Agent for treatment of poisoning with organophosphorus poisonous substances

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.

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The present invention may find application in medicine for the emergency treatment of acute organophosphorus poisoning poisonous substances with nerve action (FAUVE NAPs), in particular Surinam, soman and substance of type Vx. 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 on their destruction, ratified in the Russian Federation 05.12.97, and in case of terrorist attacks (known case of poisoning Surinam in the Tokyo subway).

Currently, treatment of poisoning with organophosphorus agents NAPs are injectable dosage forms of drugs from the group Asimov - reaktivatory cholinesterase (CHE). Well known and have found practical application of Quaternary and bischetvertichnoe derivatives pyridylamino: 2-PAM chloride (pralidoxime chloride) (Ia) and 2-PAM methanesulfonate (P2S), (IB), obidoxime (toxogonin, LuH6) (II), dipiroksim (TMB-4, trimedoxime bromide) (III) [A.P.Gray. Design and Structure-Activity Relationships of Antidotes to Organophosphorus Anticholinesterase Agents. Drug Metabolism Reviews, 15 (3), 557-589 (1984)]. They are available as ready in aqueous solutions autoinjector, spritz-tubes or in part form [Medmaravis. Drugs, vol. 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, reaktivatory cholinesterase used in combination with drugs from the group holinoblokatorov (atropine, benactyzine and others), which significantly increases the effectiveness of the treatment and allows lower doses of both drugs [..Gray. Design and Structure-Activity Relationships of Antidotes to Organophosphorus Anticholinesterase Agents. Drug Metabolism Reviews, 15 (3), 557-589 (1984); Medmaravis. Medicinal product. T.1, 201-203. Ed. 14, M, 2000]. However, it is also possible for individual application of reaktivatory.

From the above reaktivatory HE obidoxime and dipiroksim about equally effective, 2-PAM less active.

In our medical practice is used dipiroksim in the form of a 15 % aqueous solution in ampoules [Medmaravis. Drugs, vol. 1, 201-203. Ed. 14, M, 2000]. Despite certain advantages over 2-PAM, dipiroksim (as obidoxime) still not efficient enough. Moreover, derivatives of 4-pyridinoline, which include dipiroksim and obidoxime form in the process of reactivation HAE occurring during the treatment, a relatively stable phosphorylated oximes with its 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 inherent in derivative 2-pyridinethione the A.

The main task of the present invention is the creation of new drugs for emergency treatment of acute poisoning with organophosphorus agents NAPs, which have significantly higher therapeutic efficacy compared with existing tools. The creation of such tools will also help to expand the range of practically used reaktivatory HAE.

Currently in the Russian Federation reaktivatory cholinesterase not produced and purchased, import [Register of medicines of Russia - the encyclopedia of medicines. Issue 10. LLC radar-2003”, page 68, 293, 331, 844, 1052]. Production of a 15 % solution dipiroksima “ICN October” stopped due to the lack of raw materials-substances dipiroksima earlier manufactured in Latvia [Register of medicines of Russia. M., 1993, page 382]. Described in the Handbook Mudrakovskii (vol. 1, pp. 201-203) injectable form other Akimov (alloxan, isoniazid and Dietikon) clinical effectiveness significantly inferior dipiroksimu.

To solve this problem is proposed to use the 15 % aqueous solution derived 2-pyridinoline - 1-methyl-5-[2’-(benzyldimethylammonium)-ethyl]-carbamoylbiphenyl-2-aldoxime dichloride (IV):

Synthesis of oxime (IV) is carried out according to the chemical scheme I.

Phase I : Obtain 5-[2’-(dimetilan the but)ethyl]-carbamoylation-2-aldoxime (VI).

In a flask with a capacity of 1 l equipped with a stirrer and reflux condenser with a gate that prevents the contact of the reaction mixture with carbon dioxide of the air, download 27.8 g (0,315 mol) of N,N-dimethyl-aminoethylamino (VI) and of 54.0 g (0.3 mol) of 5-methoxycarbonylmethyl-2-aldoxime (V) (Landview VI, somyne I.N. and other “Method for obtaining 5-alkoxycarbonylmethyl-2-aldoxime”. Auth. mon. No. 1301829, bull. Fig. 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. To zakristallizuetsya after holding the mass is added 400 ml of ethyl alcohol and acetone, stirred at the boil to dissolve. After cooling to 0 - +5°C the precipitated product is filtered off, washed with a mixture of alcohol and acetone (1:1, 2×70 ml) and dried at 60°C to constant mass.

Output Aximand (VII) 57 g (80,5 %); melting point 180-182°C. Found (%): 55,78; N 6,90; N 23,6. With11H16About2. Calculated (%): 55,91; N 6,84; N 23,70. Range PMR (DMSO d6; δ, ppm): 2,27 to (6N, N(CH3)2); 3,3-3,7 m (4H; CH2-CH2-); 7,94; 8,3; 8,95 (3H pyridine nucleus); 8,19 (1H; CH=N); AND 8.5 (1H; CONH). UV spectrum λmax; nm: 0.01 N. NaOH 310; 0.01 N. Hcl 255; 290.

Stage II. Obtain 1-methyl-5-[2’-(dimethylbenzylamine)ethyl]-carbamoylbiphenyl-2-aldox the mA diiodide (IX).

In a flask with a capacity of 1 l is placed 59.0 g (0.25 mol) Aximand (VII), 115 ml of dimethylformamide, 34,6 g (0.27 mol) of fresh benzyl chloride, is heated up to 60°C, incubated for 5 hours. Then the reaction mass was added dropwise 107 g (0,74 mol) methyl iodide and leave in a tightly closed flask for 24 hours at 60°C. After aging the mass is then cooled to room temperature, poured 225 ml of acetone, stirred for 1 hour, cooled to 0 - +5°C and maintained at this temperature during the day. Fallen diode filtered off, washed with cold acetone (2×50 ml) and dried at 60°C to constant weight. Get 136 g (90 %) technical diiodide; basic substance content of 98.5 %; melting point 188 -189°C.

Stage III. Obtain 1-methyl-5-[2’-(dimethylbenzylamine)ethyl]-carbamoylbiphenyl-2-aldoxime dichloride (IV).

In a flask with a capacity of 1 l, equipped with an efficient stirrer, thermometer and addition funnel, load 800 ml of water, 300 mg of the trylon B and 61 g (59,6 g in terms of 100 %; 0.1 mol) of diiodide (IX). Mass with stirring is heated to 40-45°C and maintained until complete rastvoreniya. Then the flask was sequentially poured 15 ml of toluene, 14 ml (of) 0.157 mol) of 35 % hydrochloric acid and 13 ml (0,128 mol) of 30 % hydrogen peroxide. After removal of reagents to withstand the weight for 1 hour at 40-45°who, cooled to 10-20°and incubated for another 2 hours. The aqueous solution is decanted from the separated complex and filtered. The filtrate is placed in a flask, was added thereto 3 g of neutral activated charcoal and stirred for one hour at room temperature. The charcoal 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 ethanol. Precipitated white crystalline product is filtered and dried at 60°C to constant weight. The output of the oxime (IV) of 26.6 g (64 %); melting point 199-201°C (decomposition). Found (Percent): CL 17,0. Calculated (Percent): CL 17,2. Range PMR (DMSO (d6; δ, ppm): 13,5 (1H; HE); 10.5 m (1H; NH⊕); 8,7 (1H; =CH); 9,8; 9,0 d, 8.5 d (3H pyridine nucleus); 7.5 to 7.6 m (5H; C6H5); with a 4.7 (2H; CH2-C6H5); 4,4 s (3H; >N⊕CH3); 3.9 tons; 3.6 t (4H; CH2-CH2-); 3,1 (6N; N⊕(CH3)2). UV spectrum λmax; nm: 0.01 N. NaOH 356.

The finished dosage form of the proposed tools is a 15 % aqueous solution of oxime IV containing excipients that ensure the stability of the solution. The most important factor of stability is the maintenance during storage, the optimum range of pH in the range from 2.4 to 3.4. A solution of oxime IV, designed for injection, can be produced ampulnoe form dye tube or chamber in autoinjector. To obtain sterile pharmaceutical form solution of the oxime IV should be subjected to a membrane filtration under aseptic conditions with an oil spill in the ampoule, syringe-tubes or autoinjector in the atmosphere of inert gas.

Made so 15 % solution of oxime IV compared the toxicity, efficacy and therapeutic index with industrial design 15 % solution dipiroksima (see tab. 1-3). In table. 1, 2 shows the toxicity and comparative data on clinical effectiveness of individual reaktivatory III and IV, PL. 3 - when the combination of these reaktivatory with cholinergic antagonist - cyclotron [PPM Mashkovsky. Drugs, vol. 1, page 213. Ed. 14, M, 2000].

Table 1

Toxicity (LD50), a therapeutic dose (U95) and therapeutic index (TI) dipiroksima (III), 2-PAM-chloride (Ia) and oxime IV, certain rats
The oximeLD50mg/kgED95MG/KGT
Dipiroksim192±12306,4
The oxime IV297±442,511,9
2-PAM-chloride315±32407,9
Note. 1. The value of median lethal dose (LD50defined with intramuscular injection of an aqueous solution of oxime. 2. ED95the dose of oxime, ensuring the survival of 95 % of animals poisoned with a lethal dose (1 LD99) sarin (with intramuscular injection of poison and reagent-Torah). 3. T = LD50/ED95.
Table 2

Comparative therapeutic efficacy of individual Asimov III and IV for cats, poisonous substance Vx.
The oximeDose of oxime mg/kgThe survival rate in %
Dipiroksim1520
The oxime IV1560
control00
Note. Data obtained on 10 animals in the intramuscular priming substance Vxat a dose of 5 mg/kg of the Oxime was administered intramuscularly 20 minutes after the poison.

Table 3
Combined therapeutic use dipiroksima and oxime IV with a cholinergic antagonist cyclotron (0.2 mg/kg) in rats poisoned FOB NAP
The oximeVx(2 LD50)Soman (1 LD99)Sarin (1 LD99)
 ED95MG/KGTED95mg/kgTED95MG/KGT
Dipiroksim0,5038420,09,61,25153
The oxime IV0,0559402,51180,102970
Note. Intramuscular priming poison. Simultaneous intramuscular injection of reactivator and cholinergic antagonist (in same syringe) 20 minutes after a dose.

The results obtained in rats (tables 1, 3) show both at individual and combined application of both Asimov dipiroksim much inferior in efficacy to the oxime IV. Therapeutic doses last about 10 times lower than dipiroksima. As the oxime IV approximately 1.5 times less toxic than dipiroksim (PL. 1), corresponding terapeuticas the e indices oxime IV exceed these values at dipiroksima more than 10 times.

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

For the treatment of organophosphorus poisoning poisonous substances containing reactivator cholinesterase from the group bischetvertichnoe derivatives pyridylamino, characterized in that as reactivator cholinesterase using 1-methyl-5-[2’-(benzyldimethylammonium)ethyl]carbamoylbiphenyl-2-aldoxime dichloride in the form of a 15%aqueous solution.



 

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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

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