrate 0.3 g of the compound of Example 10 is dissolved in 4.6 ml of an ethanolic solution of 0.133M (-)-tartaric acid. The desired salt is isolated after filtration. Melting point: 161-166C (sublimation) Rotatory power in a 1% solution in DMSO: X(na5 (a)21.5‘C 589 - 32.9° 578 - 35° 546 - 42.8° 436 - 142,4® EXAMPLE 14 Racemic tartrate of ()-2-(Γ 2-(2-aminoethoxy) ethoxy)methvl)-4-f 2,3-dichlorophenyl)-3-e_thoxvcarbonvl~5~ methoxycarbonvl-6-methvl-l , 4-dihvdropyridine 0.45 g of the compound of Example 10 is dissolved in 20 6.9 ml of an ethanolic solution of 0.133M racemic tartaric acid. The desired salt is isolated after filtration.

Melting point: 160-170°C Rotatory power in a 1% solution in DMSO: (aj2K5*C 589 - 31.2® 578 - 33.56 546 „ in,r 436 | - 135.r PHARMACOLOGICAL STUDY EXAMPLE 15 Affinity for the dihvdroovridine binding site A study of the displacement of tritiated PN 200-110, bound in a specific manner to the dihydropyridine site associated with the slow calcium channel, by (-)-2-([2( 2-aminoethoxy) ethoxy]methyl )-4-( 2,3-dichlorophenyl)-3ethoxycarbonyl-5-methoxycarbonyl-6-methyl~l, 4-dihydropyridine and by its racemic compound has shown that the compound of the invention has an affinity for those sites that is 30 times greater than that of its racemic compound.

The study was carried out on microsome membrane preparations prepared from skeletal muscle of the rear limbs of rats (Wistar).

The rats are sacrificed by decapitation. The skeletal muscles are removed and washed in buffer I (MOPS/KOH pH 7.4 20 mM, saccharose 0.3 M, EDTA 1 mM, iodoacetamide 0.1 mM, pepstatine A 1 μΜ, leupeptine 1 mg/1 and PMSF o.l μΜ) . The muscles are then fragmented mechanically and are taken up in 4 volumes of buffer I per gramme of tissue and homogenised.

The homogenate is then centrifuged for 10 minutes at 3 200 g, the deposits are removed and the supernatants are then centrifuged for 20 minutes at 15,000 g; the supernatants are stirred for 15 minutes at 4*C in buffer ϊ containing KCl at a final concentration of 0.6 M, and are then centrifuged for 45 minutes at 70,000 g.

The deposits are taken up in buffer I and homogenised in a ’’potter. The homogenates are centrifuged at 100,000 g for 45 minutes, and the deposits so obtained correspond to the microsome fraction used for the binding and displacement studies.

The activity of the products is assessed by the displace5 ment of [3H] PM 200-110, bound in a specific manner to its receptor associated with the slow calcium channel, by increasing concentrations of the test products. The value obtained (Κθθ5) for each of the products, which represents the concentration of product that displaces 50% of the [3H] pm 200-110, allows a true dissociation constant (Kj) to be calculated: +· [£,'] x where [L*] is the concentration of free [3H] PN 200-110 and Kd is the dissociation constant at the equilibrium of the [3H] pn 200-110 complex determined by direct binding.

The Kj values of the two products are recorded in Table I: TABLE I COMPOUND Kt EXPRESSED IN nM COMPOUND OF THE INVENTION 0.28 ± 0.15 RACEMIC COMPOUND 8.2 ± 1.7 EXAMPLE 16 Study on the isolated mesenteric arterv of rabbits. contracted bv means of calcium The test is carried out on isolated organs removed from male Mew Zealand rabbits weighing from 2.5 to 3 kg which have been placed on a water diet 18 hours before sacrifice.

After rapid sacrifice of the animal, the mesenteric artery is removed and dissected into a ring 2 mm in length; the endothelium is removed mechanically. .i After a stabilisation period of 90 minutes, the preparations are subjected to a depolarising medium (35 mM KCl) without calcium (0.1 mM SGTA) for 15 minutes.

A control range is prepared by adding cumulative doses of calcium to the bath every 6 minutes until the maximum effect is achieved. The preparations are then rinsed for a period of 15 minutes and the product is incubated for one hour before renewal of the calcium range.

A single concentration of product is tested per organ.

The responses obtained in the presence of product are expressed as a percentage of the maximum value of the control range.

The pDf2 is calculated in accordance with the method of Van Rossum (1963).

The pDf2 values of the compound of the invention and of its racemic compound are shown in Table II. Those data show the very great superiority (more than double) of the compound of the invention, as compared with its racemic compound, in preventing a calcium-induced vascular contraction.

TABLE II COMPOUND pDr2 COMPOUND OF THE INVENTION 7.97 RACEMIC COMPOUND 7.64 EXAMPLE 17 Study on awake., spontaneously hvpertensive._rats_ f SHR) Male SHR rats weighing from 230 to 350 g and aged from 18 to 24 weeks are anaesthetised with Imalgene® (150 mg/kg i.p.). Two polyethylene catheters are introduced, one into the abdominal aorta for recording haemodynamic parameters, the other into the jugular vein for the administration of the products.

The catheters are tunnelled at the level of the neck. The animals are used at least 48 hours after the operation.

The systolic and diastolic abdominal arterial pressures are recorded by means of a Statham P23XL transducer on a Gould ES 1000 recorder. The products are administered by the intravenous route in a volume of 0.5 ml/kg. The doses of the test compounds administered are expressed as mg/kg 20 of base. The arterial pressure is recorded continuously until 6 hours after the treatment.

The variations is systolic arterial pressure after treatment are shown in Table III.

The compound of the invention differs from its racemic compound by the fact that its activity is more powerful and is sustained over a longer period of time, which constitutes a considerable advantage in therapeutics.

For the same dose six hours after treatment, the activity of the compound of the invention is approximately 4 times greater than that of its racemic compound.

TABLE III COMPOUND DOSE (mg/Icg) Variations in systolic arterial pressure (6mmHg) after treatment Xh3Q COMPOUND OF THE INVENTION 0.1 -16±2 -13±2 -21±5 RACEMIC COMPOUND 0.1 -11±3 -5±3 -5±2 PHARMACEUTICAL PREPARATION EXAMPLE 18 Tablets each containing a dose of 1 mg of (-)-2-((2-(2aminoethoxy) ethoxy ]methyl )-4-(2,3-dichlorophenyl )-31 5 ethoxycarbonvl-5-methoxycarbonyl~6-raethyl-l, 4-dihydropyridine (ADEMMDP): ADEMMDP ......................... 1 mg saccharose starch ....................... 64 mg cellulose excipient ......................... 25 mg alginic acid ................................ 10 mg for a tablet having a theoretical weight of 100.00 mg.

Claims (4)

1. Process for the preparation of the compound of formula I: 5 characterised in that 2~ [ 2 ( 2-chloroethoxy)ethoxy ]ethanol is condensed with potassium phthalimide, in dimethylformamide, with heating, to form 2-[2-(2-phthalimidoethoxy)ethoxy]ethanol, the compound of formula II: 10 which is then converted with the aid of Jones 3 reagent into 2-[2-(2-phthalimidoethoxy)ethoxy]acetic acid, the compound of formula III: which is treated with carbonyldiimidazole and Meldrum 15 acid in the presence of pyridine in methylene chloride, to obtain the compound of formula IV; which is then reacted with (R)~2-phenyl-2-roethoxyethanol, the compound of formula V: (R) ch-ch 2 oh (V) , och 3 to obtain the β-keto ester of formula VI: (VI), which is condensed in the presence of ammonium formate in ethanol, with a benzylidene of formula VII: (VII) to obtain (4R,4'R/4S,4R)-4-(2,3-dichlorophenyl)-5methoxycarbonyl-3- (2-methoxy-2-pheny lethoxycarbonyl) -6methyl-2~ {[ 2- ( 2-phthalimidoethoxy)ethoxy ]methyl )-1,4dihvdropyridine, the compound of formula vui: which is then either: subjected to the action of an aqueous solution of sodium 5 hydrogen carbonate, in solution in acetonitrile, to obtain (4R,, 4 f R/4S,4 ’R)-2-([ 2· [ 2~(2-carboxvphenylcarboxamido)ethoxy]ethoxy]methyl )-4-(2,3-dichlorophenyl)-5raethoxycarbonyl-3- (2-methoxy~2-phenylethoxycarbony1) -6~ methvl-1,4-dihydropyridine, the compound of formula IX: (4R4’R/4S4’R) which is treated, after separation by HPLC, with a mixture of glyme and sodium ethoxide, with heating, to obtain a mixture containing (-)-2-{[2-[2-(2-carboxvphenylcarboxamido) ethoxy]ethoxy]methyl )-4-(2,3-dichloro~ phenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl“l,4dihydropyridine, the compound of formula X; CH3OOC Cl CHj, W Cl COOC2H5 CH2OCH2CH2OCH2CH2NH-C — < and its homologue substituted in the 5-position by an ethoxycarbonyl radical, or: separated by chromatography on a silica column using as eluant a mixture of methylene chloride and ethyl acetate (95:5 v/v) to obtain the least polar isomer of 4-(2,3dichlorophenyl)~5-methoxycarbonyl~3-(2-methoxy-2~phenylethoxycarbonvl)-6-methy1-2-([2-(2-phthalimidoethoxy)ethoxy]methyl)-1,4-dihydropyridine, which is then subjected to the action of sodium ethoxide in the presence of glyme in solution in ethanol, to obtain a mixture containing the compound of formula X and its homologue substituted in the 5-position by an ethoxycarbonyl radical, which is then subjected to the action of carbonyldiimidazole in solution in a halogenated alkane at room temperature to obtain a mixture containing (-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methy1-2-([2-(2-phthalimidoethoxy) ethoxy]methyl )1,4-dihydropyridine, the compound of formula XX: CH: (Xi), O and its homologue substituted in the 5-position by an ethoxycarbonyl radical, which mixture is then purified by HPLC (reversed phase), to obtain (-)-4-(2,3-dichlorophenyl ) “3-ethoxycarbonyl-5-methoxycarbonyl~6-methyl“2{(2-( 2-phthalimidoethoxy)ethoxy ]methyl )-1,4-dihydropyridine, which is then refluxed in ethanol in the presence of hydrazine hydrate to give the compound of formula I, which may then be converted into a salt with a pharmaceutically compatible organic or mineral acid.

2. (4R,4'R/4S,4'R)“4-(2,3-dichlorophenyl)-5-raethoxycarbonyl-3-( 2-mefchoxy-2-phenylethoxycarbonyl) -6-methyl-2~ {[ 2-(2-phthalimidoethoxy)ethoxy]methyl )-1,4-dihydropyridine, the compound of formula VIII: (ijms’R/^ 8 ?,) o a useful intermediate for the preparation of the compound of formula I according to claim 1.

3. A process substantially as hereinbefore described with reference to the Examples.

4. A compound of formula I as defined in claim 1 whenever prepared by a process as claimed in claim 1 or 3. Dated this 28th day of Septembers 1989