Dioxide-beta-alaninate-molybdenum, exhibiting the properties of hepatoprotector

 

(57) Abstract:

Usage: in the chemical-pharmaceutical industry, in particular in the production method of the active ingredient, dioxo-di-beta-alaninate-molybdenum (S), a warning violation of the protein-synthesizing function of the liver in hepatitis. The inventive method of obtaining the AM provides for the reaction of molybdenum oxide (6+) with the dihydrate of oxalic acid with the formation of oxalate complex of molybdenum with the subsequent replacement of the ligand in the set of beta-alanine. The compound obtained has the following composition: Mo O2(C3H6No2)2H2O

and structure [NH -(CH) C(O)-O-O-Mo-O-O-O-C-(CH) NH] HO, yield 88%. The most effective dose for stimulation belauxinteziruushih organelles of hepatocytes 0.40 g/kg weight of the animal, toxicity LD(50) - 1814 mg/kg weight of the animal. 5 Il., 3 table.

The invention relates to chemical-pharmaceutical industry, namely to new biologically active compounds, specifically, to dioxode-beta-alaninate-molybdenum formula I

NH2-CH2-CH2-COMOOC-CH2CH2-NHH2O (I) warning the violation of the protein-synthesizing function of the liver.nomalized [1] (compound II) of the formula II

SH-CH2-COMOOC-CH2-SH3H2O (II) with Antianemic activity.

However, its effect on liver function is not installed.

A similar action is bisque, mono(michelmathonnat sulfone chloride, glycinate) copper (compound III) [2] formula III

CH2-CH2-S (III) providing a regenerative effect on the liver tissue affected by toxic hepatitis, affecting the liver parenchyma, but also stimulate the growth of connective tissue.

The lack of compound (III) is of high toxicity. In addition, although established morphological picture of his actions, but it has not been studied at the ultrastructural level. Along with reparative processes in the liver parenchyma increases the process of proliferation of connective-woven items, and this unwanted side effect.

The aim of the invention is the synthesis of biologically active compounds of molybdenum (VI) extending the existing hepatoprotectors with therapeutic and preventive effect in hepatitis, affecting the functional state of the core and reinforcing assimilatory processes in hepatocytes.

The objective is achieved with the radiated connection get the technique [3] as follows.

A mixture of 7.2 g (0.05 mol) of Moo3and 12.6 g (0.1 mol) of the dihydrate of oxalic acid in 90 ml of water is heated on a water bath until complete dissolution of Moo3(8 hours). The resulting solution of oxalate complex without distillation of water is heated to 120aboutWith and to it add a 8.9 g (0.1 mol) of beta-alanine. The mass is heated for 8 hours at the boiling temperature of the solution (120aboutC), then cooled and two days separate the precipitated crystals from the mother liquor. The target product is washed with ethyl ether and acetone and recrystallized twice from aqueous solution. Get 13,43 g (88,3% yield of theoretical) of the desired product composition of Moo2(C3H6NO2)2H2O.

Found, 22,19; N To 4.47%; N 4,48; Mo 29,75; N2About 5,31.

Calculated With 22,36; N. Of 4.35; N 8,70; Mo 29,81; N2About 5,59.

The compound obtained is a transparent blue, deliquescent crystals, soluble in water, practically insoluble in ether, acetone, chloroform, hexane and somewhat more soluble in DMSO and ethanol. To identify compounds were removed the IR spectra in the form of tablets sI and CVG Specord M-80 and M-40 ESP Specord UV Vis, molar electrical conductivity, Provita-alanine (assignment carried out by Nakamoto) and its compounds with molybdenum (PL.1) showed what changes occur in the position and intensity of the characteristic bands of vibrations of carboxyl and amino groups. The original amino acid, as is known, exists in zwitterionic form. This is evidenced by the presence of fluctuations characteristic of NH3+-group. For compound (1) is characterized by the shift of the bands of vibrations of carboxyl groups (table.1). In addition, marked the advent of his spectrum of two close absorption bands, corresponding symmetric and asymmetric vibrations of Mo On the relationship that serves as a convincing argument in favor of the CIS-position kristnovoselic atoms of oxygen.

The study of Meff.according to the method of Faraday found that the compound (I) diamagnetic. In the UV spectrum band charge transfer ligand under the influence of ion Moo22+shifted by 1000 cm-1(to 50000 49000 cm-1and lowers its intensity 3 times. The value of molar conductivity of the compound (I) (10.4 cm2/Om mol) in ethanol slightly lower than the values typical for strong electrolytes composition 1:2, which, apparently, is due to incomplete dissociation of the compound (I) due to the additional coordination anion-alanine-ion Moo22+. Heating the compound (I) spinacea decomposition is accompanied by two exothermic effects at 160 and 330aboutC. the Original acid begins osmolytes at 110aboutC.

Given the number of factors, firstly, the compound synthesized by the method [2] are obtained only composition of Moo2(L H)2; secondly, it is the most characteristic composition when L is a ligand with nitrogen and oxygen donor atoms and amino acids; thirdly, the characteristics of the IR spectra, magnetic behavior and the molar conductivity in these compounds is identical to that for the compound (I), it is possible to draw an analogy between substances with more detailed studies of the structure and compound (I). Based on this believe that dioxode-beta-alaninate-molybdenum, along with the listed substances, has a Monomeric structure with CIS-configuration of Moo2slice and coordinates alanine-ion by oxygen carboxyla. Biological action of compound (I) was determined in mice and rabbits. This was formed by several groups of animals: 1 for clinically healthy rabbits (5 goals) control group; rabbits with experimental pathology of the liver (5 goals) 2nd group receiving a dose of 0.20 g/kg; rabbits with experimental pathology of the liver (5 goals), treated with a dose of 0.40 g/kg and liver were tetrachloride at a dose of 1 ml 100% solution in sunflower oil. Monitoring the condition of the animals was based on clinical and morphological studies. For further diagnosis from each group 2 animals were subjected to liver biopsy, and it was possible to make a conclusion about the protein-synthesizing function of the liver. The electron diffraction was received at the electronic microscope according to the weekly B. In the pilot study, attention was drawn to the reactivity of animals from the introduction of the compound (1) (injection site, skin reactions, changes in the General condition and urination, defence and so on).

Histomorphologically characteristic of the liver in clinically healthy animals (Fig. 1) the active core, the presence of mitochondria and slightly extended tanks GER). The electron diffraction is well revealed electron-dense core of oval form with heterochromatin on the periphery. In the downtown core is located several nucleoli, often one and visible RNP granules. In the cytoplasm of hepatocytes are organelles: mitochondria, granular and agranular endoplasmic reticulum, ribosomes, are complementary mechanism. In addition to these organelles are oil droplets, vacuoles, spaced throughout the cytoplasm. This is probably a consequence of poor quality, inferior to the one depends on its location in the slice: on the periphery or in the center. On the vascular territory of hepatocytes contains a small number of microvilli, this is true for biliary pole. Histomorphologically characteristic of the liver in animals of the 2nd group (experimental chronic hepatosis, reproduced by carbon tetrachloride (Fig.2). Animals of the 2nd group in the liver under the action of hepatotropic poison develop degenerative and necrobiotic changes of nature. Moreover, the response of hepatocytes against carbon tetrachloride is not adequate: the individual in a state of degeneration, and the other in the stage of necrosis. Thus, in the core decreases, and in some cases disappear nucleoli, decreases the number of RNP granules. An increasing number of euchromatin, broken into small osmophobia granules. From kernel exfoliate carolima, resulting in between them increases space. First, the number and size of mitochondria increases, there is wrinkling of membranes, Christa barely visible or completely reduced. Subsequently, these organelles vacuolized and their total number decreases until complete disappearance. Endoplasmic network is granulares, and ribosomes are sprayed in the cytoplasm. On the periphery of the hepatocyte Cisterna network fragmenting the EP: the cytoplasm is filled with a huge vacuoles and fat drops. On vascular and biliary pole of hepatocytes disappear microforming. The endothelial cells, stellate reticuloendothelial exaggerated. In Messina - soicalnim space appear in the cells of the connective tissue and around the hepatocytes, leukocytes. As can be seen from the above materials, in the liver under the action of carbon tetrachloride is developing vascular tissue reaction characteristic of inflammation.

In Fig.2 shows hepatocyte rabbit after the action of carbon tetrachloride. Extension perinuclear space, GER tanks, reducing the number of mitochondria, the homogenization of cytosole.

Histomorphologically characteristic of the liver in animals of the 3rd group (dose of compound (I) 0.20 g/kg) shown in Fig.3.

Rabbits with experimental toxic hepatosis daily gave oral compound (I). It is established that the effect starts from the second day of use. Both in the nucleus and the cytoplasm develop compensatory-adaptive reactions. In particular the activation of the engine, a slight increase RNP granules, and in the cytoplasm decreases the number of lipid droplets and vacuoles. However, more significant changes when using this dose to reach Ugaritic liver in animals 4-th group (dose of compound (I) 0.40 g/kg weight) shown in Fig.4.

Rabbits with experimental toxic hepatosis daily in the dose gave the compound (I). It is established that the stimulating effect it has on the first day of injection. In the liver are activated biosynthetic processes: there are outlet glycogen, but the greatest impact connection has on belauxinteziruushih apparatus of hepatocytes. In the kernel marks the correct location of heterochromatin, appear in a large number of RNP granules that fill most of the nucleoplasm. In the nucleus there are from 1 to 3 nucleoli, and some hepatocytes multi-core. In the cytoplasm of the normalized single membrane organelles. In some hepatocyte organelles have a regular structure, while others remain dystrophic processes. In particular mitochondria increased in size, cisterns of endoplasmic reticulum expanded, preserved, although in a small number of vacuoles and lipid droplets. At the same time in the cytoplasm increased number of lysosomes, autophagosomes and several times the number of free ribosomes. After 5-10 days of application of this compound histomorphologically structure of hepatocytes up to 80% of the total number improves, activated them belauxinteziruushih abedini these studies.

Histomorphologically characteristic of the liver in animals 5-th group (dose of compound (I) of 0.60 g/kg weight) shown in Fig.5. Activation of the nucleus, the energy of the number of microvilli on the biliary pole.

In rabbits with experimental toxic hepatosis were conducted similar studies with daily giving connection. It is noted that compensatory-adaptive and regenerative processes in hepatocytes amplified and correspond largely ultrastructural characteristics obtained when using doses of 0.40 g/kg it Should be noted that at this dose in the cytosol appear osmiophilic granules, which might be related to the release of compounds (1) molybdenum and its accumulation in hepatocytes. In this regard, increasing doses of compound (1) was terminated and identified that the most suitable for stimulation belauxinteziruushih organelles of hepatocytes doses of 0.40 g/kg weight of the animal.

Thus, the proposed connection (I) a pronounced effect on the structure and function of the liver. The compound (I) has a pronounced effect on hepatocytes: increases the number of mitochondria, lysosomes, normal endoplasmic network and significantly activate the engine that corresponds to the achievement of this goal.

A wide range of compounds (1), low toxicity, availability allows without difficulty be used as therapeutic agents for the treatment and prevention of toxic liver damage that is currently relevant.

Known methods of sitesa differs from that used in the invention and allows to obtain other compounds. The method used in the claimed work, the synthesis of compound (I) is carried out in two stages. In the first stage of the process is, apparently, with the formation of oxalate complex equation

MoO3+2H2C2O4MoO(C2O4)2H2O (a)

Proof that the synthesis is formation of compound (a) is:

experimental determination of molecular weight of the selected crystals (a), is equal to 316 g against 324 g calculated for the composition of the IPO (2ABOUT4)22H2ABOUT;

the content of Mo(VI) 29,3 of 0.1(%) (29,6% calc.);

the assignment of the characteristic bands of the IR spectrum of compound (a) in accordance with Nakamotoas(C= O), 1720, 1688;s(C=O) 1410;s(C=O+ (O-C=O) 1228; (O-C=O)+Def. ring 480;(Mo-O)conc.+ (O-C=O) 372,404 (cm-1).

It should be noted that (Mo-O)bridge. marked the th signal at m 164,26 D. what is the evidence of the symmetry of the structure, since it is known that the signals are equally shielded cores are the same.

The equation underlying the second stage,

MoO(C2O4)2H2O+2NH2(CH2)2COOH __ MoO2[OOC(CH)2NH2]2+2H2C2O4Method of isolation of the resulting compounds.

As a result of synthesis at this stage initially allocated a large transparent crystals, which on elemental composition, molecular weight (experimentally defined) comply with oxalic acid. The latter may contain 0.3-0.6% of Mo (VI), probably due to adsorption of Mo-containing compounds. Then from the mother liquor was allocated the inventive compound (I). So that it contains less impurities compounds (a), the allocation of the compound (I) was performed from colorless mother liquor (obtained after separation of the crystals of the compound (a)) after further evaporation 930-40aboutC) and cooling. Stood a fine blue crystals of compound (I), which after 2 days separated from the saturated solution. The operation was repeated 3-4 times. Each time the remaining mother liquor became bluer and what about the result of many days of drying ( 30 days) at 45-55aboutWith a mixture appeared bright crystals. The resulting mass was found to be white substance, insoluble in alcohol, which has properties very different from the claimed connection:

a) IR spectra have individual bands (HE), (NH2), (COOH) and numerous (Mo-O);

b) are the spectra of the PMR1H and NMR13With other than the compound (I);

C) melting point (with decomposition) is different from that for the compound (I);

g) has a different elemental composition (the content of Mo (VI) above). The above listed properties of this compound, in which two atoms of Mo are connected via bridges carboxyl - and oxalate ions, i.e., a connection similar to that described [1-4] can be obtained, but it is quite another matter with other chemical properties.

In addition to contained in the application it is interesting to note the following features of the IR spectra of compound (I). Comparing the IR spectra of compounds (a) and (I), failed to identify asNH2at 1524 cm-1found only in compound (I) and absent in oxalate complex, and also include the bands at 1080 and 840 to CCN. It has definitely allowed to talk about asCOO (see tab.3). Some offsetasCOO in the low-frequency region is attributed to proxygroup.

The PMR spectra1N (M. D.) 3,34 t; 3,72 t (triplet from the group of CH2) and a broad band with a maximum 4,72; NMR13With 177,14; 167,90 (COOH group), 33,649; 33,634 (CH2). The number of these bands indicates the symmetry of the structure connection. Small diamagnetic shift observed for signals13With manifested in NMR spectra, taken with an external standard by comparison with the spectrum-alanine indicates a greater probability of coordination on bidentetea carboxyl.

The nitrogen content in the compound (I) 8,48%

The effectiveness of the biological activity of a compound (I) compared to the benchmark are given in table.2.

Dioxide-beta-alaninate-molybdenum formula

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exhibiting the properties of hepatoprotector.

 

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