RU2797949C1 - Ester of thioctic (α-lipoic) acid and 2-ethyl-6-methyl-3-oxypyridine, exhibiting antihypoxic activity - Google Patents

Abstract

FIELD: organic chemistry and medicine.

SUBSTANCE: invention relates to a new chemical compound, namely the thioctic ester (α -lipoic) acid and 2-ethyl-6-methyl-3-oxypyridine (2-ethyl-6-methylpyridinol-3-yl-thiooctanoate) of formula (1).

EFFECT: obtaining a non-toxic biologically active new chemical substance with antihypoxic activity.

1 cl, 2 tbl, 3 ex

Description

The invention relates to a new chemical compound, namely to 2-ethyl-6-methylpyridinol-3-yl-thiooctanoate of the formula (1):

This compound exhibits antihypoxic activity and can be used as a biologically active substance with antihypoxic activity.

The present invention relates to organic chemistry and medicine, in particular to a new chemical compound exhibiting antihypoxic activity.

Salts of 2-ethyl-6-methyl-3-oxypyridine are widely positioned as drugs with antihypoxic activity. Known pharmacological compositions based on salts of 2-ethyl-6-methyl-3-oxypyridine with organic carboxylic acids [RF Patent No. RU 2284993 C2, 2002], 2-ethyl-6-methyl-3-hydroxypyridine nitroxysuccinate [RF Patent No. RU2394815 C2 , 2008], 2-ethyl-6-methyl-3-hydroxypyridine succinate [RF Patent No. RU 2497522 C1, 2012], exhibiting antihypoxic activity. However, the widely declared dependence of the antihypoxic potential of 2-ethyl-6-methyl-3-oxypyridine salts on their antioxidant activity is not always confirmed in experimental and clinical studies [I.A. Volchegorsky, I.Yu. Miroshnichenko, L.M. Rassokhin, M.P. Malkin, Ross. physiol. magazine them. THEM. Sechenova, 105(3), 363-374 (2019); I.A. Volchegorsky, M.G. Moskvicheva, E.N. Chashchina, Clinical Medicine, 82(11), 31-35 (2004)]. There are situations in which the corresponding drugs have a multidirectional effect on resistance to hypoxia of various origins [I.A. Volchegorsky, I.Yu. Miroshnichenko, L.M. Rassokhin, M.P. Malkin, Ross. physiol. magazine them. THEM. Sechenova, 105(3), 363-374 (2019)]. This circumstance illustrates the expediency of searching for derivatives of 2-ethyl-6-methyl-3-hydroxypyridine with an optimal profile of antihypoxic action. One of the promising approaches to solving this problem is the esterification of 2-ethyl-6-methyl-3-oxypyridine with thioctic (α-lipoic) acid.

Known drugs with antihypoxic action were used as prototypes and comparison drugs: emoxipin (2-ethyl−6-methyl-3-hydroxypyridine hydrochloride) and thioctic (α-lipoic) acid [Novikov V. E., Losenkova S. O. Reviews of clinical pharmacology and drug therapy. 2004. Vol. 3. No. 1.C. 2-14; I.A. Volchegorsky, I.Yu. Miroshnichenko, L.M. Rassokhin, M.P. Malkin, Ross. physiol. magazine them. THEM. Sechenova, 105(3), 363-374 (2019)].

The objective of the invention is to expand the arsenal of biologically active substances, including those with antihypoxic activity. EFFECT: obtaining a practically non-toxic biologically active new chemical substance with antihypoxic activity.

The essence of the invention: an ester of thioctic (α-lipoic) acid and 2-ethyl-6-methyl-3-oxypyridine (2-ethyl-6-methylpyridinol-3-yl-thiooctanoate) of formula (1):

,

,

showing antihypoxic activity.

This compound and its properties are not described in the literature.

The claimed compound is synthesized by the interaction of thioctic acid and 2-ethyl-6-methyl-3-oxypyridine in accordance with the scheme below:

At the first (pre-esterification) stage of the synthesis, a mixed anhydride of thioctic and trifluoroacetic acids is obtained, which is used in the second (esterification) stage: adding 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride to the mixed anhydride at a temperature of 55 - 60 degrees Celsius after washing 0.005 M solution of hydrochloric acid and distilled water, followed by removal of water and volatile impurities on a rotary evaporator. To obtain a chromatographically homogeneous product, the ether is subjected to extraction with hexane, the residues of which are removed using a rotary evaporator. The chemical homogeneity of the obtained substance is evaluated by thin-layer chromatography on Sorbfil-type plates or similar. The eluent used is a mixture of n-heptane - isopropanol in a ratio of 5/1. Chromatograms are developed in iodine vapor. After obtaining a chromatographically homogeneous product, its state of aggregation and solubility are evaluated.

Example 1

Synthesis of the claimed compound

As starting reagents, (R, S)-thioctic (α-lipoic) acid (NuSci, USA) is used; CAS No. 1077-28-7. 2-ethyl-6-methyl-3-hydroxypyridine - the base is obtained from the substance-powder of methylethylpyridinol hydrochloride (2-ethyl-6-methyl-3-oxypyridine hydrochloride) [CJSC Obninsk Chemical-Pharmaceutical Company, Russia]). An equivalent amount of sodium hydroxide is added to a saturated aqueous solution of 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride, the precipitate is filtered off in the cold, washed on the filter with chilled water, and dried in a desiccator over solid KOH.

20.62 g (0.100 mol) of thioctic (α-lipoic) acid, 12.0 g of triethylenediamine (0.107 mol) and 75 ml of 1,2-dichloroethane (DCE) are placed in a glass conical flask. The flask is hermetically sealed and weighed on a technical balance. Then the contents of the flask are stirred to achieve complete dissolution of the solid components, and the flask is placed in an ice-water bath. After cooling the solution, 22.5 g (0.107 mol; about 15 ml) of trifluoroacetic anhydride (TFAA), pre-chilled in an ice bath, are added to the flask. TFUA is applied in portions of 2-3 ml (3-4.5 g) with a frequency of 2-3 minutes. After adding each portion of TFUA, the flask is hermetically sealed and its contents are vigorously stirred, avoiding local overheating. The amount of TFAA added is controlled by weighing the flask with the reaction mixture after the addition of each portion of the anhydride. Upon completion of the addition of TFUA, the flask with the reaction mixture is placed in a water bath (40–43 °C), where it is kept for 10–12 minutes with occasional stirring. At this stage of the synthesis, a mixed anhydride of thioctic and trifluoroacetic acids is formed.

The flask with the resulting anhydride is placed in an ice bath, and after cooling the solution, 13.72 g (0.100 mol) of 2-ethyl-6-methyl-3-hydroxypyridine, previously ground into powder and dried in a vacuum desiccator, are added to it. The vessel with the reaction mixture is placed in a water bath (56–60°C) and the contents of the flask are vigorously stirred until the complete dissolution of 2-ethyl-6-methyl-3-hydroxypyridine. The resulting solution is kept for another 20 minutes at the same temperature, then cooled to room temperature and then poured into 1.0 liters of cold (+3 - +5 ° C) distilled water. After vigorous stirring for 5 minutes, the mixture is allowed to settle until the phases separate. The upper ("water") phase containing the salt of triethylenediamine and trifluoroacetic acid is removed by decantation. The lower phase containing a solution of the desired product (2-ethyl-6-methylpyridinol-3-yl-thiooctanoate) in DCE was washed three times with 1.0 liter of distilled water at room temperature. Then the solution of the resulting ester was washed twice with 0.005 M hydrochloric acid solution (1.0 l each) and twice with water (1.0 l each). After washing, the ether solution is transferred into a flask of a rotary evaporator, with which the solvent is removed at a temperature of 25-35°C. An alternative approach is to "dry" the solution in a stream of air in a fume hood. In both cases, the "yield" of the target product is at least 85% of the calculated values.

The resulting ester may contain minor amounts of 2-ethyl-6-methyl-3-oxypyridine hydrochloride, thioctic acid and triethylenediamine. To obtain a chromatographically homogeneous target substance, the resulting ester is extracted with boiling n-hexane. During cooling of the hexane extract, the target ester is isolated as a bright yellow oil. Upon completion of the extraction, cold n-hexane is carefully decanted from the receiving flask and its residues are removed on a rotary evaporator (40-45 °C). All stages of synthesis and purification of the target compound are carried out in a fume hood.

The chemical homogeneity of the obtained substance is evaluated by thin-layer chromatography on Sorbfil-type plates. When eluting with a mixture of n-heptane-isopropanol (5:1) followed by development with iodine vapor, R _f of the target ester is 0.61. If the product is not pure enough, the cleaning procedure must be repeated.

Spectral characteristics of the compound of formula (1).

Ester of thioctic (α-lipoic) acid and 2-ethyl-6-methyl-3-oxypyridine (2-ethyl-6-methylpyridinol-3-yl-thiooctanoate)

(1)

(1)

Oily viscous yellow liquid with a slight specific odor.

IR spectrum (v, cm ^-1 ) in KBr: 1761.4 s. (v C(1)=O), 1228.3 s., 1153.5 s., 1123.1 s. broad "aerial band" [sym. and asym. vC(1)OC(13)].

^1H NMR spectrum (500.13 MHz; T=293.5K) ^1H (δ, ppm, J, Hz): 1.27 (triple 3H, C(17)H ₃ , J=7.6); 1.61(multipl. 2H, C(4)H ₂ , J=8.3); 1.78 (multipl. 2H, C(5)H ₂ , J=4.0); 1.87 (multipl. 2H, C(3)H ₂ , J=7.3); 1.97 (sext. 1H, C(7)H ₂ (2), J=7.3); 2.52 (quint. 1H, C(7)H ₂ (1), J=6.2); 2.57 (single 3H, C(15)H ₃ ); 2.66 (triple 2H, C(2)H ₂ , J=7.5); 2.74 (square 2H, C(16)H ₂ , J=7.6); 3.17 (sext. 1H, C(8)H ₂ (1), J=5.0); 3.25 (sext. 1H, C(8)H ₂ (2), J=4.7); 3.64 (quint. 1H, C(6)H, J=6.8); 7.06 (dup. 1H, C(11)H, J=8.2); 7.28 (dup. 1H, C(12)H, J=8.2).

UV spectrum (solution in 95% ethanol): λ _max 332 nm -SS- n→σ* transition.

According to cryometric analysis, the molecular weight of the target product dissolved in benzene was 324±3 g/mol, with a calculated value of 325.34 g/mol.

Physicochemical characteristics

2-Ethyl-6-methylpyridinol-3-yl-thiooctanoate is an oily viscous liquid of intense yellow color, which at low temperatures solidifies into a glassy transparent mass. In liquid form, the obtained substance has a refractive index n ^25-27 = 1.546±0.001, is insoluble in water, gradually hydrolyzes upon contact with neutral, alkaline and acidic solutions. The target compound is sparingly soluble in aliphatic hydrocarbons, sparingly soluble in benzene, readily soluble in chloroform, DCE, dimethyl sulfoxide, ethyl alcohol, isopropyl alcohol, acetone, dioxane, and also in dilute solutions of strong acids (at pH above 1.65 it precipitates from solutions in emulsion form).

The resulting ester was given the laboratory name "thioxipin", consisting of the affix "thio" and the root "xipin", respectively, denoting the acyl and alcohol components of the target substance.

Example 2

Evaluation of the toxicity of the claimed compound

Toxicological studies were performed in accordance with the recommendations for the study of acute toxicity of chemicals [A.N. Mironov, N.D. Bunyatyan, A.N. Vasiliev et al., Guidelines for conducting preclinical drug trials, Grif and K, Moscow (2012); M.L. Belenky, Elements of a quantitative assessment of the pharmacological effect, Medicine, Leningrad (1963); I.V. Berezovskaya, Khim.-farm. j., 37(3), 32-34 (2003)]. The acute toxicity of thioxipine was assessed after its single intraperitoneal injection followed by observation of the animals for 4 weeks. This section of the work was performed on female laboratory rodents of two species (Wistar rats weighing 200 ± 20 g and outbred mice weighing 30 ± 3 g). In both cases, lethality of animals was recorded after administration of thioxipine at 7 different doses, each of which was tested on 10 animals. Animals were injected with thioxypine and "comparator substances" in the form of emulsions prepared on a medium consisting of an aqueous solution of NaCl (9 g/l) and Tween-80 (10.9 g/l). The pH of the introduced emulsions did not go beyond 7.2 - 7.6. In experiments on rats, the emulsion of thioxypine was administered in a volume of 25 ml/kg. The corresponding value in experiments on mice was 50 ml/kg. The studied doses of thioxypine were calculated based on the previously calculated average therapeutic dose equivalents (ESTD=72.5 µmol/kg) of 2-ethyl-6-methyl-3-oxypyridine hydrochloride (emoxipine) [I.A. Volchegorsky, L.M. Rassokhina, I.Yu. Miroshnichenko, Experiment. and wedge. Pharmacol., 74(12), 27-32 (2011).]. In the toxicological section of the study, thioxypine was administered at doses equimolar to 4.77-25.5 EMTI of emoxipine in rats and 4.47-13.06 EMTD in mice.

In parallel, the acute toxicity of "comparator substances" was evaluated: a mixture of 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride and thioctic acid, administered in doses equimolar to those of thioxypine. The obtained data were processed by probit analysis [D.J. Finney, Probit analysis: a statistical treatment of the sigmoid response curve, Cambridge university press, Cambridge (1952)]. Results were expressed as LD50, its standard error (s), and an additional calculated 95% confidence interval (95% CI). Statistical comparison of LD50 of thioxypine and “comparator” was performed using the toxicological version of the t-test. The conclusion about the effect of esterification on the toxicity of a mixture of thioxypine components was made only with unidirectional statistically significant changes in LD50, which were established both in experiments on mice and rats.

The results are presented in table 1.

In all series of the toxicological section of the study, the death of animals was observed only during the first two days after the introduction of the studied substances. The data obtained made it possible to attribute thioxypine to the class of low-toxic compounds [I.V. Berezovskaya, Khim.-farm. j., 37(3), 32-34 (2003).]. This is evidenced by the indicators of acute toxicity (in terms of mg / kg), established in experiments on mice and rats. In both cases, the LD50 of thioxypine corresponded to the range of 101–1000 mg/kg, which characterizes the low toxicity of chemicals when administered intraperitoneally. It is important to note that the equimolar mixture of thioctic acid and emoxipin showed higher toxicity compared to their esterification product. This was manifested by a statistically significant decrease in the LD50 of the mixture of free thioxypine components compared to the LD50 of their ester derivative. This pattern was established both in experiments on mice and rats. In the first case, the LD50 of thioxypine (in µmol/kg) exceeded the corresponding indicator of the mixture of its free components by 1.63 times, in the second - by 1.27 times.

Example 3

Evaluation of the antihypoxic activity of the claimed compound on models of hypoxic, hypercapnic, hemic and histotoxic hypoxia.

This section of the study was performed on mice of both sexes. Each experimental group of 10 mice included 5 males and 5 females. 2-Ethyl-6-methyl-3-hydroxypyridine hydrochloride, thioctic acid, and their equimolar mixture were used as “comparator substances”. Thioxipine and "comparator substances" in doses equimolar to thioxypine were administered intraperitoneally 30 minutes before acute hypoxia was simulated. Animals were injected with thioxypine and "comparator substances" in the form of emulsions prepared on a medium consisting of an aqueous solution of NaCl (9 g/l) and Tween-80 (0.84 g/l). The pH of the introduced emulsions did not go beyond 7.2 - 7.6. Thioxipin was used in doses of equimolar 0.5; 1.0 and 2.0 EMTD emoxipine. Mice in the control group received an equivolume of the medium [Tween-80 (0.84 g/l) in aqueous NaCl solution (9 g/l)], which was used to emulsify thioxypine and "comparator substances". To simulate acute hypoxic hypoxia, the “asphyxia of drowning” test was used [Kulinsky V.I., Olkhovsky I.A., Kovalevsky A.N., Byul. experimental biol. and honey. 101(6), 669-671(1986).]. To reproduce hypercapnic hypoxia, mice were placed in individual, hermetically sealed glass containers with a volume of 200 ml. Hemic hypoxia was induced by a single injection of sodium nitrite at a dose of 200 mg/kg (20 ml/kg of 1% NaNO solution, subcutaneously). [A.N. Mironov, N.D. Bunyatyan, A.N. Vasiliev et al., Guidelines for conducting preclinical drug trials, Grif and K, Moscow (2012).]. Histotoxic hypoxia was induced by a single injection of sodium nitroprusside at a dose of 20 mg/kg (20 ml/kg of a 0.1% solution, intraperitoneally) [A.I. Kurbanov, N.N. Samoilov, E.N. Stratienko et al., Psychopharmacol. and biol. narcol. 6(1–2), 1164–1170 (2006).]. In all cases, the criterion for resistance to acute hypoxia was the time from the moment of its induction to the death of animals. Statistical analysis of this section of the study was performed using the SPSS-17.0 software package. The data were processed by descriptive statistics and presented as a median (Me) and a range between the "lower" (LQ, 25th percentile) and "upper" (UQ, 75th percentile) quartiles. The significance of intergroup differences was judged by the Mann-Whitney U-test. The conclusion about the antihypoxic effect of the studied substances was made with a statistically significant increase in the latency of the death of mice, which was established in at least two models of acute hypoxia. The significance of intergroup differences in mortality was assessed by Fisher's exact test. All sections of the statistical analysis met the criteria of the intersection-union test, which excludes the use of corrections for multiple comparisons. Statistical hypotheses were tested at the critical significance level Р=0.05.

The results are presented in table 2.

The decrease in the toxicity of the mixture of thioctic acid and emoxipin as a result of their esterification was accompanied by a relative increase in the antihypoxic activity of the resulting ester. This was most clearly manifested in the model of acute hypoxic hypoxia (asphyxia of drowning), resistance to which significantly increased after the administration of thioxypine at medium (EMTD) and maximum (2ESTD) doses. The antihypoxic effect of thioxipine increased in direct proportion to the dose and reached the highest severity (151% of the median control) when using the maximum dosage. A mixture of thioctic acid and emoxipin at a dose equimolar to 2ETD thioxypine also caused a statistically significant antihypoxic effect, increasing the death latency of mice up to 120% of the median of control values. In terms of the severity of the antihypoxic effect, thioxypine at the maximum dose significantly exceeded the mixture of its free components at the equimolar dosage (P=0.037). The presence of antihypoxic activity in the studied ether was confirmed in the model of hypercapnic hypoxia, resistance to which increased to 143% of the median control under the action of thioxypine at the maximum dose. An increase in the latency of death of mice, established on 2 models of hypoxia under the action of thioxypine, allows us to consider it as a true antihypoxant. The effect of thioxypine on resistance to histotoxic hypoxia was qualitatively different from its protective effects in hypoxic and hypercapnic hypoxia. This was manifested by a decrease in the latency of death of mice to 68% of the median control under the action of thioxypine at a dose of ½ EMTD. A similar effect was produced by thioctic acid at an equimolar dosage. None of the studied substances had a significant effect either on the death rate of mice (P = 0.47 - 0.56) or on the life expectancy of dead animals (P = 0.19 - 0.93) when hemic hypoxia was reproduced.

Table 1

Comparative analysis of the acute toxicity of thioxipine (2-ethyl-6-methylpyridinol-3-yl-thiooctanoate) and an equimolar mixture of its free components (thioctic acid and 2-ethyl-6-methyl-3-oxypyridine hydrochloride)

Dose
µmol/kg(mg/kg) ESTD Mortality Effect
(broken) Acute toxicity LD µmol/kg(mg/kg) ESTD Toxicological study in rats Thioxipine 345.8 (112.57) 4.77 0/10 3.04 LD ₁₆ 699.57 (227.72) 9.7 456.8 (148.68) 6.30 0/10 3.04 LD ₅₀ 1016.51 (330.87) 14.0 604.7 (196.82) 8.34 0/10 3.04 LD ₈₄ 1333.46 (434.04) 18.4 799.0 (260.07) 11.02 2/10 4.16 LD ₅₀ : 1016.51 ± 63.39 µmol/kg
95% CI (887 - 1146 µmol/kg)
330.9 ± 20.63 mg/kg
95% CI (288 - 373 mg/kg) 1057.1 (344.09) 14.58 7/10 5.52 1397.8 (455.01) 19.28 9/10 6.28 1848.8 (601.80) 25.50 10/10 6.96 Equimolar mixture of emoxipin and thioctic acid 345.8 4.77 0/10 3.04 LD ₁₆ 463.09 6.4 456.8 6.30 0/10 3.04 LD ₅₀ 799.66 11.0 604.7 8.34 2/10 4.16 LD ₈₄ 1136.23 15.7 799.0 11.02 7/10 5.52 LD ₅₀ : 799.66 ± 67.31 µmol/kg ^*
95% CI (658 – 941 µmol/kg) 1057.1 14.58 10/10 6.96 1397.8 19.28 10/10 6.96 1848.8 25.50 10/10 6.96 Toxicological study in mice Thioxipine 353.6 (206.07) 4.47 0/10 3.04 LD ₁₆ 863.41 (281.04) 6.0 467.1 (247.29) 5.35 0/10 3.04 LD ₅₀ 1313.08 (427.41) 9.1 618.3 (296.75) 6.43 1/10 3.72 LD ₈₄ 1762.76 (573.38) 12.2 817.0 (356.10) 7.71 1/10 3.72 LD₅₀: 1313.08 ± 89.94 µmol/kg
95% CI (1131 – 1495 µmol/kg)
427.41± 29.28 mg/kg
95% CI (368 – 487 mg/kg) 1080.9 (427.31) 9.26 2/10 4.16 1429.2(512.78) 11.11 6/10 5.25 1890.4(615.33) 13.06 10/10 6.96 Equimolar mixture of emoxipin and thioctic acid 353.6 4.47 0/10 3.04 LD ₁₆ 429.27 3.0 467.1 5.35 0/10 3.04 LD ₅₀ 806.83 5.6 618.3 6.43 4/10 4.75 LD ₈₄ 1184.38 8.2 817.0 7.71 5/10 5.00 LD ₅₀ : 806.83 ± 75.51 µmol/kg*
95% CI (649 – 964 µmol/kg) 1080.9 9.26 10/10 6.96 1429.2 11.11 10/10 6.96 1890.4 13.06 10/10 6.96

Note to table. 1.

1. * - significant differences from the "thioxipin" group according to the results of comparing LD50 in the dimension of µmol/kg (P<0.05 by t-test)

table 2

Effect of thioxypine (2-ethyl-6-methylpyridinol-3-yl-thiooctanoate) and its free components (thioctic acid, 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride and their equimolar mixture) on resistance to acute hypoxia

Indicators
Groups Latency of hypoxic death (s) Me (LQ-UQ) hypoxic hypoxia hypercapnic hypoxia hemic hypoxia histotoxic hypoxia Control Twin-80
0.84 g/l for 0.9% NaCl 29.5
(28-35) 1663.5
(1314-1984) 2610.5
(1933-2915) 8
10 2014
(1510-2452) Thioxipine** ½ESTD 33.5
(29-36) 1301
(1163-2087) 2173
(1853-2710) 7
10 1379.5*
(1003-1635) ESTD 36.5*
(33-43) 2041
(1622-2442) 2362
(1899-2537) 9
10 1466
(1265-1730) 2 ESTD 44.5*
(35-51) 2379*
(2157-3158) 4115.5
(2309-4680) 6
10 1418
(1167-1948) Emoxipin ½ESTD 32.5
(29-37) 1565
(1103-1752) 2117.5
(1867-2399) 8
10 1830.5
(992- 2146) ESTD 32
(28-34) 1817
(1647-2888) 2243
(1783-2569) 10
10 1629.5
(1299-1677) 2 ESTD 29
(27-31) 1740
(1303-2181) 2219.5
(2093-2614) 10
10 1851.5
(1477-2151) Thioctic acid ½ESTD 38*
(31-46) 1716
(1183-2095) 2293.5
(1943-2392) 10
10 1363.5*
(1110-1700) ESTD 34.5
(32-38) 1845.5
(1547-2122) 2018
(1897-2786) 10
10 1731.5
(1042-1948) 2 ESTD 31.5
(29-38) 2104.5
(1507-2297) 2624
(2415-2965) 9
10 1527.5
(954-1885) Equimolar mixture of emoxipin and thioctic acid ½ESTD 30.5
(27-35) 1542.5
(1312-1718) 2318
(2010-3221) 9
10 1508.5
(1156-1692) ESTD 30.5
(28-34) 1955.5
(1559-2530) 2492.5
(1959-3611) 10
10 1710.5
(1516-1970) 2 ESTD 35.5*
(32-39) 1573.5
(1232-2125) 3029
(1980-3176) 9
10 1471.0
(1127-1784)

Notes to the table. 2

1. Experiments were carried out on outbred mice of both sexes, each group consisted of 5 males and 5 females; in all series (with the exception of "hemic hypoxia") modeling of acute hypoxia resulted in 100% lethality of mice. The number of animals in the "hemic hypoxia" series is represented by a fraction, the numerator of which is the number of dead animals, and the denominator is the total number of animals in the group; none of the groups in this series differed from the control group in terms of mouse death (P = 0.47 - 0.56, Fisher's exact test).

2. * - statistically significant differences from the control (P<0.05 according to the Man-Whitney U-test)

3. ** - true antihypoxic effect (according to the criterion of antihypoxic activity, established on at least 2 models of hypoxia).

Claims (3)

1. Ester of thioctic (α-lipoic) acid and 2-ethyl-6-methyl-3-oxypyridine (2-ethyl-6-methylpyridinol-3-yl-thiooctanoate) of formula (1)

(1). 2. The compound according to claim 1, showing antihypoxic activity.