RU2397175C1 - 1-alkenylimidazole derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to 1-alkenylimidazole derivatives of general formula 1

, where R is vinyl, allenyl or isopropenyl, R₁ is hydrogen or methyl, E is Zn (II) or Fe(III), An is chlorine or acetate, n equals 1, 2 or 4, except compounds where R is vinyl, R₁ is hydrogen, E is Zn(II), An is chlorine or acetate and n equals 2.

EFFECT: compounds have antihypoxic properties for different types of hypoxia.

5 ex, 8 tbl

Description

The invention relates to new compounds from among metal complexes of derivatives of 1-alkenylimidazole having biological activity, in particular antihypoxic.

Antihypoxants that have been introduced into medical practice do not meet the needs of doctors due to the low efficiency and narrow range of current doses or the inability to provide a therapeutic effect for hypoxia of various origins. Therefore, the search for new chemical compounds with high antihypoxic activity in various types of hypoxia is an urgent problem of modern pharmacology.

Zinc metal complexes with derivatives of bis-1-vinylimidazole and -ethyl vinylimidazole are known to have antihypoxic properties in case of carbon monoxide poisoning (patents No. 2038079, No. 2115653), and cobalt as a hemostatic stimulator (patent No. 2157813).

The purpose of the invention is a new metal complex compounds of derivatives of 1-alkenylimidazole with valuable biological activity, in particular antihypoxic properties in various types of hypoxia.

This goal is achieved by synthesizing new metal complexes with derivatives of 1-alkenylimidazole and studying their biological activity in experimental pharmacological studies.

Below are examples of the synthesis of new derivatives of 1-alkenylimidazole and the results of a study of their pharmacological activity.

Synthesis of complexes based on 1-vinyl-, 1-allenyl- and 1-isopropenyl-imidazoles

Example 1. Tetra (1-vinylimidazole) iron trichloride (code F4). At room temperature, with stirring, 17.57 g (0.065 mol) of iron (III) chloride hydrate are gradually added to 50.0 g (0.52 mol) of 1-vinylimidazole. At the end of the reaction from the reaction flask at a residual pressure of 10-20 mm Hg azeotropic mixture of 1-vinylimidazole with water is distilled off, a yellow-brown precipitate is separated, dried. Obtain 33.37 g of tetra (1-vinylimidazole) iron-trichloride (98.79%) complex with so pl. 155-157 ° C. Found,%: C 44.61; H 4.88; N, 28.77; Cl 20.14. C ₂₀ H ₂₄ N ₈ Cl ₃ Fe. Calculated,%: C 45.3; H 4.71; N, 28.81; Cl 20.51.

Structural formula

Example 2. Bis (1-allenylimidazole) zinc diacetate (code AL1). 5.11 g (0.051 mol) of 1-allenylimidazole is dissolved in 200 ml of a solution of a mixture of absolute ether and acetone (3: 1). 4.69 g (0.025 mol) of zinc diacetate are added to the resulting solution at room temperature with stirring. After 2 hours, the white precipitate formed is separated, washed with ether, dried, and 8.18 g (85.83%) of bis (1-allenylimidazole) zinc diacetate are obtained with mp. 122-124 ° C. Found,%: C 48.17; H 4.35; N, 14.21; Zn 16.62 C ₁₆ H ₁₈ N ₈ O ₄ Zn. Calculated,%: C 48.56; H 4.55; N, 14.16; Zn 16.54.

Structural formula

Example 3. (1-Allenyl-5-methylimidazole) zinc diacetate (code AL2). 6.90 g (0.0575 mol) of 1-allenyl-5-methylimilimidazole is dissolved in 350 ml of a solution of a mixture of absolute ether and acetone (3: 2). 6.35 g (0.0351 mol) of zinc diacetate are added to the resulting solution at room temperature with stirring. After 3 hours, the resulting white precipitate was separated, washed with ether, dried, and 13.45 g (77.12%) of 1-allenyl-5-methylimidazole) zinc diacetate was obtained with mp. 123-124 ° C. Found,%: C 43.17; H 4.65; N, 9.17; Zn 21.43. C ₁₁ H ₁₄ N ₂ O ₄ Zn. Calculated,%: C 43.59; H 4.97; N, 9.23; Zn 21.55.

Structural formula

Example 4. (1-Isopropenylimidazole) zinc diacetate (code PL1). 5.70 g (0.052 mol) of 1-isopropenylimidazole is dissolved in 300 ml of a solution of a mixture of absolute ether and acetone (2: 1). 9.54 g (0.052 mol) of zinc diacetate are added to the resulting solution at room temperature with stirring. After 24 hours, the white precipitate formed is separated, washed with ether, dried, and 14.27 g (92.72%) of (1-isopropylimidazole) zinc diacetate are obtained with mp. 124-125 ° C. Found,%: C 41.37; H 4.53; N, 9.42; Zn 22.27. C ₁₀ H ₁₄ N ₂ O ₄ Zn. Calculated,%: C 41.18; H 4.80; N, 9.61; Zn 22.44.

Structural formula

Example 5. (1-Isopropenyl-2-methylimidazole) zinc diacetate (code PL2). 3.00 g (0.0246 mol) of 1-isopropenyl-2-methylimidazole are dissolved in 140 ml of a solution of a mixture of absolute ether and acetone (3: 1). 4.52 g (0.0246 mol) of zinc diacetate are added to the resulting solution at room temperature with stirring. After 24 hours, the resulting white precipitate was separated, washed with ether, dried, and 5.97 g (79.49%) of (1-isopropenyl-2-methylimidazole) zinc diacetate were obtained, mp. 114-115 ° C. Found,%: C 43.28; H 5.25; N, 9.31; Zn 21.63. C ₁₁ H ₁₆ N ₂ O ₄ Zn. Calculated,%: C 43.22; H 5.24; N, 9.17; Zn 21.41.

The study of the biological activity of vinylimidazole derivatives

The studies were carried out in accordance with Article 11 of the Helsinki Declaration of the World Medical Association (1964), International Recommendations for Biomedical Research Using Animals (1985) and the Laboratory Practice Rules in the Russian Federation (Order of the Ministry of Health of the Russian Federation No. 267 of 06/19/2003) .

Research Methodology

The experiment was conducted on 260 white outbred male mice weighing 20-23 g using adequate methods of experimental acute hypoxia [1]. Acute hypobaric hypoxia (OGBG) and acute histotoxic hypoxia (OGTG) were induced in mice by injecting sodium nitroprusside (200 mg / kg) under the skin of the back. Experimental mice 1 hour before acute hypoxia were injected intraperitoneally in doses of 5-200 mg / kg of the studied compounds, and control animals at the same time and in the same way - an equal volume of distilled water. The antihypoxic effect of the substances was evaluated by the life span of the mice in minutes.

Digital experimental data were processed statistically using t student criterion [2].

Research results

It was found that the studied metal complex compounds of vinylimidazole derivatives have antihypoxic activity, the severity of which depends on the compound, dose and model of hypoxia (Table 1).

The highest antihypoxic effect in 4 hypoxia models was shown by acizole. The protective effect of acyzole was manifested in OGsGK in 6 doses, OGBG and OGTG in 5 doses, OGeG in 3 doses. The antihypoxic effect of the compound of the invention tetra (1-vinylimidazole) ironotrichloride (F4) was statistically significant with OGTG in 3 doses, OGBG and OGsGK in 2 doses, OGeG in 1 dose. Cobazol exerted an antihypoxic effect with OGBG in 5 doses, with OGTG in 3 doses, with OGsGK and OGeG in 1 dose. The severity of the antihypoxic effect was greater in acyzole with OGBG, and then followed by OPT, OGeG and OGsGK. Under the influence of F4, the most pronounced antihypoxic effect was with OGBG compared with OGTG, OGsGK and OGeG. Compared to acizole and F4, cobazole exhibited a more pronounced antihypoxic effect in OGBH than in OGTG and especially OGeG and OGsGK.

Comparison drugs had different effects on the life span of mice, depending on the hypoxia model, drug, and dose. The antihypoxic effect of nooglutil was manifested in OGsGK in 3 doses, OGBG, OGeG and OGTG in 2 doses. Hypoxene had a protective effect with OGBG in 3 doses, and with OGsGK, OGeG and OGTG in 2 doses.

Thus, the metal complex compound F4 is low toxic (Table 8) in comparison with other drugs, has a pronounced antihypoxic effect in models of acute hypoxia, and can be recommended for further in-depth study as a possible drug that increases the body's resistance under conditions of acute hypoxia of various genesis.

The study of the biological activity of derivatives of allenyl and isopropenylimidazole

Research Methodology

The experiments were performed on 2100 white outbred male mice weighing 20-23 g. Appropriate methods of experimental acute hypoxia were used [1]. Acute hypobaric hypoxia (OGBG) was induced in mice by “rising” at a speed of 50 m / s to a height of 10,000 m above sea level in the Vita pressure chamber, acute hypoxia with hypercapnia (OGsGK) by placing each mouse in a 250 ml transparent glass vessel, acute hemic hypoxia (OHG) - by the introduction of sodium nitrite (400 mg / kg) under the skin of the back, acute histotoxic hypoxia (OHG) - by the introduction of nitroprusside (200 mg / kg) under the skin of the back. The experimental mice 1 hour before acute hypoxia were injected intraperitoneally at doses of 5-200 mg / kg of the studied compounds, and the control animals at the same time and in the same way the same volume of distilled water. The antihypoxic effect of the substances was evaluated by the life span of the mice in minutes. Oxygen consumption by laboratory animals was determined using a closed-type apparatus in the modification of Miropolsky (I.V. Sanotsky, 1970) within 10 minutes after a 10-minute adaptation in the working chamber. The measurement results were calculated in ml per 1 minute per 100 g of body weight. Body temperature was measured with an electric thermometer in the rectum (O.N. Elizarova, 1974). Acute toxicity parameters were determined according to the Litchfield-Wilcoxon method (M.L. Belenky, 1963).

Research results

It was established that the magnitude and severity of the antihypoxic effect depend on the compound, dose and hypoxia model.

Under OGeG conditions, all four studied allenyl- and isopropenylimidazole derivatives increased the life expectancy of mice (Table 2). A more pronounced antihypoxic effect both in terms of the breadth of the current doses and the severity of the effect was exerted by the connection under the code AL2. So, AL2 in three doses of 10, 25 and 50 mg / kg increased the life time of animals by 49, 63 and 42%, respectively. The compound under the code AL1 at doses of 50 and 100 mg / kg increased the life time of mice by 27 and 36%, PL1 at doses of 50 and 100 mg / kg - by 82 and 42%; PL2 in doses of 50 and 100 mg / kg - by 66 and 36%, respectively.

In the OGsGK model, three of the four compounds increased the life time of mice: AL1, AL2, and PL2 (Table 3). The severity of the antihypoxic effect and the breadth of effective doses were greater for the complex compound allenilimidazole under the code AL1. Thus, AL1 in four doses of 10, 25, 50, and 100 mg / kg increased the life expectancy of mice by 23, 79, 94, and 91%, respectively. AL2 also increased the life expectancy of mice in four doses of 25, 50, 100 and 150 mg / kg, respectively, by 24, 96, 95 and 70%. The compound under the code of PL2 exhibited an antihypoxic effect in three doses (25, 50 and 100 mg / kg), increasing the life time of animals by 25, 54 and 88%, respectively. The reference drug hypoxene exerted an antihypoxic effect, increasing the life expectancy of mice by 20-33 and 27%.

The antihypoxic effect under OGBG conditions was exhibited by all four compounds, which in three doses increased the life time of mice by 269, 197, 169 and 255% (Table 4). Among the comparison preparations studied, hypoxene exerted a pronounced antihypoxic effect, increasing the life expectancy of experimental mice in doses of 50, 100 and 150 mg / kg by 144, 151 and 166%.

Under OGTG conditions, the life expectancy of mice was also increased by all four of the studied derivatives of allenyl- and isopropenylimidazole (Table 5). The most active in terms of the severity of the effect was the connection under the code PL1, which increased the life time of mice in three doses equal to 10, 25 and 50 mg / kg by 55, 76 and 48%, respectively. AL1 in three doses of 25, 50 and 100 mg / kg increased the life time of animals by 35, 56 and 24%, respectively. AL2 in doses of 25, 50 and 100 mg / kg at 20, 57 and 63%. PL2 in doses of 10, 25 and 50 mg / kg at 45, 63 and 27%. Among the comparison drugs, a pronounced antihypoxic effect was exerted by hypoxene, increasing the life time of animals in doses of 50 and 100 mg / kg by 40 and 94%, respectively.

All studied compounds significantly reduced oxygen consumption and body temperature (Tables 6, 7), which also indicates their antihypoxic activity.

The parameters of acute toxicity are given in table.8. Tetra (1-vinylimidazole) ironotrichloride has the least toxicity - the toxicity determination was suspended after intraperitoneal administration of the drug at a dose of 1 g / kg of body weight.

Thus, the results of the experiments allow us to conclude that the newly synthesized metal complexes of derivatives of vinyl-, allenyl- and isopropenylimidazole are low-toxic and have a pronounced protective effect on four models of acute hypoxia. The antihypoxic effect of these compounds in terms of the breadth of the current doses and severity significantly exceeds that of the well-known antihypoxant hypoxene.

Information sources

1. Lukyanova L.D. Guidelines for the experimental study of drugs intended for clinical study as antihypoxic drugs. - M., 1990. - 18 p.

2. Samoilov N.N. Tables of values of the average error and the reliable interval of the arithmetic mean of the variational series. - Tomsk, 1970 .-- 63 p.

Table 1 Comparative antihypoxic activity of new metal complex compounds of vinylimidazole derivatives and antihypoxants with various hypoxia models in relation to the control, taken as 100% Chemical compound code Dose mg / kg Hypoxia model OGBG OGsGK OGeG OGTG one 2 3 four 5 6 Vinylimidazole Derivatives Acizole 5 98 ± 13 93 ± 7 - 114 ± 4 * 10 216 ± 4 * 119 ± 3 * - 143 ± 7 * 25 374 ± 6 * 139 ± 8 * 104 ± 6 172 ± 8 * fifty 305 ± 13 * 153 ± 5 * 179 ± 3 * 224 ± 9 * one hundred 137 ± 6 * 157 ± 4 * 174 ± 3 * 126 ± 3 * 150 126 ± 7 * 157 ± 4 * 149 ± 7 * 107 ± 7 200 106 ± 11 156 ± 4 * 104 ± 3 - F4 10 - - - 103 ± 8 25 106 ± 3 113 ± 6 113 ± 3 127 ± 7 * fifty 377 ± 5 * 128 ± 8 * 141 ± 3 * 133 ± 5 * one hundred 364 ± 8 * 135 ± 4 * 111 ± 6 115 ± 4 * 150 95 ± 12 111 ± 7 - 94 ± 7 Cobazole 5 118 ± 5 * 88 ± 5 - - 10 138 ± 6 * 115 ± 2 * - 96 ± 6 25 158 ± 2 116 ± 5 100 ± 7 130 ± 5 * fifty 230 ± 8 * - 142 ± 5 * 174 ± 8 * one hundred 268 ± 9 * - 94 ± 7 133 ± 4 * 150 124 ± 15 * - - 110 ± 8 200 101 ± 12 - - - Nooglutil 25 104 ± 9 119 ± 5 * 99 ± 12 104 ± 5 fifty 144 ± 10 * 128 ± 6 * 118 ± 4 * 113 ± 7 * one hundred 139 ± 7 * 133 ± 7 * 119 ± 3 * 129 ± 5 * Hypoxene 25 110 ± 18 - - 101 ± 8 fifty 224 ± 9 * - - 140 ± 6 * one hundred 251 ± 7 * 99 ± 2 111 ± 2 * 194 ± 7 * 150 266 ± 8 * 133 ± 2 * 119 ± 2 * 115 ± 9 200 123 ± 18 128 ± 6 * 110 ± 6 - (*) P <0.05 compared with the control.

table 2 Comparative effect of new metal-complex compounds of allenyl- and propenylimidazole derivatives and comparison drugs on the life expectancy of mice in conditions of acute hemic hypoxia compared with the control taken as 100% (n = 10) No. p / p Chemical compound code Dose mg / kg 0.5 one 5 10 25 fifty one hundred 150 200 one AL1 99 ± 9 101 ± 2 120 ± 6 * 127 ± 7 * 136 ± 5 * 92 ± 3 2 AL2 106 ± 3 149 ± 3 * 163 ± 4 * 148 ± 4 * 99 ± 2 - 3 AP1 - 107 ± 2 123 ± 7 * 182 ± 3 * 142 ± 4 * 97 ± 3 four AR2 98 ± 3 136 ± 3 * 166 ± 5 * 169 ± 4 * 136 ± 7 - 5 Hypoxene 111 ± 2 * 119 ± 2 * 110 ± 6 1. An asterisk (*) indicates significant differences (P <0.05) compared with the control. 2. The sign (-) indicates doses not used in the experiments.

Table 3 Comparative effect of new metal-complex compounds of allenyl- and propenylimidazole derivatives and comparison drugs on the life expectancy of mice in conditions of acute hypoxia with hypercapnia compared with the control taken as 100% (n = 10) No. p / p Chemical compound code Dose mg / kg one 5 10 25 fifty one hundred 150 200 one AL1 - 105 ± 4 123 ± 4 * 179 ± 23 * 194 ± 10 * 191 ± 7 * - 2 AL2 - - 110 ± 7 124 ± 9 * 196 ± 13 * 195 ± 10 * 170 ± 7 * - 3 AP1 - 107 ± 8 110 ± 7 100 ± 6 - - - - four AR2 - - 100 ± 5 125 ± 2 * 154 ± 7 * 188 ± 7 * 194 ± 3 * - 5 Hypoxene - - - - 99 ± 2 120 ± 7 133 ± 2 * 127 ± 5 * 1. An asterisk (*) indicates significant differences (P <0.05) compared with the control. 2. The sign (-) indicates doses not used in the experiments.

Table 4 Comparative effect of new metal-complex compounds of allenyl- and propenylimidazole derivatives and comparison drugs on the life expectancy of mice under conditions of acute hypobaric hypoxia compared with the control taken as 100% (n = 10) No. p / p Chemical compound code Dose mg / kg 0.5 one 5 10 25 fifty one hundred 150 200 one AL1 117 ± 7 319 ± 4 * 369 ± 2 * 279 ± 10 * 107 ± 3 - 2 AL2 98 ± 4 143 ± 3 * 167 ± 8 * 191 ± 14 * 297 ± 12 * 117 ± 14 3 AP1 94 ± 13 123 ± 3 * 127 ± 6 * 323 ± 2 * 269 ± 5 * 134 ± 10 * 97 ± 10 four AR2 103 ± 5 142 ± 6 * 219 ± 11 * 310 ± 8 * 355 ± 8 * 274 ± 15 * 228 ± 7 * 109 ± 2 5 Hypoxene 110 ± 18 244 ± 9 251 ± 7 * 266 ± 8 * 123 ± 18 1. An asterisk (*) indicates significant differences (P <0.05) compared with the control. 2. The sign (-) indicates doses not used in the experiments.

Table 5 Comparative effect of new metal-complex compounds of allenyl- and propenylimidazole derivatives and comparison drugs on the life expectancy of mice under conditions of acute histotoxic hypoxia compared with the control taken as 100% (n = 10) No. p / p Chemical compound code Dose mg / kg 0.5 one 5 10 25 fifty one hundred 150 200 one AL1 - - - 118 ± 4 * 135 ± 3 * 156 ± 3 * 124 ± 5 * 105 ± 9 - 2 AL2 - - - 105 ± 3 120 ± 7 * 157 ± 4 * 163 ± 4 * 114 ± 5 - 3 AP1 101 ± 4 118 ± 4 * 123 ± 4 * 155 ± 2 * 176 ± 2 * 148 ± 1 * - - - four AR2 117 ± 4 * 139 ± 4 * 145 ± 5 * 163 ± 3 * 127 ± 2 * 110 ± 6 - - - 5 Hypoxene - 101 ± 5 140 ± 3 * 194 ± 2 * 115 ± 8 - 1. An asterisk (*) indicates significant differences (P <0.05) compared with the control. 2. The sign (-) indicates doses not used in the experiments.

Table 6 Oxygen consumption by mice by intraperitoneal administration of new metal complex compounds of imidazole derivatives No. p / p Chemical compound code Dose mg / kg Oxygen consumption,% Source After 1 hour After 3 hours In 6 hours After 24 hours one AL1 fifty one hundred 68 ± 4 * 64 ± 4 * 70 ± 8 * 95 ± 3 2 AL2 fifty one hundred 76 ± 3 * 73 ± 4 * 81 ± 7 * 99 ± 3 3 AP1 fifty one hundred 63 ± 4 * 65 ± 4 * 73 ± 3 * 94 ± 2 four AP2 fifty one hundred 73 ± 4 * 66 ± 4 * 77 ± 3 * 96 ± 3 5 F4 fifty one hundred 88 ± 5 * 86 ± 4 * 104 ± 3 91 ± 4 6 Cobazole fifty one hundred 68 ± 5 * 82 ± 8 * 69 ± 4 * 96 ± 3 7 Acizole fifty one hundred 59 ± 5 * 63 ± 4 * 56 ± 5 * 98 ± 3 Asterisk (*) indicates significant differences (P <0.05) compared with the initial value.

Table 7 Rectal temperature of mice with intraperitoneal administration of new metal complex compounds of imidazole derivatives No. p / p Chemical compound code Dose mg / kg Rectal temperature,% Source After 1 hour After 3 hours In 6 hours After 24 hours one AL1 fifty one hundred 95 ± 0.7 * 90 ± 0.7 * 97 ± 0.7 * 99 ± 1 2 AL2 fifty one hundred 95 ± 0.7 * 77 ± 2 * 96 ± 0.7 * 96 ± 1 3 AP1 fifty one hundred 95 ± 1 * 89 ± 1 * 91 ± 1 * 99 ± 1 four AP2 fifty one hundred 94 ± 1 * 89 ± 1 * 95 ± 0.7 * 101 ± 0.6 5 F4 fifty one hundred 96 ± 0.6 * 95 ± 1 * 97 ± 1 98 ± 1 6 Cobazole fifty one hundred 88 ± 1 * 92 ± 1 * 93 ± 1 * 98 ± 0.6 7 Acizole fifty one hundred 90 ± 0.7 * 89 ± 0.2 * 94 ± 1 * 99 ± 1 Asterisk (*) indicates significant differences (P <0.05) compared to the original value.

Table 8 Acute toxicity of new metal complex compounds of imidazole derivatives upon intraperitoneal administration to mice No. p / p Chemical compound code Toxicity mg / kg Ld ₁₆ LD ₅₀ LD ₈₄ one AL1 105 130 165 2 AL2 165 200 245 3 AP1 92.5 105 115 four AP2 one hundred 190 325 5 F4 More than 1000 mg / kg - -

Claims (1)

Derivatives of 1-alkenylimidazole of the general formula 1

where R is vinyl, allenyl or isopropenyl,
R ₁ is hydrogen or methyl,
E - Zn (II) or Fe (III),
An is chlorine or acetate,
n is 1, 2 or 4,
excluding compounds
where R is vinyl, R ₁ is hydrogen, E is Zn (II), An is chlorine or acetate, n is 2.