IE832716L

IE832716L - Betaxolol

Info

Publication number: IE832716L
Application number: IE832716A
Authority: IE
Original assignee: Synthelabo
Priority date: 1982-11-22
Filing date: 1983-11-21
Publication date: 1984-05-22
Also published as: BE898277A; IE56282B1; AU559204B2; FR2536390A1; GB2130585A; IT1169131B; GB2130585B; GB8331038D0; FR2536390B1; NL8304000A; CH658049A5; IT8323803A0; DE3341983A1; IL70282A0; AU2155883A; LU85099A1; ZA838682B; JPS59108745A

Abstract

(S)(-) Betaxolol of the formula: <IMAGE> and its pharmaceutically-acceptable acid addition salts, are new compounds which are, in particular, useful for the treatment of cardiovascular diseases and glaucoma. (S)(-) Betaxolol can be prepared by reacting 4-(2-cyclopropylmethoxyethyl)phenol with the tosyl derivative of (S)-2-phenyl-5-hydroxymethyl-3- isopropyloxazolidine. [GB2130585A]

Description

"S ISOMER OF BETAXOLOL, ITS PREPARATION AND ITS APPLICATION IN THERAPY" The present invention relates to the S isomer of betaxolol, its preparation and its application in therapy, e.g. pharmaceutical compositions containing it.

The compound of the invention is the (S)(~) isomer of betaxolol corresponding to the formula: H and its phazmaceutically-acceptable acid addition salts.

The compound of the invention is prepared, according to a feature of the invention, by the process which comprises reacting 4-(2-cyclopropylmethoxyethyl)-phenol with the (S)-oxazolidine of the formula: OH I II 2 CHjOSOjjCgH^CH 2 6 4 3 in an organic solvent, such as dinethylfonnamide, in the presence of a base such as sodium hydroxide, potassium hydroxide or, preferably, sodium hydride. 4-(2-Cyclopropylmethoxyethyl)-phenol can be prepared in the manner described in Patent Specification No. 43645.

Pharmaceutically-acceptable acid addition salts of the S isomer of betaxolol, e.g. methanesulphonates, mandelates, fumarates, oxalates, maleates, malonates, citrates, hydrochlorides, hydrobramides and hydroiodides, may be obtained by methods known per se. for example by treatment of the isomer base with the appropriate acid in a solvent medium, e.g. an alkanol or ether, or mixtures thereof.

By the term 'methods known per se' as used in this specification is meant methods heretofore used or described in the literature.

The Example which follows illustrates the process of the invention.

EXAMPLE 22.lg (0.1 mol) of (S)-2-phenyl-5-hydroxymethyl-3-isopropyloxazolidine of the formula: Y f"V~C6H5 h_4-4 i s CH2QH (described by Baldwin et al-, J. Med. Chem. 1979, Vol. 22, No- 11) are dissolved in 37.5 al of pyridine, and 19.Og of tosyl chloride are added in portions, the temperature 5 being kept at about 25°C.

When the addition has ended, the reaction mixture is stirred for 2 hours at ambient temperature and a solution of 13.8g of I^CO^ in 75 ml of water is then added cautiously. The mixture is extracted 3 times with 100 ml 10 of CH2C12, the organic phase is dried with MgSO^ and filtered, and the filtrate is evaporated at a temperature below 50 °C, initially under a water pump vacuum and then under 0.1 mm of mercury. This gives 33-9g of an oil, which is used in the crude state for the subsequent reaction. 15 A solution of 17.3g (0.09 mol) of h-(2-cyclo- propylmethoxyethyl)-phenol in 50 ml of dimethylfonnaitu.de (DMF) is added dropwise to a suspension of 4.8g (0.1 mol) of 50% HaH in 50 ml of DMF, and the mixture is stirred J until the evolution of hydrogen has ceased. The mixture 20 is cooled using a bath of iced water, and a solution of 4 III - 4 - 33.9g of the previously obtained oil in 50 ml of DMF is added in portions; the mixture is then heated at 60-70°C for 2 hours. The mixture is left to stand overnight and heated again at a temperature of about 60°C for 4 hours. 5 The mixture is cooled, poured onto ice and extracted twice with diethyl ether. The ether phase is washed with water, dried over MgSO^ and filtered, and the filtrate is evaporated. The oil is taken up in water and the mixture is acidified with 50 ml of concentrated HCl, stirred for 10 1/2 hour at ambient temperature and then extracted twice with diethyl ether.

The aqueous phase is rendered alkaline with sodium hydroxide and extracted with diethyl ether. The ether phase is washed with water, dried over MgSO^ and 15 filtered, and the filtrate is evaporated.

The residual oil is taken up in diethyl ether, a stoichiometric amount of maleic acid is added to this solution, and the maleate salt of the (S)(—) isomer of betaxolol crystallises slowly. The maleate melts at 96°C, 20 [a]^p = -16.2° (C = 1.87 %; CH30H) (S)(-)-Betaxolol is prepared from its maleate salt by alkalinisation with a dilute solution of sodium hydroxide. It is an oil; [a]2® = -0.5° (C - 3.56*, CH30H) - 5 - The compound of the invention was subjected to pharmacological tests in the cardiovascular field and in the treatment of glaucoma. (1) Effect of (S)(-)-betaxolol maleate on the chronotropic ^ 5 and inotropic responses of guinea-pig atrium to isoprenaline, after depletion of the catecholamines. ^ The method used is similar to that recommended by O'Donnell and Wanstall (1979).

Guinea-pigs (Hartley), weighing 250 to 300g, are given 10 a subcutaneous injection of syrosingopine (5.0 mg/kg) approximately 18 hours before the start of the experiment, in order to cause depletion of catecholamines in the peripheral tissue reserves. The guinea-pigs are sacrificed by dislocation of the cervix and the whole hearts are 15 removed and placed in a Krebs solution, at airibient temperature (21°C), oxygenated with a mixture containing 95% of 0j and 5% of C02- The composition of the solution, in mM, is: NaCl 114.0; KC1 4.7; CaCl2 2.5; KH2P0^ 1.2; MgSO^ 1.2; NaHCO^ 25.0; glucose 11.7. Ascorbic acid 20 (1*1 mM) is added to the isoprenaline solutions in order to reduce the oxidation thereof. After the two atria have been separated, each is attached by its base to a hook fixed to a support. A wire is then attached to the apex of each atrium, and the atria are inmersed in an isolated * 25 organ bath containing 30 ml of Krebs solution at 37 C.

They are connected to a displacement force transducer * - 6 - (Grass, model TF03 C) by the wire attached to the apex, and are placed under a rest tension of 0.5g. The right atrium beats spontaneously whereas the left atrium is driven electrically by a current consisting of 2 millisecond 5 pulses of about 30 V (supramaximal voltage) delivered 120 times/ninute. The atrial rhythm and the contractile force are recorded on a polygraph (Grass 79B).

The atria are left to stand in the isolated organ bath for 30 minutes. The mechanisms of neuronal and extraneuronal 10 capture of the catecholamines are then blocked by keeping the atria in contact with phenoxybenzamine (50 (iM) for 30 minutes* After washing with Krebs solution, each preparation is sensitised by adding isoprenaline (0.3 |iM) 20 minutes before the first curve of concentration-effect of the 15 isoprenaline is plotted. Ihe isoprenaline is added to the bath in cumulative increasing concentrations (semi-log interval)- The maximum changes in the contractile force and the heart rate which are caused by each dose are the values used for analysing the results. 20 Approximately 45 minutes after the first curve of concentration-response to the isoprenaline has been plotted, when the parameters studied have returned to their initial values, the preparations are immersed for 30 minutes in a Krebs solution containing (S)(-)-betaxolol maleate (0.3 |iM). 25 Each change in the atrial rhythm or the contractile force which is generated by the isoprenaline is expressed - 7 - as a percentage of the response of the atrium to a aupraniaximum dose of isoprenaline. A more detailed analysis of the results is only carried out if the second dose/effect curve is parallel to the control curve and if 5 the mayima of the two curves do not differ more than + 20%.

The pA2 values are calculated according to van Rossum (1963). The average pAg values are compared by variance analysis. The differences between the averages are considered to be significant when t corresponds to p<^0.05. 10 The pA2 value of the compound of the invention is - 8.76+0.06 in respect of the chronotropic effects on the isoprenaline (spontaneously beating atrium), and - 8.78 + 0.12 in respect of the inotropic effects (electrically stimulated atrium) of the isoprenaline. 15 (2) Effect of (S)(-)-betaxolol maleate on glaucoma.

Drops are prepared by dissolving a sufficient amount of the maleate salt of the compound of the invention in distilled water so as to give solutions containing 0.1%,0.5%, 0.75% and 2% of compound. 2 drops of solution are 20 adninistered to a normal rabbit eye and to an ocularly hypertensive rabbit eye. The intraocular pressure of the two rabbit eyes (normal and ocularly hypertensive) is reduced significantly and measured at intervals of 6 hours. The S isomer of betaxolol and its pharmaceutically-25 acceptable salts can be used for the treatment of cardiovascular diseases and, in particular, for coronary complaints, complaints affecting the myocardium and disorders of the heart rate, and for the treatment of glaucoma.

The invention consequently includes pharmaceutical 5 compositions containing (S)(->) betaxolol, or a pharmaceutically-acceptable acid addition salt thereof, in combination with any excipient suitable for oral, rectal or parenteral administration.

Exanples of suitable pharmaceutical forms are tablets, 10 coated tablets, gelatine capsules, ordinary capsules, cachets, solutions and suspensions to be taken orally, suppositories and stabilised and/or buffered injectable solutions, prepared in advance or for immediate use.

The daily dosage can range from 5 to 50 mg of (S)(-) 15 betaxolol.

For the treatment of glaucoma, the concentration of the eye solutions can range from 0.25 to 3% of (S)(-) betaxolol.

Claims

1. * (S)(-) Betaxolol of the foxmula: OH R and its pharmaceutically-acceptable acid addition salts.

2. > (S)(-) Betaxolol maleate.

3. A process for the preparation of (S)(-) betaxolol which comprises reacting 4-(2-cyclopropylaiethoxy-ethyl)phenol with the (S) oxazolidine of the formula: in an origanic. solvent in the presence of a base.

4. A process according to claim 3 in which the organic solvent is dimethylformamide and the base is sodium hydride. 5 i 10 15 - 10 -

5. A process according to claim 3 or 4 followed by the step of converting (S)(—) betaxolol so obtained by a method known per se into a pharmaceutically-acceptable acid addition salt.

6. A process for the preparation of (S)(-) betaxolol, and pharmaceutically-acceptable acid addition salts thereof, substantially as hereinbefore described with especial reference to the foregoing Example.

7. Pharmaceutical compositions which comprise, as active ingredient, (S)(~) betaxolol, or a pharmaceutically-acceptable acid addition salt thereof, in association with a pharmacologically-acceptable excipient.

8. (S)(-) Betaxolol and pharmaceutically-acceptable acid addition salts thereof for use as medicaments and, more especially, for the treatment of cardiovascular diseases and, in particular, for coronary complaints, complaints affecting the myocardium and disorders of the heart rate, and for the treatment of glaucoma. Dated this the 21st day of November, 1983 EXECUTIVE 27 Clyde Boad,-'Ballsbridge, Dublin 4 AGENTS FOR THE APPLICANTS. t