DE2621227C3 - Non-depolarizing myorelaxant - Google Patents

Description

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

The use of mycrelaxanticn by surgeon! - See operations first began in 1942 at the suggestion of Griff its. Are currently at all operations in which total anesthesia is required, myorelaxants used Depending on the mechanism of blocking the neuro- Muscular connections, myorelaxants are divided into two groups: depolarizing and non-depolarizing.

Currently used by the non-depolarizing Myorelaxants in clinical practice only use dicholine ether of succinic acid, which is below various names are known: ditilin, myorelaxin, listhenon 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 hypofunction or with a liver 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 accompanies the increase caused by depolarizing myorelaxants, ω including also by 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 cyclo propane, fluorotane 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. Under consideration of With the disadvantages of ditilin and other depolarizing myorelaxants listed above, the anesthesiologists came to the conclusion that non-depolarizing myorelaxants should preferably be used in clinics.

Over the course of several years, the group of non-depolarizing myorelaxants became surgical clinical practice particularly often oc-tubocurarine (Burroughs Wellcome CO London) and Pyrolaxon (synonyms: Gallamin, Flaxedyl) used. However, these preparations also have disadvantages. α-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.

During the past few years, the non-depolarizing myorelaxant - Pankuronhini (Pavulon, Company Organon Ina W. Orange N.J. 07052) is gaining broader recognition, representing a bis-tertiary aminosteroid

Pankuronium is 5 to 10 times more active than d-tubocurarine in its neuromuscular blocking effect and 2 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 myoparalyittic 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 It is absolutely safe to use and has a high selectivity and specific effect 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 a Non-depolarizing myorelaxant has been found that according to the invention is dibenzene sulphanate as the active ingredient Contains η, η '' - bis-triethylammonium-p-terphenyl

The carrier substance for the active substance mentioned is water. This myorelaxant can be used as a 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 grater of advantages over the known non-depolarizing myorelaxants d-tubocurarine and pancuronium. These advantages are detailed 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 and rabbits. Mice and pigeons, in experiments with phrenic diaphragm preparations a ve «! Rats and the straight abdominal muscles of frogs (rana temporaria) The properties of Terkuronium have been carried out with the properties of d-tubokurarine and pankuronhim compared.

Try with cats

Cats under anesthesia (chloralose - 50 mg / kg and Urethane 500 mg / kg intraperitoneally) or decerebrated in the area of the pair of four hills. If necessary, done artificial ventilation of the lungs. Contractions were registered »m. tibialis ant «in the isotonic regime as a reaction to electrical stimulation of the peripheral segment "n peroneus" with siipramaximal Pulses with a duration of 0.1 nuek and one Frequency from 0.1-100 Hz.

When a muscle was indirectly stimulated at a frequency of 0.1 Hz, the block of neuromuscular transmission (95-100% block) developed and reached it in 40-60 seconds after intravenous terkuronium introduction at a dose of 0.08 ± 0.002 mkM / kg Maximum in 2–2½ minutes and lasted 2–4 minutes (10 attempts). The contractions of the muscle re-excited completely within 10 ± 1.5 minutes after the introduction of terkuronium. An equally effective dose of d-tubocurarine was 0.5 ± 0.03 mkM / kg (5 experiments) and of pancuronium 0.04 ± 0.001 mkM / kg under these conditions.

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 introduction of terkuronium, its blocking increased Activity as well as the activity of d-tubocurarin and pancuronium (by 60-80%).

The blocking effect of the terkuronium is due to its action on the postsynactic membrane of the Traced back to skeletal musculature. The introduction of acetylcholine in the »close intraarteriae injection «procedures caused con * simultaneous tractions with blockade of neuromuscular transmission suppressed during the full μ digen suppression of contractions of a muscle in response to indirect stimulation of the muscle 20g the same together in response to its direct irritation.

The action of terkuronium was under the influence of the neostigmine of succinylcholm, Dekamethoniutn and AcetylchoHn weakened and increased by d-tubocurarine. The blocking effect of the terkuronium is expressed more strongly, the higher the frequency of the impulses. 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, muscle contractions are restored in response to indirect stimulation 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 canceled. The antagonism of neostigmine is stronger when exposed to terkuronium than when exposed to d-tubocurarine and pancuronium. This is how the muscle contractions began even with a 5-fold increase in the dose of terkuronium in the range of 2 to 5 minutes after a single introduction of neostigmine at 0.1 mg / kg, and in 15-20 minutes the muscular contractions were completely restored record.

Upon exposure to pancuronium and d-tubocurarine, recovery was so rapid Muscle contractions after the introduction of neostigmine only occur if the dose is increased by 2 to 3 times Myorelaxants have been recorded. When the pancuronium dose was increased 4 to 5 times, weak ones developed Muscle contractions no later than 9-10 minutes and the complete restoration of contractions no later than 30 minutes after experiencing Neostigmine (6 attempts). An even more blatant delay in restoring the transmission was at Observe the effect of d-tubocurarine. With a 4-fold increase in the dose of d-tubocurarin occurred weak muscle contractions only occurred in 20-25 minutes and were complete in 40-70 Minutes again (3 attempts), and with a 5-fold increase in 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) caused, 0.22 ± 0.009 mkM / kg. The complete blocking effect developed in 14-2 minutes Introduction of terkuronium and lasted 3-5 minutes. A few minutes later the behavior stopped of the respective animal normal. An equivalent effective dose of d-tubokurarine was

0.18 ± 0.02 mkM / kg (6 experiments) 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 Exit from paralysis of the respiratory muscles upon their intervenous introduction in 50% of animals, that is, LDm ■ LD50 was found in terkuronium equal to 0.03 mkM / kg, for d-tubocurarine equal to 0.25 mkM / kg and the same for pancuronium 0.026 mkm / kg. Thereby the area of muscular slackening exposure was 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), the one causing complete blockage of the sciatic nerve and calf transmission was 0.025 ± 0.005 mkm / kg (5th Experiments), the introduction of neostigmine at a dose of 0.1 mg / kg intravenously during the full block & de always led to an immediate developing and complete restoration of ι ο muscle contractions.

Try with mice

In trials with white mice, the dose of terkuronium when introduced into the tail vein, which caused loss of the lateral turn symptom (ED50), was 0.06 mkM / kg (18 trials) and death due to Paralysis of the respiratory muscles occurred after the introduction of terkuronium at a dose of 0.09 mkM / kg in 50% of the animals (LD50). As a result, the area of the muscular slackening action (LD50) XED ₅₀ ) of the terkuronium was 14 · ED50 and the LD50 of the pancuronium is 0.042 mkM / kg and 0.062 mkM / kg and the area of the muscular slackening action is IA ED ₅₀ and LD _{50 of} the d-tubokurarin according to the literature is 0.17 mkm / kg or 0.24 mkm / kg and consequently LD50 / ED50 is -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 intravenous introduction of terkuronium at a dose of 0.2 mkM / kg (ED 50), the Pale the development of flaccid paralysis of muscles lasting from 2.5 to 3 minutes watch. As a result, terkuronium has a non-depolarizing effect even in experiments with pigeons Effect on.

In experiments with Phreniko diaphragm preparations to rats, which were isolated by Bülbring method, the blockage of neuromuscular transmission upon exposure to the Terkuroniums developed in a concentration of 2 χ 10- ⁶ m / l.

In experiments on isolated straight abdominal muscles of frogs - rana temporiaria - the terkuronium concentration is the weakening of the action caused by acetylcholhi, same

2.0 ± 0.04 χ 10- ⁷ m / l. Terkuronium does not cause muscle contraction.

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 progressed with the simultaneous development of the Blockade of neuromuscular transmission »m. tibialis am «. Breathing was restored while muscle contraction was restored. The same was observed upon exposure to d-tubocurarine and pancuronium. Under the terms of Even with the artificial respiration and pulmonary ventilation, no bronchospasm developed 200 to 100 fold increase in dose of terkuronium. The same result was also found in experiments with Rabbits The ratio LD »to ED» in experiments with rabbits and mice achieved the above gives an idea of the in fl uence of terkuronium on respiration. there is no significant differences in the ratios LDWED50 of the terkuronium, d-tubocurarine and pancuronium have been found, the blocking doses of these myorelaxants consequently suppress breathing to the same extent.

Terkuronium acting 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 pankuronium ie a dose that the Breathing suppression evokes an ascetic one Increase in arterial pressure. Under the conditions of artificial ventilation of the lungs Introducing terkuronium in a dose that causes a complete blockage of neuromuscular transmission, arterial pressure does not change When the myoparalytic dose of terkuronium was increased tenfold (03 mkM / kg) it was a small one A decrease in mercury acid by 10 to 20 mm and a short-term decrease in arterial pressure can be observed. 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 Exceeding its myoparalytic dose. There is a rapid and extremely strongly expressed decrease 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 by 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, there was always an expressed short-term decrease in arterial pressure. at When the d-tubokurarin dose was increased 5 times, the depressor effect was expressed so strongly that it immediately led to the death of the animal in question, 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, d. H. Action on sympathetic ganglia

Experiments were carried out with anesthetized cats. Electrical stimulation of the peripheral section of the trunk was carried out on the neck part with a very high frequency of 5 Hz. The duration of a stimulation course - 1 msec, amplitude = 5 V. The third eyelid was twitched and the blood pressure in the temporal vein was measured using a mercury

overpressure indicator registered. The dose was determined of terkuronium, d-tubocurarine and pankuronium with intravenous introduction, which reduce the level of Twitching of the third eyelid by 50-60% under the conditions of constant irritation of the trunk caused.

A ganglion-blocking effect developed after the introduction of terkuronium at a dose of 0.8— Ι, Ό mkm / kg, which is 10 to 15 times its myoparalytic dose exceeds. Parallel to the relaxation of the third eyelid, the Observe arterial pressure. The maximum effect lasted 2-3 minutes, then recovery the contractions of the third eyelid and restoration of arterial pressure began and in 8-10 minutes after the introduction of terkuronium, the contractions of the third eyelid and the level of the Arterial pressure completely 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 was found to be 1.2-1.6 mkM / kg, which is 30 times as much exceeds myoparalytic dose.

Action on M-cholino receptors and on the
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

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Exposure to narcotics
on the effect of terkuronium

The influence of ether, fluorothane and thiopental was found to be narcotic in decerebrated cats 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 myoparalytic effect of terkuronium increased just like that of d-tubocurarine and pancuronium by an average of 20-30%. Terkuronium influx 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 Maintain neostigmine.

Investigation of the "chronic"

Tosicity of Terkuronium
) ">

In four rabbits was once a day during

12 days one intravenous introduction of terkuronium carried out at a dose which elicits the nodding symptom (HDD) -0.02-0.024 mkM / kg. At two

4 (i other control rabbits were used instead of

frequency according to an electrocardiogram (EKG) and blood pressure in the hip vein using a mercury pressure indicator.

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 the depressor reaction after intravenous Introduction of acetylcholine at a dose of 3 mg / kg does not

As a result, terkuronium does not work in a dose 20 times its myoparalytic dose on the parasympathetic section of the autonomic nervous system- This is also due to results other experiments on animals confirmed, when carried out, no development of bronchospasm and salvation have been observed after the introduction of a very large dose of terkuronium.

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 changed in the course of the experiment not. There were no changes in their behavior and no major change in their behavior Rectal temperature records pathological inclusions and changes in blood and urine analyzes were not found. Histological examination of the organs was also not found to be pathological Changes noted. No irritant effects of terkuronium on the ear vein were detected.

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

The Arthus-Sakharov phenomenon was used to investigate the allergic effects of terkuronium Experiments were carried out with 3 rabbits. Each rabbit was 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 Dislocated allergic reaction observed: hyperemia, swelling of water 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 animal experiments, the neuromuscular blocking activity of the terkuronium 6 to 8 times higher than the activity of d-tubocurarin and £ tu / ac nipHricxAr alc Hi ** Λ Irtiyitöt Wpc Pjinlftironitimc

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. One develops in experiments with cats weak and short-term decrease in arterial pressure only when the terkuronium dose is increased tenfold; such a reduction in arthritis pressure is recorded after the introduction of a myoparalytic dose of d-tubokurarine. Affects terkuronium not even with a tenfold increase in the myoparalytic dose, the heartbeat rate. Pancuronium Just like that of the terkuronium according to the invention, it does not secrete histamine and does not block the vegetative ganglia, as a result of a previously unknown mechanism, pancuronium causes a stable increase arterial pressure, which leads to increased haemophilia during surgical interventions and accelerated pulse rates.

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 / ke of the animal weight, which Exceeding 200 times its myoparalytic dose under the same conditions will be a fatal decrease 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 in the Exposure to terkuronium as expressed by exposure to d-tubocurarine and pancuronium. So completely eliminated neostigmine at a dose of 0.1 mg / kg intravenously in experiments with cats blocking effect of five myoparalytic doses of terkuronium for 5 minutes and only three myoparalytic doses of d-tubocurarine and pancuronium.

In experiments with decerebrated cats, no mutual enhancement of the fluorothane and terkuronium effects on blood pressure was observed, while d-tubokurarine intensifies the negative effects of fluorothane, and therefore their combined use applies as a result of the development of the heart and Circulatory collapse as dangerous.

The terkuronium examination as a myorelaxant was used in surgical interventions on organs of the abdominal and thoracic cavity in 150 patients. The operations were carried out under the conditions of the Intubation anesthesia and artificial ventilation of the Lungs carried out. Ether, fluorothane, nitrous oxide (laughing gas) and barbiturates were used as anesthetics used.

> In a first series of observations, the 120 Operations involved, terkuronium was used as the main myorelaxant to maintain myorelaxation used. The intubation of the trachea was carried out under the conditions of myorelxation, which are carried out by

in the introduction of 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

I) 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 at the appearance of the first mprlcmale of the restoration of the muscelto nus and active breathing the repeated intravenous se injection of terkuronium at a dose that is 1/3 to 72 of the original dose was carried out, complete myorelaxation took 1–1.5 Hours.

2 ") The introduction of prostigmine at the end of a Operation in an amount of 2.5 mg always resulted in a rapid - within a few minutes - restoration of active breathing in full. It there were no cases of insufficient effectiveness of the

jo prostigmins, the muscle weakness, the insufficiency of the active breathing in the postoperative period and no recurrence detected. The electromyographic analysis of the character of the effect on the neuromuscular transmission showed that terkuronium

s really a nondepolarizing myorelaxant represents.

A second series of observations, which involved performing 30 operations, was Terkuronium not only for the maintenance of the myorela-

4n xation, but also for intubation of 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

4 ") free implementation of the intubation. The action this dose of terkuronium was not caused by any cardiovascular disorders or any Accompanied by other complications The myorelaxation lasted about 1 hour. For the implementation A prolonged myorelaxation was repeated terkuronium injections at a dose of 0.05-0.08 mg / kg necessary. In this series of observations, the effectiveness of prostigmin as an enibioekieriingsmättel was also complete; there were no cases of the Muscle weakness, respiratory insufficiency and recurarization in the postoperative period were demonstrated. The clinical observations confirmed thereby the experimental data and showed that terkuronium is a non-depolarizing myorela xant represents that of the disadvantages of d-Tubokura The rins, pyrolaxons and pancuroniums are free Use in clinical practice of the myorelaxant according to the invention - terkuronium - with such Properties, compared to d-tubocurarine, Pyrolaxon and even pancuronium are safer and perform controllable myorelaxation. The use of terkuronium for intubation of the Trachea also makes it possible to focus on the

1ΐ

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

(C ₂ Hj) ₃ N-

Terkuronium is the dibenzenesulfonate n, n "- bis-Iriäthylammy / iium-p-terphenyl of the following formula

N (C ₂ H ₅ )., - 2CH ₅ SO,

Understood. It represents a white crystalline powder, which becomes a little greenish in the air, with a melting point = 228-229 ° C with decomposition. The powder is good water-soluble, its aqueous solution is colorless, transparent and in the presence of a stabilizer (3 ml 0.1 n-HCI per 1 liter of water) stable for a long time. the

O, N

H, N-

(C ₂ H ₅ ) ₂ N

(C ₂ H ₅ )., N

0.0012% solution of the substance in 0.01 standard solution 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:

- NO,

C ₂ H ₅ J

QH ₅ SO ₃ C ₂ H ₅

N (C ₂ H ₅ ),

N (C ₂ H ₅ ), · 2C "H ₅ SO,

The process for obtaining the dibenzenesulfonate jo n, n "- bis-triäthylammonium-p-terphenyls includes the Reduction of n, n "-Dinitro-p-terphenyl to the n, n" -Diamino-p-terphenyl, alkylation η, η "-diaminio-p-terphenyl to the n, n" -bis-diethylamino-p-terphenyl with Ethyl iodide, quaternization of the η, η '' - bis-diethylamino-p-ter- r, phenyl with ethyl ester of benzenesulfonic acid for

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 iyi "-Dinitro-p-terphenyl can in different procedures can be carried out. You can do it catalytically in an autoclave, for example hydrogenate for 2-3 hours. 4>

It is also possible to reduce η, η "- 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 im Obtain ethylene glycol by heating. This reduction takes a few minutes. the Alkylation of! ^ "- diamino-p-terphenyl can be carried out with the help of various alkylating agents. Alkylation with ethyl iodide is particularly easy in the presence of an iodine-binding agent in one inert organic solvent with heating. The quaternization of ly ^ '- bis-diethylamino-p-terphenyl is carried out in a solution of the ethyl ester of Benzenesulfonic acid under heating.

The process for obtaining dibenzenesulfonate des iyi "-bis triethylammonium-p-terphenyls is thus three-stage, which runs quickly and with a good yield. During the synthesis, reactants and Solvent used; The cleaning of the end product is also no problem. Dab The specified process can easily be carried out even under industrial-scale conditions.

To make it easier to rework, the synthesis of dibenzenesulfonate η, η '' - bis-triethylammonium-p-terphenyl is explained in more detail:

Production of dibenzenesulfonate η, η '' - bis-triethylammonium-p-terphenyl

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

In the flask with a content of 1 l, equipped with a reflux condenser, a stirrer, thermometer and an iron funnel, the suspension of 10 gn, n "-Dinitro-p-terphenyI in 500 ml of ethylene glycol is added to 5 ml of freshly prepared Raney Ni and then added dropwise whereby strong foaming is avoided it while mixing and heating (temperature inside the piston 165-170 ⁰ C) carefully 15 ml of 99% strength hydrazine hydrate to. within a few minutes is all in the solution, which is activated carbon is added. in 10- The hot solution is filtered off for 15 minutes and the filtrate is cooled. The precipitate which has separated out is washed on the filter with alcohol 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 ⁰ C).

b) alkylation of n ^ i "-diamino-p-terphenyl

8 g of iyi "-diamino-p-terphenyl, 10 g of calcium carbonate, 100 ml of dimethylformamide, 10 ml of water and 23 ml of ethyl iodide are placed in the flask with a volume of 250 ml, equipped with a reflux condenser and a stirrer, and heated to the temperature of a heating bath 120-130 ⁰ C. Within a few minutes, it goes into the solution and immediately begins the precipitate

failure 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 flask having a capacity of 100 ml to 7.5 g heated η, η-bis-Oiäthylamino-p-terphenyl with? 0 ml of ethyl ester of benzenesulfonic acid at a temperature of the heating bath of 140 ⁰ C for 1 hour.

The solution formed during the first 30 minutes becomes final at the end of the heating 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) dibenzenesulfonate of η, η '' - bis-TriäthyIammonium-p-terphenyls are obtained, white turns greenish in the air. Melting point = 228-229 ° 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;

C ₄₂ H ₅₂ N ₂ O ₆ S ₂ .

Manufacturing example

Preparation of the dosage form of

Dibenzenesulfonate of η, η '' - bis-triethylammonium-p-terphenyls

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

Its aqueous solution contains a stabilizer, which hydrochloric acid in an amount of 0.01 mg per is an injection.

For the preparation of 1 1 0.5% solution of the substance, 5 g of the same are placed in a volumetric flask with a content of 1 1 and ^{distilled water is poured in at 20 0} C up to the mark , 1-n-hydrochloric acid is added per 1 liter of water. The solution is mixed, filtered and filled into 1 ml ampoules made of neutral glass. 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).

Reactions with potassium iodide can be used as reactions for determining the authenticity of the preparation and potassium rhodanide, which are capable of forming soluble precipitates with it when heated.

The authenticity of the fabric is also confirmed by the 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 perform based on the determination of the optical density of the solution to be tested. The ampoules will stored in a room protected from light.

Claims (1)

Claim: Non-depolarizing myorelaxant for injection, characterized in that it is as Contains active ingredient dibenzene sulfonate n, n "-bis triethylammonium-p-teφhenyI 10