Complex compounds substituted imidazoles, showing antidote and antihypoxant activity

 

(57) Abstract:

The invention relates to new chemical compounds, complexes of 1-vinyl - 1-ethylimidazole with zinc and cobalt salts of organic and inorganic acids with the General formula given in the text description. An object of the invention is directed synthesis of complex compounds substituted imidazoles having high protective efficacy in acute inhalation poisoning, carbon monoxide and nitrogen dioxide, as well as pronounced biological activity during hypobaric hypoxia. Found that bis(1-vinylimidazole)Cinescore improves survival in experimental animals acute effects of carbon monoxide up to 67%. Complex 1-ethylimidazole with succinate zinc has a high protective activity to acute effect of nitrogen dioxide, reducing the number of experimental animals that died from toxic pulmonary edema, and increases their survival rate to 75%. Complex 1-ethylimidazole with zinc acetate shows the greatest protective activity in acute hypobaric hypoxia, increases the survival of experimental animals to 83%. 3 C.p. f-crystals, 3 tables.

The invention relates to new chemical soedinenii General formula

,

where

R = C2H3C2H5;

A = Zn(CH3COO)2; Zn(CH2COO)2; Zn(X6H6O6); CoC2,

showing antidote and antihypoxant activity.

Seek medical remedies that are designed to assist personnel of the armed forces and people affected by accidents and disasters chemical etiology, in extreme situations in the chemical, metallurgical, mining and other industries provides for the development of antidotes of carbon monoxide and antidote means that copies the development of toxic pulmonary edema in the administration of substances with oxidising action type.

Know the use to protect the body from damage by nitrogen dioxide glutamic acid (Koperski FK abstract of Cand. Kida. the biological. of Sciences, Kishinev, 1983), glucocorticoids (E. Engelhard-Arzneim.-Forsch 1987, N 5, P. 519). However, these drugs do not provide lasting up to 24 h) effect in a single application that requires multiple injections to maintain the protective effect. The closest properties to the proposed connection is prednisolone (Diller W. F. BGA Schriften, 1986, N 4, p. 301), which odnokratno the th small biological effect and the use of high doses of the drug complicate its use for the affected by nitrogen dioxide. As antidotes of carbon monoxide tried to use compounds of iron, cobalt (Paulet G., Archmalad proff, 24, 426, 1963), which accelerate its elimination from the body. The prospects of the use of zinc compounds in acute poisoning in this poison (EN, 2043998, class C 07 F 3/06, 1995).

The closest properties to the complex compounds of imidazoles, showing antidote activity in acute poisoning carbon monoxide is bis(1-vinylimidazole) zincchloride that after a single intraperitoneal dose of 50 mg/kg reduce mortality by 25.5% compared with the control. Biological activity of this complex is insufficient. Among the complex compounds of imidazoles known complex 1-ethylimidazole with ascorbate zinc (accusol) with antihypoxant activity during hypobaric hypoxia (EN, N 2024514, class C 07 F 3/06, 1994).

An object of the invention is directed synthesis of complex compounds substituted imidazoles having high protective efficacy in acute inhalation poisoning, carbon monoxide and nitrogen dioxide, as well as pronounced biological activity during hypobaric hypoxia.

Found that bis(1-vinylimidazole)Cinescore after a single intraperitoneal administration in equimolar dose equal to 10-4M, which is approximately 1/2 of L16had a reliable protective effect, increasing the survival rate of experimental animals acute effects of carbon monoxide up to 67%. Complex 1-ethylimidazole with succinate zinc has a high protective efficacy for acute exposure to nitrogen dioxide, reducing the number of experimental animals that died from toxic pulmonary edema, and increases their survival rate to 75%. In addition, it significantly increases the body's resistance to developing intoxication hypoxic condition of the body. Its use does not require additional use of other drugs in the treatment of acute poisoning with this poison in the recovery period. Complex 1-ethylimidazole with zinc acetate - bis(1-ethylimidazole)cindicates shows the greatest protective activity in acute hypobaric hypoxia, increasing the survival rate of experimental animals to 83% compared with 7% survival in centroidal)incaccurate complex compound 1-vinyl - 1-ethylimidazole with zinc salts of organic acids and cobalt dichloride can be used as effective antidotes of carbon monoxide and dioxide nitrogen with simultaneous manifestation antihypoxant activity. The method of obtaining these compounds is simple and lies in the interaction of 1-vinyl - or 1-ethylimidazole with salts of the corresponding acid in acetone or acetone-air mixture at room temperature. The output of the complex compounds is 65-90%. Their composition and structure are confirmed by the data of elemental analysis and IR-spektroskopie.

Example 1. Synthesis of complex 1-vinylimidazole with ascorbate zinc.

To a suspension of 0.4 g of zinc ascorbate (synthesis of zinc ascorbate published in the patent N 2024514 (Russia), 1994) in 50 ml of acetone, heated to 35-40oC, poured 0.31 g (0.3 ml) of 1-vinylimidazole. The reaction mixture is stirred for 30 minutes After removing from it the mass of the acetone anhydrous ethyl ether isolated complex of 1-vinylimidazole with ascorbate zinc powder yellow-brown, soluble in water, DMSO. The output of the complex 69% (0,49 g), So pl. 182oC. the Composition of the complex is 2:1 (bis(1-vinylimidazole)Cinescore).

Calculated, %: C 44,92; H 4,21; N 13,1; O 22,46; Zn 15,3.

C16H18N4O6Zn.

Found, %: C 44,09; H 4,06; N 12,5; O 23,4 (by difference); Zn 15,95.

The IR spectrum of the complex contains bands of deformation and out-of-plane fluctuations of the imidazole ring preppy at 1600 cm-1C= O band at 1670 cm-1, OH-band at 3300-3400 cm-1, strip-CH2, -CH-groups in the region 2800-3000 cm-1confirm the occurrence of ascorbate zinc in a complex.

Example 2. Synthesis of succinate zinc.

To a suspension of 0.99 g of zinc hydroxide Zn(OH)2in 40 ml of acetone, heated to 50oC add a suspension of 1.18 g of succinic acid in 30 ml of acetone. The reaction mixture was stirred for 5 h at 50oC. the resulting reaction powder light yellow color is separated by filtration on SCHOTT funnel, washed with acetone, alcohol. Get 2,04 g (94%) succinate zinc in the form of a fine white powder, soluble in hot water, DMSO. Salt contains, wt%: C 26,1; H 2,40; Zn 35,63; O 35,87 (by difference); it So pl. > 300oC.

Calculated, %: C 26,47; H 2,23; Zn 36,03; Of 35.27.

The IR spectrum succinate zinc contains bands at 720, 1310, 1445 cm-1(-CH2group); 1380, 1540 cm-1(-CO-2anion of carboxylic acid).

Example 3. Synthesis of complex 1-ethylimidazole with succinate zinc.

To a suspension of 0.5 g succinate zinc in 30 ml of acetone was added dropwise to 0.53 g (0.51 ml) 1-ethylimidazole in 10 ml of acetone. The reaction mixture is stirred at 35-40oC is Azola with succinate zinc in the form of a white powder, soluble in water and DMSO. The output of the complex 75% (0,77 g), So pl. 198oC. complex 2:1 - bis(1-ethylimidazole)tincalconite.

Calculated, %: C 44,98; H Are 5.36; N 14,99; O 17,17; Zn 17,5.

C14H20N4O4Zn.

Found, %: C 45,25; H 5,24; N Shed 15.37; O 16,51 (by difference); Zn 17,63.

The IR spectrum of the complex contains bands of deformation and out-of-plane fluctuations of the imidazole ring at 660 cm-1in the field of 800-1100 cm-1the band CH3group 1-ethylimidazole at 1380 cm-1. Bands of C=O band at 1580, 1600 cm-1CH2groups in the field of 2900-3000 cm-1confirm the occurrence of succinate zinc in a complex.

Example 4. Synthesis of complex 1-ethylimidazole with zinc acetate.

To a suspension of 1.0 g of anhydrous zinc acetate in 10 ml acetone-ether mixture (1: 1 ml) of 1-ethylimidazole. The reaction mixture was stirred for 2 h at room temperature and then at 0 - 5oC for 30 minutes, Dropped white fine precipitate of the complex 1-ethylimidazole with zinc acetate is separated from the mother liquor over the SCHOTT. The complex is soluble in water, ethanol, DMSO. Output connections 80% (1,61 g), So pl. 110oC. complex 2:1 - bis(1-ethylimidazole)zinmacmat.

The IR spectrum of the complex contains bands of deformation and out-of-plane fluctuations of the imidazole ring at 670 cm-1in the field of 800-1100 cm-1the band of stretching vibrations of C=N group of the imidazole ring at 1520 cm-1the band CH3band at 1380 cm-1confirming the occurrence of the complex 1-ethylimidazole. The band of C=O band at 1690 cm-1indicates the occurrence of zinc acetate.

In the same way was the complex of 1-vinylimidazole with zinc acetate (yield 85%) of the 2:1 - bis(1-vinylimidazole)zinmacmat. It is a white powder with So pl. 103-106oC, soluble in water, ethanol, DMSO.

Calculated, %: C 45,2; H 4,84; N 15,08; Zn 17,6; O 17,28.

Found, %: C 45,2; H 4,84; N 15,41; Zn 18,16; O 16,49 (by difference).

Complex 1-ethylimidazole with cobalt dichloride obtained in the same way in acetone with a yield of 75% in the form of powder lilac color, soluble in water, ethanol. Its so pl. 157oC.

Calculated, %: C 37,22; H 4,94; N 17,4; Co 18,31; Cl 22,03.

Found, %: C to 37.9; H 5,2; N 17,1; Co 18,1; Cl 21,7;

In the complexes of 1-vinyl - 1-ethylimidazole metal salts and the ligand coordinated by nucleophilic N3the atom, which is the highest is the electronic charge, is b is s 1-ethyl - 1-vinylimidazole with chlorides of transition metals (in our case, Co+2and salts of zinc leads to a shift of the bands of stretching vibrations of heterokonta (C=N) in 1495, 1510 cm-1in the short-wave region of 10-20 cm-1and deformation (818 cm-1) 15-25 cm-1. The offset of the valence vibrations of heterokonta to high frequencies while changing the intensity of the bands of deformation vibrations indicates participation unshared pair of electrons N3-atom in the donor-acceptor interaction. All studied complexes of 1-ethyl - 1-vinylimidazole represent Monomeric molecule donor-acceptor type.

To establish the localization coordinate communication used method of PMR spectroscopy with the use of paramagnetic additives (for example, complex VIM NiCl2, AIM NiCl2) [1, 2]. Investigating the dependence of the broadening of resonance lines of the protons of ring temperature in the spectra of 1-ethyl - 1-vinylimidazole clearly demonstrated that the complexation of these ligands is on the N3the atom with the implementation of the N-metal interaction in type. The investigated complexes are powders, to obtain single crystals failed. However, using x-ray crystallography single crystal com is S="ptx2">

Thus, spectral studies confirm the monodentate nature of the substituted imidazoles that coordinate metal ions through the nitrogen atom in the third position of the imidazole cycle.

Example 5. The influence of complex compounds 1-ethyl - 1-vinylimidazole on the body's resistance to acute hypobaric hypoxia.

Hypobaric hypoxia was simulated by raising animals (white mice-males) in the chamber to a height of 9000 m with a speed of 30 m/s, followed by exposure for 10 minutes the Drugs were injected intraperitoneally for 40 min before the start of the experiment in equimolar dose equal to 10-4M/kg, about 0.5 from L16. Control group animals were administered saline in the same volume. Recorded survival rate and the average lifetime of the animals (see table. 1).

Example 6. The influence of complex compounds substituted imidazoles on the body's resistance to the action of nitrogen dioxide.

Toxicity and comparative efficacy of the drug was investigated on white mice-males weighing 18-22, Toxic pulmonary edema with the development of respiratory failure caused by a 60-minute dynamic seed white mice AZ h after priming. The drugs were injected intraperitoneally in the form of aqueous solutions in a volume of 0.1 ml per 10 g of the weight of the animal. Control animals were injected with saline. This route of administration provides rapid absorption of the substance and their entry into the bloodstream, leading to conditions intravenous injection. Toxicity study drug was assessed by the values L50that was calculated by the method of Behrens at 2-week observation of the animals after administration of drugs. The standard error L50was determined using the formula of Gaddam. Criterion protective actions served as indicators of the survival of experimental animals. The introduction of complex compounds substituted imidazoles has improved the survival of experimental animals compared to control (see table. 2).

The results suggest that complex 1-ethylimidazole with succinate zinc has the highest protective effect in relation to nitrogen dioxide. Used for similar purposes (as an antitumor drug) is widely known prednisolone reduces the mortality of mice in the administration of oxides of nitrogen by only 15%.

Example 7. Protective activity of complex compounds 1-ethyl - 1-vinylimidazole when astrocytoma displacement of 0.005 m3and the seed chamber with the volume of 0.45 m3when the concentrations of carbon monoxide 6 g/m3for mice and 9 g/m3for rats, the duration of the 30 minutes the Drugs were administered intraperitoneally in the form of aqueous solutions for 45 min to seed in equimolar doses of 10-4M/kg (see table. 3).

Thus, with sharp blades carbon monoxide greatest antidote activity have a complex compound of 1-vinylimidazole with zinc ascorbate and 1-ethylimidazole with cobalt dichloride.

Sources of information

1. Ravens C. K., Ivlev, Y. N. and other Assignment of the resonance lines in the spectra of the PMR 1-vinyl - 1-ethylimidazole. CHC. 1971. N 10. S. 1416-1420.

2. Ravens C. K., Ivlev, Y. N. and other Paramagnetic shifts in complexes of 1-vinylimidazole with the chlorides of manganese, iron, cobalt, Nickel, copper. CHC. 1972. # 7. S. 994-995.

1. Complex compounds substituted imidazoles of General formula

< / BR>
where if R is vinyl, then A is zinc acetate or zinc ascorbate,

if R is ethyl, A - dichloride, cobalt, succinate zinc, zinc acetate, zinc ascorbate,

showing antidote and antihypoxant activity.

2. Connection on p. 1, where R is vinyl, A - zinc acetate or zinc ascorbate, poeavleaysi is - ignored cobalt, zinc ascorbate or succinate zinc manifesting protective activity in acute action of oxides of nitrogen.

4. Connection on p. 1, where R is ethyl, and A is acetate, ascorbate or succinate zinc manifesting antihypoxant activity in acute hypobaric hypoxia.

 

Same patents:

The invention relates to the field of deep purification of organic compounds, in particular to the purification of alkyl compounds of non-transition elements of groups II-VI of the Periodic system from the admixture of alkyl halide by rectification and improvement of distillation columns for its implementation

-oxyethyl)-2-methyl-5-nitroimidazol] zinc (ii) hydrate exhibiting bacteriostatic activity" target="_blank">

The invention relates to new derivatives of metronidazole [1-(-oxyethyl)-2-methyl-5-nitroimidazol] with bacteriostatic action and finds application in medicine

The invention relates to the field of chemical industry, in particular to a method of obtaining a new water-binding aluminosilicate dispersed systems

The invention relates to the derivatives of alkylpyridine, in particular, to the monohydrate complex of cobalt chloride N-oxide 2-methylpyridine gross formulaYou have received a new chemical compound in ethanol at 25 - 78oWith

The invention relates to a method for dialkyldithiophosphoric phthalo - and naphthalocyanines that can be used as oxidation catalysts, optical and electronic materials

The invention relates to coordination chemistry, specifically to new chemical compound Bi c(2-ethylhexanoate(bis(Triethylenetetramine)cobalt (II), General formula:

< / BR>
shows the properties of a stimulator of hematopoiesis KAT-122) kat -122 by its effect exceeds the effect of Hamida

The invention relates to the field of production of fluorinated polymers

-oxyethyl)-2-methyl-5-nitroimidazol] zinc (ii) hydrate exhibiting bacteriostatic activity" target="_blank">

The invention relates to new derivatives of metronidazole [1-(-oxyethyl)-2-methyl-5-nitroimidazol] with bacteriostatic action and finds application in medicine

The invention relates to medicine, in particular to the treatment of polielementnom in patients with clinical manifestations of zinc States

The invention relates to medicine and for the production of the antidote

FIELD: organic chemistry, medicine, dermatology.

SUBSTANCE: invention relates to zinc and aliphatic halogen-carboxylic acid salts that can be used in treatment of benign neoplasms of skin and visible mucosa tissues. Invention proposes the following formula of zinc and aliphatic halogen-carboxylic acid salts: (1): wherein R means -CHal3, -CHHal2, -CH2Hal and (2): wherein R' means Alk, hydrogen atom (H); R'' means Hal; R' means Alk; R'' means H, Alk wherein in these formulae halogen atom can be represented by fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J). Invention provides the development of original preparation used in treatment of benign neoplasms of skin and visible mucosa tissues with low toxicity, rapid effect, expressed therapeutic effect and eliciting good tolerance, absence of complications in treatment, healing without formation of scar tissue. The development of the preparation provides expanding assortment of agents used in treatment of such diseases.

EFFECT: enhanced and valuable properties of agents.

13 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with applying a multi-purpose complex preparation that contains the following components in 1 l of distilled water: sodium selenite 1.0; vitamin E/in the form of combinal E/7500 mg; succinic acid 10.0; zinc sulfate 10.0 and pharmazine 50000 U. The preparation should be introduced as intramuscular injections 45, 30, 15 d before delivery and during the day of delivery: in cows per 10-15 ml, for pigs and sheep per 5 ml, for youngsters after the birth: in calves - 5 ml, in piglets and lambs per 1-2 ml, in hens per 0.5 ml once/2 wk. The innovation is very efficient in increasing the quality and quantity of production, improving the growth and development in fetus and offspring, preventing some surgical and obstetric-gynecological pathologies.

EFFECT: higher efficiency of correction.

5 cl

FIELD: veterinary science.

SUBSTANCE: invention relates to a composition used in prophylaxis and treatment of anemia in agricultural animals and poultry that comprises a mixture of chelates of iron, copper, zinc, cobalt, sodium, calcium with ethylenediamine-N,N'-disuccinic acid in the following ratio of components, wt.-%: copper chelates with ethylenediamine-N,N'-disuccinic acid, 0.45-0.60; zinc chelates with ethylenediamine-N,N'-disuccinic acid, 1.40-1.45; cobalt chelates with ethylenediamine-N,N'-disuccinic acid, 0.075-0.08; sodium chelates with ethylenediamine-N,N'-disuccinic acid 42.0-44.0; calcium chelates with ethylenediamine-N,N'-disuccinic acid, 12.0-13.0, and iron chelates with ethylenediamine-N,N'-disuccinic acid, the balance. Agent provides enhancing the blood hemoglobin content in animals by 28% as compared with animals receiving neither anti-anemic agents and by 12% as compared with animals receiving the preparation-analog.

EFFECT: enhanced effectiveness of composition.

4 tbl, 4 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with obtaining compositions being of bactericidal, antiphlogistic, regenerating, antioxidant and antimicrobial properties at no allergic action. Wound-healing preparation (variant 1) contains: stearic acid 4.5-6.0; purified lanolin and its derivatives 3.0-6.0; vegetable oil 3.0-5.0; Vaseline 1.5-2.5; glycerol 4.0-8.0; castor oil 8.0-12.0; zinc stearate 1.0-2.5; 70%- alcoholic extract of phytospecies 2.5-3.5; extract of common John's wort grass 3.5-8.5; dog rose oil or sea buckthorn oil 2.6-6.0; Na-salts of fatty acids of wool fat 0.3-0.6; triethanolamine 0.7-1.1; anesthesin 2.0-3.0; 10%-butyric solution of propolis 0.3-1.0; boric acid 0.4-0.6; purified water - the rest. Wound-healing preparation (variant 2) contains: stearic acid 4.5-6.0; purified lanolin and its derivatives 3.0-6.0; vegetable oil 3.0-5.0; Vaseline 1.5-2.5; glycerol 4.0-8.0; castor oil 8.0-12.0; zinc stearate 1.0-2.5; 70%-alcoholic extract of phytospecies 2.5-3.5; extract of common John's wort 3.5-8.5; dog rose oil or sea buckthorn oil 2.6-6.0; Na-salts of fatty acids of wool fat 0.3-0.6; triethanolamine 0.7-1.1; anesthesin 2.0-3.0; levomycetin or gentamycine 2.0-3.0; 10%-butyric solution of propolis 0.3-1.0; boric acid 0.4-0.6; purified water - the rest. Additional introduction of the extract of common John's wort has increased antioxidant properties; 10%-butyric propolis - antioxidant and bactericidal properties, and levomycetin and gentamycine - has widened the range of antimicrobial action. Application of the preparation suggested in patients with burns and wounds revealed positive therapeutic effect without any cicatricial neoplasms and allergic action. No contraindications had been established.

EFFECT: higher efficiency of application.

4 cl, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to application of Acizol, namely bis(1-vinylimidazole) zinc diacetate as coronary active anti-ischemia and anti-arrhythmia agent. Acizol makes it possible to limit development of necrosis zone in acute myocardium ischemia, to reduce frequency of complications and fatal cases, to normalize antrioventricular and intraventricular electrical conductivity , to prevent ciliary arrythmia.

EFFECT: improved anti-ischemia and anti-arrhythmia agent.

15 tbl, 7 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: method involves administering Acizol (bis1-vinyl imidazole zinc diacetate).

EFFECT: stable remission; improved bone tissue resorption in postoperative period; accelerated periodontium tissue recovery.

3 dwg, 3 tbl

FIELD: chemical-pharmaceutical industry, metalloorganic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to polyacrylic acid incomplete zinc salt corresponding to the formula: (-CH2-CHCOOH-)n(-CH2CHCOOZn0.5-)m wherein n = 12000-35000; m = 1650-6650 wherein the content of zinc is (6-8 wt.-%) 0.0009-0.0012 g-at, the content of carboxyl groups is 0.0117-0.0122 g-equv/1 g of polymer, and molecular mass is in the limits 1000000-3000000 Da. Also, invention proposes a method for preparing this salt that involves addition of zinc acetate aqueous solution to polyacrylic acid solution, stirring the reaction mixture for 120-300 min and drying the prepared solution under vacuum at temperature 50°C, not above. Agent is prepared as a solution in the ratio 1-10 g of polyacrylic acid incomplete zinc salt in 100 ml of water. Agent shows antiseptic, hemostatic and wound-healing effect in its external using.

EFFECT: improved preparing method, valuable medicinal properties of agent.

3 cl, 1 tbl, 4 ex

Up!