Bis-(2-ethylhexanoate)bis(triethylenetetramine) cobalt (ii) showing the properties of a stimulator of hematopoiesis

 

(57) Abstract:

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 Comida. Stimulates bone marrow erythropoiesis and encourages earlier regeneration of red and white blood cells. 6 Il.

The invention relates to coordination chemistry, specifically to new chemical compound of General formula:

< / BR>
shows the properties of a stimulator of hematopoiesis. The specified connection and its properties are not described in literature.

Known similar structure

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Connection decaocto(Triethylenetetramine)cobalt (II), formed by the interaction of cobalt (II) with Triethylenetetramine (THETA) [1]

Known for a similar purpose preparation "Hamid", which is a complex compound of chloride of cobalt with Amida nicotinic acid - dichlorobis(nicotinamide)cobalt (II) [2]

< / BR>
It is used when posthemorrhagic, hypochromic anemia caused by radiotherapy and defeat anitation fast regeneration of the red growth of bone marrow;

2. in some cases, insufficient hemoglobinuria erythrocytes;

3. Poorly marked effect in normalizing the blood picture after radiation damage.

To solve this problem, synthesized a new coordination compound of cobalt bis(2-ethylhexanoate)bis(Triethylenetetramine)cobalt (KAT-122), the General formula:

< / BR>
N registration 10591294

"KAT-122" get in terms of the known method [1] by reacting 2-Telehansa.net cobalt (II) with Triethylenetetramine in an ethanol medium, after removal of the solvent, washing and drying receive bis(2-ethylhexanoate)bis(Triethylenetetramine)cobalt (II) in the form of a powder reddish-brown color, with TPL=84,0oC, which is moderately soluble in water, alcohols, acetone, bad in non-polar solvents. Output 94,1% Acute toxicity of bis(2-ethylhexanoate(di(etilendiamin) cobalt were determined in rats by Cerberus with intramuscular injection. (see tab. 1).

The connection belongs to the 3rd class of toxicity and is moderately hazardous substance classification K. K. Sidorov [3]

Erythropoiesis stimulating (ED50action connection KATH-122 was determined graphically by the dependence "dose-effect" [4] to change to snasti dose of 0.45 G/min) (see table. 2).

From the table it follows that KAT-122 causes pronounced position in the number of erythrocytes already on the 6th day (11.9 million class. mm3), while the increase in this indicator in the group treated "Hamid", required a longer period of time. On day 14, the number of red blood cells in the group treated "Coamidum", 8.5 mol. CL mm3in the group treated with KAT-122 14.1 million class. mm3. In total dose infusion "KAT-122" and "Hamid" was 66 and 107 mg/kg, respectively. In this connection KATH-122 1.7 times the active Hamida, therapeutic range of more than 3.8.

The effect of compounds KAT-122 on the course of experimental posthemorrhagic anemia were studied for changes of peripheral blood: hemoglobin and hematocrit, erythrocytes, reticulocytes and leukocytes, and leukocyte formula.

The number of erythrocytes and leukocytes were counted in the Goryayev camera according to the standard technique. The concentration of hemoglobin was determined by hemoglobin-laminim method using standard reagents. Hematocrit was determined in heparinized capillaries after centrifugation in MCG-8 at 8.000 rpm 6 min Reticulocytes were identified the indicators of time of maturation of reticulocytes in the intensity of erythropoiesis [5,6]

Posthemorrhagic anemia played dosed bloodletting in rats from retroorbital sine and sublingual veins to the standard technique [7]

Observations were conducted in 2 series of experiments for 25 and 35 days. Comparison of the changes of peripheral blood was performed relative to the values observed on the day after playing anemia (100%), group 1 rats received compound KAT-122, II-group drug Hamid, group III served as control. The drugs were administered intramuscularly in a day, during the whole experiment in the doses indicated in Example 3.

Connection KATH-122 contributed to a significant increase in hemoglobin level during all days of observations regarding the influence of Hamida and control group rats (p<0,001), whereas in groups 2 and 3 and 35 days this indicator remained below baseline values by 15% and 19%, respectively (Fig. 1). Hematocrit under the influence of KAT-122 on the 7th (165%) and 15th (176%) day significantly (p<0,001) exceeds the value with the introduction of Hamida (149% and 157% for 7 and 15 days, respectively) and in untreated rats (152% and 168% for 7 and 15 days, respectively). The nature of the changes in the number of erythroid cells in blood stream after blood loss corresponds to those of the NGOs, the surge in the number of reticulocytes with a reduction to 14 days after anemizatsii (Fig. 2).

The intensity of erythropoiesis (table. 3) with the introduction of KAT-122 remained above baseline at 7 and 14 days. In all groups there was a slow maturation of reticulocytes.

The change in the number of cells (Fig. 3) is of an undulating character with a peak at 14 and 35 days of experiment. Connection KATH-122 promotes a significant increase in the number of leukocytes and content of neutrophils and monocytes throughout the experience.

A sharp reduction of the time of maturation of reticulocytes and increased erythropoiesis in groups 2 and 3 to the 25-th day of the experiment (tab. 3) in combination with corresponding data on hemoglobin content (Fig. 1), proves ineffective erythropoiesis in animals of these groups, the prevalence of immature forms of red blood cells. At the same time, in the 1st group increased erythropoiesis is accompanied by intensification of the process of entering the bloodstream of viable red blood cells (PL. 4).

Thus, the connection KATH-12 on the background of acute blood loss stimulates the process of regeneration of blood earlier in relation to lamido and untreated rats.

60Co., the dose of 0.45 G/min) on the device "ROCUS-M".

The effect of compounds KAT-122 relative to Hamida in blood was estimated by the change of peripheral blood counts (hemoglobin, hematocrit, the number of erythrocytes/ reticulocytes, white blood cells) and bone marrow (erythroblastosis Islands) at 3, 7, 14, 21 and 30 days after irradiation. The definition of the above indicators was carried out according to standard techniques described in example 4.

The number and morphological identification erythroblastosis Islands (EA) was performed according to the method of isolated EA [8, 9, 10]

Compounds were administered in a therapeutic mode intramuscularly every other day at a dose equal to U50after a single dose. Group 1 animals were administered the test compound KAT-122, group 2 Hamid, group 3 rats served as a control.

The impact of ionizing radiation on the 3rd day after irradiation caused a decrease in the number of cells to 2.5 and 3 thousand cells/Ál in the 3rd and 2nd groups of rats, respectively. The number of leukocytes in 1 group is 5.5 thousand cells/Ál (p<0,001). By day 30, this figure was approaching baseline values (13.9 thousand cells/ml) in the 1st group it was equal to 12.1 thousand cells/ml that s is/Ál. The connection KATH-122 inhibited the decrease of white blood cells and stimulated a rapid recovery to normal values. All indicators of red blood in the treatment of rats connection KATH-122 in all the follow-up period were significantly higher than those in the 2nd and 3rd groups of animals (p<0,001). In the 1st group the increase in hemoglobin was held at a higher rate and its level was fully restored to the original data (144 g/l) to 30 days (p<0,01), whereas at this time the values in the 2nd and 3rd groups, respectively, constitute 108 (p<0.02) and 100 g/L. KATH-122 preventing the drop of hematocrit (47%) (p<0,01), relative to the original values (44,2%) (3-day). The value of this index in the 2nd and 3rd groups at this time were respectively 43% and 41% during the experiment, the increase in hematocrit in group 1 was superior to that of the compared groups, and 30 day 1, 2, 3 groups were, respectively, 54, 52, 3, and 45% Differences in groups 1 and 2 compared to the control are significant.

The test compound was also prevented the decrease in the number of erythrocytes and reticulocytes (Fig. 4, 5) after irradiation and contributed to their increase during the observed period. Growth of cells was accompanied by a corresponding Aveley, observed in the bone marrow of rats. Already on day 3 after irradiation the number erythroblastosis Islands (EA) of the bone marrow in the 1st group was significantly higher than in intact rats and significantly higher than that of (p<0.001) in animals 2 and 3 groups (Fig. 6). In the control there was a significant and persistent inhibition of erythropoiesis during the entire observation period. The introduction of Hamida kept reducing the number of EO in the early days (Fig. 6), but 30 day their numbers have not recovered.

The essence is illustrated by examples of specific performance.

Example 1. Obtaining bis(2-ethylhexanoate) bis(Triethylenetetramine)cobalt (II). To a solution in ethanol 3,47 g (0,01 mol) 2-ethylhexanoate cobalt (II) is added under stirring of 2.92 g (0,02 mol) of Triethylenetetramine, then when ponie. the pressure and t 50 60oC remove the solvent, washed and dried the resulting substance. The yield of the target product of 5.84 g (91,4%) powder reddish-brown color. Melting point 84oC. sparingly soluble in water, alcohols, acetone. Bad in non-polar solvents.

According to elemental analysis

Found: C 53,01; H 10,24; N 17,42; O is not defined, With 9,02.

Calculated C 52,89; H 10,15; N 17,63; O 10,07; 9,27.

In the IR-spectrum synthetic the amino group with 3300 cm-1to 3200 cm-1that confirms their participation in the formation of complex compounds of this ligand with 2-ethylhexanoate cobalt.

Example 2. Determination of acute toxicity of the compounds of bis-(2-ethylhexanoate)di(etilendiamin)cobalt (KAT-122). Toxicity was determined in rats by Cerberus with intramuscular injection (PL. 1). The connection belongs to the 3rd class of toxicity and is moderately hazardous substance.

Example 3. The definition of a unit of activity (U50) drug Quantity U50erythropoiesis-stimulating activity of a compound KAT-122 was determined graphically by the dependence "dose-effect" [3] to change the number of red blood cells at 6 and 14 days after a single total gamma-irradiation of rats at a dose of 6.0 Gy (60Co., the dose of 0.45 G/min). The count value U50was carried out according to the method of Lichfield and Wilcoxon signed [II] Compound KAT-122 causes a marked increase in the number of erythrocytes already on day 6 (11.9 million class. mm3), on day 14 the number of erythrocytes was 14.1 mol. CL mm3. In total dose infusion was 66 mg/kg

Example 4. Determining the effectiveness of KAT-122 with posthemorrhagic anemia. We investigated the changes of indicators per the tov. Posthemorrhagic anemia played dosed bloodletting in rats from retroorbital sine and sublingual veins. KATH-122 is injected through the day during the whole experiment in the doses indicated in Example 3. Observation for 25 and 35 days showed a significant increase in haemoglobin levels in all observation days from 100 to 137 (p<0,001). The hematocrit on the 7th day (165%) on 15-e (176%) accuracy (p<0,001).

The intensity of erythropoiesis with the introduction of KAT-122 remained above the initial value (9,00,3 g/l day) throughout the entire experience (11,8 g/l day on the 7th day of 18.1 g/l day on the 25th day, the process was accompanied by the slow maturation of reticulocytes (table. 3)

From level anemizatsii (129%) increase in the number of red blood cells to the 25th day amounted to 167% Degree of hemoglobinopathy their data on day amounted to 153% in relation to control and 126,6% compared to hamidu (PL. 4).

Connect the FL CAT-122 on the restoration of blood in acute radiation defeat. The influence of the connection KATH-122 to the stimulation of erythropoiesis was studied on the model of acute radiation sickness in rats irradiation at a dose of 6.0 Gy. Determination of peripheral blood hemoglobin, hematocrit, number of erythrocytes, reticulocytes, leukocytes was carried out according to standard techniques. The condition of the bone marrow after irradiation the number and morphological identification erythroblastosis islets was performed according to [7, 8, 9]

The compound was administered in a therapeutic mode intramuscularly every other day at a dose equal to U50when a single dose. Exposure to ionizing radiation causes a decrease in the number of cells on the 3rd day after irradiation 5.5 thousand cells/ml of This indicator with the introduction of KAT-122 to the 30th day restored to 12.1 thousand cells/ml at its original value (before anemizatsii) 13.9 thousand cells/ml Increase in hemoglobin was held at a good pace and level it was fully restored to the original data (144 g/l) 30-day KAT-122, preventing the fall of hematocrit (47%) compared to the original value (44,2%) 3-day. To the 30th day he was 54%

The test compound was also prevented the decrease in the number of erythrocytes and reticulocytes (Fig. 4, 5) after irradiation and contributed, and the income level of 6.9 million cells/ml and increased to 30-days to 8.8 million cells/ml. Reticulocyte count is already on the 7th day exceeded the initial level (39%) 56% and was increased to 30 days up to 93% of the Growth of cells was accompanied by a corresponding increase in hemoglobin.

Activation of erythropoiesis with the introduction of KAT-122 was confirmed by the observed changes in the bone marrow. Already on the 3rd day after irradiation the number erythroblastosis islets, bone marrow was 123103/thigh at an initial level 97103/thigh (Fig. 6). To the 30th day, this figure was increased to 138103/hip.

The proposed connection has the following advantages:

1. Has less toxicity, LD50250 mg/kg for CAT 122 and 125 mg/kg for Hamida;

2. has higher activity U50to 66.0 mg/kg for CAT 122 and 107,0 mg/kg for Hamida;

3. promotes a higher degree of hemoglobinuria erythrocytes with posthemorrhagic anemia by 53% compared to the control and by 26.6% compared with coamidum;

4. prevents the development of erythropenia the irradiation of animal-source in sublethal doses, the number of red blood cells throughout the experience has not declined below the original level, while for Hamida reduction (Fig. 4), and the level of hemoglobin using KAT-122 was restored fully to the 30th day (144 g/l), while when using Hamida recovery wasn't the hemoglobin level to the end of the experiment amounted to 108 g/l (100 g/l).

5. Promotes regeneration of red Rostock bone marrow in irradiated animals g-source in sublethal doses, the number erythroblastosis Islands in the group, using the KAT-122 throughout the experience has not declined below the original level, while when using Hamida reduced to 7 days amounted to 40% (control 60%) and this figure has not recovered to the end of the experiment on the 30th day he was 34% lower than the initial (control 58%).

Thus, the connection KATH-122 has a pronounced effect on the blood on the background exposure to ionizing radiation at sublethal doses. In its action it surpasses the effect of Comida. The compound stimulates bone marrow erythropoiesis and encourages earlier regeneration of red and white blood cells.

1. Bis(2-ethylhexanoate)bis(Triethylenetetramine)cobalt (II), General formula

shows the properties of a stimulator of hematopoiesis.

 

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