DE3705055C2 - - Google Patents

Description

The invention relates to the use of 2- (3-fluoro-4-methylphenylimino) imidazolidine and its pharmacologically acceptable acid addition salts for the treatment of coronary heart disease.

It is known that 2-phenyliminoimidazolidines and their acid addition salts have valuable pharmacological properties. Thus, German Offenlegungsschrift No. 28 54 659 discloses the preparation of 2- (3-fluoro-4-methylphenylimino) imidazolidine, its acid addition salts and its processing into pharmaceutical applications. The published patent application states that the compounds described there bring about a presynaptic stimulation of the peripheral α- adrenoreceptors and thereby exert a peripheral neurosympathetic and neurovagal transmission inhibition. They are preferably suitable for migraine prophylaxis.

It has now surprisingly been found that 2- (3-fluoro-4-methylphenylimino) imidazolidine and its Acid addition salts for the treatment of coronary Heart disease can be used.

In experiments on the dog it could be shown that the above connection sympathetic conditional poststenotic coronary constrictions and the case occurring also sympathetically triggered oxygen-consuming myocardial stimulation inhibits.

Pharmacological examination methods

Under physiological conditions, the Myocardial perfusion through local metabolic factors adapted to the current needs.  

The influence of the autonomic nervous system is insignificant or is compensated by the local regulatory mechanisms. In contrast, under pathological conditions, ie when the metabolic possibilities of coronary expansion (coronary reserve) are exhausted, the activation of α ₂-adrenoceptors causes an increase in coronary resistance. In coronary patients, such a condition is likely to occur in poststenotic vascular sections during exercise. Increases in local interstitial potassium ion concentrations and accumulation of metabolic products induce sympathetic reflexes that are coronary -stringing and aggravate the situation by stimulating myocardial metabolism. In anesthetized dogs, such a condition can be achieved by mechanically restricting the blood flow in the circumflex branch, with the sympathetic tone increasing over time and the coronary resistance increasing in the supply area of the vessel.

method

Five mixed breed male dogs in weight from 32-37 kg were given with 2 mg / kg morphine hydrochloride and 0.5 mg / kg atropine sulfate i. m. pretreated. 90 min later, hexobarbital sodium became a mild anesthetic for intubation i. v. injected. After that and each hour, 2 ml / animal piritramide (= 15 mg Dipidolor®, 2 ml / animal Thalamonal® (= 0.1 mg Fentanyl base + 5 mg droperidol) and 0.3 mg / kg Alcuronium chloride i. v. to neuroleptanalgesia administered.  

After the insertion of the tracheal tube continuous nitrous oxide (4: 1) ventilation by an Engström respirator. The O₂ content and the O₂ saturation of the arterial and coronary venous Blood, the arterial partial pressures of O₂ and CO₂ and the acid-base balance, as well as the CO₂ content in the exhaled air, hemoglobin and Hematocrit was determined regularly and remained during the trial period within physiological Values. The ventilation was based on the CO₂ content of Expirationsluft and after the arterial blood gas values regulated. To avoid metabolic acidosis and maintaining physiological values constantly 2-3 drops / min physiol. Saline, Macrodex 6% E, normofundin and glucose 5 i. v. administered.

The pulsatile aortic pressure was transmitted via a into the brachial artery. integrated Rüschelit® catheter in conjunction with a pressure transducer and a pressure intensifier registered on a multi-channel recorder. With an over the brachial artery dext. and aorta in the left ventricle advanced Millar catheter PC 350, the pressure was recorded there. From this pressure curve, the maximum rate of pressure rise (d p / d t _max ) was calculated using a differentiator DPE-3A (IFD). A Rüschelit® catheter was advanced from the right jugular vein, through the coronary sinus, into a coronary vein (vena cordis magna, ramus circumflexus), which draws blood from the myocardial area, which is supplied by the circumflex branch of the coronary artery. With this catheter, the coronary venous pressure is measured and blood taken. Subcutaneous needle electrodes were used to remove the limb ECG in lead II, the heart rate was determined by a pulse frequency monitor (FR-4, IFD) and displayed digitally.

For flow measurement was an electromagnetic Flowmeter placed around the aorta ascendens. On Stimulation catheter was over the left vein brachialis introduced into the right atrium.

After left thoracotomy, the pericardium was opened and the circumflex branch of the left coronary artery on a distance of about 3 cm distal to its origin sparing the nerves accompanying it dissected. Here was to measure the flow Electromagnetic Flußmeßkopf and distally thereof Vasoconstrictor installed. The latter consists of a U-shaped metal loop with an inner Diameter of 3 mm and a length of 4 mm. The open end of the loop may be gradual with a Screw to be narrowed with a micrometer connected is. Distal of this constrictor was in a lateral branch of the circumflexus ramus Millar micro-tip catheter integrated for pressure acquisition.

The oxygen content was in the aorta and Coronary venous and myocardial Oxygen consumption according to the formula

Coronary haemorrhage × arteriocoronarous Difference of oxygen content

determined. The peripheral coronary artery resistance in the myocardial coverage area of the circumflex branch was calculated as follows:

Avg. peripheral coronary artery d. minus coronary venous pressure
divided by
Coronary blood flow × 100 g left ventricle

The mean peripheral coronary artery pressure is the Half of the sum of systolic and diastolic Print.  

Aqueous solutions of 2- (3-fluoro-4-methyl phenylimino) imidazolidine hydrobromide. The Dose was 33 μg / kg i. v. For the tables were the mean ± SEM formed. The statistical Processing (1-min stenosis value against control, 20-min stenosis value against 1-min stenosis value, carotid occlusion value against 20-min stenosis value; control after substance against control before substance) with the t-test after STUDENT (comparison of two Averages).

To keep the heart rate constant after the Administration of 2- (3-fluoro-4-methylphenylimino) imidazolidine Left atrial via stimulation catheter gepaced.

The investigations described above show that a 20 min. continuous stenosis of the ramus circumflex of the left coronary artery with about 50% Reduction of mean blood flow a decrease in mean peripheral coronary artery pressure and a Increase in the calculated peripheral Coronary artery resistance causes. Besides, took the coronary venous oxygen content and the myocardial Oxygen consumption and to a lesser extent the Cardiac contraction force. All others measured Parameters (systole and enddiastol Ventricular pressure, systole. and diastole. aortic pressure, Heart rate and the O₂ content in the aorta) remained in the context of biological scattering (Table 1).  

An additional 60-second bilateral occlusion of the carotid artery caused a re-increase in mean peripheral coronary artery pressure and a further increase in peripheral coronary artery resistance. Other hemodynamic and energetic parameters were now changed: increase in ventricular pressure and d p / d t _max, heart rate, and increase in systolic aortic pressure and coronary venous oxygen content. However, myocardial oxygen consumption remained at the reduced level (Table 1).

33 μg / kg of 2- (3-fluoro-4-methylphenylimino) imidazolidine hydrobromide iv caused a significant decrease in cardiac contraction force (d p / d t _max ) 5 min after bolus injection under stimulated conditions per se and a slight decrease in myocardial oxygen consumption (Tab. 2).

During the stenosis took the middle peripheral Coronary artery pressure after 2- (3-fluoro-4-methylphenylimino) imidazolidine something more clearly; the peripheral Coronary artery resistance, however, remained in contrast to the effect of substance during the 20 minutes Stenosis unaffected. The myodardial Oxygen consumption is also in 4 out of 5 animals 2- (3-fluoro-4-methylphenylimino) imidazolidine in addition reduced.

In addition to coronary artery stenosis induced bilateral carotid occlusion after the gift of 2- (3-fluoro-4-methylphenylimino) imidazolidine none Recovery of the middle peripheral Coronary artery pressure, no change of peripheral  Coronary artery resistance, no change in the Cardiac contraction force and only a small one Recovery of oxygen consumption (Table 2).

Based on the available results could be shown be that 2- (3-fluoro-4-methylphenylimino) imidazolidin the sympathetically triggered poststenotic Coronary artery resistance increase and thus one Poststenotic myocardial ischemia can prevent.

Reflective stimulation of the cardiac sympathetic due to carotid occlusion also causes the increase of Heart rate, cardiac contractile force and systolic aortic pressure.  

Table 1

Table 2

Based on the available findings 2- (3-fluoro-4-methylphenylimino) imidazolidine as well its acid addition salts as active ingredient for Medicines for the treatment of coronary heart disease suitable.

The compounds can be both enteral as well parenterally. The single dosage is from 0.5 to 70 mg, preferably from 5 to 30 mg for oral administration.

Suitable applications are, for example Tablets, capsules, suppositories, solutions, juices, Emulsions, aerosols or dispersible powders. Corresponding tablets, for example, by Mixing the active ingredient with known excipients, for example, inert diluents, such as Calcium carbonate, calcium phosphate or lactose, Disintegrants, such as cornstarch or alginic acid, Binders such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents for Achieving the depot effect, such as carboxypolymethylene, Carboxymethyl cellulose, cellulose acetate phthalate, or Polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Correspondingly, coated tablets can be prepared by coating analogously cores made with the tablets, usually in Dragee shells used agents, for example Kollidone or shellac, gum arabic, talc, Titanium dioxide or sugar. to Achieving a depot effect or avoidance of Incompatibilities, the core can also consist of several Layers exist. Likewise, the Dragee cover to achieve a depot effect consist of several layers, with the above at the Tablets mentioned adjuvants can be used.  

Juices of the active compounds according to the invention or In addition, active ingredient combinations can be added Sweetening agents, such as saccharin, cyclamate, glycerol or Sugar as well as a taste-improving agent, e.g. B. Flavorings, such as vanilin or orange extract, contain. You can also use suspending aids or thickening agents, such as sodium carboxymethylcellulose, Wetting agents, for example condensation products of Fatty alcohols with ethylene oxide, or protective substances, such as p-hydroxybenzoates.

Injection solutions are in the usual manner, for. B. under Addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as Alkali salts of ethylenediaminetetraacetic acid, prepared and in injection bottles or ampoules bottled.

The one or more active substances or Capsules containing active ingredient combinations can be used For example, be prepared by the Active ingredients with inert carriers, such as lactose or Sorbitol, mixed and filled into gelatine capsules.

Suitable suppositories can be, for example, by mix with appropriate carriers, such as Neutral fats or polyethylene glycol or its Produce derivatives.

For a transdermal application are suitable Carrier systems, eg. B. in the form of a plaster from the State of the art, for. B. from DE-OS 29 30 500, known.  

Examples Production example of the active ingredient Example 1 2- (3-fluoro-4-methylphenylimino) -imidazolidine

14.03 g (0.043 mol) of N- (3-fluoro-4-methylphenyl) -S-methyl-thiuronium iodide are refluxed together with 4.35 ml (150%) of ethylenediamine in 58 ml of methanol with stirring for 8 hours. Then the solvent is distilled off in vacuo and the residue is dissolved in 1 N hydrochloric acid. The hydrochloric acid solution is buffered with 5 N KOH to pH 7 and extracted twice with ether (the ether extracts are discarded) and then alkalized with 50% potassium hydroxide solution. It falls out of an oil, which crystallized in a short time. After filtration with suction, it is washed with water and dried.
Yield: 6.1 g = 73.41% of theory
M .: 109.5-110.5 ° C
Rf: 0.1 system: benzene 50, dioxane 40, ethanol 5, k. NH₄OH 5
Support: silica gel G + luminescent pigment, visualization: UV and potassium iodine platinate

formulation Examples

tablets Active substance | 5 mg corn starch 160 mg sec. calcium phosphate 150 mg magnesium stearate  5 mg a total of 420 mg

manufacturing

The individual components become intense with each other mixed and granulated the mixture in a conventional manner. The granules become 420 mg tablets compressed, each containing 55 mg of active ingredient.

gelatin capsules

The contents of the capsules are as follows:

Active substance according to invention | 3 mg corn starch 172 mg a total of 175 mg

manufacturing

The ingredients of the capsule contents become intense mixed and 175 mg portions of the mixture in Bottled gelatin capsules of suitable size. Every capsule contains 3 mg of active ingredient.  

injection solutions

The solution is made up of the following components:

active substance 1.0 parts by weight Sodium salt of ethylenediaminetetraacetic acid 0.2 parts by weight distilled water ad 1000.0 parts by weight

manufacturing

The active ingredient and the sodium salt of ethylenediamine Tetraacetic acid are dissolved in enough water and with Water is filled to the desired volume. The solution is filtered by suspended particles and placed in 2 ml Ampoules filled under aseptic conditions. Last the ampoules are sterilized and sealed. each Ampoule contains 2 mg of active ingredient.

drops Active ingredient according to the invention | 0.20 g p-hydroxybenzoate 0.07 g p-hydroxybenzoate 0.03 g demineralised water ad 100 ml

Claims (1)

Use of 2- (3-fluoro-4-methylphenylimino) -imidazolidine and its pharmacologically acceptable acid addition salts for the treatment of coronary heart disease