RU2243770C1 - Agent for treatment of poisoning with organophosphorus poisonous substances - Google Patents

Abstract

FIELD: medicine, toxicology.

SUBSTANCE: invention proposes applying 15% aqueous solution of 1-methyl-5-[2'-(benzyldimethylammonio)ethyl]carbamoyl pyridinium-2-aldoxime dichloride that exceeds the 15% solution of dipiroxime (TMB-4, trimedoxime bromide) used in native medicinal practice by the curative effectiveness. Invention can be used in urgent treatment of acute poisoning with organophosphorus poisonous substances eliciting neuroparalytic effect.

EFFECT: enhanced effectiveness, valuable medicinal properties of agent.

3 tbl

Description

The present invention may find application in medicine for the emergency treatment of acute poisoning with organophosphorus toxic agents having a nerve-paralytic effect (FOV NPA), in particular sarin, soman, and a substance of type V _x . Such poisoning is possible during the destruction of chemical weapons stockpiles, carried out in accordance with the “Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and Their Destruction”, ratified in the Russian Federation on 12/05/97, as well as in terrorist attacks (a known case of poisoning sarin in the Tokyo subway).

At present, injectable dosage forms of preparations from the group of oximes, cholinesterase reactants (CE), are intended for the treatment of poisonings of FOV NPA. Quaternary and bis-quaternary derivatives of pyridinaldoximes are well known and found practical application: 2-PAM chloride (pralidoxime chloride) (Ia) and 2-PAM methanesulfonate (P ₂ S) (Ib), obidoxime (toxogonin, LuH6) (II), dipiroxim (TMB -4, trimedoxime bromide) (III) [APGray. Design and Structure-Activity Relationships of Antidotes to Organophosphorus Anticholinesterase Agents. Drug Metabolism Reviews, 15 (3), 557-589 (1984)]. They are available in the form of ready-made aqueous solutions in autoinjectors, syringe tubes, or in ampouled form [M.D. Mashkovsky. Medicines, t. 1, 201-203. Ed. 14, M., 2000 I. Ricordel, J. Meunier. Armes chimiques: antidotes. Apercu sur les moyens actuel, perspectives. Ann. Pharm. Fr., 58 (1), 5-12 (2000)].

As a rule, cholinesterase reactivators are used in combination with drugs from the group of anticholinergics (atropine, benzactisine, etc.), which significantly increases the effectiveness of treatment and can reduce the dose of both drugs [A.R. Gray. Design and Structure-Activity Relationships of Antidotes to Organophosphorus Anticholinesterase Agents. Drug Metabolism Reviews, 15 (3), 557-589 (1984); M.D. Mashkovsky. Medicines T.1, 201-203. Ed. 14, M., 2000]. However, it is also possible individual use of reactivators.

Of the reagents listed above, CE, Obidoxime and Dipiroxim are approximately equally effective, 2-PAM is less active.

In domestic medical practice, dipiroxim in the form of a 15% aqueous solution in ampoules is used [M.D. Mashkovsky. Medicines, t. 1, 201-203. Ed. 14, M., 2000]. Despite certain advantages over 2-PAM, dipiroxim (like Obidoxime) is still not effective enough. In addition, derivatives of 4-pyridinaldoxime, which include dipiroxim and obidoxime, form during the reactivation of CEs that occur during treatment, relatively stable phosphorylated oximes with their own high toxicity [F. Worek et al., Seventh international Symposium on protection against. GB warfare agents. Stockholm, Sweden, 15-19. June. 2001, p. 55]. This property is less intrinsic to 2-pyridinaldoxime derivatives.

The main objective of the present invention is the creation of a new drug for emergency treatment of acute poisoning FOV NPA, which has a significantly higher therapeutic efficacy compared to existing drugs. The creation of such a tool will also allow expanding the range of practically used reactivators CE.

At present, in the Russian Federation, cholinesterase reagents are not manufactured or purchased by import [Russian Drug Register - Encyclopedia of Medicines. Issue 10. LLC “RLS-2003”, p. 68, 293, 331, 844, 1052]. The production of a 15% solution of dipiroxime on “ICN October” was discontinued due to the lack of raw materials-substance dipiroxim, previously produced in Latvia [Russian Medicines Register. M., 1993, p. 382]. The injection forms of other oximes (alloxime, isonitrosine and diethixime) described in the reference book of M.D.Mashkovsky (v. 1, p. 201-203) are significantly inferior to dipiroxim in therapeutic efficacy.

To solve this problem, it is proposed to use a 15% aqueous solution of 2-pyridinaldoxime derivative - 1-methyl-5- [2 ’- (benzyldimethylammonio) ethyl] -carbamoylpyridinium-2-aldoxime dichloride (IV):

The synthesis of oxime (IV) is carried out according to chemical scheme I.

Stage I. Obtaining 5- [2 ’- (dimethylamino) ethyl] -carbamoylpyridin-2-aldoxime (VI).

A flask with a capacity of 1 l, equipped with a stirrer and a reflux condenser with a shutter preventing the contact of the reaction mixture with carbon dioxide of air, is charged with 27.8 g (0.315 mol) of N, N-dimethyl-aminoethylenediamine (VI) and 54.0 g (0, 3 mol) 5-methoxycarbonylpyridin-2-aldoxime (V) (Lantvoev V.I., Somin I.N. et al. “Method for the production of 5-alkoxycarbonylpyridin-2-aldoximes”, Auth. Certificate No. 1301829, Bull. No. 13, 1987). The mass is heated to 60 ° C, stirred until complete homogenization and maintained at a given temperature for 60 hours without stirring. 400 ml of ethyl alcohol and acetone are added to the crystallized mass after exposure, and they are stirred at the boil until they are completely dissolved. After cooling to 0 - + 5 ° C, the precipitated product is filtered off, washed with a mixture of alcohol with acetone (1: 1, 2 × 70 ml) and dried at 60 ° C to constant weight.

The yield of oxymoamide (VII) 57 g (80.5%); melting point 180-182 ° C. Found (%): C 55.78; H, 6.90; N, 23.6. C ₁₁ H ₁₆ O ₂ . Calculated (%): C 55.91; H 6.84; N, 23.70. PMR spectrum (DMSO d6; δ, ppm): 2.27 s (6H, N (CH ₃ ) ₂ ); 3.3-3.7 m (4H; -CH ₂ -CH ₂ -); 7.94; 8.3; 8.95 (3H, pyridine nucleus); 8.19 s (1H; CH = N); 8.5 (1H; CONH). UV spectrum, λ _max ; nm: at 0.01 n. NaOH 310; 0.01 n HCl 255; 290

Stage II. Preparation of 1-methyl-5- [2 ’- (dimethylbenzylammonio) ethyl] -carbamoylpyridinium-2-aldoxime diiodide (IX).

59.0 g (0.25 mol) of oxymoamide (VII), 115 ml of dimethylformamide, 34.6 g (0.27 mol) of freshly distilled benzyl chloride are placed in a 1-liter flask, the mass is heated to 60 ° C, held for 5 hours. Then, 107 g (0.74 mol) of methyl iodide are added dropwise to the reaction mass and left in a hermetically sealed flask for 24 hours at 60 ° C. After completion of exposure, the mass is cooled to room temperature, 225 ml of acetone are poured, stirred for 1 hour, cooled to 0 - + 5 ° C and kept at this temperature for 24 hours. The precipitated diiodide is filtered off, washed with cold acetone (2 × 50 ml) and dried at 60 ° C to constant weight. 136 g (90%) of technical diiodide are obtained; the content of the main substance is 98.5%; melting point 188 -189 ° C.

Stage III. Preparation of 1-methyl-5- [2 ’- (dimethylbenzylammonio) ethyl] -carbamoylpyridinium-2-aldoxime dichloride (IV).

In a 1 L flask equipped with an effective stirrer, thermometer and dropping funnel, 800 ml of water, 300 mg of Trilon B and 61 g (59.6 g in terms of 100%; 0.1 mol) of diiodide (IX) are loaded. The mass with stirring is heated to 40-45 ° C and maintained until complete dissolution. Then 15 ml of toluene, 14 ml (0.157 mol) of 35% hydrochloric acid and 13 ml (0.128 mol) of 30% hydrogen peroxide are successively poured into the flask. After draining the reagents, the mass is kept for 1 hour at 40-45 ° С, cooled to 10-20 ° С and kept for another 2 hours. The aqueous solution is decanted from the separated complex and filtered. The filtrate was placed in a flask, 3 g of neutral activated carbon was added to it and stirred for one hour at room temperature. The coal is filtered off, the solvent is removed in a vacuum rotary evaporator at a temperature of 45-50 ° C. The residue is crystallized from 125 ml of ethyl alcohol. The precipitated white crystalline product is filtered off and dried at 60 ° C to constant weight. The yield of oxime (IV) is 26.6 g (64%); melting point 199-201 ° C (with decomposition). Found (%): Cl 17.0. Calculated (%): Cl 17.2. PMR spectrum (DMSO (d ₆ ; δ, ppm): 13.5 s (1H; OH); 10.5 t (1H; NH⊕); 8.7 s (1H; = CH); 9, 8 s; 9.0 d; 8.5 d (3H of the pyridine core); 7.5-7.6 m (5H; C ₆ H ₅ ); 4.7 s (2H; CH ₂ -C ₆ H ₅ ) ; 4.4 s (3H;> N⊕-CH ₃ ); 3.9 t; 3.6 t (4H; -CH ₂ -CH ₂ -); 3.1 s (6H; N⊕ (CH ₃ ) ₂ ). UV spectrum, λ _max ; nm: in 0.01 N NaOH 356.

The finished dosage form of the proposed funds is a 15% aqueous solution of oxime IV containing auxiliary substances that ensure the stability of the solution. The most important stability factor is maintaining the optimal pH range from 2.4 to 3.4 during storage. The solution of oxime IV, intended for injection, can be produced in ampoule form, syringe tubes or in a single chamber autoinjector. To obtain a sterile dosage form, the solution of oxime IV should be subjected to membrane filtration under aseptic conditions, spilling into ampoules, syringe tubes or autoinjectors in an inert gas atmosphere.

Thus prepared 15% solution of oxime IV was compared in terms of toxicity, therapeutic efficacy and therapeutic index with an industrial sample of a 15% solution of dipiroxim (see table. 1-3). In the table. 1, 2 shows toxicity and comparative data on the therapeutic efficacy of individual reactants III and IV, in table. 3 - with a combination of these reactivators with an anticholinergic blocker - cyclosyl [M.D. Mashkovsky. Medicines, t.1, p. 213. Ed. 14, M., 2000].

Table 1
Toxicity (LD ₅₀ ), therapeutic doses (ED ₉₅ ) and therapeutic index (TI) of dipiroxim (III), 2-PAM-chloride (Ia) and oxime IV, determined in rats Oxime LD ₅₀ mg / kg UNIT ₉₅ MG / KG TI Dipiroxim 192 ± 12 thirty 6.4 Oxime IV 297 ± 44 2,5 11.9 2-PAM chloride 315 ± 32 40 7.9 Note. 1. The values of the average lethal dose (LD ₅₀ ) are determined by intramuscular injection of an aqueous solution of oxime. 2. ED ₉₅ - a dose of oxime that ensures the survival of 95% of animals poisoned by a lethal dose (1 LD ₉₉ ) of sarin (with intramuscular injection of poison and a reactant). 3. TI = LD ₅₀ / ED ₉₅ . table 2
Comparative therapeutic efficacy of individual oximes III and IV for cats poisoned with substance V _x . Oxime Dose of oxime mg / kg % Survival Dipiroxim fifteen twenty Oxime IV fifteen 60 the control 0 0 Note. Data were obtained on 10 animals with intramuscular inoculation with V _x at a dose of 5 μg / kg. Oxime was administered intramuscularly 20 minutes after the poison.

Table 3
The combined therapeutic use of dipiroxime and oxime IV with the anticholinergic cyclosil (0.2 mg / kg) in rats poisoned with FOB NAP Oxime V _x (2 LD ₅₀ ) Soman (1 LD ₉₉ ) Zarin (1 LD ₉₉ ) UNIT ₉₅ MG / KG TI IU ₉₅ mg / kg TI UNIT ₉₅ MG / KG TI Dipiroxim 0.50 384 20,0 9.6 1.25 153 Oxime IV 0.05 5940 2,5 118 0.10 2970 Note. Intramuscular poisoning. Simultaneous intramuscular administration of a reactivator and anticholinergic blocker (in the same syringe) 20 minutes after inoculation.

The results obtained in rats (Tables 1, 3) indicate: both in case of individual and combined use of both oximes, dipiroxim is significantly inferior in therapeutic efficacy to oxime IV. Therapeutic doses of the latter are about 10 times lower than that of dipiroxim. Since oxime IV is approximately 1.5 times less toxic than dipiroxim (Table 1), the corresponding therapeutic indices of oxime IV exceed these values in dipiroxim by more than 10 times.

The data obtained on cats (Table 2) confirm the superiority of oxime IV: with equal therapeutic doses of both drugs, the survival rate of animals differs three times in favor of oxime IV.

Claims (1)

An agent for the treatment of organophosphorus poisoning poisoning containing a cholinesterase reactant from the group of bis-quaternary pyridinaldoxime derivatives, characterized in that 1-methyl-5- [2 '- (benzyl dimethylammonio) ethyl] carbamoylpyridiide % aqueous solution.