Hydrochloride of 2-benzylaminocarbonyl exhibiting anti-hypoxic and anti-toxic effect when exposed to various convulsive agents

 

(57) Abstract:

The invention relates to the creation of new chemical compounds with anticonvulsant, antihypoxic and antioxidant activity and belonging to a new class of anticonvulsants. The proposed connection manifests a pronounced antispasmodic and anti-toxic effect 1.5 times above or at the level of the prototype poisoning such chemical agents as strychnine, picrotoxin, korazol, phosphocol and antihypoxic effect. It is 5 times less toxic than the prototype. The proposed compound is dissolved in the form that will allow you to create a dosage form intended for emergency care. The proposed connection can be used in medicine as an anticonvulsant and antihypoxic agent. 5 table.

The invention relates to the chemistry of organic substances, concerns the synthesis of new chemical compounds exhibiting anti-hypoxic and anti-toxic effect when exposed to various convulsive agents, and which can be used in medicine.

Currently there are a large number of anticonvulsants, including the imides [8], benzdiazepine [9 - 10], benzamide [11] and others

On chemical structure of the inventive connection closest to the Dibazol-2-benzylbenzimidazole, known in medical practice as antihypertensives [12]. However, information about anticonvulsant and toxic effects Dibazol and its derivatives in the literature are missing.

The known compound 5-methoxy(bromo)-2-(N,N-dibutylamino)-benzimidazole, showing minor anticonvulsants effect when exposed to maximum shock [13].

In medical practice as anticonvulsant agents are derivatives of barbituric acid (phenobarbital, benzonal) [14]. When used for this indicator, the main drawback is the manifestation of barbiturate hypnotic effect and inhibitory effect on the respiratory centers. As the anticonvulsants are also used [15] derived as (phenytoin, hexahydropyridine (primidone), amide 3-chloropropionic acid (beclamide, fencon), oxazolidinedione (trimethadione), imide succinic acid (ethosuximide, puramed). In General, these drugs are used to treat epilepsy, and their effectiveness when exposed to x recognized derivative of benzdiazepine [16, 17] , in particular, diazepam (prototype). It is known that diazepam (sibazon) eliminates seizures caused by carazolol, novocaine, strychnine, cocaine, organophosphorus compounds and other chemical agents.

The disadvantage of the prototype is that it is insoluble in water and this makes it difficult to use when providing emergency care.

The aim of the invention is a drug that has both anti-hypoxic and anti-toxic effect, and also soluble in water, which will allow you to create a dosage form intended for emergency.

The objective is achieved by the hydrochloride of 2-benzylaminocarbonyl connection related to the derivatives of benzimidazole, information about them as about the antihypoxants and antitoxidant when exposed convulsive agents are missing.

The invention meets the criterion of "novelty", as compared with the prototype synthesized and studied a derivative of benzimidazole that belong to another class of chemical compounds.

The invention meets the criterion of "substantial differences", because changes in the chemical structure gave a statement the etching convulsive agents, as well as the ability to dissolve in water.

The possibility of achieving positive effect is proved by the following examples.

Example 1. The method of obtaining the proposed substance.

A mixture of 1.8 g (0.01 mol) of hippuric acid and 1.2 g (to 0.011 mol) of O-phenylenediamine alloy at a temperature of 180 - 200oC with stirring for 1 h the Observed allocation of water vapor. The reaction mass is then cooled to 90oC and add 100 ml of 80% ethyl alcohol. Treated activated carbon boiling and filter the solution hot. Precipitated upon cooling, the precipitate is filtered off, washed with a small amount of cold dilute alcohol and crystallized from 80% ethanol. The absence of impurities in the product the hippuric acid test method TCX. Yield 1.2 g (50%).

Received the base 2-benzylaminocarbonyl transferred into the hydrochloride. So pl. 232 - 235oC (decomposition).

In the analysis of the product found %: C 62,03; H 4,55; N 14,89; Cl 12,53.

From composition C15H14ClN3O calculated, %: C 62,61; H to 4.87; N 14,61; Cl 12,35.

TLC: Rf = 0,45 0,04; Silufol UV - 254; system: chloroform-methanol-acetic acid (60:15:25). The expression in UV-light.

IR - spectrum (tab is 0 -

1550 - NH (secondary amide);

1320 - 1310 (benzimidazole).

The proposed connection is easily soluble in water. You can prepare a 20% solution.

Example 2. The definition of toxicity.

Acute toxicity was evaluated by the average lethal dose (LD50(mg/kg) determined in experiments on outbred mice weighing 18 to 24 g intraperitoneal injection. For evaluation used a tabular method Prozorovsky Century. B [18], which is based on the introduction of a series of standard doses of the same number of groups of animals with the subsequent finding of dose and its error on a predetermined computer table.

It has been found that the toxicity LD50the proposed connection is equal to (180 1290) mg/kg Toxicity prototype, according to literature data [19], equal (240 60) mg/kg

Thus, the proposed connection 5 times less toxic than the prototype.

Example 3. Anticonvulsant and toxic effects in case of poisoning by strychnine.

Experiments were performed on outbred mice weighing 18 to 20 g Strychnine was administered at a dose of 1.2 mg/kg, subcutaneously. At the same time 100% of the animals were observed convulsions, and 92% of the heavy mortality was 92%. Investigational drugs is the ATA conducted by three indicators:

- the number of animals, which were filmed severe cramps,%;

- the number of animals that have no cramps,%;

- the number of surviving animals, in %.

The investigated dose prototype - 10 mg/kg - largest close to the median effective dose (ED50) in mice in the administration of strychnine (shown in the literature to 9.2 mg/kg [20]). This dose is equal to 1/24 from LD50. A proposed dose of the compounds taken 50 mg/kg, which is 1/25 of its LD50. Increasing doses of the prototype to 15 - 20 mg/kg resulted in a decrease of the protective action, which is associated with unwanted side effects. We offer same connection at increasing doses up to 100 mg/kg increased anticonvulsant and toxic effects not showing any side effects. The data obtained are presented in table. 1.

Thus, the proposed connection has a pronounced antispasmodic and anti-toxic effect of strychnine poisoning, and anticonvulsant effect 1.5 times stronger than that of the prototype.

Example 4. Antihypoxic effect.

Antihypoxic effect was evaluated in experiments on outbred mice weighing 18 to 20 g on the model of hypoxia confined space on led is implemented compounds were compared not only with the prototype, but with a known antihypoxic drug - lesions [21]. The drugs were injected intraperitoneally before placing animals in thermocamera. The results obtained are presented in table. 2.

From the data table. 2 shows that the proposed connection has antihypoxic effect. With the introduction of the proposed connection of the latent period in hypoxia increased 1.35 times, and survival is above 1.1 times as compared with the prototype and 1.3 times compared with the lesions.

Example 5. Anticonvulsant and toxic effects poisoning picrotoxinin.

Experiments were performed on outbred rats weighing 180 - 200 g of Picrotoxin was administered subcutaneously at a dose of 5.85 mg/kg With 100% of the animals were observed severe convulsions, death was 82%. The study drugs were injected intraperitoneally at the first signs of intoxication (light shaking). Evaluation of anticonvulsant and toxic effects of the drugs was performed on the same three parameters, as in the case of poisoning by strychnine. Introduced rats dose prototype 2 mg/kg limited by the fact that close to ED50the manifestation of tranquilizing action on behavioral tests [22]. The results obtained are presented in table. 3.

Example 6. Anticonvulsant and toxic effects poisoning postagola.

Experiments were performed on outbred rats weighing 180 - 200 g Phosphocol was injected intramuscularly at a dose equal to 0.45 mg/kg, with 100% of the animals were observed severe convulsions and death was 83%. The proposed connection and the prototype was introduced at the same time with postagola intraperitoneally. Evaluation of therapeutic effect of the drugs was performed on the same three parameters, as in the case of poisoning by strychnine. The data obtained are presented in table. 4.

Thus, the proposed connection has anticonvulsant and toxic effects poisoning postagola at the level of a prototype.

Example 7. Anticonvulsant and toxic effects poisoning carazolol.

Experiments were performed on outbred rats weighing 180 - 200 g Korazol was administered subcutaneously at a dose LD50equal to 110.0 mg/kg With 100 animals experienced severe cramps, slight wince). Evaluation of anticonvulsant and toxic effects was performed on the same three parameters, as in the case of self-poisoning other convulsive agents. The data obtained are presented in table. 5.

Thus, when the poisoning of rats carazolol the proposed connection exhibits anticonvulsant and toxic effects is not statistically different from the actions of the prototype.

The proposed connection belongs to a new class of chemical compounds has not been studied as anticonvulsants.

The positive effect from the use of connection is that it has a broad spectrum of anticonvulsant and anti-toxic action (effective for poisoning with strychnine, picrotoxin, postagola, carazolol), and also takes antihypoxic activity. In addition, it allatoxin, soluble in water, which will allow you to create a dosage form intended for emergency.

The proposed connection can be widely used in medical practice.

Hydrochloride of 2-benzylaminocarbonyl formula

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showing anticonvulsant, antihypoxic and antitoxic the

 

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