NO156651B - ANALOGUE PROCEDURE FOR THE PREPARATION OF COMPOUNDS SUITABLE FOR TREATMENT OR PROPHYLAXATION OF HEART DISEASES. - Google Patents

Description

The present invention relates to an analogue method of compounds which are suitable for the treatment or prophylaxis of heart diseases. More particularly, the invention relates to β-adrenergic blocking agents, so-called β-blockers.

The therapeutic and prophylactic use of compounds that block sympathetic nervous stimulation of islet-adrenergic receptors in the heart, lungs, blood system and other organs is well known. Typically, such compounds are administered therapeutically to patients suffering from ischemic heart disease or myocardial infarction for the purpose of reducing cardiac work, i.e. heart rate and force of contraction. That to

reducing the work of the heart reduces the oxygen demand, and can increase the oxygen supply. Thus reducing the work of the heart can support the prevention of further tissue damage and can relieve angina pectoris.

6-adrenergic stimulation can also enhance or cause arrhythmias due to increased levels of catecholamines. Thus, island-blocking agents can be used to reduce the risk of arrhythmias.

Compounds have been discovered that selectively block iso-adrenergic receptors in various organs. ø-receptors in the heart are generally designated as ø^-receptors and those associated with vasodilatation and bronchodilation are ø2-receptors. Selective island-blocking agents are preferred for treatment

of cardiac diseases, because they may have less potential to cause hypertension or bromococonstriction.

A number of ø1 selective adrenergic* blocking agents are described by L.H. Smith in "J. Appl. Chem. Biotechnol.", 28, 201-212 (1978). Most such compounds are structural variations of 1-amino-3-aryloxy-2-propanol.

Until now, the emphasis for islet-blocking research has been on developing compounds that can be entered into in cardiac patients over a longer period of time. However, it has often been desirable in critical cases to use fast-acting agents as well. for the purpose of reducing cardiac activity or improving rhythmicity during a cardiac crisis, e.g. during or shortly after a myocardial infarction.

Conventional e-blocking agents can be used for such treatment, but their duration of activity can be much longer than desired by the doctor. An e-blocking agent having a long duration of action does not allow an accurate control of the heart's work or immediate reversal of the e-blocking action, which may be necessary in emergency situations. If e.g. pumped out. amount from the heart becomes dangerously low, it is desirable to quickly reduce or eliminate the B-blocking effect. The palliative effect of available B-blocking agents can be counter-directed and greatly complicate the therapeutic decisions that the doctor has to make during emergency work with a cardiac patient.

There is thus a need for pharmaceutical preparations and methods which use 8-adrenergic blocking agents with a short duration of activity.

In respect this present invention relates to an analogous method for the preparation of a compound with the formula

in which

n is 1 or 2;

R is alkyl of 1 to 5 carbon atoms; and

R^ is alkyl of 1 to 5 carbon atoms,

or a pharmaceutically acceptable salt of the compound.

These compounds are produced by a phenol derivative with the formula

where R and n are as stated above, is reacted with epichlorohydrin to form a 1,2-epoxy-3-aryloxypropane derivative of the formula: where R and n are as stated above, and that the 1,2-epoxy-3-aryloxypropane derivative is reacted with an amine of the formula R-^-NH, where R-^ has the above meaning, and that the obtained compound is, if desired, converted into a pharmaceutically acceptable salt. Certain ester-containing 6-blocking compounds are known. Thus describes GB Ps. 2,046,259, Kyowa Hakko Kogyo Co., compounds of the formula

wherein A is hydrogen, methyl, phenyl, acetamido, nitro or

1 2 -CO2H, R is C(i-4) alkyl and R is isopropyl or butyl.

This reaction is preferably carried out in an alcoholic solvent identical to the ester adduct in order to prevent alcoholysis side reactions, when e.g. R 1 is methyl, the reaction solvent is preferably methanol.

The phenol derivatives used as starting substances in the reaction scheme as described above are generally commercially available compounds or they can be prepared by known methods. For the preparation of certain preferred compounds according to the invention, e.g. suitable starting materials

methyl 2-hydroxybenzoate, methyl (4-hydroxyphenyl) acetate, methyl 4-hydroxyphenylpropionate, etc.

The compounds produced according to the invention are preferably administered parenterally, e.g. by intravenous injection or intravenous infusion. Formulations for intravenous injection preferably include the active compound as a soluble acid addition salt in a suitable buffered isotonic solution.

The dosage administered to a patient and the duration of the infusion depend on the needs of the patient and the particular compound used. For shorter infusion periods, e.g. less than approx. 3 hours, the lasting effect is assumed to be determined both by the metabolic effects and distribution phenomena. For relatively long infusion periods, e.g. more than approx. 3 hours, the duration is believed to depend mainly on metabolic effects. Although the compounds produced according to the invention gene-

are generally useful for short-term infusion therapy, certain compounds are preferred for longer infusion durations. The compounds have been found to be generally non-toxic within conventional dosage ranges. Dosages of approx. 0.001 to approx. 100 mg per

kg body weight per hour is generally used, while the preferred dosages range from approx. 0.01 to approx. 10 mg per kg body weight

per hour.

The invention shall be illustrated in more detail with reference to the

non-limiting examples.

EXAMPLE I

This example describes an experimental procedure for the preparation of the compound of the formula

Methyl 3-(2-hydroxyphenyl)propionate

A solution of 17 g (0.1 mol) of 3-(2-hydroxyphenyl)propionic acid in 500 ml of methanol and 2 ml of concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was refluxed for 27 hours and the sieves were replaced at 24 hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 ml toluene and extracted with 3 x 100 ml water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to give a clear oil. The NMR spectrum was consistent with the assumed structure and the material was used directly in the next step.

Methyl 3-[2-(2,3-epoxypropoxy)phenyl]propionate

A mixture of the above described oil, 0.2 moles of potassium carbonate and 31 ml (0.4 moles) of epichlorohydrin in 250 ml of acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated. The residue was taken up in 100 ml of toluene and washed with 100 ml of 1.0 N NaOH and 2 x 100 ml of water. The toluene phase was dried over magnesium sulfate and evaporated to provide the crude product as an oil. The purification was effected by vacuum distillation (156°C, 0.4 mm pressure). The NMR spectrum of the clear oil obtained was consistent with the assumed structure and the elemental analysis was consistent with the molecular formula <C>13<H>16°4<C1>-

Methyl 3-[ 2-[ 2- hydroxy- 3-( isopropylamino) propoxy] phenyl] propionate oxalate

A mixture of 50 g (0.21 mol) of methyl 3-[2-(2,3-epoxypropoxy)-phenyl]propionate and 100 ml of isopropylamine in 100 ml of methanol was heated to reflux for 4 hours. The reaction medium was then evaporated bg the resulting oil recrystallized as the oxalate salt from methanol:ether. The product melted at 92-94°C and the NMR spectrum and elemental analysis were consistent with the assumed structure.

EXAMPLE II

Several compounds were tested for e-blocking activity in vitro using guinea pig right atria and guinea pig tracheal strips placed in a tissue bath containing oxygenated (95% O 2 - 5% CO 2 ) Krebs physiological saline solution at 37°C. Each tissue was clamped between an attached glass rod and a Statham Universal Transducer connected to a Beckman printer. Atria were allowed to beat spontaneously under load voltages

about. 0.5 g. Changes in the rate of response to isoproterenol, a standard B receptor agonist, were measured in the absence and presence of the test compound. Spiral strips of guinea pig trachea were tensioned under 5 g resting tension and incubated with phentolamine, tropolone and cocaine. Active tension was generated by addition of carbachol (3.0 x 10 -7M) and reductions in tension in response to isopoterenol were quantified. Cumulative concentration response curves were set up with isoproterenol both before and after 60 minutes incubation of the test compounds with atria and trachea. Compounds with B-blocking action (shifted concentration response curves to the right. The blocking potency of the test compounds was assessed by evaluating pA2~ values (-log Kg) by the method according to Furchgott ("The Pharmacological Differentiation of Adrenergic Receptors", Ann. N.Y. Acad (Sei., 139:553-570, 1967). Comparison of the blockade of right atrial and tracheal responses to isoproterenol permits an assessment of the cardioselectivity of the test compounds, meaning that cardioselective compounds are relatively more effective in blocking the atrial degree than tracheal. -the force response to isoproterenol.The degree of cardioselect-

j tivity was judged from the ratio Kg-trachea/Kg-atria 10(PA2~atr<ia >-pA2~trachea) . Efc fQj-^Q^^ more than one suggests cardioselectivity.

The results obtained with several test compounds are contained in Table I. All compounds are B-blockers.

in

EXAMPLE III

The duration of the B-blockade was determined in vivo using pentobarbital-anesthetized dogs instrumented for heart rate measurement using a Beckman cardiotachometer controlled electronically by a phasic aortic blood pressure signal. Both vagus nerves were cut in the neck region and the animals were ventilated mechanically. Two experimental designs were used. The first used a 40 minute infusion of the test compound and the second a 3 hour infusion of the test compound. In the 40-minute model, isoproterenol was infused into a saphenous vein at a rate of 0.5 mg/kg/minute to induce a 6-receptor mediated tachycardia. In the 3-hour infusion model, bolus doses of isoproterenol (0.5 g/kg) were used to

ensure the degree of B-blockade and recovery from ø-blockade after completion of the infusion. Doses were set at 10 minute intervals and were given before, during and after infusion of the test compounds. Various doses of the test compounds were then infused into a femoral vein over 40 minutes. This infusion was then terminated and recovery from the blockade was quantified. The percentage inhibition of the heart rate response to isoproterenol after a 40 minute infusion of the test compound was assessed along with the total cumulative doses received during the 40 minute period.

This cumulative dose is expressed in mg/kg and is an indicator of potency. The time period required for 80% heart rate recovery for each dose of the test drug was also measured to quantify the duration of action. Potency and duration of action were normalized to a level of 50% inhibition of the isoproterenol response via least squares regression of data from each animal. The test compound was dissolved in 0.9% NaCl and infused at a rate of 0.05 ml/kg/minute or less. The infusion rate was adjusted so that the degree of isoproterenoline inhibition at the end of the 3-hour infusion gave an average of approx. 50% of the control. The results are shown in Table II.

EXAMPLE IV

This example describes experiments that show the disappearance of test compounds produced according to the invention in vitro in human whole blood, dog whole blood and dog liver homogenate. The degree of disappearance of the test compound is expressed as the half-life (T^), which is the time period during which half of the original amount of the tested compound disappears. In each experiment, 1 ml of a solution containing 5 µg of the test compound was tested against 1 ml of whole blood or 1 ml of a 33% (w/v) liver homogenate. The samples were incubated in a Dubnoff shaking metabolic incubator

1 2.5, 5.0, 10.0, 20.0, 30.0 and 60.0 minutes at 37°C. At the indicated time periods, the sample mixtures were removed from the incubator and transferred to a 0°C ice bath. Acetonitrile (2 ml)

was added immediately and the mixtures were then mixed to stop enzymatic hydrolysis. Zero-time samples were prepared by adding 2 ml of acetonitrile to denature the proteins before adding the test compounds. After centrifugation to precipitate denatured proteins, 2 ml of the supernatant was removed and analyzed by high performance liquid chromatography using a mobile phase of 60% acetonitrile/40% 0.05M sodium phosphate buffer (pH 6.6), a U.V. detector, and a Waters and Bondapak phenyl column. The half-life of the test compound was determined graphically by plotting the decrease in concentration as a function of time. The results of the experiments are shown in Table III.

Claims (1)

Analogy method for the preparation of a therapeutic active compound with the formula there a is 1 or 2; R is alkyl of 1 to 5 carbon atoms; and R 1 is alkyl of 1 to 5 carbon atoms, all a pharmaceutically acceptable salt thereof, characterized in that it comprises reacting that phenol derivative with the formula Jer R and n are as indicated above, with epichlorohydrin under Proof of a 1,2-epoxy-3-aryloxypropane derivative of the formula: where R and n are as stated above, and that the 1,2-epoxy-3-aryl-oxypropane derivative is reacted with an amine of the formula R-^-NH. where R 1 has the above meaning, and that the compound obtained is, if desired, converted into a pharmaceutically acceptable salt.