RU2430090C2 - 1-allylimidazole derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 1-allylimidazole with metal salts

, where R denotes allyl, E denotes a metal, e.g. Zn (II) or Co (II), An denotes chlorine or acetate, n equals 2.

EFFECT: novel 1-allylimidazole derivatives having antihypoxic activity are obtained.

1 cl, 7 tbl, 2 ex

Description

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

The search for new chemical compounds with pronounced 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-allylimidazole with valuable biological activity, in particular, antihypoxic properties in various types of hypoxia.

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

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

Synthesis of complexes based on 1-allylimidazoles

Example 1. Bis (1-allylimidazole) cobalt dichloride (CoAL code)

The compound was prepared at room temperature by adding a stoichiometric amount of cobalt chloride to a solution of allylimidazole in ethanol. To a solution of 5.41 g (50.0 mmol) of 1-allylimidazole in 150 ml of absolute ethanol, 5.94 g (25.0 mmol) of CoCl ₂ · H ₂ O was added over 30 minutes with stirring at room temperature. Formed after 20 After stirring for 4 hours, the intensely blue precipitate was filtered off, washed with ether, dried in vacuo to constant weight to obtain 7.26 g (83.9%) of bis (1-allylimidazole) cobalt dichloride with mp. 122-123 ° C. The product is soluble in water, acetone, chloroform, dimethyl sulfoxide (DMSO), insoluble in ether, alcohol. Nuclear magnetic resonance (NMR) spectra due to the paramagnetism of the obtained complex could not be removed. IR spectrum, ν, cm ^-1 : 554 s, 591 s, 627, 656 s, 750 s, 763, 778 s, 829 s, 857, 875 s, 930 s, 952 s, 962 shoulder, 988, 995 shoulder, 1028 s, 1093 s, 1108 s, 1116, 1220 s, 1235 s, 1288 s, 1334 s, 1343 s, 1397, 1419, 1443, 1452, 1509 shoulder, 1522 s, 1532 s, 1587 s, 1612 s , 1647 cl (C = CH ₂ ), 2940 cl, 2984 cl, 3017 cl, 3044 cl, 3112, 3131.

Found,%: C 41.94; H 4.61; Cl 20.34. C ₁₂ H ₁₆ N ₄ Cl ₂ Co. Calculated,%: C 41.64; H 4.66; N, 16.19; Cl 20.49, Co 17.02

Structural formula

Example 2. Bis (1-allylimidazole) zinc diacetate (code ALL)

The compound was obtained at room temperature by adding zinc acetate to a solution of allylimidazole [Zn (OAc) ₂ : allylimidazole = 1: 2.0-2.2] in a mixture of acetone and ether (3: 1).

To a solution of 3.20 g (29.6 mmol) of 1-allylimidazole in 100 ml of a mixture of absolute ether: acetone (3: 1), 2.54 g were gradually added (over 0.5-1 h) with stirring at room temperature (13, 8 mmol) Zn (OCOCH ₃ ) ₂ . The white precipitate formed after 48 hours of stirring was filtered off, washed with ether, dried in vacuo to constant weight, and 5.24 g (94.9%) of bis (1-allylimidazole) zinc diacetate with a melting point of 0.82 g were obtained. 114-116 ° C. The product is soluble in water, alcohol, acetone, chloroform, DMSO, insoluble in ether. ¹ H NMR spectrum, δ, ppm: 8.13 s (1Н, Н ⁵ ), 7.34 s (1Н, Н ⁵ ), 6.90 s (1Н, Н ⁴ ), 5.90 m (1Н, СН =), 5.31 d (1H, = CH _cis , J _cis = 10.0 Hz), 5.23 d (1H, = CH _trans , J _trans = 17.0 Hz), 4.56 d (2H, NCH ₂ , J = 5.9 Hz), 2.06 s (3H, MeCOO ); ¹³ C NMR spectrum, δ, ppm: 179.02 (COO), 139.09 (C ² ), 131.49 (CH =), 128.77 (C ⁴ ), 120.13 (C ⁵ ), 119.37 (= CH ₂ ), 50.32 ( NCH ₂ ), 23.12 (MeCOO). IR spectrum, ν, cm ^-1 : 490 s, 499 s, 555 s, 586 s, 621, 627 shoulder, 657 s, 663 s, 673 s, 750, 758, 776, 877, 890, 926, 936, 953 s, 991, 1010 s, 1069 s, 1094 s, 1108 s, 1240, 1284, 1293, 1333 s, 1388 s, 1440, 1515, 1535, 1585 s, 1619 s, 1646 (C = CH ₂ ), 2928 s , 2991 cl, 3013 cl, 3122.

Found,%: C 47.69; H 5.59; Zn 15.60. C ₁₆ H ₂₂ N ₄ O ₄ Zn. Calculated,%: C 48.07; H 5.55; N, 14.02; Zn 16.36.

Structural formula:

Study of the biological activity of allylimidazole 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 experiments were carried out on 210 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 “lifting” 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 transparent glass vessel with a capacity of 250 ml, acute hemic hypoxia (ОГеГ) - administration of sodium nitrite (400 mg / kg) under the skin of the back, acute histotoxic hypoxia (ОГТГ) - administration of nitroprusside (20 mg / kg) under the skin of the back. Experimental mice were injected intraperitoneally 1 hour before acute hypoxia doses of 5-200 mg / kg of the studied compounds, and control equal volume of distilled water at the same time and in the same way. The antihypoxic effect of the substances was evaluated by the life span of the mice in minutes. 10 minutes after 10 minutes of adaptation in the working chamber 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). Digital experimental data were processed statistically using t-student test [2].

Research results

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

Under OGeH conditions, the life expectancy of mice was increased among the studied allylimidazole derivatives (Table 1) CoAL in four doses (10, 25, 50, and 100 mg / kg). At the same time, the life expectancy of mice increased by 46, 35, 55, and 77%, respectively. The drug under the ALL code did not show effectiveness.

In the model of OGsGK (Table 2), both compounds increased the life time of mice. The severity of the antihypoxic effect and the breadth of effective doses were greater for the complex compound ALL. So, ALL in doses of 10, 25, 50 and 100 mg / kg increased survival by 25, 29, 90 and 95%, and CoAL in the same doses by 17, 17, 42 and 38%, respectively. The hypoxene reference drug had an antihypoxic effect, increasing the life expectancy of mice by 20, 33 and 27%.

A high antihypoxic effect under OGBG conditions was exhibited by all compounds that, in three doses, increased the life time of mice by 269, 197, 169, 255, 289 and 186% (Table 3). 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 increased the compound under the CoAL code in four doses (10, 25, 50, and 100 mg / kg) by 17, 45, 67, and 83%, respectively (Table 4). The connection with the ALL code did not show an antihypoxic effect. Among the comparison drugs, a pronounced antihypoxic effect was exerted by hypoxene, increasing the life time of animals at doses of 50 and 100 mg / kg by 40 and 94%, respectively.

All studied compounds significantly reduced oxygen consumption and body temperature (Tables 5, 6), which also indicates their antihypoxic activity.

The parameters of acute toxicity are shown in table 7.

Thus, the results of the experiments allow us to conclude that the newly synthesized metal complexes of allylimidazole derivatives are low toxic and have a pronounced protective effect on acute hypoxia models. 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.

General formula 1 of allimidazole derivatives:

E is a metal, for example Zn (II) or Co (II);

An anion Cl ^- or CH ₃ COOH ^-

Literature

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 effect of new metal complex compounds of allylimidazole and hypoxene derivatives on the life expectancy of mice under 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 ALL - - - 100 ± 4 91 ± 8 108 ± 3 100 ± 3 - - 2 Coall - - 108 ± 3 146 ± 8 * 135 ± 7 * 155 ± 4 * 177 ± 4 * - - 3 Hypoxene - - - - - - 111 ± 2 * 119 ± 2 * 110 ± 6 Note. 1. An asterisk (*) indicates significant differences (P <0.05) compared with the control. 2. The sign (-) indicates doses not used in the experiments.

table 2 Comparative effect of new metal complex compounds of allylimidazole and hypoxene derivatives 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 ALL 105 ± 5 115 ± 3 125 ± 3 * 129 ± 4 * 190 ± 7 * 195 ± 4 * - - 2 Coall - - 117 ± 5 * 117 ± 5 * 142 ± 6 * 138 ± 8 * - - 3 Hypoxene - - - - 99 ± 2 120 ± 7 133 ± 2 * 127 ± 5 * Note. 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 allylimidazole and hypoxene derivatives on the life span 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 ALL - - 130 ± 5 * 349 ± 8 * 389 ± 7 * 284 ± 10 * 310 ± 8 * - - 2 Coall - - 123 ± 6 * 151 ± 6 * 168 ± 8 * 271 ± 9 * 286 ± 7 * - - 3 Hypoxene - - - - 110 ± 18 244 ± 9 251 ± 7 * 266 ± 8 * 123 ± 18 Note. 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 allylimidazole and hypoxene derivatives on the life span 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 ALL - - - 108 ± 8 92 ± 10 87 ± 5 80 ± 4 - - 2 Coall - - 108 ± 2 117 ± 2 * 146 ± 6 * 160 ± 4 * 183 ± 7 * - - 3 Hypoxene - - - - 101 ± 5 140 ± 3 * 194 ± 2 * 115 ± 8 - Note. 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 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 ALL fifty one hundred 62 ± 3 * 60 ± 3 * 79 ± 4 * 96 ± 3 2 Coall fifty one hundred 63 ± 4 * 60 ± 3 * 79 ± 4 * 95 ± 3 Note. Asterisk (*) indicates significant differences (P <0.05) compared with the initial value.

Table 6 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 ALL fifty one hundred 95 ± 0.8 * 81 ± 1 * 95 ± 0.7 * 100 ± 1 2 Coall fifty one hundred 92 ± 2 * 91 ± 1 * 92 ± 1 * 100 ± 1 Note. Asterisk (*) indicates significant differences (P <0.05) compared with the initial value.

Table 7 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 ALL 125 160 185 2 Coall 135 160 187

Claims (1)

Derivatives of 1-allylimidazole of general formula 1 with antihypoxic effects

where R is allyl,
E is a metal, for example: Zn (II) or Co (II),
An is chlorine or acetate,
n - 2.