RU2485953C1 - Complex of 3-(2,2,2-trimethylhydrazinium)propionate-2-ethyl-6-methyl-3-hydroxypyridinium disuccinate possessing antihypoxic and adaptogenic action, and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound that is a complex of 3-(2,2,2-trimethylhydrazinium)propionate-2-ethyl-6-methyl-3-hydroxypyridinium disuccinate of formula:

. Additionally, the invention refers to stable crystalline forms of the complex of 3-(2,2,2-trimethylhydrazinium)propionate-2-ethyl-6-methyl-3-hydroxypyridinium disuccinate, as well as to methods for preparing the above complexes.

EFFECT: what is prepared and characterised is the new compound which possesses antihypoxic and adaptogenic action, and also low toxicity and storage stability, and which can find application in medicine and veterinary science.

11 cl, 17 ex, 10 tbl, 4 dwg

Description

FIELD OF THE INVENTION

The invention relates to the field of medicine and veterinary medicine, namely to a new biologically active compound - a complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate, which has an antihypoxic and adaptogenic effect and stable during storage.

State of the art

2-Ethyl-6-methyl-3-hydroxypyridine succinate (EMHPS) has been widely used in medicine as an antioxidant - antihypoxant for a variety of reasons, primarily for cardiovascular diseases (pre-infarction and post-infarction conditions, angina pectoris, etc.). ), diseases of the brain (diseases associated with circulatory disorders, strokes, etc.) [Russian Medicines Register - 17th issue. / Ch. ed. G.L. Vyshkovsky. - M .: "Radar-2009", 2008. - 1440 s]. Meldonium (3- (2,2,2-trimethylhydrazinium) propionate dihydrate, TMHP DG) is mainly used for the same reasons, having an antihypoxic effect, however, the main effect in this case is associated with the inhibition of γ-butyrobetaine hydroxylase and, ultimately, optimization of intracellular metabolism in conditions of hypoxia [Russian Medicines Register - 17th issue. / Ch. ed. G.L. Vyshkovsky. - M .: "Radar-2009", 2008. - 1440 s]. The expected synergy of these drugs is obvious, for this reason, their combined use is proposed for the treatment of a number of pathologies [RU 2270025, publ.: 02.20.2006; RU 2009118345, publ. 11/20/2010, RU 2284192, publ.: 09/27/2006; RU 2367388, Published: 09/20/2009; Nazarova L.S. Cardio-respiratory disorders in patients with lung cancer at the stages of combined treatment, diss. for a job. student step. Cand. honey. sciences. Tomsk: Research Institute of Onkol. TSC SB RAMS. 2008].

However, both drugs have a number of features of physico-chemical properties that create difficulties in the development of finished dosage forms. So, EMHPS is quite easily oxidized, especially in injection solutions, and the rate of oxidation leading to the formation of a brown color of the solution depends on the remaining air in the ampoule, the quality of the glass, and a number of other parameters still not fully identified. As a result, the EMGPS injection solution during storage is colored at different speeds in different ampoules of the same series, which leads to rejection in terms of “heterogeneity” and “color”, etc. Even more technological problems are associated with the use of meldonium - this drug is a very unstable hydrate that loses water and changes quality even at temperatures above 25-30 ° C. On the other hand, meldonium is very hygroscopic and is almost unlimitedly soluble in water, which makes the preparation of solid oral forms extremely difficult. The substance of meldonium during storage cakes very quickly and requires subsequent grinding. In the manufacture of injection forms, the aqueous solution of meldonium strongly leaches the glass, while it practically does not have buffering properties (and even, on the contrary, has a differentiating effect when the pH changes) - as a result, after sterilization and storage, the injection solution becomes alkaline above the permissible limit. Quality control injection solutions of meldonium quickly destroy pH-sensitive glass electrodes, which also causes certain technological difficulties and leads to economic losses. Alkaline solutions of meldonium (with a pH above 8) are painful during intramuscular injection and can cause tissue necrosis.

The above factors determine the significant price of EMGPS preparations that are extremely important for medicine (Mexidol, Mexidant, Mexifin, Medemexi, Mexico, Mexiprim ...) and meldonium (Vasomag, Idrinol, Cardionate, Midolat, Mildronate ...) because the price of the substance of these drugs is currently low. To obtain more technologically advanced products with biological activity similar to meldonium, in patent WO 2005012233, decl. 07/15/2004 (prior. 04/08/2003 LV) salts are proposed that do not form crystalline hydrates, including succinates of 3- (2,2,2-trimethylhydrazinium) propionate (1: 1), (2: 1); but, they, like meldonium, are quite hygroscopic and prone to caking. In addition, in the application RU 2005125660, publ.: 02.20.2007 in order to enhance the antihypoxic effect, pharmaceutical compositions are proposed containing TMHP DG and sodium, potassium or magnesium succinates. However, these close technical solutions do not allow to eliminate all the physicochemical disadvantages of meldonium and its salts; and, in addition, they retain the main drawback - the effect on only one element of the pathological process in hypoxic conditions - as well as in the case of EMHPS.

The objective of the invention is to obtain a stable compound with the pharmacological properties of EMHPS and meldonium, convenient for preparing finished dosage forms and affecting the body in a complex way. This problem is solved by synthesis of a complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate of the formula:

Disclosure of the invention.

It is known that meldonium forms stable ion pairs with some dyes, which is used as a "reaction of authenticity"; for example, in FS 42-2961-93, the formation of a complex of 3- (2,2,2-trimethylhydrazinium) propionate (TMHP) with bromothymol blue is used. It turned out that TMHP succinate forms a strong complex with EMHPS, which has an individual diffraction spectrum and IR spectrum, as well as significantly different behavior from individual salts in thermal analysis (melting point, exo and endo effects) (see example 1). This complex is preserved in aqueous solutions, as evidenced by the UV spectrum (see example 1). For salts of 2-ethyl-6-methyl-3-hydroxypyridine (EMHP) in general, it is typical that the absorption maximum at 225 nm is characteristic of the unprotonated pyridine ring; for salts with strong acids (hydrochloric, sulfuric) this maximum disappears; for salts with organic acids (acetic, succinic) in this area there is a "shoulder", characterizing a certain degree of hydrolysis of the salt. For the proposed complex, a pronounced maximum is observed at 225 nm, which is associated with the formation of a strong hydrogen bond with the nitrogen proton of the pyridine cycle, with the redistribution of the electron density in the pyridine cycle to a level close to the unprotonated pyridine cycle (see example 1), although the pH of aqueous solutions of the proposed complex at an equal molar concentration is slightly lower than for EMHPS (for 0.01 M solutions, 4.17 and 4.59, respectively).

Unusual and confirming the formation of a stable complex is also the oxidation stability of its aqueous solutions that is unexpected for EMHP salts — when a 10% solution is kept in contact with air and without protection from light, the sample remains colorless, while the concentration of an equimolar solution of EMHP acquires dark brown color. This phenomenon, in our opinion, also proves the existence of the complex, including and in solutions; it is likely that the structure of the protonated adduct (EMHP × TMHP) is retained by the presence of strong hydrogen bonds, which prevents the attack of OH •, UN • • radicals during oxidation to oxidation-sensitive centers of the oxypyridine structure:

The inventive complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate is convenient for the preparation of solid dosage forms, because possesses favorable physicochemical properties - good flowability, slight hygroscopicity compared to meldonium. Aqueous solutions of the complex do not leach glass, do not oxidize, and do not stain during storage, which makes it possible to obtain high-quality and storage-stable injection forms.

A study of the biological activity of the complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate found that it is significantly less toxic than EMHPS, and as an antihypoxant more active in an equivalent dose than individual EMGPS and meldonium (see example 13). In addition, the adaptogenic effect of the complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate was also found (see Example 17).

The inventive complex can be obtained by the interaction of equimolar amounts of EMHPS, succinic acid and TMHP DG, the reaction proceeds easily and quickly even in the absence of solvent, however, 2 moles of water are released and a concentrated solution (“syrup”) is formed, which crystallizes relatively slowly and requires drying under vacuum. It is more convenient to use water-free reagents (EMHPS and TMHP succinate; or EMHP, succinic acid and TMHP succinate; or EMHP, succinic acid and TMHP), which easily interact under mechanochemical conditions. In this case, in the first and second cases, a stable crystalline modification is formed, which does not change during storage with the following parameters:

Angle 2θ, ° Interplanar distance d, Å Intensity, s ^-1 Relative intensity,% 11.2942 7.8280 523.33 40.36 12.5284 7.0595 556.67 42.93 13.3364 6.6335 536.67 41.39 14.2629 6.2046 243.33 18.77 15.9527 5.5510 326.67 25.19 16.2642 5.4454 133.33 10.28 17.1699 5.1601 176.67 13.62 17.5796 5.0408 126.67 9.77 17.8419 4.9672 233.33 17.99 19.1735 4.6252 233.33 17.99 19.5455 4.5380 833.33 64.27 19.8408 4.4711 543.33 41.90 20.7198 4.2834 1296.67 100.00 21.2173 4.1840 153.33 11.83 21.9306 4.0495 646.67 49.87 22.6669 3.9196 316.67 24.42 23.2765 3.8183 466.67 35.99 23.8739 3.7241 456.67 35.22 24.2570 3.6662 690.00 53.21 24.5044 3.6297 880.00 67.87 25.7518 3.4567 500.00 38.56 26.5811 3.3507 363.33 02/28 26.8792 3.3142 313.33 24.16 10/28/29 3.1726 140.00 10.80 28.6456 3.1137 210.00 16.20 29.7913 2.9965 106.67 8.23 30.5538 2.9234 100.00 7.71 31.7791 2.8135 190.00 14.65 32.7890 2.7291 116.67 9.00 33.5788 2.6667 93.33 7.20 34.9325 2.5664 236.67 18.25 35.7622 2.5087 156.67 12.08 36.0112 2.4919 110.00 8.48 36.9890 2.4283 120.00 9.25 38.1490 2.3571 170.00 11/13

The X-ray powder diffraction spectrum was measured under the conditions:

- Thermo ARL X'TRA diffractometer, semiconductor detector;

- radiation CuKα, voltage 45 kV, intensity 35 mA;

- shooting in θ-2θ mode;

- measurement range - from 10 to 60 °;

- an increase between each measurement - 0.02 °;

- time step of measurement - 0.3 s;

- deflecting slot of the tube - 2.0 mm;

- scattering gap of the tube - 4.0 mm;

- scattering slit of the detector - 0.5 mm;

- reference slit of the detector - 0.3 m;

- lack of an internal signal;

- The experimental data were processed using WinXRD 2.0 software.

The economic and environmental effect is provided by the use of commercially available EMHP, succinic acid and dehydrated TMHP DG as reagents, in this case the stages of synthesis of succinates of EMHP and TMHP, which have a low yield and are associated with the formation of difficult to recover mixtures of isopropanol and acetone, are excluded. Mechanochemical synthesis is carried out similarly to RU 2442774, publ. 02/20/2012, using an inert aprotic solvent (aliphatic ketone, ether or aliphatic hydrocarbon) as a “wetting agent”, which is volatile, low toxicity and is easily removed from the product. Acetone or methyl ethyl ketone is used as an aliphatic ketone, diethyl ether, tetrahydrofuran or dioxane are used as an ether, and hexane, heptane or petroleum ether are used as an aliphatic hydrocarbon.

When studying the inventive complex in acute and subchronic toxicological experiments, its biosafety and low toxicity were confirmed (see examples 14, 15, 16).

Thus, a new compound was obtained - a complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate of the formula:

stable in aqueous solutions, with antihypoxic and adaptogenic effects with low toxicity, methods for its preparation are proposed and the crystal structure of the claimed compound is characterized.

The proposed compound can be used in medicine and veterinary medicine as an active, low-toxic, safe and storage-stable antihypoxant, including for the prevention of cardiovascular diseases and other diseases based on hypoxic conditions, tissue ischemia, etc., as well as an adaptogen in animal husbandry and poultry farming.

A brief description of the drawings.

Figure 1 shows the IR spectrum of the complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate.

Figure 2 shows the UV spectrum of the complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate,

where 1 is 2-ethyl-6-methyl-3-hydroxypyridine succinate;

2 - a complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate.

Figure 3 shows the diffraction pattern of the complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate.

Figure 4 presents the results of thermal analysis of the complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate (200 mg sample).

The implementation of the invention

Example 1. (Synthesis from EMHPS, succinic acid and TMHP DG)

255.27 g of EMHPS (1 mol), 118.09 g of succinic acid (1 mol), 182.26 TMHP DG (1 mol) are placed in a flask of a rotary film evaporator (FIR), the mass is stirred during rotation of the flask (speed 60 rpm) and heated to 45-50 ° C; this forms a viscous liquid. The contents of the flask are poured onto a fluoroplastic tray and dried under a vacuum of 0.9 at at 30-35 ° C to constant weight. The hardened product is ground in a ball mill, additionally dried at 20 -25 ° C under vacuum for 5 hours. Get 519, 6 g (1 mol) of a product having a pronounced crystallinity. Yield 100% of theory. Elemental analysis:

Calculated,%: С 58.00, Н 8.20, N 9.22, О 24.58

Found,%: С 57.47, Н 8.33, N 9.18, О 25.02

pH of a _{10% solution} = 4.08

pH _{0.01 M solution} = 4.17

IR spectrum (in KBr), cm ^-1 : see Figure 1.

3440 (valent-OH); 3045.44 (NH, mld); 2360 ÷ 2780 (valent.-OH, assoc. Group); 2922.49 (valent.-CH ₃ , -CH ₂ ); 1705.47 (-C = O, carbon. To-you); 1637.00, 1571.42 (-C = O, mld); 1385.30 (deform. -CH ₃ , -CH ₂ -); 1306.22 (-CO-, carbon. To-you); 1218.47 (deform. -OH); 1185.68 (valence. -CO in COO ^- , salts of carbon, acids); 849.12 (deform. Ar-H).

UV spectrum (in water): λ _max = 195 nm, λ _min = 214 nm, λ _max = 224 nm, λ _min = 245 nm, λ _max = 295 nm (see Figure 2).

Solubility: very easily soluble (GP XII, p. 92).

The results of x-ray phase analysis: see Figure 3.

Angle 2θ, ° Interplanar distance d, Å Intensity, s ^-1 Relative intensity,% 11.2942 7.8280 523.33 40.36 12.5284 7.0595 556.67 42.93 13.3364 6.6335 536.67 41.39 14.2629 6.2046 243.33 18.77 15.9527 5.5510 326.67 25.19 16.2642 5.4454 133.33 10.28 17.1699 5.1601 176.67 13.62 17.5796 5.0408 126.67 9.77 17.8419 4.9672 233.33 17.99 19.1735 4.6252 233.33 17.99 19.5455 4.5380 833.33 64.27 19.8408 4.4711 543.33 41.90 20.7198 4.2834 1296.67 100.00 21.2173 4.1840 153.33 11.83 21.9306 4.0495 646.67 49.87 22.6669 3.9196 316.67 24.42 23.2765 3.8183 466.67 35.99 23.8739 3.7241 456.67 35.22 24.2570 3.6662 690.00 53.21 24.5044 3.6297 880.00 67.87 25.7518 3.4567 500.00 38.56 26.5811 3.3507 363.33 02/28 26.8792 3.3142 313.33 24.16 10/28/29 3.1726 140.00 10.80 28.6456 3.1137 210.00 16.20 29.7913 2.9965 106.67 8.23 30.5538 2.9234 100.00 7.71 31.7791 2.8135 190.00 14.65 32.7890 2.7291 116.67 9.00 33.5788 2.6667 93.33 7.20 34.9325 2.5664 236.67 18.25 35.7622 2.5087 156.67 12.08 36.0112 2.4919 110.00 8.48 36.9890 2.4283 120.00 9.25 38.1490 2.3571 170.00 11/13

The results of thermal analysis: T _pl. = 60 ° C, at 150 ° C decom. (see Figure 4).

At 60 ° C, the sample melts with a significant endothermic effect, mass loss is not observed. After melting, at 100 ° C there is an exoeffect, although the sample remains liquid, mass loss is also not observed. Starting from 150 ° C, a mass depression is observed, at 170 ° C the mass of the sample decreases rapidly, while the process at 170-190 ° C is slightly exothermic, the endothermic process is observed from 190 ° C and the weight reduction is somewhat slowed down; at 230 ° C, a pronounced exothermic process takes place and the product is almost completely gasified (pitch mass less than 5% after complete decomposition of the sample).

Example 2. (Synthesis from EMHPS and succinate 3- (2,2,2-trimethylhydrazinium) propionate)

255.27 g of EMHPS (1 mol), 264, 31 g of 3- (2,2,2-trimethylhydrazinium) propionate succinate (1 mol) are placed in a flask of a rotary film evaporator, 50 ml of acetone are added. Fluoroplastic balls are introduced into the flask and the mass is stirred while the flask is rotating (rotation speed 60 rpm) for 2 hours at room temperature. The resulting bulk mass is discharged onto a fluoroplastic tray and dried to constant weight and no odor of acetone. Get 519.6 g of product (yield 100.0% of theory) with the following parameters:

Elemental analysis:

Calculated,%: С 58.00, Н 8.20, N 9.22, О 24.58

Found,%: С 58.20, Н 8.21, N 9.20, О 24.39

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 3. (Synthesis from EMHP, succinic acid and succinate TMHP)

137.18 g of 2-ethyl-6-methyl-3-hydroxypyridine (1 mol), 264, 31 g of 3- (2,2,2-trimethylhydrazinium) propionate succinate (1 mol) and 118 are placed in a flask of a rotary film evaporator 09 g succinic acid (1 mol). Fluoroplastic balls and 50 ml of diethyl ether are placed in the flask; turn on the drive and rotate the flask for 1 hour at room temperature. After that, without stopping stirring, a vacuum of 0.9 ata is applied; after 30 minutes the vacuum is removed, the flask is removed and the contents are unloaded onto a sieve. After sieving, 512.5 g of a white crystalline powder are obtained (yield 98.6% of theory, loss during sieving) with the following parameters:

Elemental analysis:

Calculated,%: С 58.00, Н 8.20, N 9.22, O 24.58

Found,%: С 57.98, Н 8.21, N 9.19, О 24.62

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 4. (Synthesis from EMHP, succinic acid and succinate TMHP)

137.18 g of 2-ethyl-6-methyl-3-hydroxypyridine (1 mol), 264, 31 g of 3- (2,2,2-trimethylhydrazinium) propionate succinate (1 mol) and 118 are placed in a flask of a rotary film evaporator 09 g succinic acid (1 mol); add 30 ml of acetone. Fluoroplastic balls are placed in the flask and the mass is stirred during the rotation of the flask (rotation speed 60 rpm). The mass first sticks together, after 30 minutes it hardens and turns into a powder. The process is carried out for 3 hours at room temperature; after that, the mass with balls is unloaded on a pallet, dried until there is no smell, and then sieved. After sieving, 518.5 g of a white crystalline powder are obtained (yield 99.8% of theory, loss during sieving) with the following parameters:

Elemental analysis:

Calculated,%: C 58.00, H 8.20, N 9.22, O 24.58

Found,%: C 57.68, H 8.24, N 9.18, O 24.90

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 5. (Synthesis from EMHP, succinic acid and dehydrated TMHP DG)

182.22 g (1 mol) of TMHP DG is dried at 80 ° C and a vacuum of 2 mm Hg until theoretical weight loss corresponding to complete dehydration (2-3 hours); when the change in mass ceases, moisture is checked according to Fisher (should be less than 0.1%). Coarse-grained powder becomes a powdery white fine powder, while not having significant hygroscopicity (Fischer moisture change in contact with air occurs very slowly until monohydrate forms, which is more hygroscopic and quickly absorbs moisture from the air).

After dehydration, 146.2 g of TMHP (1 mol) with a moisture content of 0.1% (Fischer) are obtained. This powder is transferred to an RPI flask, 236.18 g of succinic acid (2 mol) and 137.18 g of recrystallized EMHP (1 mol) are loaded therein. Fluoroplastic balls and 100 ml of hexane are placed in the flask; turn on the drive and mix the mass while rotating the flask (rotation speed 60 rpm) for 3 hours at room temperature. First, the mass agglomerates, then crumbles into powder. At the end of the process, the product is dried on a fluoroplastic tray to a constant weight and odorless hexane and then sieved. After sieving, 517.9 g of a white crystalline powder is obtained (yield 99.7% of theory, loss during sieving) with the following parameters:

Elemental analysis:

Calculated,%: C 58.00, H 8.20, N 9.22, O 24.58

Found,%: C 58.32, H 8.24, N 9.17, O 24.27

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 6

The synthesis is carried out analogously to example 5, but as a “wetting agent” take 100 ml of heptane. 518.8 g of a white crystalline powder are obtained, yield 99.8% of theory.

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 7

The synthesis is carried out analogously to example 5, but as a “wetting agent” take 50 ml of petroleum ether (with a boiling range of 50-70 ° C). Obtain 518.6 g of crystalline powder with a barely noticeable cream tint, yield 99.8% of theory.

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 8

The synthesis is carried out analogously to example 5, but as a “wetting agent” take 40 ml of methyl ethyl ketone. After completion of the synthesis, the mass is separated from the balls, dried under vacuum of 10-15 mm Hg. first 2 hours at room temperature, then 3 hours at 30 ° C until there is no smell of methyl ethyl ketone. Obtain 516.2 g of a crystalline powder of almost white color, the yield of 99.3% of theory.

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 9

The synthesis is carried out analogously to example 3, but as a "wetting agent" take 50 ml of tetrahydrofuran. Get 515.3 g of white with a barely noticeable yellowish tinge of crystalline powder, yield 99.2% of theory.

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 10

The synthesis is carried out analogously to example 3, but as a "wetting agent" take 50 ml of dioxane. After completion of the synthesis, the mass is separated from the balls, unloaded onto a fluoroplastic tray and dried under a vacuum of 0.98 ata at 30-35 ° C until a constant mass and no smell of dioxane. Obtain 516.8 g of a white to yellowish crystalline powder, yield 99.5% of theory.

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

The results of x-ray phase analysis, °: 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15

Example 11. (Studying the stability of aqueous solutions of the proposed compounds and EMHPS)

To study the stability of solutions of the claimed compounds and the known EMHPS, unipolar solutions are prepared in distilled water. The optical density of the solutions is determined at 450 nm relative to water. The initial solutions of both compounds differ little from water (optical density 0.01 for the claimed compound and 0.02 for EMHPS). Solutions in the amount of 50 ml are placed in 100 ml volumetric flasks, closed with polished glass stoppers. Samples are stored under normal conditions without protection from light, and every 6 months the optical density of the solutions and the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate are determined by HPLC. The results are shown in Table 1, which shows that the solution of the claimed compounds for 3 years has not undergone changes, while EMHPS was oxidized with the formation of colored compounds and a decrease in the content of the basic substance.

Table 1 The stability of aqueous solutions of the claimed compounds and EMHPS Storage time EMGPS The claimed connection Optical density, 450 nm Content, g / 100 ml Optical density, 450 nm Content, g / 100 ml Source 0.02 2,55 0.01 5.20 6 months 0.38 2,51 0.02 5.20 1 year 0.88 2.15 0.02 5.20 1,5 years 1.28 1.88 0.02 5.20 2 years Not determined, brown 0.99 0,03 5.19 2.5 years Not determined, brown 0.86 0,03 5.18 3 years Not determined, brown 0.54 0.04 5.17

Example 12. (The stability of the injectable form of the claimed compounds in comparison with meldonium)

In a container equipped with a stirrer, add 900 ml of water for injection, 100 g of the inventive compound and mix until completely dissolved. The solution is filtered through a sterilizing filter, poured into 5 ml ampoules of HC-3 glass, and sterilized. After sterilization, mechanical inclusions are checked; conditional ampoules are packaged in a group package and stored under normal conditions. Similarly, prepare a 10% solution of meldonium. During storage, check the pH, the presence of mechanical impurities, the organoleptic properties of the solution (smell). From Table 2 it is seen that the injection solution of the claimed compound did not change the indicated parameters, while the pH value increased in the meldonium solution (especially after sterilization), mechanical inclusions appeared in some ampoules and the injection solution acquired a strong “fishy” smell.

Table The stability of the injectable form of the claimed compounds and meldonium Storage time Meldonium The claimed connection pH Mechanical inclusion,% ampoules pH Mechanical inclusion,% ampoules Source 7.5 0 4.2 0 After thermal sterilization 8.4 28 4.2 0 1 year 8.5 38 4.2 0 2 years 8.6 42 4.2 0 3 years 8.8 62 4.2 1,2

Example 13. (Study of the antihypoxic activity of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate)

A measure of the sensitivity of animals to acute hypobaric hypoxia was the life time at the "height". For this purpose, the coefficient of protection efficiency (CEC) was calculated, which was the ratio of life in experience to life time in control.

Materials and methods:

The preparations 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxy-pyridine disuccinate, meldonium and EMHPS were administered to rats at doses of 65 mg / kg, 20 mg / kg and 30 mg / kg intragastrically (through a probe) and intramuscularly. In the experiment, a total of 70 animals were used, 10 animals in each group, 10 intact. Testing was performed on day 14 after the start of the experiment (after the first injection of the drug).

Each animal was "raised" to a critical height (11.5 thousand m) at a speed of 165 m / s, where it was located to an agonal state.

Results:

According to the results of studies to identify the effect of drugs on the resistance of rats to acute hypobaric hypoxia (see Table 3), it was found that all drugs with different methods of administration (oral and intramuscular) on the 14th day of the study had a high antihypoxic activity. It manifested itself in a significant extension of the life of experimental animals at a "height" in comparison with their counterparts in the control groups. Intramuscular administration of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate significantly increased the resistance of animals to acute hypobaric hypoxia, which resulted in an increase in life time at the “height”. The coefficient of protection efficiency (CEC) for 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate was 11, which exceeded the indices for other preparations by more than 2 times (CEC for EMGPS - 5.4, for meldonium - 3.5).

Table 3 The effectiveness of the protection of drugs in acute hypobaric hypoxia in rats Route of administration VL in the control group, sec Experimental group VZh on the 14th day of the experiment KEZ * Intragastric 62.5 ± 7.2 EMGPS 247 ± 18.9 3.9 meldonium 468.5 ± 59.97 7.4 The inventive complex 335 ± 36.38 5.3 Intramuscularly 62.5 ± 7.2 EMGPS 338 ± 67.3 5,4 meldonium 220 ± 30.15 3,5 The inventive complex 691.5 ± 114.6 11.0

* - $$\frac{\mathrm{TO}\mathrm{about}\mathrm{uh}ff\mathrm{and}c\mathrm{and}ent\mathrm{uh}ffe\mathrm{to}t\mathrm{and}\mathrm{at}n\mathrm{about}\mathrm{from}t\mathrm{and}s\mathrm{but}u\mathrm{and}ts}{\mathrm{AT}Rem\mathrm{I\; am}\mathrm{well}\mathrm{and}sn\mathrm{and}\mathrm{at}\mathrm{to}\mathrm{about}ntR\mathrm{about}le}$$

VZh - life time at "height" (before the appearance of atonal breathing)

Example 14. (Acute toxicity of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate compared with acute toxicity of EMHPS)

Materials and methods:

The study of acute toxicity of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate and EMHPS was carried out on white outbred male mice weighing 18-20 g with intragastric (using a gastric tube) and intraperitoneal administration in the form of an aqueous solution of the drug in various dosages. Acute toxicity was assessed using the Litchfield and Wilkinson method.

Results:

It was found that LD50 (v / f)> 16000 mg / kg, which allows this drug to be classified as hazard class 4 (low hazard substances) according to GOST 12.1.007-76.

The results of determining the parameters of the acute toxic effect of the drugs with the intraperitoneal and intragastric route of administration are presented in Table 4. The results of the experiment show that the proposed complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate is significantly less toxic than a well-known drug with close indications of EMHPS. Moreover, with intragastric administration, the manifestation of toxicity could not be detected, whereas for EMHPS in this case LD50 6200 mg / kg (toxic effect mainly on brain tissue).

Table 4 The parameters of acute toxicity with intraperitoneal and intragastric administration (mouse) of the claimed complex and EMGPS Route of administration A drug LD0 LD16 LD50 LD84 LD100 Intraperitoneally The inventive complex 940 1500 2700 3600 4700 EMGPS 210 365 475 620 860 Intragastric The inventive complex Animals do not die at a dose of more than 16,000 mg / kg EMGPS 1600 1900 6200 8400 9800

Example 15. (Assessment of the irritating effect of 3- (2,2,2-trimethylhydrazinium) pro-pionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate)

Materials and methods:

The irritating effect of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate was evaluated in outbred white rats of both sexes, weighing 230-250 g at 2.5 months of age. The drug was administered to animals inside in the form of an aqueous suspension at a dose of 270.0 mg / kg.

After administration of the drug, the behavior and reactions of animals were monitored. The rats were slaughtered after 6; 24 and 48 hours after administration of the drug. For each term of slaughter, 3 rats were used.

Results:

A visual examination of the mucous membranes of the pharynx, esophagus, stomach, thin and large intestines of rats treated with the drug at a dose of 270.0 mg / kg did not reveal pathological signs: hemorrhages, ulcerations, and other damage to the digestive tract.

Thus, oral administration of the drug at a dose of 270.0 mg / kg does not cause local irritating effect of the mucous membranes of the digestive tract.

Example 16. (Subchronic toxicity of 3- (2,2,2-trimethylhydrazinium) pro-pionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate)

Materials and methods:

A subchronic experiment was performed on sexually mature non-linear male rats with an initial weight of 212.0 ± 7.6 g for 30 days. Rats were kept in the vivarium of the NTsBMT RAMS in plastic cages under natural light and a temperature of 20-22 ° C, fed with briquetted compound feeds. Animals were taken after 7 days of quarantine. Groups were formed by random sampling. In each group there were 6 animals. Experimental animals were injected subcutaneously with 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate at doses of 1/10 and 1/100 from LD50 for a month, which amounted to 270, respectively mg / kg (group 1) and 27 mg / kg (group 2). The rats of the control group were in similar conditions as the experimental animals. Throughout the experiment, we monitored the state of animals in dynamics by the integral and functional indicators of the main organs and systems, including physiological, hematological and biochemical.

After the completion of the experiment, an autopsy was performed with the animals followed by determination:

- local irritant effect;

- macroscopic picture of the autopsy.

Conclusion:

The studied preparation did not have a significant effect on the dynamics of body weight, consumption of dry and wet food and water, general condition and behavior of animals.

Experimental data indicate that with a 30-day exposure to the 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate complex, there were no significant differences in the experimental groups and in the control of the indicators peripheral blood (see Table 5), biochemical blood parameters characterizing the metabolism and function of vital organs (see Table 6), as well as from the state of the excretory system (see Table 7).

Table 5 Rat peripheral blood status on day 30 of the experiment Blood counts Groups of animals 1 group 2 group The control Red blood cells, M / μl 8.4 ± 0.25 8.3 ± 0.5 7.9 ± 0.3 Hemoglobin, g / l 130.8 ± 0.45 120.7 ± 1.20 120.8 ± 0.21 White blood cells, T / μl 12.3 ± 1.0 11.5 ± 1.3 9.32 ± 099 Platelets T / μl 716.5 ± 55.9 695.0 ± 41.3 670 ± 46.3

Table 6 Biochemical parameters of rat blood after administration of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate Indicators 1 group 2 group The control Glucose, mmol / l 5.7 ± 0.04 6.2 ± 0.01 5.5 ± 0.04 ALT, U / l 65.1 ± 4.59 74.5 ± 2.7 74.3 ± 2.65 ACT, U / l 164.1 ± 3.96 184.4 ± 6.52 176.0 ± 9.79 Alkaline phosphatase, U / l 261 ± 34.7 284.7 ± 10.6 263.2 ± 9.37 Cholesterol, mg / dl 26.0 ± 2.31 34.2 ± 1.1 34.7 ± 1.2

Table 7 Rat urine values when exposed to 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate Indicators 1 group 2 group The control Diuresis in 18 hours, ml 22.7 ± 1.15 21.6 ± 0.1 22.9 ± 1.1 Urine ph 6.8 ± 0.002 6.85 ± 0.002 6.9 ± 0.01 The density of urine, g / cm ³ 1.005 ± 0.0001 1.007 ± 0.0001 1.01 ± 0.0001 Protein, mg / 100 ml 0.8 ± 0.67 1.7 ± 1.1 2.5 ± 1.25

No effect of the drug on respiratory rate, rectal temperature, spontaneous motor activity, search reactions, and emotional state of experimental animals was noted.

A macroscopic examination revealed no signs of local irritating effect on the mucous membranes of the gastrointestinal tract and any pathological changes in the internal organs.

When determining the mass of the internal organs of experimental animals, there was no significant deviation from the control group (see Table 8).

Table 8 The effect of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate on the relative mass of the internal organs of rats Group of animals Mass of organs heart liver lungs the kidneys spleen brain 1 group 3.90 ± 0.23 37.5 ± 1.65 8.30 ± 0.68 7.10 ± 0.36 2.90 ± 0.32 6.10 ± 0.22 2 group 3.60 ± 0.11 33.80 ± 0.96 8.50 ± 0.59 9.40 ± 0.42 3.40 ± 0.29 7.10 ± 0.56 The control 4.50 ± 0.25 36.90 ± 2.63 8.50 ± 0.36 8.50 ± 0.22 3,50 ± 0,15 6.20 ± 0.32

Example 17. (Effects of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate on the weight gain of birds and some indicators of immunocompetent organs)

The study of the effect of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate on the body of a productive bird (broiler chickens) was carried out by adding the drug to a standard diet in daily doses of 10 mg / kg from the first day of life (2nd group) and from 14 days of age (3rd group). The weight gain of the bird was determined by a change in the immunocompetent organs. The 1st experimental group (control) received a standard diet without supplementation.

Thymus, cloacal bursa and spleen are the main organs in the body of the bird, responsible for the formation of immune defense. In the experiment, we studied the weight changes in these organs in intact broiler chickens in the age aspect, as well as when using 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate. The absolute mass of the thymus at day old in chickens was 0.26 g in the control, 0.24 g in the first experimental group, and 0.29 g in the second

We found that in all chickens, the absolute thymus mass increased with age. If in diurnal age the difference in the absolute thymus mass between the intact and experimental livestock was not established, then in all subsequent age periods the thymus mass in experimental chickens was larger compared to the control. At two weeks of age, the weight of the thymus in experimental chickens of the first group exceeded this indicator in the control by 0.24 g, in the second experimental group by 0.31 g. At 32 days of age, the differences were: in the first experimental group by 1.62 g , in the second - by 2.49 g.

The maximum increase in the absolute mass of the thymus in chickens and in the control and experimental groups was noted in the period from 14 to 32 days of age.

Our studies showed that after hatching in intact chickens, the absolute weight of the bursa in the control group was 0.117 ± 0.01 g, in the first experimental group - 0.116 ± 0.04 g, in the second 0.118 ± 0.02 g. Throughout the entire growing period in intact chickens, the absolute weight of the bursa increased, reaching a maximum size of 32 days: in the control - 1.23 ± 0.02 g, in the first experimental group - 1.27 ± 0.06 and in the second - 1.32 ± 0.01 g.

Tracing the changes in the absolute mass of the spleen of chickens, it was noted that by the time of hatching in the chickens in the control group, its weight corresponded to 0.03 g, in the experimental group - 0.02 g. In intact broilers, the spleen continued to grow up to 32 days of age to 2.32 g , in the first experimental - up to 2.44 g, in the second - 2.56 g.

3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate did not have a significant effect on changes in chickens spleen mass.

Thus, the use of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate in broiler chickens has a positive effect on growth (see Table 9), bird safety and hematopoiesis (see Table 10), which can be described as a pronounced adaptogenic effect.

Table 9 Change in bird gain Time, day Mass g The control 2 group 3 group one 40.07 ± 1.89 39.77 ± 1.68 40.36 ± 1.57 fourteen 438.44 ± 18.1 487.17 ± 15.4 509.7 ± 16.2 35 2122.6 ± 21.3 2182.5 ± 33.4 2261.3 ± 29.7

Table 10 Change in the main parameters of hematopoiesis in birds Age of chickens, days Red blood cells, × 10 ¹² / l Hemoglobin, g / l White blood cells × 10 ⁹ / L Control group one 1.89 ± 0.06 71.2 ± 0.05 27.1 ± 0.8 fourteen 1.93 ± 0.02 75.4 ± 0.1 31.1 ± 1.1 32 2.2 ± 0.01 75.3 ± 0.06 35.9 ± 1.0 2 experimental group one 2.02 ± 0.02 72.6 ± 0.06 29.1 ± 0.7 fourteen 2.04 ± 0.01 76.8 ± 0.03 31.2 ± 0.5 32 2.34 ± 0.03 * 77.7 ± 0.11 * 37.3 ± 0.4 3 experimental group one 1.97 ± 0.21 71.2 ± 0.4 25.5 ± 0.4 fourteen 2.18 ± 0.21 * 76.1 ± 0.6 30.5 ± 0.2 * 32 2.42 ± 0.41 * 88.1 ± 0.9 * 38.1 ± 03 * * - P <0.05

Claims (11)

1. The complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate of the formula

possessing antihypoxic and adaptogenic action and resistant to oxidation in aqueous solutions. 2. The stable crystalline form of the complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine di-succinate, which is characterized by a powder x-ray containing characteristic peaks at (2θ): 11.29; 12.53; 13.34; 14.26; 15.95; 16.26; 17.17; 17.84; 19.17; 19.55; 19.84; 20.72; 21.22; 21.93; 22.67; 23.28; 23.87; 24.26; 24.50; 25.75; 26.58; 26.88; 10/28; 28.65; 29.79; 30.55; 31.78; 32.79; 33.58; 34.93; 35.76; 36.99; 38.15. 3. The stable crystalline form of the complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate according to claim 2, characterized by the following x-ray powder diffraction pattern recorded using a diffractometer (CuKα anticathode), represented in units of angle 2θ, with the following interplanar distances d and the corresponding intensities and relative intensities:
Angle 2θ, 0 Interplanar distance d, Å Intensity, s-1 Relative intensity,% 11.2942 7.8280 523.33 40.36 12.5284 7.0595 556.67 42.93 13.3364 6.6335 536.67 41.39 14.2629 6.2046 243.33 18.77 15.9527 5.5510 326.67 25.19 16.2642 5.4454 133.33 10.28 17.1699 5.1601 176.67 13.62 17.5796 5.0408 126.67 9.77 17.8419 4.9672 233.33 17.99 19.1735 4.6252 233.33 17.99 19.5455 4.5380 833.33 64.27 19.8408 4.4711 543.33 41.90 20.7198 4.2834 1296.67 100.00 21.2173 4.1840 153.33 11.83 21.9306 4.0495 646.67 49.87 22.6669 3.9196 316.67 24.42 23.2765 3.8183 466.67 35.99 23.8739 3.7241 456.67 35.22 24.2570 3.6662 690.00 53.21 24.5044 3.6297 880.00 67.87 25.7518 3.4567 500.00 38.56 26.5811 3.3507 363.33 02/28 26.8792 3.3142 313.33 24.16 10/28/29 3.1726 140.00 10.80 28.6456 3.1137 210.00 16.20 29.7913 2.9965 106.67 8.23 30.5538 2.9234 100.00 7.71 31.7791 2.8135 190.00 14.65 32.7890 2.7291 116.67 9.00 33.5788 2.6667 93.33 7.20 34.9325 2.5664 236.67 18.25 35.7622 2.5087 156.67 12.08 36.0112 2.4919 110.00 8.48 36.9890 2.4283 120.00 9.25
38.1490 2.3571 170.00 11/13 4. The method of producing the complex according to claim 1, comprising reacting equimolar amounts of 2-ethyl-6-methyl-3-hydroxypyridine succinate, succinic acid and 3- (2,2,2-trimethylhydrazinium) propionate dihydrate, followed by dehydration and crystallization under conditions vacuum drying. 5. The method for producing the complex according to claim 1, comprising reacting equimolar amounts of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 3- (2,2,2-trimethylhydrazinium) propionate succinate under mechanochemical conditions in an inert aprotic solvent. 6. The method for producing the complex according to claim 1, comprising reacting equimolar amounts of 2-ethyl-6-methyl-3-hydroxypyridine, succinic acid and 3- (2,2,2-trimethylhydrazinium) propionate succinate under mechanochemical conditions in an inert aprotic environment solvent. 7. The method for producing the complex according to claim 1, comprising reacting 2-ethyl-6-methyl-3-hydroxypyridine, 3- (2,2,2-trimethylhydrazinium) propionate and succinic acid (molar ratio 1: 1: 2) under conditions mechanochemical effects in an inert aprotic solvent. 8. The method according to any one of claim 5, 6 or 7, characterized in that an aliphatic ketone, ether or aliphatic hydrocarbon is used as an inert aprotic solvent. 9. The method of claim 8, characterized in that acetone or methyl ethyl ketone is used as an aliphatic ketone. 10. The method according to claim 8, characterized in that diethyl ether, tetrahydrofuran or dioxane are used as the ether. 11. The method according to claim 8, characterized in that hexane, heptane or petroleum ether are used as an aliphatic hydrocarbon.

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