Tetrakis-(l-histidine)--peroxidizability (iii) heptahydrate, showing antianemic, radioprotective and anti-arrhythmic activity

 

(57) Abstract:

The invention relates to new chemical compound, namely, tetrakis-(L-histidinate)--peroxidizability (III) the heptahydrate formula Co2(His)4O27H2O. the Aim of the invention is the finding of a new amino acid complex of cobalt with Antianemic, radioprotective and anti-arrhythmic activity. During pharmacotoxicological tests established that tetrakis-(L-histidinate)--peroxidizability (III) heptahydrate is low-toxic compound that exhibits anti-anemic, radioprotective and anti-arrhythmic activity and does not stimulate tumor growth. 20 table.

The invention relates to new chemical compound, namely, tetrakis-(L-histidine) -peroxidizability(III) the heptahydrate formula Co2(His)4O27H2O showing Antianemic, radioprotective and anti-arrhythmic activity and can find application in medical practice.

Despite the fact that the compounds histidinate complexes of cobalt (II) with dioxygen is well known as a reversible oxygen carriers in solutions [Sundberg, R. J. , Martin R. B. Interactions of histidine and other imidazole derivativ 1978. - T. 2. - S. 71], select them in crystalline form still failed. Here for the first time synthesized in crystalline form of the compound of the formula Co2(His)4O27H2O. a Connection similar to this composition and indication for use, not described.

In the available literature there is no information about amino acid complexes of cobalt, manifesting at the same time Antianemic action antiarrhythmic activity and radioprotective properties comparable or superior to those properties of the reference drugs. Patented bis(2-ethylhexanoate)bis(Triethylenetetramine)cobalt(II) (KAT-122) as a stimulator of hematopoiesis [Patent 2078767 (RU). MKI56 07 F 15/06]. Bis(2-ethylhexanoate)bis-(Triethylenetetramine)cobalt(II) showing the properties of a stimulator of hematopoiesis [Tolstikov, A. , Murinov Y. I., concina I., and others, Publ. 10.05.97, bull. N 13]. Described moderately positive influence of a complex of cobalt(II) with methionine on postradiation recovery of hematopoiesis in rats [Salihojaev 3., Atabay T. A. , Sadykov N. D., Rahimov I. T. Stimulation of postradiation recovery of hematopoiesis in rats drug cobalt/ Radiobiology. - 1991. , 31, N 6. - S. 835-837]. Known cobalt containing medicines with antianthrax trace elements with bioactive substances. Ed. 2-E. - Tashkent: Medicine, 1969. - S. 127-187], and cyanocobalamin (vitamin B12) [Mashkovsky M. D. Drugs: a DSS. Ed. 12-E. - M.: Medicine, 1993. - 4.2. - S. 18 - 21]. However, Hamid is a moderately toxic compound has a low therapeutic breadth and ineffective radiation lesion of the blood. On the other hand, ciankobalamin, being highly Antianemic drug that can stimulate tumor growth [Ostryanina A. D., Neumann, I. M. the Effect of vitamin B12on the induction of skin tumors in mice// Pathol. Fiziol. and experimental. therapy. - 1971. -N 1. - S. 48-53; Belousov Y. B. Moiseev, B. C., Lepakhin C. K. Clinical pharmacology and pharmacotherapy. - M.: The Universe, 1993.- S. 309-310], which limits its use for the correction of anemia in cancer patients. In addition, when using ciankobalamin in individuals with ischemic heart disease may experience pain in the heart, tachycardia [Mashkovsky M. D. Drugs: a DSS. Ed. 12-E. - M.: Medicine, 1993. - 2 hours. -S. 18-21].

The aim of the invention is the finding of a new amino acid complex, cobalt, has both anti-anemic, radioprotective and antiarrhythmic activity.

The objective is achieved by the synthesis of tetrakis-(L-histidines, radioprotective and anti-arrhythmic action. Connection get the reaction of cobalt (II) dichloride with L-histidine (HisH), oxygen and lithium hydroxide in aqueous medium

2CoCl2+ 4HisH + O2+ 4LiOH = Co2(His)4O2+ 4LiCI + 4H2O

followed by crystallization from water-ethanol solution at a temperature below 0oC.

Example 1. In chemical glass poured about 40 ml of distilled water, placed hanging 3.10 g (0.02 mol) of L-histidine and 0.84 g (0.02 mol) of the monohydrate of lithium hydroxide. After dissolution hanging add a solution of cobalt(II) dichloride (0.01 mol) and the total solution is brought to 50 ml With prolonged stirring, the pH value of the environment support equal to 7.0 additives drops of HCl or LiOH. Then to the solution was added with stirring 150 ml of 96% ethanol. The obtained brown solution was placed in the freezer of the refrigerator for 1 hour. The precipitation is filtered through a Buchner funnel and dried at a temperature of 40oC. For recrystallization of the precipitate 0.30 g dissolved in 25 ml of distilled water, and then add 100 ml of 96% ethanol. The resulting solution was placed in the freezer of the refrigerator for 3 days. The resulting Chris small needle crystals, diamagnetic, soluble in water, soluble in dimethylsulfoxide, and insoluble in ethanol, acetone, acetonitrile.

The product yield is 27% of theoretical.

Found, %: C 31.69; H, 5.27; N, 19.22; 13.72.

Calculated for Co2(His)4O27H2O,%: 32.30; H, 5.19; N, 18.83; Co 13.21.

According to the results of the elemental analysis of the obtained substance can be attributed to the formula C24H46N12O17Co2. The structure of the compound was confirmed by means of thermogravimetry. On thermogravimetric curve at 105oC finds the first space corresponding to the loss of 14.8% by weight or 7 hydrate molecules H2O (Teoret. 14.13% of the weight), and at 150oC - the second space corresponding to the loss of a further 4.1% weight or one molecule O2(Teoret. 3.59% of the weight). The oxidation of Co(III) certified by the diamagnetism of solutions Co2(His)4O27H2O, and also the characteristic brown color of them, due to the band charge transfer from the bridging peroxide ion (O22-) to Co(III) with a maximum at 370 nm [Sundberg, R. J. , Martin R. B. Interactions of histidine and other imidazole derivatives with transition metal ions in chemical and biological systems// Chem. Rev. -1974. - Vol. 74, No 4. - P. 509]. As determined by the method of AGEIA, 1978. - 220 S.], adding nitric or perchloric acid to the compound Co2(His)4O27H2O all contained in the cobalt goes into solution as a paramagnetic ion With2+that confirms the functioning of the Co2(His)4O27H2O as a reversible carrier of oxygen. The substance undergoes thermal decomposition without melting at temperatures up to 320oC.

During pharmaco-Toxicological studies defined the parameters of acute toxicity of the compounds of Co2(His)4O27H2O for mice and rats, it Antianemic, radioprotective and anti-arrhythmic activity in experiments in vivo.

Example 2. Parameters of acute toxicity of the compounds of Co2(His)4O2(later in the calculations of hydrated molecules of H2O do not count) was determined after a single intraperitoneal injection of aqueous solutions of the drug on line mice Balb/C57both sexes average weight 200.7 g of white and non-linear rats-females average weight 24020.0, observation of the animals were within two weeks. Median lethal dose (Dl50) was determined by the method of Behrens, its average error according to the formula of Heddema [Belenky, M. A. Elements of quantitative OC the drug caused 3-5 minutes after the injection of short hyperemia of the ears and limbs, General oppression, ptosis, catalepsy, breathing problems, and seizures. The death of animals came in one day from respiratory depression. Urine was the color of the drug. At showdown - plethora lung, heart, and other visible change is not detected.

Parameters of acute toxicity of the preparation are shown in table. 1. The medium lethal dose for mice is 225 mg/kg, and in rats of 300 mg/kg Thus, the oxygenated histidinate cobalt refers to toxic substances according to the classification Sidorov [Izmerov N. F., Sanotski I. C., Jones, K. K. Parameters toxicometric industrial poisons in a single exposure. - M. : Medicine, 1977. - S. 196 - 197] and exhibits species specificity: mouse more sensitive than rats. The proposed connection of cobalt is less toxic than drugs comparison - Hamid [Patent 2078767 (RU). MKI56 07 F 15/06]. Bis(2-ethylhexanoate)bis- (Triethylenetetramine)cobalt(II) showing the properties of a stimulator of hematopoiesis [Tolstikov, A., Murinov Y. I., concina I., and others, Publ. 10.05.97, bull. N 13; Matkovskiy K. L., Balan N. A., Batyr D., and others studying the biological activity of dioxidine cobalt(III), Izv. Academy of Sciences of the mold. SSR. Ser. Biol. and chem. Sciences. - 1969. - #4. -C. 3-5] and KAT-122 [Patent 2078767 (RU). MKI56 07 F 15/06. The G. A., Murinov Y. I., concina I., and others, Publ. 10.05.97, bull. N 13] (table. 1).

Example 3. Antianemic activity of the drug was evaluated in 48 rats of both sexes with hemolytic anemia induced by phenylhydrazine. Anemia was modeled in rats subcutaneous once daily for 4 days by the introduction of a 0.9 % solution of hydrochloric acid phenylhydrazine in a dose of 30 mg/kg [Lazarev N. Century Reproduction diseases in animals for experimental and therapeutic research. - L.: Medgiz, 1957. - S. 296-312].

On the 6th day of the experiment started 4 times a day intraperitoneal administration to rats oxygendemanding histidinate cobalt at a dose of 30 mg/kg, which corresponds to 1/10 DL50drug. Drug comparison ciankobalamin was administered in a dose corresponding therapeutic 0.0015 mg/kg, in a similar way. Blood sampling was made from the tail vein of rats before treatment, after treatment and one week after its completion. Counting the number of red blood cells was carried out according to the standard technique, the hemoglobin content was determined by calorimetric method using standard reagents. The experimental results are processed statistically by the indirect method of difference.

As can be seen from the table.2,3,4, Kastela at 29.1% and a decrease in the number of peripheral blood erythrocytes by 11.8% to 13 days of the experiment compared with values in healthy animals. Course introduction of the new compounds of cobalt promoted normalization of these parameters. Drug comparison ciankobalamin inferior in its performance investigated the connection: the content of hemoglobin in the peripheral blood of treated rats remained reduced compared with values in healthy animals at the end of treatment (table.2,3,4). Treatment coamidum animals with phenylhydrazine anemia also did not lead to the full restoration of hemoglobin to the original [I. Popova Y., Tolstikova So on, Lazarev A. N., Saudi F. C. the Effect of complex compounds of cobalt in experimental anemia// Pathology of respiration, blood and regulate body systems and principles of correction of violations. Proc. Dokl. XIII scientific, proc. patofiziologiv of the Urals. - Izhevsk, 1989. - S. 84].

Example 4. Evaluation of the effectiveness oxygendemanding histidinate cobalt when gipoplasticheskaya anemia were performed on model lead anemia [Lazarev N. Century Reproduction diseases in animals for experimental and therapeutic research. - L.: Medgiz, 1957. - S. 296-312; Yaverbaum P. M., Skvortsova R. C. , Skrabakova L. M., Kurylev A. C. Physico-chemical characteristics of membranes of erythrocytes in the process of developing anemia, simulated introduction is used 40 rats of both sexes, have anemia simulated daily subcutaneous single introduction within 7 days 50 mg/kg of lead nitrate. Treatment animals were started on the next day after the termination of the injection of lead nitrate. A new connection cobalt and vitamin b12was administered intraperitoneally at a dose of 30 mg/kg and 0.0015 mg/kg, respectively 8 times a day. Study of peripheral blood of untreated (control) and treated (experimental) animals was performed immediately after priming and after 10, 15, 25 and 50 days after the last injection of lead nitrate. Some experimental results are presented in table. 5-7.

Immediately after the end of the course introduction to animals of lead nitrate in the control rats developed anemia, accompanied reliable decrease in the number of peripheral blood erythrocytes in all periods of observation with the restoration of this indicator to 25 days after priming. The hemoglobin content was reduced by only 15 days, but remained lower than in healthy animals even 50 days after the introduction of lead salts. Change the color of the indicator control rats were differently. So, 5 days after priming it was higher than in healthy animal is the compounds of cobalt promoted the normalization of the number of erythrocytes in the peripheral blood of the experimental rats immediately after treatment (15 days after priming), as well as the hemoglobin is 50 days after priming, and the color indicator on the 25th day after the seed though and was lower than that in the intact animals, but exceeded the control by 20.6%.

In the group of animals treated with the drug comparison12only on the 5th day there was a reliable increase in the number of peripheral blood erythrocytes, on the rest of the observation period, this figure did not differ from that of untreated animals. The hemoglobin content was significantly lower than in the group of healthy rats throughout the experiment. Thus, a new drug cobalt effective model gipoplasticheskaya the anemia of lead nitrate on which the reference product cyanocobalamin was less active.

Example 5. Antianemic action of the studied complex of cobalt was estimated in experiments at 60 outbred rats of both sexes weighing 18020 g the effect on the blood system after radiation exposure. For modeling radiation sickness animals from the control and experimental groups were subjected to a single total - irradiation at a dose of 4.5 Gy on the Agat-M (60With dose -0.504 Gy/min). Animals of the experimental group with 3 d which corresponds to 1/20 DL50. The peripheral blood counts (number of erythrocytes, hemoglobin, reticulocyte count, hematocrit, color index, the average amount of hemoglobin in the erythrocyte (PG/er), the average concentration of hemoglobin in the erythrocyte (%), the average volume of erythrocytes (μm3)) and total cellularity of the bone marrow of the animals were evaluated in the dynamics of the conventional methods. The results of the experiments are presented in table. 8-14.

As can be seen from the table. 8-14, on the third day after irradiation in the control group of animals were recorded decrease in the number of peripheral blood leukocytes and the total number of bone marrow cells, and on the eighth day has evolved irradiation anemia with subsequent restoration cellularity of the bone marrow to the 18-th day after irradiation without complete normalization of peripheral blood. Treatment new connection cobalt rats subjected to radiation exposure, resulted in normalization investigated and determined by calculation of peripheral blood 4 days after its completion (table. 8-14). The overall cellularity of the bone marrow of treated animals were significantly higher than that in control group at 40.6% (table.9).

Thus, the s T. A., Sadykova N. D., Rahimov I. T. Stimulation of postradiation recovery of hematopoiesis in rats drug cobalt// Radiobiology. - 1991. , 31, N 6. - S. 835-837] complex of cobalt(II) with methionine also had a positive impact on the course of acute radiation sickness in rats subjected to a single exposure at a dose of 4.5 Gy in the x-ray apparatus RUM-17 dose of about 1 Gy/min, However, the content of hemoglobin in the peripheral blood of the experimental animals was lower than the control throughout the experiment.

Example 6. Assessment Antianemic and radioprotective activity oxygendemanding histidinate cobalt in comparison with ciankobalamin conducted on the model of post anaemia in rats. In the experiments used 76 nonlinear white rats-males average weight 15520 g whose anemia was called total-irradiation at a dose of 4.5 Gy on the Agat-M (60Co., dose - 0.444 G/min). In parallel was estimated radioprotective properties of drugs. Animals, starting from the third day after irradiation, began to enter the drugs once intraperitoneal through day four: oxygendemanding histidinate cobalt at a dose of 6 mg/kg (1/50 from DL50and ciankobalamin dose of 0.0015 Itow, hematocrit, color index, the average amount of hemoglobin in the erythrocyte (PG/er), the average concentration of hemoglobin in the erythrocyte (%), the average volume of erythrocytes (μm3)) and total cellularity of the bone marrow of the femur animals were evaluated in the dynamics before and after treatment, one week and two weeks after its completion by the conventional methods, the survival of rats after irradiation was determined by the method of Fisher. Comparative evaluation of radioprotective activity of a compound with the reference drug casamino was not conducted because the latter was not studied therapeutic and prophylactic protective effect during irradiation. The most significant results are presented in table. 15-17.

After irradiation the animals of the control group recorded a significant decrease in the number of red blood cells by 45%, hemoglobin - 31.9% without changing the color of the indicator, the overall reduction in cellularity of the bone marrow to 79.9% with subsequent restoration to 18 days after exposure without complete normalization of peripheral blood (table. 15-17). Treatment the drug of cobalt resulted in increase in the number of erythrocytes in 33.8% immediately on its completion, compared with control, whereas EFTA dose, the corresponding 1/50 DL50not affect the content of hemoglobin in the peripheral blood as compared to untreated animals, but the latter was 78.5 % higher than that immediately after treatment in the group of animals treated with ciankobalamin (PL. 15-17).

Thus, Antianemic activity oxygendemanding histidinate cobalt manifested at an earlier time than the comparison drug12namely directly after the end of treatment.

It should be noted that in the experimental group of animals subjected to radiation and treated with the new connection cobalt, from 18 animals, none were killed, and in the group of animals treated with ciankobalamin, killed three of the 18 rats in the control (irradiated and untreated) group - four of the eighteen. The estimates of survival statistical method Fisher showed that the new drug of cobalt in 1/50 DL50reliably protects animals from death in the total-irradiation compared to control (P=0.05), vitamin B12dose of 0.0015 mg/kg not have a radioprotective effect (P=0.11), and used the dose causes death 22.2% of male rats weighing 150 g (P=0.04).

Thus, oxygenated Evie.

Example 7. The impact of the new complex compounds of cobalt on tumor growth was studied in 40 outbred rats females with inoculated intraperitoneally tumor of the ovary. Daily intraperitoneal administration of the drug at a dose of 30 mg/kg for 7 days was started one day after inoculation of ascitic fluid, control animals received distilled water in equival. At the end of the experiment measured the volume of ascitic fluid in the abdominal cavity of rats. It is established that the preparation of cobalt had no effect on tumor growth, the average volume of ascitic fluid in the control animals was 19.61.7 ml, and in the experimental group - 16.90.9 ml (P>0.05).

Thus, in contrast to the comparison drug - ciankobalamin, which are not recommended for cancer patients, as it can stimulate the growth and metastasis of tumors [Ostryanina A. D., Neumann, I. M.

The influence of vitamin B12on the induction of skin tumors in mice// Pathol. Fiziol. and experimental. therapy. - 1971. - N 1. - S. 48-53; Belousov Y. B. Moiseev, B. C., Lepakhin C. K. Clinical pharmacology and pharmacotherapy. - M.: The Universe, 1993. - S. 309-310], the oxygenated histidinate cobalt does not affect tumor growth.

Example 8. P is particularly adrenaline model arrhythmias in mice [E. N. Moore, Spear J. F. Acute animal models for the study of antiarrhythmic drugs for the prevention of sudden coronary deat// Clin. Pharmacol. Antiarrhythmic Therapy. -New York, 1984. - P. 31-46]. In the experiments used 33 mouse.

Antiarrhythmic activity oxygendemanding histidinate cobalt and drug compare inderal (obsidian) were evaluated for their ability to prevent the appearance of premature ventricular complexes or reduce their severity, which was reflected in a decrease in the frequency of ectopic contractions (BSEC). In addition, they evaluated the ability of the investigated substances to prevent death of mice caused by the introduction of epinephrine hydrochloride. Compounds were injected into the tail vein 5 minutes before injection analyzer, the solution of which does not exceed 0.5 ml. the Results are presented in table. 18, which shows that the new complex compounds of cobalt in the dose of 10 mg/kg completely warned the death of animals and significantly reduced the risk of adrenaline arrhythmias, than it differs from the comparison drug.

Example 9. Antiarrhythmic activity of new complex compounds of cobalt studied the effect on heart rhythm disorder caused by intoxication strophanthin [Herzenstein E. I., S. Lemkin, M. Cardiotoxicity of stray heart failure //bul. the experimental. biology and wedge. medicine. - 1984. -N 6.- S. 683-686]. The experiments were carried out on 32 mice.

In 100% of cases through 617 with after intravenous strofantina To the dose of 10 mg/kg recorded heart rhythm disturbances, which were in the nature of group and paired PVCs, ventricular paroxysmal tachycardia with BSEC 11013 per minute at total HR 45623 min and duration 14412 C. All animals of the control group died. The proposed connection cobalt fully warned appearance strofantinom arrhythmias and mortality of animals, excelling on the effectiveness of the Comparators obzidan and lidocaine (PL. 19).

Example 10. Antiarrhythmic activity of the new compounds of cobalt was estimated by the effect on ventricular fibrillation in mice induced by the intravenous injection of calcium chloride [Malinow, M. R., F. F. Battle, Malamud Century Prevention of neurogenio ventricular arrhythmias blocking drugs// Amer. J. Physiol. - 1953. - Vol. 175, No 1. -P. 8-10]. In our experiments we used 38 mice. The results of the evaluation of the effectiveness of the compounds of cobalt in comparison with beta-blocker-obsidiana and a blocker of Ca-channels panoptikum model chloralkali arrhythmia in mice are presented in table. 20.

As can be seen from the table.20, new soedineniya bradycardia 62% of the animals. On protivopellargnoe activity and the ability to prevent the death of experimental animals a new connection cobalt excelled in this model, the Comparators.

Therefore, a new connection cobalt at a dose of 10 mg/kg shows a pronounced antiarrhythmic effect in models of adrenaline, strofantinom and chloralkali arrhythmias and more efficient compared to all the Comparators.

Thus, the oxygenated histidinate cobalt is toxic compound exhibiting simultaneously Antianemic, radioprotective and anti-arrhythmic action. A new connection cobalt comparable or superior in effectiveness Comparators.

Tetrakis-(L-histidinate)--peroxidizability (III)heptahydrate formula

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showing Antianemic, radioprotective and anti-arrhythmic activity.

 

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