DE3705055A1 - Use of 2-(3-fluoro-4-methylphenylimino)imidazolidine for the treatment of coronary heart disease - Google Patents

Abstract

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

Description

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

It is known that 2-phenyliminoimidazolidines and their acid addition salts have valuable pharmacological properties. For example, 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 forms of use. In the published patent application it is pointed out that the compounds described therein cause a pre-synaptic stimulation of the peripheral α- adrenoreceptors and thereby exert peripheral neurosympathetic and neurovagal transmission inhibition. They are particularly 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 arteries Heart disease can be used.

Tests on the dog have shown that the above connection sympathetic post-stenotic coronary constrictions and the ones involved occurring also sympathetically triggered inhibits oxygen consumption increasing myocardial stimulation.

Pharmacological test methods

Under physiological conditions, the Myocardial blood flow due to local metabolic factors adapted to the current needs.  

The influence of the autonomic nervous system is insignificant or is compensated for 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 the coronary resistance. In the case of coronary patients, such a condition is likely to be reached in post-stenotic vascular sections during physical exertion. An increase in local interstitial potassium ion concentrations and the accumulation of metabolic products trigger sympathetic reflexes that have a coronary stringency and exacerbate the situation by stimulating the myocardial metabolism. In anesthetized dogs, such a condition can be achieved by mechanical throttling of the blood flow in the ramus circumflexus, whereby the sympathetic tone increases with time and the coronary resistance in the supply area of the vessel increases.

method

Five mixed-breed male dogs in weight of 32-37 kg were with 2 mg / kg morphine hydrochloride and 0.5 mg / kg of atropine sulfate i. m. pretreated. 90 min later hexobarbital sodium became a light anesthetic for intubuation i. v. injected. After that and Furthermore, 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. for neuroleptanalgesia administered.  

After the tracheal tube was introduced continuous nitrous oxide (4: 1) ventilation an Engström respirator. The O₂ content and O₂ saturation of the arterial and coronary venous Blood, the arterial partial prints of O₂ and CO₂ and the acid-base household, and the CO₂ content in exhaled air, hemoglobin and Hematocrit was determined regularly and remained during the test period within physiological Values. Ventilation was based on the CO₂ content Expiratory air and according to 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 via a sinus artery. integrated Rüschelit® catheter in connection with a pressure transducer and a pressure booster registered on a multi-channel recorder. With one over the brachial artery dext. and aorta in the left ventricle advanced Millar catheter PC 350 the pressure was recorded there. The maximum rate of pressure rise (d p / d t _max ) was calculated from this pressure curve with the aid of a DPE-3A (IFD) differentiator. 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 ramus circumflexus of the coronary artery. This catheter measures the coronary venous pressure and takes blood. Subcutaneous needle electrodes were used to take the extremity ECG in lead II, the heart rate was determined using a pulse rate monitor (FR-4, IFD) and displayed digitally.

An electromagnetic was used to measure the flow Flow measuring head placed around the ascending aorta. A Stimulation catheter was placed over the left vein Brachialis introduced into the right atrium.

The pericardium was opened after left thoracotomy and the circumflex ramus of the left coronary artery over a distance of about 3 cm distal to its origin while protecting the nerves accompanying him prepared. Here was used to measure the flow electromagnetic flow measuring head and distal thereof Vasoconstrictor installed. The latter consists of a U-shaped metal loop with an inner one 3 mm in diameter and 4 mm in length. The open end of the loop can be graded with a Screw to be narrowed with a micrometer connected is. Distal to this constrictor was in a branch of the circumflex ramus Millar micro-tip catheter integrated for pressure absorption.

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

Coronary artery bleeding × arteriocoronarvenous Difference in oxygen content

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

Mean peripheral coronary artery dr. minus coronary venous pressure
divided by coronary blood flow × 100 g left ventricle

The mean peripheral coronary artery pressure is 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 values ± SEM are formed. The statistical Processing (1-minute stenosis value against control, 20 min stenosis versus 1 min stenosis, carotid occlusion value against 20 min stenosis value; control after substance versus control before substance) with the t-test according to STUDENT (comparison of two Means).

To keep the heart rate constant after the Administration of 2- (3-fluoro-4-methylphenylimino) imidazolidine left atrial paced using a stimulation catheter.

The investigations described above show that a 20 min. continuous stenosis of the ramus Circumflexus of the left coronary artery with about 50% A decrease in the mean blood flow mean peripheral coronary artery pressure and a Increase in calculated peripheral Coronary artery resistance causes. Also took the coronary venous oxygen content and the myocardial Oxygen consumption and to a small extent also Heart contraction. All other measured Parameters (systole and enddiastole. Left Ventricular pressure, systolic. and diastolic. Aortic pressure, Heart rate and the O₂ content in the aorta) remained within the scope of biological scatter (Tab. 1).  

An additional bilateral occlusion of the carotid artery lasting 60 seconds caused a rise in the mean peripheral coronary artery pressure and a further increase in the peripheral coronary artery resistance. Other hemodynamic and energetic parameters have now also been changed: increase in ventricular pressure and d p / d t _max , heart rate, as well as increase in systolic aortic pressure and coronary venous oxygen content. However, myocardial oxygen consumption remained at the reduced level (Tab. 1).

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

During the stenosis, the middle peripheral took Coronary artery pressure after 2- (3-fluoro-4-methylphenylimino) imidazolidine somewhat more clearly; the peripheral Coronary artery resistance, however, remained in contrast on the effect before substance administration during the 20-minute period Stenosis unaffected. The myodardiale Oxygen consumption is also through in 4 out of 5 animals 2- (3-fluoro-4-methylphenylimino) imidazolidine additionally reduced.

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

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

The reflex stimulation of the cardiac sympathetic nervous system carotid occlusion also causes the increase in Heart rate, heart contraction 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 an active ingredient for Medicines used to treat coronary artery disease suitable.

The connections can be both enteral as well administered parenterally. The single dose is 0.5 to 70 mg, preferably 5 to 30 mg with oral application.

Suitable forms of use are, for example Tablets, capsules, suppositories, solutions, juices, Emulsions, aerosols or dispersible powders. Appropriate tablets can, for example, by Mixing the active ingredient with known auxiliary substances, for example inert diluents, such as Calcium carbonate, calcium phosphate or milk sugar, Disintegrants, such as corn starch 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 coated by analog the cores usually produced in tablets Coated tablets used means, for example Kollidon or shellac, gum arabic, talc, Titanium dioxide or sugar. For To achieve a deposit effect or to avoid The core can consist of several incompatibilities Layers exist. The same can also Drage envelope to achieve a deposit effect consist of several layers, the above in the Tablets mentioned excipients can be used.  

Juices of the active substances according to the invention or Active ingredient combinations can also be a Sweeteners such as saccharin, cyclamate, glycerin or Sugar as well as a taste-improving agent, e.g. B. Flavorings, such as vanilin or orange extract, contain. You can also use suspension aids or thickeners, such as sodium carboxymethyl cellulose, Wetting agents, for example condensation products from Fatty alcohols with ethylene oxide, or protective substances, such as p-hydroxybenzoates.

Injection solutions are made in the usual way, e.g. More colorful Addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as Alkali salts of ethylenediaminetetraacetic acid, made and in injection bottles or ampoules bottled.

The one or more active ingredients or Capsules containing active ingredient combinations can for example, by making the Active ingredients with inert carriers, such as milk sugar or Sorbitol, mix and fill in gelatin capsules.

Suitable suppositories can be, for example mix with intended carriers such as Neutral greases or polyethylene glycol or its Manufacture derivatives.

Suitable for transdermal application Carrier systems, e.g. B. in the form of a plaster from which State of the art, e.g. B. from DE-OS 29 30 500, known.  

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

14.03 g (0.043 mol) N- (3-fluoro-4-methylphenyl) -S-methyl-thiuronium iodide together with 4.35 ml (150%) ethylenediamine in 58 ml Methanol was heated under reflux for 8 hours with stirring. The solvent is then distilled off in vacuo and the residue dissolved in 1N hydrochloric acid. The hydrochloric acid Solution is buffered to pH 7 with 5N KOH and twice with Ether extracted (the ether extracts are discarded) and then alkalized with 50% potassium hydroxide solution. It's falling thereby an oil, which in a short time completely crystallized. After vacuuming with water washed and dried.

Yield: 6.1 g = 73.41% of theory
Mp: 109.5-110.5 ° C
Rf: 0.1 system: benzene 50, dioxane 40, ethanol 5, k.
NH₄OH 5
Carrier: silica gel G + luminous pigment, visualization: UV
and potassium iodine platinum

Formulation examples

Tablets

Active ingredient 5 mg corn starch 160 mg sec. Calcium phosphate 150 mg magnesium stearate 5 mg total 420 mg

Manufacturing

The individual components become intense with each other mixed and the mixture granulated in the usual way. The granules become tablets weighing 420 mg pressed, each of which contains 55 mg of active ingredient.

Gelatin capsules

The content of the capsules is made up as follows:

Active ingredient according to the invention 3 mg corn starch 172 mg total 175 mg

Manufacturing

The contents of the capsule contents are mixed intensively and 175 mg portions of the mixture are filled into gelatin capsules of a suitable size. Each capsule contains 3 mg of active ingredient.
Injection solutions

The solution is made up of the following ingredients:

Active ingredient 1.0 parts by weight Sodium salt of ethylenediamine tetraacetic acid 0.2 parts by weight distilled water ad1000.0 parts by weight

Manufacturing

The active ingredient and the sodium salt of ethylenediamine tetraacetic acid are dissolved in enough water and with Water topped up to the desired volume. The solution is filtered from suspended particles and 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-Hydroxybenzoic acid methyl ester 0.07 g Propyl p-hydroxybenzoate 0.03 g demineralised water ad100 ml

Claims (2)

1. Use of 2- (3-fluoro-4-methylphenylimino) - imidazolidine and its pharmacologically acceptable Acid addition salts for the treatment of coronary arteries Heart disease 2. Use of 2- (3-fluoro-4-methylphenylimino) - imidazolidine and its acid addition salts for Manufacture of a medicament for the treatment of coronary artery disease.