NO763555L - - Google Patents

Description

Method for the production of

1-(Trialkylamino)-3-phenylphenoxy-2-propanol quaternary salts.

The present invention relates to a method for the production of new 1-(trialkylamino)-3-phenylphenoxy-2-propanol quaternary salts of the general formula:

where R, R' and R" are alkyl radicals of 1-4 carbon atoms and X is the anion of a pharmaceutically acceptable non-toxic acid.

Preferred compounds are those wherein R and R' are methyl and R" is isopropyl. Particularly preferred are those compounds wherein R and R' are methyl, R" is isopropyl, X is halide, and the phenylphenoxy substituent is 2-phenylphenoxy.

Anions of suitable pharmaceutically acceptable non-toxic acids are the halides, namely chloride, iodide, bromide and fluoride, the ortho-, meta- and pyrophosphates, the sulphate and the alkyl sulphate where the alkyl radicals contain 1-4 carbon atoms, e.g. methyl sulfate and ethyl sulfate; benzenesulfonate, toluenesulfonate, acetate, lactate, succinate, maleate, tartrate, citrate, gluconate, ascorbate, benzoate and cinnamate. Other salts will preferably be prepared from these salts using ion exchange methods.

Particularly preferred anions are the iodide and the chloride.

The alkyl groups are straight-chain or branched groups with 1-4 carbon atoms including methyl, ethyl, propyl, isopropyl etc.

The new compounds of formula I are conveniently prepared by reacting tertiary amines of the general formula: where R and R' are alkyl radicals with 1-4 carbon atoms, with a compound of the general formula:

where the alkyl group contains 1-4 carbon atoms and X is a halide, sulfate or phosphate to form the quaternary compounds with the formula I.

An alternative method for preparing the compounds of formula I involves the reaction of a secondary amine of the general formula: where R has the meaning given above, with 2 molecular equivalents of a compound of the general formula:

where alkyl and X have the meaning given above.

It will be understood that when the first equivalent of the alkyl halide, alkyl sulfate or alkyl phosphate reacts with the secondary amine of formula (III), the tertiary amine of formula (II) is formed. This alternative method is thus used for compounds of formula (II).

The starting materials for the production of compounds of formula I are obtained by reacting (2, 3 or 4)-phenylphenol with epichlorohydrin and aqueous sodium or potassium hydroxide to form intermediates of the formula:

These intermediates are allowed to react with a primary alkylamine at reflux to form the corresponding secondary amines of formula (III). These intermediates can also be reacted with a suitable secondary amine to obtain the corresponding tertiary amines of formula (II).

It is clear that analogue production methods in which e.g. methyl group ends are added initially followed by addition of the isopropyl moiety, are available by proper choice of the particular amine at each step of the synthesis.

The compounds of formula I are useful because of their ability to reverse cardiac arrhythmia. They also have long-term activity and are effective against heart rhythm disturbances associated with myocardial ischaemia and infarction. The compounds are also advantageous compared to known anti-arrhythmic agents in that they unexpectedly lack the undesirable 3-adrenergic receptor blocking activity possessed by related compounds. A further advantage of the compounds prepared according to the present invention is their lack of local anesthetic activity and their relative lack of sustained cardiovascular depressant effects. The above-mentioned properties are demonstrated by the following tests: Local anesthetic activity: Female frogs (Rana pipiens) are killed and the hip-tibial muscle nerves (the sciatic trunk) are removed bilaterally and placed in Ringer's solution. Ringer's solution has the following composition expressed as millimol per liters: NaCl, 111; KCl, 2.7; CaCl 2 . 2 H 2 O, 1.4; and NaHCO 3 , 2.4. The solution has a pH value of 7.4 and is kept at a temperature of 25 C. In a series of experiments, the epineurium of the nerve is removed by the method according to Feng and Liu, J. Cell. Comp. Physiol. 23, 1 (1949).

The test method is described in greater detail by Lucchesi and Iwami, J. Pharmacol. Exp. Therap., 162, 49 (1968). Briefly, a sciatic trunk is passed through a plastic T-tube and the whole is placed in connection with platinum electrodes in a nerve chamber with a moist atmosphere. Ringer<1>'s solution can then be pumped at a constant rate into the vertical branch of the T-tube. The pump used also serves to remove liquid from the chamber at the same speed.-

Uniphasic spikes are recorded by crushing the part of the nerve that is in contact with the most distant recording electrode. The nerves are stimulated at their peripheral ends so as to produce a maximal peak potential for the A a group of fibers. Since the height of the voltage peak is an expression of the number of fibers conducting impulses and since the response is maximal, any reduction in the height of the voltage peak can be attributed to a blockage of some fibers in the treated segment. The influence potential is amplified through a preamplifier, displayed in an oscilloscope and photographed. The peak potentials are photographed every 15 minutes for 1 hour, stratifying by the time the drugs are allowed to act on the main nerve trunks. The percentage change from the control peak amplitude is calculated from the photographed markings.

Tests for beta-adrenergic receptor blockade: Dogs weighing 9.2-12.8 kg are anesthetized with intravenous pentobarbital sodium, 30 mg/kg. The right ventricle is exposed at the 5th right intercostal space, the pericardium is opened and a calibrated Walton-Brodie strain gauge is sutured to the right ventricle. The muscle segment between the foot of the load-measuring arc is stretched to a length that produces a contraction of maximum amplitude. The animals are given air that is in the room with a Håvard respirator. Femoral artery pressure is measured with a Statham P23dB pressure transducer. The heart rate is recorded with a Grass tachometer which is applied to the electrical signal from the load on the small intestine. Registrations are made on a Grass polygraph (model 7). All drugs are administered via a cannulated jugular vein.

Changes in heart rate and right ventricular isometric force to geometrically increasing doses of isoproterenol administered intravenously are determined before and after administration of test compounds. Each dog thus serves as its own control. Statistical analysis of the obtained data is carried out by pairwise comparisons as described by Hill (1961).

Studies of cardiovascular effects of experimental compound-hemodynamic measurements: Dogs (13.6-7.0 kg) are anesthetized with intravenous pentobarbital sodium, 30 mg/kg. Positive pressure respiration is maintained with a Harvard respirator. The cervical vagus is torn free and the jugular vein is provided with a cannula for the administration of drugs. The chest is opened through the fourth right intercostal space, the pericardium is opened and fixed with suture to the chest wall so that a support for the heart is formed. A calibrated Walton-Brodie strain gauge is sutured to the right ventricle. The heart rate is recorded using a cardiotachometer

which is deposited by the electrical signal from the load measuring arc. Blood pressure is measured from a cannulated femoral artery using

a Statham P23dB pressure transducer. Cardiac output is measured using the thermal dilution method using a flow-directed balloon catheter containing a thermistor near its distal end (Swan-Ganz thermal dilution catheter). The distal end of the balloon catheter is advanced until it is wedged in the pulmonary artery. The electrical signal from the thermistor is delivered to a Columbus Instrument Cardiac Output Computer. The proximal port of the flow-directed catheter is placed in the right heart chamber. Cardiac effect is achieved by rapid injection of 2.0 ml at room temperature of 0.9% sodium chloride solution into the right heart chamber. Each determination of cardiac output is the mean of three separate measurements. After obtaining satisfactory baseline recordings, the test compound is infused via the jugular vein at a rate of 5 mg/min. Measurements of the various hemodynamic parameters are taken when cumulative doses of 1.0, 5.0 and 10.0 mg/kg are administered to each of the animals.

All data are expressed as means + S.E. and analyzed

by means of paraanalysis.

Isolated papillary muscles:

Right ventricular papillary muscles are rapidly removed from cats (3.7 - 5.2 kg) anesthetized with pentobarbital sodium, 30 mg/kg intraperitoneally and suspended in a 50 ml organ bath. The lower non-stage-containing end of the muscle is held with a spring-loaded Lucite clip attached to a rigid stainless steel rod. The superior stage-containing end of the muscle is ligated with a short length of 4-0 braided surgical silk thread that is connected to a calibrated Grass FT-03 force transducer. The muscles are stimulated electrically through electrodes at a frequency of 30/min., with square wave stimuli of 1.0 msec. duration and a voltage that is 10% higher than the threshold value. The muscle baths are filled with a solution of the following compositions, expressed as mM/litre: Na<+>, 143, Ca<++>2.5, K<+>5.9, Mg<++>1.19, Cl" 126, HC03~ 25.4, HP04~ 1.19, and Dextrose 5 mM and adjusted to a pH value of 7.4. The solution is maintained at a temperature of 32.5°C and bubbled through with 95% O 2 and 5 % CO2.

Each muscle is stretched to the peak of its longitudinal active tension curve and is allowed to stabilize for a period of 2 hours before being exposed to increasing concentrations of the test compound. Data are expressed as % of initial control force per mm<2> cross-sectional area and analyzed by paranolysis. The electrical signal from the force transducer is electronically differentiated to obtain the force development ratio, dF/dt, expressed as

2

g/sec./mm .

Ouabain-induced arrhythmias in anesthetized dogs:

Male mixed breed dogs (8.0 - 13.5 kg) are anesthetized with intravenous pentobarbital sodium, 30 mg/kg. Blood pressure is measured from the femoral artery with a Statham pressure transducer. All drugs are administered into the cannulated left external jugular vein. The right vagus nerve is incised and its distal end is stimulated with 1.0 msec. square wave stimuli at a frequency of 4 0 Hz at 6.0 - 8.0 V.

Ventricular tachycardia is induced by administration of ouabain, 40 ug/kg, i.v., followed for 30 min. of 20 yg/kg and every 15 min. then by a further 10 yg/kg until ventricular tachycardia is induced.

The criteria used to determine antiarrhythmic activity are: 1) reversion to normal sinus rhythm for a period of not less than 30 min., 2) failure to stimulate the distal right vagus nerve for exposure of automatic ectopic ventricular activity during vagal-induced sinoatrial arrest, and 3) reversal of abnormal rhythm after intravenous administration of insulin, 80 U, to ensure continued presence of ouabain in concentrations sufficient to induce cardiotoxicity. Electrocardiograms are continuously monitored on an oscilloscope and all recordings are made on a Grass polygraph (model 7).

Ventricular arrhythmias after coronary artery ligation: One-stage ligation: Dogs (8.6 - 16.4 kg) are anesthetized with pentobarbital sodium, 30 mg/kg, i.v. and is allowed to breathe using a Harvard respirator. The heart is exposed through the 5th intercostal space. The pericardium is opened and attached to the chest wall so that the heart is supported. The left anterior descending coronary artery is dissected free at a point near its origin. A silk suture is passed under the blood vessel and the free ends are passed through a short polyethylene tube. The artery can be closed by pressing the tube on the blood vessel while simultaneously pulling on the free ends of the suture. The closure can be terminated and blood perfusion continued by releasing the suture and pulling the tube away from the blood vessel. In these experiments, a sharp occlusion of the anterior descending coronary artery is maintained for a period of 20 min. after which the closure is lifted.

Two groups of animals are studied: control animals, which receive a saline infusion; and animals treated with the test compound at a dose of 10 mg/kg i.v. Electrocardiogram and femoral artery pressure are recorded on magnetic tape (Harvard Physiological Tape Recorder) for subsequent analysis and recording on a Grass polygraph (model 7).

Two-stage restraint: Mixed breed dogs (10.8 - 12.8 kg) are anesthetized with intravenous pentobarbital sodium, 30 mg/kg and placed on positive pressure ventilation with room air via a cuffed endotracheal tube. Under aseptic conditions, a thoracotomy is performed in the 5th, left intercostal space and a 5-8 mm segment of the left, anterior descending coronary artery is dissected free at a point just below the edge of the left atrial appendage. A double underligature or ligature is passed under the artery and the blood vessel is closed in two steps according to the method described by Harris, Circulation, 1, 1318 (1950). Sterile catheters (0.040 in I.D.) are placed in the external carotid artery and the left carotid artery. These are exposed via a small puncture wound in the neck and kept open by periodic flushing with sterile heparin solution. The animals are studied 24 and 48 hours later in an unanesthetized state. Electrocardiogram and arterial blood pressure are recorded continuously while the animals are supported by a harness and kept in a quiet environment. The test compound is administered at a constant infusion rate of 5 mg/min. via the catheter in the jugular vein. The electrocardiographic recordings are analyzed according to the method of Moran et al. (1962), whereby only heartbeats of sinoatrial origin are considered normal and all other QRS complexes are classified as ectopic.

Determination of ventricular fibrillation threshold value:

These experiments are carried out on mixed breed dogs

(10.2 - 11.6 kg) anesthetized with pentobarbital sodium, 30 mg/kg, i.v. The animals are maintained on positive pressure respiration using a Harvard respirator pump. The heart is exposed by thoracotomy in the 5th intercostal space and suspended in a pericardial support. The electrical diagram is continuously monitored on an oscilloscope.

Double bipolar silver-silver-chloride electrodes embedded

in an acrylic sheet is attached by means of suture to the surface of the right ventricle. One pair of electrodes delivers the basic pacing stimulus while the other pair of electrodes delivers a train of impulses. The sinoatrial node is crushed and the heart rate is maintained by electrical pacing of the ventricle at a rate of 2 eps. The ventricular fibrillation threshold value is determined by delivery of a train of impulses during the ventricular vulnerable_period starting at 50 msec. after ventricular activation and lasts 250 msec. Impulse train, 60 Hz, 2 msec. duration, is synchronized to the ventricular . "pacing" stimulus and is delivered 50 msec. after every sixth main heartbeat. The supplied current is measured directly on an oscilloscope by recording the voltage drop across a 100 ohm resistor in series with the electrodes. The current strength is increased in steps of 0.5 mA until a ventricular fibrillation develops. The ventricular fibrillation threshold value is defined as the smallest current in milliamps (mA)

of the test pulse that induces ventricular fibrillation. When fibrillation results, the heart is immediately defibrillated using a capacitor-type DC defibrillator (Physio-Control.L Series 70). Threshold values are determined before and after administration of test compound, 10 mg/kg. The results are compared using the Student's t-test for pairwise comparisons.

The new compounds prepared according to the present invention can be combined in preparations with pharmaceutically acceptable carriers. These preparations can be administered either orally or parenterally. For oral administration, tablets, capsules, dragees, pills or powders are suitable, while aqueous solutions, non-aqueous solutions or suspensions are suitable for parenteral administration. Acceptable pharmaceutical carriers are e.g. gelatin capsules, sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose and cellulose acetate phthalate, gelatin, talc; calcium phosphate such as dicalcium phosphate or tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; acacia polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma; agar; alginic acid; benzyl alcohol; isotonic saline and phosphate buffer solutions as well as other non-toxic compatible substances.

The preparations can also be used in combination with other known pharmaceutical agents. They can e.g. used together with known anti-anginal agents such as long-acting nitrites. They can also be used in combination with other known anti-arrhythmic agents such as quinidine. Furthermore, they can be used together with known hypotensive agents.

The invention shall be further illustrated by the following examples where the quantity of materials is in parts by weight if parts by volume are not specified.

Example 1

34.0 g (0.20 mol) of 2-phenylphenol and 10.2 g (0.25 mol) of sodium hydroxide were dissolved in 250 ml of water. The reaction mixture was cooled in ice and 25.0 g (2.27 mol) of epichlorohydrin was added

slowly while stirring. Stirring was continued at room temperature for approx. 42 hours. Then the mixture was extracted with chloroform and the chloroform extracts were washed with water until neutral reaction. The chloroform extract was dried over anhydrous potassium carbonate and the solvent was evaporated under reduced pressure. This gave 2,3-epoxy-1-(2-phenylphenoxy)propane as a blue-green oil.

Example 2

Substitution of an equivalent amount of 3-phenylphenol in the procedure of Example 1 gave 2,3-epoxy-1-(3-phenylphenoxy)-propane as an amber oil.

Example 3

Substitution of an equivalent amount of 4-phenylphenol and replacement of sodium hydroxide with potassium hydroxide in the procedure of Example 1 gave 2,3-epoxy-1-(4-phenylphenoxy)propane as a white solid melting at ca. 112-116°C.

Example 4

22.7 g (0.1 mol) of 2,3-epoxy-1-(2-phenylphenoxy)propane was dissolved in 30 ml of methanol. Then 15 ml (0.2 mol) of methylisopropylamine was added slowly to the reaction mixture while stirring. The mixture was refluxed on a steam bath for 48 hours, after which the solvent and excess amine were evaporated under reduced pressure. The residue was dissolved in 200 ml of ether and the solution was washed with water. The ether phase was extracted with 5% aqueous hydrochloric acid and the aqueous extracts washed once with ether. The aqueous phase was neutralized with ammonium hydroxide and then extracted with methylene chloride. The methylene chloride extract was dried over anhydrous potassium carbonate and the solvent evaporated under reduced pressure to give 1-(N-isopropyl-N-methylamino)-3-(2-phenylphenoxy)-propan-2-ol as a blue-green oil.

Example 5

When an equivalent amount of 2,3-epoxy-1-(3-phenylphenoxy)propane was used in the process of Example 4, 1-(N-isopropyl-N-methylamino)-3-(3-phenylphenoxy)-propane was obtained -2-ol as an amber colored oil.

Example 6

By using an equivalent amount of 2,3-epoxy-1-(4-phenylphenoxy)propane and 30 ml of a 1:1 methanol-chloroform solution in the procedure of Example 4, 1-(N-isopropyl-N- methyl-amino)-3-(4-phenylphenoxy)propan-2-ol obtained.

Example 7

To a solution of 10.0 g (0.033 mol) 1-(N-isopropyl-N-methylamino)-3-(2-phenylphenoxy)propan-2-ol and 30 ml of acetone placed in a pressure vessel cooled in a bath of dry ice and acetone, 30 ml of methyl chloride was added. The container was closed and the mixture stirred at room temperature for 8 days, after which the mixture was again cooled in a bath of dry ice and acetone. The container was slowly opened to reduce any excess pressure and the solvent and excess methyl chloride were removed by evaporation under reduced pressure. The remaining material was dissolved in 30 ml of absolute ethanol and then evaporated under reduced pressure. This was repeated and the residue was crystallized from anhydrous acetone to give [3-(2-phenylphenoxy)-2-hydroxypropyl]isopropyldimethylammonium chloride, m.p. about. 124 - 127°C.

Example 8

Using an equivalent amount of 1-(N-isopropyl-N-methylamino)-3-(3-phenylphenoxy)propan-2-ol in the procedure of Example 7 gave [3-(3-phenylphenoxy)-2-hydroxypropyl] isopropyl-dimethylammonium chloride, m.p. about. 254-256°C.

Example 9

By using an equivalent amount of 1-(N-isopropyl-N-methylamino)-3-(4-phenylphenoxy)propan-2-ol in the procedure of Example 7, [3-(4-phenylphenoxy)-2- hydroxypropyl]isopropyl-dimethylammonium chloride, obtained, m.p. about. 254-256.5°C.

Example 10

By using an equivalent amount of dimethylamine instead of methylisopropylamine as used in example 4 and then following the procedure in this example and in example 7, [3-(2-phenylphenoxy)-2-hydroxypropyl]trimethylammonium chloride was obtained.

Example 11

By using an equivalent amount of ethylisopropylamine in place of methylisopropylamine as in Example 4 and then following the procedures set forth in Example 4 and Example 7, [3-(2-phenylphenoxy)-2-hydroxypropyl]ethylisopropylmethylammonium chloride was achieved.

Example 12

By using an equivalent amount of methyl iodide in the method according to example 1_, [3-(2-phenylphenoxy)-2-hydroxypropyl]isopropyldimethylammonium iodide was obtained.

Claims (5)

1. Method for preparing a compound of the formula: where R, R<1> and R" are lower alkyl of 1-4 carbon atoms, inclusive, and X is the anion of a pharmaceutically acceptable non-toxic acid, characterized in that / one compound of the formula where R and R' are alkyl radicals with 1-4 carbon atoms, are reacted with a compound of the general formula: where the alkyl group contains 1-4 carbon atoms and X is a halide, sulfate or phosphate. 2. Process according to claim 1, characterized in that methyl chloride is used as alkyl halide. 3. Process according to claim 1 for the production of [3-(2-phenylphenoxy)-2-hydroxypropyl]isopropyldimethylammonium chloride, characterized in that 1-(N-isopropyl-N-methylamino)-3-(2-phenylphenoxy) propan-2-ol is reacted with methyl chloride. 4. Process according to claim 1 for the production of [3-(3-phenylphenoxy)-2-hydroxypropyl]isopropyldimethylammonium chloride, characterized in that 1-(N-isopropyl-N-methylamino)-3-(3-phenylphenoxy) propan-2-ol is reacted with methyl chloride. 5. Process according to claim 1 for the production of [3-(4-phenylphenoxy)-2-hydroxypropyl]isopropyldimethylammonium chloride, characterized in that 1-(N-isopropyl-N-methylamino)-3-(4-phenylphenoxy)propane -2-ol is reacted with methyl chloride.