DE2621227B2 - Non-depolarizing myorelaxant - Google Patents

Description

The present invention relates to a preparation having a curare-like effect, specifically, a non-depolarizing one Myorelaxant. The non-depolarizing myorelaxants are used with the goal of blocking neuromuscular connections of the skeletal muscles in surgical operations, in treatment used by tetanus and in some endoscopic examinations

The use of myorelaxants in surgical operations first began in 1942 Suggestion from handle its. At present, all operations involving total anesthesia required myorelaxants used. Depending on the mechanism of blocking the neuromuscular Compounds, myorelaxants are divided into two groups: depolarizing and non-depolarizing.

Currently, of the non-depolarizing myorelaxants in clinical practice, only Dicholine ether of succinic acid is used, which is known under various names: Ditilin, Myorelaxin, Listhenone and succinylcholine.

The use of other preparations of this group, in particular Dekamethonium and Imbretyl, was mainly because there is no means by which to act if necessary would be able to interrupt.

A wide application of the dicholine ether of succinic acid, i. H. of Ditilin, is on a fast Development and due to its relatively short duration of action, what happens when carrying out a brief myorelaxation is of great importance. In patients with underactive liver or with a however, low levels of plasma cholinesterase may interfere with a normal dose of the preparation last for a few hours.

If there is a need for long myorelaxation with the help of ditilin, it is introduced several times or a continuous drop infusion is carried out. However, that can lead to development permanent paralysis of skeletal muscles and apnea (failure of breathing, lack of active breathing) in patients with normal levels of cholinesterase. Since the depolarizing myorelaxants are no Having enough effective antidote can make fighting this serious complication Cause difficulties. The effects of ditilin are also enhanced by the development of muscle pain accompanied. The increase caused by depolarizing myorelaxants, including ditilin of potassium levels in the blood can have serious consequences in patients with cardiovascular disorders to lead. Ditilin also usually causes a slight increase in arterial pressure accompanied by Tachycardia.

From time to time bradycardia is reversed with hypotension, especially in combination with cyclopropane, Fluorotan and Digitalis observed Repeated introduction of ditilin is possible because of the possible Disturbance of the heart rhythm up to cardiac arrest dangerous. This applies particularly to patients with Heart disease and patients with impaired potassium metabolism. Taking into account the disadvantages of ditilin and others listed above The anesthesiologists came to the conclusion with depolarizing myorelaxants, in hospitals preferring non-depolarizing ones To use myorelaxants.

From the group of non-depolarizing myorelaxants become a-tubocurarine particularly often over the course of several years in surgical clinical practice (Burroughs Wellcome CO London) and pyrolaxone (synonyms: Gallamin, Flaxedyl) are used However, these preparations also have disadvantages. oc-tubocurarine secretes in a myoparalytic dose Removes histamine from tissues and blocks sympathetic ganglia, thereby lowering blood pressure. Pyrolaxone blocks parasympathetic ganglia and therefore causes tachycardia.

In recent years, the non-depolarizing myorelaxant - pankuronium (Pavulon, company Organon Inc. W. Orange N.J. 07052) is gaining widespread recognition as a bis-tertiary aminosteroid represents.

Pankuronium is 5 to 10 times more active than d-tubocurarine in its neuromuscular blocking effect and 2.5 times weaker in its Ability to block transmission in sympathetic ganglia. The duration of the myoparalythic The effect is the same as with d-tubocurarine. Pancuronium does not induce the secretion of histamine Tissues out and does not decrease arterial pressure. The myoparalythic effect of the pancuronium is well taken care of by Proserine and therefore difficulties arise during decurarization in the clinic less than the effects of d-tubokurarine. Since this drug does not lower blood pressure, so it does Introduction of a higher dose permitted. So after the introduction of Pakuronium in a dose of 0.15 mg / kg created excellent conditions for intubation of the trachea. This means that the Pankuronium the disadvantages of d-tubokurarine and pyrolaxone and it is considered the best preparation of the group of the non-polarizing myorelaxants.

However, the pancuronium has its own drawbacks. In a myoparalythic dose pancuronium often causes an acceleration of the pulse and an increase in arterial pressure. This will make the Increase in bleeding during surgical operations explained after introduction of pancuronium is watching.

The aim of the present invention is to find a new non-depolarizing myorelaxant, that free from the disadvantages of d-tubocurarin, pyrolaxon and pancuronium and with clinical Application is absolutely safe, which has a high selectivity and specific effect and on other physiological systems do not act as well as the implementation of a safe and controlled Myorelaxation would secure.

The goal set was achieved by finding a non-depolarizing myorelaxant which according to the invention contains dibenzenesulphanate η, η "- bis-triethylammonium-p-terphenyl as active ingredient.

The carrier substance for the active substance mentioned is water. This myorelaxant can be 2.5% aqueous

Solution can be used. The amount of active substance for an intravenous injection is 5 mg / ml. That The preparation advantageously contains hydrochloric acid as a stabilizing agent. The amount of hydrochloric acid is 0.01 mg / ml for an intravenous injection.

The mentioned myorelaxant is hereinafter referred to as Called terkuronium

Terkuronium is a non-depolarizing myorelaxant with high activity and selectivity of action and has a number of advantages over the κι known non-depolarizing myorelaxants d-tubocurarine and pancuronium. These advantages are set out in detail in the pharmacological test description of the terkuronium below.

Neuromuscular blocking (curare-like)
Effect of terkuronium

The investigation was carried out in acute experiments with cats, rabbits, mice and pigeons, in experiments with phrenic diaphragm preparations from rats as well as on the straight abdominal muscles of frogs (rana temporaria). The properties of terkuronium were matched with the properties of d-tubocurarine and pancuronium compared.

Try with cats

Cats under anesthesia (chloralose - 50 mg / kg and urethane 500 mg / kg intraperitoneally) or decerebral in the area of the pair of four hills. If necessary, artificial ventilation of the lungs is carried out. Were registered in Contractions »m. tibialis ant «in the isotonic regime in response to electrical stimulation of the peripheral Section "n peroneus" with supramaximal pulses with a duration of 0.1 msec and one Frequency from 0.1-100 Hz. Π

When a muscle was indirectly stimulated at a frequency of 0.1 Hz, the blockage developed neuromuscular transmission (95-100% block) in 40-60 seconds after intravenous terkuronium introduction at a dose of 0.08 ± 0.002 mk M / kg and -w reached its maximum in 2-2.5 minutes and lasted 2-4 minutes (10 attempts). The contractions of the Muscle irritated again completely within 10 ± 1.5 minutes after introduction of terkuronium. An equally effective one The dose of d-tubokurarine under these conditions was 0.5 ± 0.03 mkM / kg (5 trials) and of pancuronium to 0.04 ± 0.001 mkM / kg.

The duration of the terkuronium action is on average 8 minutes, the pancuronium 9 minutes and the d-tubokurarins 10 minutes the same. With repeated in The introduction of terkuronium increased its blocking activity as did the activity of d-tubocurarin and pancuroniums (by 60-80%).

The blocking effect of the terkuronium is on its action on the postsynactic membrane of the ■> > Attributed to skeletal musculature. The introduction of acetylcholine in the »close intraarteriae injectionw procedures caused simultaneous contractions with blockade of the neuromuscular Transmission suppressed. During the complete suppression of the contractions of a muscle in response to indirect stimulation of the muscle, it retracted in response to its direct stimulation together.

The effect of terkuronium was under the influence of n> of neostigmine is weakened by succinylcholine, decamethonium and acetylcholine and by d-tubocurarine increased. The blocking effect of the terkuronium is more pronounced, the higher the Frequency of the pulses is. If the blockage is incomplete the transmission of rare single impulses (0.1 Hz) leads to the tetanization of the motor nerves with a Frequency of 50-100 Hz for the development of a pessimal response of the muscle. In the post-tetanus period is the restoration of muscle contractions in response to indirect stimulation through to observe rare single impulses.

The blocking effect of terkuronium was increased by introducing neostigmine into one intravenous Dose of 0.05-0.1 mg / kg immediately and completely abolished. The antagonism comes from Neostigmine stronger when exposed to terkuronium than when exposed to d-tubocurarine and pancuronium to carrion. So the muscle contractions began even with a 5-fold increase in the dose of terkuronium im Range of 2-5 minutes after a single introduction of neostigmine in an amount of 0.1 mg / kg itself The muscle contractions were completely restored in 15-20 minutes record.

Upon exposure to pancuronium and d-tubocurarine, there was one such rapid recovery Muscle contractions after the introduction of neostigmine only when the dose is increased 2 to 3 times Myorelaxants have been recorded. With a 4 to 5-fold increase in de; Pancuronium dose emerged weak Muscle contractions no later than 9-10 minutes and full recovery of the contractions no later than 30 minutes after the introduction of neostigmine (6 attempts). An even more blatant delay the restoration of the transmission was observed after exposure to d-tubokurarine. at When the dose of d-tubokurarin was increased fourfold, weak muscle contractions occurred in only 20-25 Minutes up and completely recovered in 40-70 minutes (3 attempts), and at 5-fold Increasing the d-tubokurarin dose, neostigmine proved to be less effective at the dose mentioned (3rd Try).

Try rabbits

In tests with rabbits (20 tests) without anesthesia, the dose of terkuronium that led to the development of the head drop dose HDD symptom, 0.22 ± 0.009 mkM / kg. The complete blocking effect Developed in 1.5-2 minutes after the introduction of terkuronium and lasted 3-5 Minutes. A few minutes later, the behavior of the respective animal became normal. An equivalent effective dose of d-tubokurarine

0.18 ± 0.02 mkM / kg (6 trials) and pancuronium dose - 0.18 ± 0.001 mkM / kg (6 trials). The time of The development and duration of the blocking effect in all three preparations were the same. The blocking So activity of terkuronium is slightly lower than the activity of pankuronium and 8 times higher than the activity of d-tubocurarine.

In a further series of experiments, the dose of myorelaxants was determined that the fatal Cause paralysis of the respiratory muscles during their intervenous introduction in 50% of animals, that is, LDw · LD50 was found to be 0.03 mkM / kg for terkuronium and the same for d-tubocurarine 0.25 mkm / kg and for pancuronium equal to 0.026 mkm / kg. This made the area of muscular slacking action, expressed by

the ratio LD »to HDD, for all three substances 1.4.

In experiments with rabbits under anesthesia (chloralosa 50 mg / kg and urethane 500 mg / kg intravenously). The dose of terkuronium (intravenous), which causes a complete blockage of the nerve and calf transmission, was 0.025 + 0.005 mkM / kg (5 experiments). The introduction of neostigmine in a dose of 0.1 mg / kg intravenously during the complete blockade always led to immediately developing and complete recovery of w Mu.skelkon contractions.

Try with mice

In experiments with white mice, the dose of terkuronium upon introduction into the tail vein, which caused the loss of the symptom of turning over from the side position in 50% of the mice (ED ”), was 0.06 mkm / kg (18 experiments), and the Death due to paralysis of the respiratory muscles occurred in 50% of the animals (LD ₅₀ ) after the introduction of terkuronium at a dose of 0.33 mkM / kg. As a result, the area of muscular slackening action (LD50) (ED50) of the terkuronium was 1.5. The ED ₅₀ and LD50 of the pancuronium are 0.042 mkM / kg and 0.062 mkM / kg and the area of the muscular slackening action is r> 1.5. According to the literature, the ED ₅₀ and LD50 of the d-tubocurarin are 0.17 mkM / kg and 0.24 mkM / kg and consequently the LD50 / ED50-1.4.

The myoparalytic activity of terkuronium in experiments with mice is thus somewhat lower than that Activity of pancuronium and several times greater than the activity of d-tubocurarin.

Try with pigeons

After an intravenous introduction of Terkuronir> at a dose of 0.2 mkm / kg (ED50) the pigeons developed flaccid paralysis of Observe muscles for 2.5 to 3 minutes. As a result, terkuronium also shows in Try a non-depolarizing m Effect on.

In experiments with phrenic diaphragm preparations on rats, which were isolated by the Bülbring method, the blockade of the neuromuscular transmission developed under the action of the terkuronium in a concentration of 2 10- ^b m / l.

In experiments on isolated straight abdominal muscles of frogs - rana temporiaria - the terkuronium concentration, which causes the weakening of the action of acetylcholine, equal to> ο

2.0 ± 0.04 χ 10-'m / l. Terkuronium does not cause muscle contraction emerged.

Affecting breathing

In experiments with anesthetized and decerebrated >> cats, the suppression and respiratory arrest caused by curar-like paralysis of the diaphragm caused by terkuronium proceeded with the simultaneous development of the blockade of neuromuscular transmission »m. tibialis m> ant «. Breathing was restored while muscle contraction was restored. The same was observed upon exposure to d-tubocurarine and pancuronium. Under the conditions of artificial respiration and pulmonary ventilation ti5, no bronchospasm developed even with the 200 to 100-fold increase in the dose of terkuronium. The same result was also obtained in experiments with rabbits. The ratio LD »to ED ₅₀ in experiments with rabbits and mice, which was given above, gives an idea of the influence of terkuronium on respiration. Since there were no significant differences in the LD50 / ED50 ratios of the terkuronium, d-tubocurarine and pancuronium, the blocking doses of these myorelaxants consequently suppress breathing to the same extent.

Effect of terkuronium on arterial pressure.

Experiments were carried out with anesthetized cats and rabbits (Chloralosa - 50 mg / kg) and urethane - 500 mg / kg (intravenous) as well as with the cats decerebrated in the area of the four-mound pair. The blood pressure in the sleeping artery was registered with the help of a mercury pressure indicator. The preparations were introduced intravenously.

In conditions of active ventilation of the lungs, the introduction of terkuronium caused d-tubocurarine or pancuronium in a dose that provokes the suppression of breathing, an ascetic one Increase in arterial pressure. Under the conditions of artificial ventilation of the lungs Introduction of terkuronium in a dose that completely blocks neuromuscular transmission arterial pressure does not change. At 10 times the magnification of the myoparalytic Terkuronium dose (0.8 mkM / kg) was a slight decrease in mercuric acid 10 to 20 mm and observe short-term lowering of arterial pressure. Animals (7 cats and 5 rabbits) have the Introduction of a very large amount of terkuronium up to 10-20 mkm / kg tolerated, which is about 200 times as much exceeds its myoparalytic dose. There is a rapid and extremely strongly expressed lowering and thereafter a slow recovery of arterial pressure was noted. Achieved in all attempts or the arterial pressure approached the initial values in 1–2 hours.

There was also no lowering of arterial pressure after the introduction of a myoparalytic dose of Pancuronium observed. When the pancuronium dose was increased 3 to 5 times, it was stable Increase in arterial pressure by 20 to 40 mm of the mercury column. When the Pancuronium dose around 20 times, a moderately expressed depressor effect was observed.

After the introduction of a myoparalytic dose of d-tubokurarine, it was always an expressed short-term one Reduction in arterial pressure was recorded. When the dose of d-tubocurarine was increased 5 times, the was Depressor effect expressed so strongly that it immediately led to the death of the respective animal, or it was irreversible during 2-3 hours of observation.

Of three myorelaxants examined, terkuronium had a particularly weak effect the arterial pressure detected.

Action on the autonomic nervous system,
ie action on sympathetic ganglia

Experiments were carried out with anesthetized cats. Electrical stimulation was applied of the peripheral section of the trunk at the neck with a frequency of 5 Hz. The duration of a stimulation course = 1 msec, amplitude = 5 V. The third eyelid and the Blood pressure in the temporal vein using a mercury

pressure indicator registered. The dose was determined of terkuronium, d-tubocurarine and pankuronium intravenous introduction, which reduces the level of twitching of the third eyelid by 50-60% below the Caused conditions of persistent irritation of the trunk.

A ganglion-blocking effect developed after the introduction of terkuronium at a dose of 0.8-1.0 mkM / kg, which is 10 to 15 times greater than its myoparalytic dose. Parallel to relaxation A decrease in arterial pressure was observed in the third eyelid. The maximum effect Lasted 2-3 minutes, after which the restoration of the contractions of the third eyelid and restoration the arterial pressure began and in 8-10 minutes riaui introduction of terkurufiium, the contractions were of the third eyelid and the level of arterial pressure fully restored.

The same decrease in the level of third eyelid contractions developed after the introduction of d-tubocurarine in a dose of 0.8-1.0 mkm / kg, which is only 1.5 to 2 times its myoparalytic Dose exceeds. The decrease in arterial pressure was greater than when an equivalent was applied Terkuronium dose expressed.

The ganglion-blocking pancuronium dose proved equals 1.2-1.6 mkm / kg, which exceeds 30 times its myoparalytic dose.

Action on M-cholino receptors and on transmission in parasympathetic ganglia

The experiments were carried out with anesthetized cats (chloralose and urethane intraperitoneally).

In experiments with 5 animals, the left vagus nerve was cut. On the peripheral Section were platinum electrodes to stimulate the nerve with pulses with a duration of 0.1 msec and amplitude = 5 V applied. The nerve was stimulated with a duration of 10 seconds each Pulse frequency of 30 Hz. The following were recorded: pulse frequency according to an electrocardiogram (EKG) and Blood pressure in the femoral artery using a mercury pressure gauge.

Outside the stimulation conditions of the vagus nerve was after intravenous introduction of terkuronium in a dose of 0.1 and 1.0 mkM / kg no change in the frequency of cardiac contractions record.

During the irritation of the vagus nerve there was bradycardia (slow heart rate) and Observe lowering of the arterial pressure. After the introduction of terkuronium at a dose of 0.1 mkM / kg and 1.0 mkM / kg did not change the response to irritation of the vagus nerve.

In experiments with 3 anesthetized cats, the introduction of terkuronium at a dose of 0.1-1.0 mkM / kg did not affect the depressor response after intravenous introduction of acetylchofin at a dose of 3 mg / kg. ι

Accordingly, in a dose 20 times its myoparalytic dose, terkuronium does not act on the parasympathetic part of the autonomic nervous system. This is also confirmed by the results of other experiments with animals, no development of bronchospasm and the Salvation were observed after the introduction of a very large Terkuroniumdosis in their ι implementation.

Exposure to narcotics
on the effect of terkuronium

In decrebrated cats the influence of ether, fluorothane and thiopental became narcotic Concentrations (doses) on the neuromuscular blocking activity and the repressor effect (effect examined for articular pressure) of the terkuronium and for antagonism of neostigmine terkuronium.

After intravenous introduction of sodium thiopental in an amount of 10 mg / kg, the change was made Curare-like activity and the effect of the terkuronium on blood pressure are not.

Under the conditions of deep ether anesthesia, the myoparaiyiic effect of terkuronium increased just like that of d-tubocurarine and pancuronium by an average of 20-30%. Terkuronium influence on the arterial pressure has not changed significantly.

The myoparalytic effect increased under the conditions of deep fluorothane anesthesia insignificant and no enhancement of the depressor effect was observed. The antagonism of Neostigmine was sustained upon exposure to terkuronium under the influence of anesthetics.

As a result, terkuronium is quite compatible with anesthetics: ether, fluorothane and sodium thiopental. The antagonism of neostigmine is fully retained.

Investigation of the "chronic"
Tosicity of Terkuronium

Four rabbits were given intravenous terkuronium once a day for 12 days performed at a dose that elicits the nod symptom (H DD) -0.02-0.024 mkM / kg. At two other control rabbits were introduced with a physiological solution in place of terkuronium. Daily the weighing of the animals, the measurement of the rectal temperature and the behavior of the Animals controlled. Clinical blood counts and urinalysis were performed three times. Carried out were histological examinations of the liver, kidneys, heart, adrenal glands, spleen, as well Rim vein into which terkuronium has been inserted.

The sensitivity of the animals to the terkuronium did not change in the course of the experiment. No changes in their behavior and no significant change in rectal temperature were recorded. Pathological inclusions and changes in blood and urine analyzes were not found. Histological examination of the organs also did not reveal any pathological changes.

In acute tests with 2 rabbits (without anesthesia) and with 2 cats under anesthesia, the influence of terkuronium on the rate of blood coagulation and erythrocyte resistance was not demonstrated.

To investigate the allergic effects the Arthus-Sakharov phenomenon was used by terkuronium. Experiments were carried out with 3 rabbits Each rabbit was administered subcutaneously in the

Back left side terkuronium in a dose of 0.02 mkM / kg in a volume of 0.2-0.25 ml and 1 ml of horse serum is injected subcutaneously on the right side of the back. The fourth (control) rabbit was in only injected horse serum in the same order.

In all animals, after the fifth or sixth stage, a Expressed allergic reaction observed: hyperemia, water swelling and punctiform bruising. No reaction could be detected at the site of the repeated terkuronium injections.

Results of a pharmacological investigation of the myorelaxant '- terkuronium according to the invention - allows the following conclusions to be drawn in comparison with the known myorelaxants.

1. in experiments with animals is the neuroniuscular blocking activity of the terkuronium 6 to 8 times higher than the activity of d-tubocurarin and slightly lower than the activity of the pancuronium.

2. In contrast to d-tubocurarine, terkuronium secretes no histamine in a myoparalytic dose, does not block the vegetative ganglia and therefore does not affect blood pressure and heart rate. In experiments with cats, a slight and short-term decrease in arterial pressure develops only with a 10-fold increase in the dose of terkuronium; such a reduction in articular pressure is after the introduction of a myoparalytic dose of d-tubocurarine was recorded. Terkuronium does not affect the myoparalytic vision even at ten times the magnification Dose the heart rate. Pankuronium secretes just like that of the invention Terkuronium does not release histamine and does not block the vegetative ganglia, as a result of a previously unknown Mechanism causes pancuronium a stable increase in arterial pressure, which leads to increased hemophilia during surgical interventions as well as accelerating the pulse.

3. Under the conditions of artificial ventilation of the lungs, cats and rabbits tolerate the Introduction of a very large amount of terkuronium of 10-20 mkm / kg of the animal's weight, which is about Exceeds 200 times its myoparalytic dose. Under the same conditions there will be a fatal drop of arterial pressure with a 5 to 10 fold increase in the myoparalytic dose of d-tubocurarin observed.

4. The antagonism (unblocking effect) of neostigmine the main antagonist of the non-depolarizing Myorelaxants - comes more strongly when exposed to terkuronium than when exposed expressed by d-tubocurarine and pancuronium. So eliminated neostigmine at a dose of 0.1 mg / kg intravenously in experiments with cats completely the blocking effect of the five myoparalytic doses of terkuronium during 5 minutes and only 3 myoparalytic doses of d-tubocurarine and pancuronium.

In experiments with decerebrated cats, there was no mutual enhancement of the fluorothane and terkuronium effects on the blood pressure to be observed, while d-tubokurarine increases the negative effects of fluorothane, and therefore their combined applies Use as dangerous due to the development of cardiovascular collapse.

The terkuronium examination was used as a myorelaxant performed during surgical interventions on organs of the abdominal and thoracic cavities in 150 patients. the Operations were under the terms of the

Intubation anesthesia and artificial ventilation of the lungs were performed. Ether was used as an anesthetic, Fluorothane, nitrous oxide (laughing gas) and barbiturates are used.

In a first series of observations, which included 120 operations, the terkuronium was identified as the main myorelaxant used to maintain myorelaxation. The intubation of the trachea was under the Conditions of myorelxation carried out by introducing an active ingredient from the ditilin group is excited. Upon completion of the intubation, intravenous terkuronium injection was given at a dose of 0.12-0.15 mg / kg (1-2 ml 0.5% solution). The change in arterial pressure and the Heart rate was not observed after introduction of this dose. A complete myorelaxation with the deactivation of active breathing took an average of 40 minutes. If when the first features of the restoration of muscle tone and active breathing the repeated intravenous Terkuronium injection at a dose that is '/ 3 -' / 2 the original dose was carried out, complete myorelaxation took 1–1.5 Hours.

The introduction of prostigmine at the end of an operation in the amount of 2.5 mg always led to a quick - within a few minutes - restoration of active breathing to the full extent. It there were no cases of insufficient effectiveness of prostigmin, muscle weakness, insufficiency of the active breathing in the postoperative period and no recurrence detected. The electromyographic Analysis of the character of the effect on neuroniuscular transmission showed that terkuronium really is a nondepolarizing myorelaxant.

A second series of observations, which involved performing 30 operations, was Terkuronium not only to maintain myorelaxation, but also to intubate the trachea used. With this aim, terkuronium was injected intervenously at a dose of 0.25-03 mk / kg. the complete relaxation of the muscles developed in 80-90 seconds after injection and ensured one free implementation of intubation. The exposure to this dose of terkuronium was not observed by any cardiac or Circulatory disorders or any other complications. Myorelaxation took about 1 hour. Repeated terkuronium injections were required to carry out a longer myorelaxation required at a dose of 0.05-0.08 mg / kg. In this series of observations was the effectiveness of prostigmin as a deblocking agent also complete, there were no cases of muscle weakness, respiratory insufficiency, or Recurarization demonstrated in the postoperative period. The clinical observations confirmed thereby the experimental data and showed that terkuronium is a non-depolarizing myorelaxant represents that of the disadvantages of d-tubokurarin, The use in clinical practice of the invention is free of pyrolaxons and pancuronium Myorelaxans' - terkuronium - allowed with such properties, compared to d-tubocurarine, Pyrolaxon and even pancuronium perform a safer and more controllable myorelaxation. the The use of terkuronium to intubate the trachea also makes it possible to focus on the

In order to avoid using preparations of the ditilin type, the depolarizing myorelaxants with their own Represent disadvantages.

Terkuronium is the dibenzenesulfonate n, n "- bis-triethylammonium-p-terphenyl of the following formula

/ N (C ₂ Il ₅ )., - 2CH ₅ SO.,

Understood. It is a white crystalline powder that is slightly greenish in the air, with melting point = 228-229 ⁰ C. with decomposition. The powder is readily soluble in water, its aqueous solution is colorless, transparent and stable for a long time in the presence of a stabilizer (3 ml of 0.1 N HCl per 1 liter of water). The 0.0012% solution of the substance in 0.01 standard solution of hydrochloric acid has a characteristic absorption spectrum in the UV range with a maximum of 285 ± 2 nm and a minimum of 237 ± 1 nm.

This connection is obtained according to the following scheme:

O, N

NO,

III]
CII ₅ J

11.N.

Nile.

| C ₂ I1 _S ) ₂ N - <ζ "ζ <( > - <ζ / ■ N | C, H _S ),

'(C ₂ H ₃ IjN f y-'ζ '> \ V- N (C ₂ H ₅ )., -2C ₁₁ H ₅ SO.,

The process for obtaining the dibenzenesulfonate n, n "- bis-triäthylammonium-p-terphenyls includes Reduction of n, n "-Dinitro-p-terphenyl to n, n" -Diamino-p-terphenyl, Alkylation of n, n "-diamino-p-terphenyl to n, n" -bis-diethy! Amino-p-terphenyl with ethyl iodide, Quaternization of η, η '' - bis-diethylamino-p-terphenyl with ethyl ester of benzenesulfonic acid to

Dibenzenesulfonate-n.n ^ bis-triethylammonium-p-terphenyl a.

The starting material -η, η "- Dinitro-p-terphenyl- is a well known substance and is obtained by nitrating p-terphenyl with fuming nitric acid.

The reduction of n, n "-Dinitro-p-terphenyl can be carried out in different processes for example it can be catalytically hydrogenated in an autoclave for 2-3 hours.

One can also reduce n, n "-dinitro-p-terphenyl in a solution of tin dichloride in concentrated hydrochloric acid for three hours.

However, n, n "-diamino-p-terphenyl can be obtained more quickly and with a greater quantitative yield by reducing n, n "-Dinitro-p-terphenyl with hydrazine hydrate in the presence of Rangey-Ni in one inert organic :; Solvents, for example in ethylene glycol, can be obtained by heating. These Reduction takes a few minutes. The alkylation of n, n "-diamino-p-terphenyl can be with the help of various alkylating agents. Alkylation with ethyl iodide is particularly easy in the presence of an agent which binds the iodine in an inert organic solvent with heating. The quaternization of η, η '' - bis-diethyIamino-p-terphenyl is carried out in a solution of the ethyl ester of benzenesulfonic acid with warming.

The process for obtaining dibenzenesulfonate des n ^ i "-bis triethylammonium-p-terphenyl is thus three-stage, which takes place quickly and with a good yield. The synthesis uses reactants and Solvent used; no trouble also cleans the end product. The specified process can also take place under large-scale Conditions are easy to run.

To facilitate reworkability, the synthesis of dibenzenesulfonate η, η '' - bis-triäthylammo-

r> nium-p-terphenyl explained in more detail:

Production of dibenzenesulfonate
n, n "-bis-triethylammonium-p-terphenyl

a) Reduction of n, n "-Dinitro-p-terphenyl

In the flask with a content of 1 l, provided with a reflux condenser, a stirrer, thermometer and a dropping funnel is added to the suspension of 10 g of n, n "-dinitro-p-terphenyl in 500 ml of ethylene glycol

■ Γι 5 ml of freshly prepared Raney Ni and then carefully added dropwise with mixing and heating (temperature within the flask 165-170 ⁰ C), 15 ml of 99% hydrazine hydrate, avoiding excessive foaming. Within a few minutes

"in everything goes into the solution, which is activated carbon admits. In 10-15 minutes the hot solution is filtered off and the filtrate is cooled. The unusual one Precipitate is washed with alcohol on the filter and dried

The η, η '' - diamino-p-terphenyl, 8.1 g (quantitative yield) flesh-colored, does not require any additional cleaning. M.p. = 240 ⁰ C (literature 241-242 ° C).

^w) b) alkylation of n, n "-diamino-p-terphenyl

In the flask with a content of 250 ml, equipped with a reflux condenser and a stirrer, 8 gn, n "-Diamino-p-terphenyl, 10 g calcium carbonate, 100 ml dimethylformamide, 10 ml water and 23 ml ethyl iodide are placed and heated at the temperature of one heating bath of 120-130 ⁰ C. Within a few minutes all goes into the solution and immediately begins the precipitate

fail. The heating is continued for two hours with vigorous mixing and then becomes the suspension is cooled.

The filtered precipitate is crystallized and from 100 ml of dimethylformamide one gets 7.65 g (70%) n, n "-bis-diethylamino-p-terphenyl, light beige, Melting point = 198 ° C.

Ber. in%: C 83.82; H 8.65; N 7.52.
Found in%: C 83.30, 83.42; H 8.68, 8.61;
N 7.63, 7.61 • C ₂₆ H ₃₂ N ₂ .

c) Quarternization of
n, n "-bis-diethylamino-p-terphenyl

In the flask with a capacity of 100 ml, 7.5 g of η, η-bis-diethylamino-p-terphenyl are heated with 20 ml of ethyl ester of benzosulfonic acid at a heating bath temperature of HO ⁰ C for 1 hour.

The solution formed during the first 30 minutes becomes final at the end of the heating process crystallized. After cooling, the reaction mass is processed with absolute ether and filtered.

The light beige precipitate is crystallized from 100 ml of acetone with water 10: 1 with activated charcoal. 10 g (70% of the theoretical) dibenzenesulfonal des η, η "- bis-triethylammonium-p-terphenyls, white, turns greenish in the air. Mp = 228- 229 ⁰ C with decomposition. It is dried in a vacuum and stored in a room protected from light.

Ber. in%: C 67.72; H 7.04; N 3.76; S 8.59.
Found in%: C 67.97; 68.22; H 7.76, 7.66;
N 3.80, 3.90; S 8.75, 8.55;

n, n

Manufacturing example

Preparation of the dosage form of

Dibenzenesulfonate des
'-bis-triethylammonium-p-terphenyls

Dibenzenesulfonate-n.p ^ bis-trialhylammonium-p-terphenyl is used as a 0.5% aqueous solution in an amount of 5 mg of active ingredient per one intervenous injection used.

in its aqueous solution contains a stabilizing agent, which is hydrochloric acid in an amount of 0.01 mg per one injection.

For the preparation of 1 l of 0.5% solution of the substance, 5 g of the same are poured into a volumetric flask

ι brought a capacity of 1 I and distilled at 20 ⁰ C up to the mark poured, to which a stabilizer is added on the basis of the calculation 3ml of 0.1 N hydrochloric acid per 1 1 of water. The solution is mixed, filtered and dispensed into ampoules

.'ti neutral glass filled with 1 ml each. The vials are sterilized with steam at a temperature of 100 ⁰ C for 30 minutes, pH = 3.6 the final solution pH of the solution after sterilization = 3.7 (potentiometric determination).

As reactions for determining the authenticity of the

The preparation can show its reactions with potassium iodide

and potassium rhodanide, which are capable of forming soluble precipitates with it when heated.

The authenticity of the material is also confirmed by the

in characteristic ultraviolet spectrum with a maximum of 285 ± 2 nm and a minimum of 237 ± 1 nm.

The quantitative determination of the 0.5% solution can be done using the spectrophotometric method

r. perform that on determining the optical density based on the solution to be tested. The ampoules are stored in a room protected from light.

Claims (1)

Claim: Non-depolarizing myorelaxant for injection, characterized in that the active ingredient is dibenzene sulfonate n, n "-bis triethylammonium p-terphenyl contains 10