SK77695A3 - Derivative of 3,7-diazabicyclo (3,3,1) nonane and method of preparation - Google Patents

Abstract

Treatment of supraventricular arrhythmias comprises admin of N-isobutyl-N'-isopropyl-9,9-pentamethylene-3,7- diazabicyclo(3,3,1)nonane (I) or addn salt. (I) has the alternative name bertosamil and is known from EP103833.

Description

Technical field

The present invention relates to the use of N-isobutyl-N'-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3.3.1] nonane (Obertosamil) and its physiologically acceptable acid addition salts for the preparation of a novel pharmaceutical composition for the treatment of supercentricular arrhythmias .

BACKGROUND OF THE INVENTION

European Patent Application No. 0 103833 describes 9.9, N, N'-tetrasubstituted-3,7-diazabicyclo [3.3.1] nonane derivatives which save heart oxygen consumption, affect heart rate and have a rhythmic effect on the heart. Due to the high incidence of heart disease, there is an attempt to develop new pharmaceutical compositions for the treatment of cardiac rhythm disorders which originate in the atrium of the heart.

SUMMARY OF THE INVENTION

The present invention provides the use of N-isobutyl-N'-isopropyl

9.9-Pentamethylene-3,7-diazabicyclo [3.3.11] nonane according to formula

and physiologically acceptable acid addition salts thereof for the manufacture of a pharmaceutical composition for the treatment of supercentricular arrhythmias.

Suitable physiologically acceptable acid addition salts of bernsamil are salts with inorganic acids such as hydrohalic acids or with organic acids such as lower aliphatic inonocarboxylic or di-carboxylic acids.

for example acetic, fumaric or tartaric acid, or aromatic carboxylic acids, for example salicylic acid.

The compounds used according to the invention for the treatment of superciliary arrhythmias are within the scope of the European derivatives described

9.9, N, N'-tetrasubstituted 3,7-diazabicyclo [3.3.1] nonane, which save heart oxygen consumption, affect heart rate and have a rhythmical effect on the heart. Such compounds may be prepared by the method described in the patent application or by analogous methods.

It is known from said application. The compounds according to claim 1, wherein the compounds exhibit an antiarrhythmic action with a favorable ratio of antiarrhythmic or refractory heart-prolonging effects and negative isotropic side effects. The rhythmic contractions of the cardiac muscle depend heavily on the ability to re-excite (i.e., the refractory phase) and the duration of the electrical excitation (i.e., depolarization) of the cardiac muscle tissue. The effect of chemicals on the heart rhythm is examined by measuring the electrophysiological parameter of, for example, the refractory phase and the duration of depolarization (i.e., the action potential time). The refractory phase of the heart is determined by the mostly flowing potassium bearing ion across the cell membranes. In particular, the transient potassium output (10) and the delayed potassium output (Ik) play a role. Ito is a fast activating outflow of ions, time dependent on the inactivating flux of potassium ions. It is a repolarizing current in the previous phase and is therefore physiologically important in tissues with previous repolarization. for example in atrial tissues. Ik is a slow activating outflow of potassium ions and is time independent. It is a repo l arcing current in late ventricular tissues. Blocking of refractory phase and time insensitive to undesirable

Surprisingly, the acid addition salts have been shown to act on the refractory in the late reparation. of these currents repo1ar i zác i e. In particular, by inhibiting the antiarrhythmic rhythm found, the Phase I phase and therefore has importance, for example, in tissues leading to prolongation in which the heart is external stimuli, or blocking effects.

that bertosamil and its selective elongation phase and the duration of depolarization of the atrial atrium. Research on the action of bertosamil and its acid addition salts on the refractory phase and depolarization of isolated guinea pig atrial and ventricular heart muscle preparations has been shown. that, despite the markedly prolonged effect on the atrium, there is no, or only a slight, shortening effect on the heart chamber. Research into the effect of bertosamil and its acid addition salts on the potassium output streams Tto and Ik confirm selectivity in favor of blockade of the output transient flow

Ito.

Selective delay of the arousal ability in the atrium found in bertosamila. which is a significant antiarrhythmic action, particularly in the heart atrium, makes bertosamil suitable for the treatment of arrhythmias that originate in the heart atrium. This offers a previously unexpected possibility of treating super-ventricular arrhythmias. The selective antiarrhythmic action of bertosamil and its acid addition salts on the atrial atrium and on the transient output potassium flow can be demonstrated by standard pharmacological tests in vit.ro.

The following pharmacological tests will further illustrate the invention.

A. Measurement of the action of a substance on the action potential refinery.

The tests are performed on the isolated phase and on the duration of the heart muscle tissue from the atrium and the guinea pig heart chamber.

The tissue pieces are mounted in a nutrient solution, through which oxygen bubbles are bubbled and two metal excitation electrodes induce continuous contractions by electrical pulses (2 Hz).

duration

0.5

The contraction or graphically records the accounts.

The functional refractory phase is for the shorter interval between the double electric pulse.

which is responsible for the double contraction. It is determined separately from the refractory phase of the atrial tissue of the chamber by varying the interval between the constant (driving) pulse and the additional test pulse. To test the effect of the test substance, the test substance is added to the nutrient solution and the refractory phases before and after the test substance are added to each other.

To measure the duration of the action potential, one microelectrode (in the form of a fine glass capillary filled with a 3 molar potassium chloride solution) is introduced into the cell

and the electrical activity at each contraction (action potential) is registered. Duration of action potentials

i the period of electrical excitation (depolarization) is determined before and after addition of the test substance to the nutrient solution.

Table I shows the results with 5 pmol / l hertosamyl.

Table 1

Test substance, dose

Influenced by bert.osamil. Symol / l.

prolongation of functional refractory sesame and hydrogenphosphate phase in ms salt of the heart atrial chamber ventricular +33

Test substance, dose

Effect of bertusani. Spinol / l.

prolongation of the action time and the hydrogen hydrogel in ms rata salt of cardiac anterior chamber +56

B. Measurement of ionic currents

Tests in isolated strains of guinea pigs and rats are performed by tensioning. Tto rat heart cells and guinea pig heart Ik cells are measured. The heart is washed with proteolytic enzymes (collagenase) to release connective tissue. The tissue is then mechanically compressed and thinned. after which the individual cells in the nutrient solution are separated on a vibrating bath. Subsequent centrifugation yields a suspension of cardiac muscle cells. Using the method of tensioning between the terminals for measuring the membrane currents, the microelectrode (in the form of a glass capillary filled with an electrolyte solution) connects the cells with an amplifier that delivers the membrane bias. If now the ionic current flows through the membrane («opening the ion channel of the protein) and shifts the membrane voltage, the amplifier compensates for this shift against the current, i.e. the voltage is so-called tightly clamped. The measured countercurrent corresponds to its physiological ion current with the opposite sign. The activation of different ion currents in the cell membrane characteristically depends on voltage and time. Therefore, by selecting a suitable voltage, different currents can be differentiated. In this way, the effect of the addition of the test compound in an amount of 1 µmol / L on the different streams is examined. The results obtained with bertosamil are shown in Table TI below.

Table II.

Test substance, dose

Treatment with bertose 1, 5 pmol / l.

blocking of ionic currents in% sesqu i hydrogenfumarate salt of previous value Ito *

Although ’*’ * ** outward-flow transit direct-outward flow

The results of the pharmacological tests show. that bertosamia is a pharmaceutically acceptable acid-selective salt thereof for the atrial atrium and is therefore suitable for the treatment of supercenrial arrhythmias. The doses administered may vary individually and vary depending on the condition to be treated and the dosing people and larger

In general, pharmaceutical forms comprising the form are suitable for administration to a mammal.

active ingredient in an amount of 50 to 150 mg per single dose.

According to the invention it may be. the active ingredient contained together with the pharmaceutical excipient and / or carrier in a solid or liquid pharmaceutical composition. Examples of solid compositions are for oral administration of tablets, dragees, capsules, powders or granules, or even lace. These pharmaceutical compositions may contain pharmaceutically acceptable inorganic and / or organic carriers. such as talc, milk sugar or starches alongside such pharmaceuticals

t. Liquid pharmaceutical compositions such as solutions, suspensions, or emulsions of the active ingredient may contain conventional diluents such as water, oils and / or suspending agents such as polyethylene glycols. The additives may contain other excipients, for example preservatives and flavorants.

The active ingredient may be mixed and formulated with the pharmaceutical excipients and / or carriers in a manner known per se. For the production of solid forms, the active ingredient can, for example, be admixed with the excipient and / or carrier in a known manner and can be granulated in wet or dry form. The granulate or powder may be directly filled into capsules or compressed into tablet cores in a known manner. These cores can optionally be processed into dragees in a known manner.

The following examples further illustrate the manufacture of pharmaceutical compositions. however, they are not intended to limit the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Tablets.

Ingredients Parts of bertosamil sesquihydrogen fumarate 100 Corn starch 100 Corn starch (per glue) 20 Precitol ato ^R Partial glycerin palmitate stearate) 5 Aerosil 200 ^H High disperse silicic acid) 1 talc 3 TOTAL 229

Production order

The active ingredient is mixed with an equal amount of corn starch in a mixer. The resulting mixture is moistened with a corn starch sizing agent in demineralized water and granulated. The wet granulate is passed through a 2mm mesh screen. it is dried at a temperature of 40 ° C and finally passed through a sieve with a mesh diameter of 1 mm C (Previ 11). After mixing the granulate with Precirol. Talc and highly disperse silicic acid are compressed to form 229 mg tablets so that each tablet contains 100 mg of active ingredient.

Example 2

The capsule.

ingredients

Parts of sesquihydrogen fumarate bertosami 1u 100 Avicel® (microcrystalline cellulose) 80 hydroxymethylpropylcellulose 20 talc 4

stearate magnesium 1 Aerosi 1 200 ^H High dispersive silicic acid) 6 TOGETHER 211 manufacturing prescription effective the substance is mixes with microcrystalline cellulose at the mixer. obtained the mixture is moisten with a solution hydroxy

methylpropylcellulose in demineralized water and granulated. The wet granulate is passed through a sieve with a mesh diameter of 1.6 mm (Frewitt), dried at 40 ° C, and finally through a sieve with a mesh diameter of 1 mm (Frewitt). After mixing the granules with talc, magnesium stearate and highly disperse silicic acid (Aerosil 200 ^R from Degussa), the mixture is always filled into hard gelatin capsules of size 1 each in an amount of 211 mg on an automatic capsule machine so that each capsule contains 100 mg of active ingredient.

Industrial usability

The use of N-isobutyl-N'-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3.3.1] nonane and its physiologically acceptable acid addition salts for the manufacture of a pharmaceutical composition for the treatment of supentricular arrhythmias.

Claims (2)

PATENT CLAIMS 1. Use of N-isobutyl-N'-isopropyl-9,9-pentamethylene-3,7- diazabicyclo [3.3.1] linonane of the formula I and its physiologically acceptable acid addition salts for the manufacture of a pharmaceutical composition for the treatment of supentricular arrhythmias. 2. A process for the preparation of a pharmaceutical composition for the treatment of super-ventricular arrhythmias, characterized by. The composition of claim 1, wherein the compound of formula I or a physiologically acceptable acid salt thereof is formulated with pharmaceutically acceptable excipients.