Compounds of palladium and derivatives of aromatic amines and method of production thereof

 

(57) Abstract:

The inventive compounds of f-crystals [NH2R1R2]2PdCl4where R1connection f-crystals of 1 are presented in the description, where R2= CH3C2H5; Y= H,OH; NO2; X1=H, OH; X2-OH, CH3; X3-H, CH3CH2OH. Reagent 1 : palladium dichloride. Reagent 2: 1-(4-nitrophenyl)-2-methylaminoethanol, 1-(4-nitrophenyl)-2-aminopropan-1,3-diol or 2-(3-hydroxyphenyl)-2-ethylaminoethanol 2-phenyl-1-methylaminopropane-2-ol. Reaction conditions in aqueous medium acidified with hydrochloric acid, when the stoichiometric ratio of the components at 30 to 80C. 2 C. p. F.-ly, 8 PL.

The invention relates to chemistry and medicine, in particular for compounds based on palladium and derivatives of aromatic amines and the method of their derivation, and can be used in radiation medicine for the protection of mammals from exposure to ionizing radiation, with the introduction of the proposed compounds in the bodies both before and after exposure to ionizing radiation, as well as in conditions of chronic exposure to ionizing radiation in small doses.

The results of liquidation of consequences of Chernobyl accident and other emergency radiation situations of active substances, with radiomodification activity.

Known, for example, sulfur-containing radioprotectors, acting directly on the target cells or the conditions of existence of these cells.

Also known radioprotectors, reducing radiation damage to the body due to himicheskoi tissue or circulatory hypoxia (indolealkylamines are, cyanides).

However, all known radioprotectors have a number of significant drawbacks. The preparations on their basis are characterized by high toxicity, which does not allow for a significant radioprotective effect, which is directly connected to c the dose of an administered drug. In addition, the high toxicity precludes the possibility of their frequent reuse. A quirk of radioprotectors is a significant reduction in their radioprotective action when repeated fractionation of the radiation dose and the practical absence of irradiation with low dose rate.

An important feature of radioprotectors is that radioprotective effect is manifested only when administered before irradiation. This makes it impossible to use them for the treatment of radiation damage, kotoryj (the accident at the Chernobyl NPP and others) are intensively developed other ways of correction of radiation damage. This plan proposes the use of a complex of vitamins and minerals, usually in the form of substances of plant origin and other biological active compounds. The preparations on their basis are usually mediated through the body and help to speed up processes, post-radiation recovery irradiated tissues of the body. However, therapeutic effect of these drugs is poorly defined.

Compounds based on palladium with radiomodification activity, the literature is not detected. Thus, the most urgent problem of radiation medicine remains the development of compounds with radiomodification activity, which manifests itself when introduced into the body both before and after exposure to ionizing radiation, as well as in conditions of chronic exposure to ionizing radiation in small doses.

The aim of the invention is to obtain an effect of protecting the body from exposure to ionizing radiation with the introduction of compounds into the body both before and after exposure to ionizing radiation, as well as in conditions of chronic exposure to low doses.

The basis of the invention is to develop new compounds with the radio is under chronic exposure to ionizing radiation in small doses, and in addition, to develop a method of obtaining these compounds.

The aim is achieved in that according to the invention offers new connections based on palladium and derivatives aromatic amines of General formula I

[NH2R1R2]2PdCl4where R1=

R2=CH3; C2H5;

Y=H; OH; NO2;

X1=H; OH;

X2=OH; CH3;

X3= H; CH3; CH2OH; except for the case when Y=X1=H; X3=R2=CH3; X2=OH, with radiomodification activity.

Moreover, there is a method of obtaining compounds of General formula (I), namely, that according to the invention compounds of General formula

[NH2R1R2] Cl (II), is subjected to the interaction with palladium dichloride when the stoichiometric ratio of the components at a temperature of 30-80aboutAnd from the resulting reaction mass produce the target product. It is recommended in this case the selection of the target product are carried out at a temperature of 30-80about.

The proposed compounds have radiomodification activity when introduced into the body both before and after exposure to ionizing radiation, as well as in conditions of chronic Yoni who's connection is achieved with a dose of the substance in the procedure below the maximum-tolerated by the body. In addition, the proposed compounds have low toxicity in therapeutic doses does not give side effects such as allergenicity, teratogenicity, undesirable effects on the kidneys and other effects.

Proposed connection aerogene, have antibacterial properties against some bacteria and germs.

The proposed compound (General formula I) are crystalline substances yellow-brown, hygroscopic, soluble in water and isotonic saline solution (0.9% NaCl), odorless, above 100-120aboutTo begin to decompose without melting, photostability, as in the solid state and in the form of solutions, the solutions proposed compounds in 0.9% NaCl are acidic reaction, such as a 0.25% solution of fasola in 0.9% NaCl 15 min after the preparation has a pH from 3.6 to 4.1.

The proposed connection at 25-35aboutTo save without changing the physical-chemical properties and biological activity for more than 3 hours

The proposed structure of the compounds of General formula I is established by the method of IR-spectroscopy.

Conclusion about the structure of the claimed compounds made on the basis of the analysis of the IR spectra of the complexes and free ligands in obesigenic in the field of 1500-4000 cm-1different, which allows for IR-spectra to highlight the spectral changes occurring during the formation of the complex. For ligands observed IR bands characteristic of the hydrochloric acid salts and their complexes with hydrogen bond type

Z . . Cl , where Z =, for which the characteristic IR band 2470 cm-1. The doublet band 3340/3300 cm-1due to the intramolecular hydrogen bond OH ... Cl.

Main frequency observed in the IR spectra of the proposed compounds and their classification are given in table. 1.

In the IR spectra of the complexes disappears band 2470 cm-1related to hydrogen bonds NH . .. Cl and streaking cation R with frequencies 2860-2880 cm-1and 1562-1570 cm-1( NH+2) see table. 1).

Intense doublet band 3404-3460/3380-3408 cm-1refers to valence fluctuations of the Oh-group that is involved in intramolecular hydrogen bonds HO ... Cl atoms of chlorine acidaemia.

The complex nature of the IR spectra of the complexes in the area 2300-3400 cm-1indicates the existence in these compounds as intermolecular and intramolecular hydrogen bonds NH Cl....

The presence of investigated compounds anion [PdCl4]2-dCl4]2-. In the compounds of the K2PdCl4and (NH4)2[PdCl4]PdCl=326 cm-1. The presence of the anion [PdCl4]2-in (NH4)2PdCl4confirmed by the data rengenostrukturnyi analysis.

Thus, according to IR-spectroscopy of the proposed connections are cation-anion complexes structure

(NH2R2R1)2[PdCl]4in which, there are two types of hydrogen bonds: the intramolecular hydrogen bond NH Cl ... and OH ... Cl intermolecular hydrogen bond NH Cl....

By electron spectroscopy the spectrometer Specord M-40" investigated the status of the proposed compounds in 0.9% NaCl solutions and in aqueous solutions depending on their concentrations and exposure times.

Electronic absorption spectra were recorded immediately after prilipanie of 0.9% NaCl to the sample tested compound. From the experimental data it follows that in the initial moment of time in the electronic absorption spectra in the region 350-500 nm is observed broad band with = 460-463 nm ( = 149-153). It should be noted that the solution for H2PdCl4in 0.9% NaCl solution in the electronic absorption spectrum, the absorption band of the anion [PdC connection is connected, apparently, with the influence of bulky organic cation.

The spectral characteristics of the solutions proposed compounds of General formula I in various concentrations in the physiological solution, depending on the exposure time are given in table. 2.

As follows from the data table. 2, in time there is a change in the electronic absorption spectra of solutions of compounds of General formula I in 0.9% NaCl solution: observed shift of the maximum absorption in the wavelength region with virtually no change in the intensity of this band. The observed change is due to aquatalia anion [PdCl4]2-and establishment of physiological solution equilibrium: tetraacetate triacetonamine complex

[PdCl4]2-+H2O [PdCl3(H2O)]-+Cl-(1).

In accordance with spectrochemical next substitution chlorideion on the water molecule should lead to a shift in the wavelength region. This process of education triacetonamine more pronounced in solutions with lower concentration of palladium. The obtained results do not contradict known data aquatalia anion [PdCl4]2-. Using data on equilibrium constants (1), was conducted by the reader to 75% [PdCl4]2and 25% of [PdCl3(H2O)]-.

We studied the stability of the solutions proposed compounds in 0.9% NaCl solution at different temperatures: 4oC, 25oC, 40oC, 100oC. it is Shown that the solutions can not be heated above 40aboutC. lowering the temperature to 4aboutTo stabilize solutions of these compounds, so in practice it is advisable to store the prepared solutions in the refrigerator.

The measured electronic absorption spectra of the solutions of some compounds of General formula I in water concentration of 20 mg/10 ml, 40 mg/10 ml was Found that in these spectra in the region 350-500 nm is observed in the intensive absorption band of C = 424 nm (= 207). The next day electronic spectrum of solutions is undergoing significant changes: the shift of the maximum absorption in the wavelength region from = 411 nm, this significantly increases the intensity of this band (= 247). The observed results allow to conclude that in water, these compounds are undergoing a more profound changes, the hydrolysis of the anion [PdCl4]2-goes to diacetoacetate [PdCl2(H2O)2], or to allotrichoma [PdCl(H2O)3]+.

Thus, the study of which allows to make a conclusion, that the water may not be used to prepare solutions of these compounds from going in aqueous solutions processes deep hydrolysis.

For the preparation of solutions proposed connections should be used only with 0.9% NaCl solution. The use of saline solution stabilizes in solution, the equilibrium tetraacetate triacetonamine. For practical purposes, suitable concentrations of these compounds 0,05-0,2% .

Tests of the proposed compounds on the toxicity and biological activity. Experiments conducted on mice - hybrids F1(CBA x C57BL) males. Only used about two thousand animals. Acute toxicity of the proposed compounds of General formula I were determined in mice after a single intravenous and intraperitoneal administration. The substance was administered as 0.1 wt. % to 1.0 wt.% solutions using a syringe and injection needle. In the stomach was introduced suspended substances in 1% starch paste using a syringe and a metal probe. Animals were observed within one month after the introduction of substances. Noted the number of the fallen and the time of their death, followed by the state and behavior of animals. Dose, characterizing toxicity, Rosstroy toxicity of the proposed compounds are presented in table. 3.

Sub-chronic toxicity of the proposed compounds of General formula I were investigated in rats and dogs at daily fivefold or tenfold intravenously.

It is shown that the introduction to therapeutic doses of the proposed connection will not affect the basic mechanisms of cellular and humoral immunity, does not have a pathological actions on the biochemical and morphological composition of blood. When injected into paravenozhnykh fiber of the claimed compounds can cause local tissue reactions, similar to the action of commonly used drugs, such as calcium chloride, nicarbazin and others. In high, lethal and related doses compounds can cause changes in the cerebral blood vessels (mydriasis, exophthalmos, decrease breathing, vomiting) may pathologically affect the cardiovascular system, changing the value of teeth R and S electrocardiogram, to cause sinus arrhythmia.

Total gamma-irradiated animals was carried out by setting the "Stem-3-A dose of 8.3 P/s (Cesium-137).

Control groups before irradiation was intravenously injected isotonic solution of sodium chloride in a volume of 0.3 ml per mouse. Experienced GRE sodium chloride at doses of 2.5-80 mg/kg

Mice were placed in a glass chamber for 3-4 animals and introduced into the radiation zone of the installation location of the sources by type "squirrel wheel". Doses were established by the time the animals in the active zone. Dosimetric control recorded the difference of doses inside the container is not more than 10%. Irradiation of animals produced in the dose range of 4.0-10 Gr

Observation of animals were conducted for 30 days. Followed the state and behavior of animals, said the number of dead and timing of their death. Survival of animals was determined in % on the 8-th and 30-th observation days. On the basis of these observations were obtained survival curves of mice on a scale probit of percent, depending on dose and extrapolated to the scale of doses was determined LD50/8and LD50/30.

Radiomodification effect of the proposed compounds were evaluated by determining the magnitude of the change factor dose (PID), which is a ratio LD50in the experience to LD50in the control.

The data obtained for the proposed compounds of General formula I are presented in table. 4-8. Just used from 10 to 40 animals at each "point" (dose).

Radiomodification effect of the proposed connection is only after him with a feed 1,07-1,14 at doses of 10 mg/kg, identified as intestinal and bone marrow death (see tab. 4).

On bone marrow death radiomodification effect of the proposed compounds begins to manifest itself with a dose of 2.5 mg/kg (see table. 5).

The use of drugs in the dose of 10 mg/kg for 4 h before irradiation showed no radiomodification actions as the introduction of the drug at this dose after 4 and 6 h after irradiation (see tab. 6, 7).

Equally effective radiomodification proposed compounds obtained directly before irradiation, and right after it shows that the effect occurs after irradiation (see tab. 4).

Thus, based on the obtained data suggest that the compounds of General formula I are not classical radioprotectors. Their effective application for 15 min before irradiation, it would seem, suggests radioprotective properties. However, the lack of a stronger effect with increasing doses of the drug in this mode does not confirm this postulate. Obviously, radiomodification action is prolonged and is associated with increased repair of sublethal damage. No radiomodification de the e drugs does not exceed this period. Thus, a significant reduction radiomodification of action of these drugs when administered 4 h after irradiation and the total lack of it in the introduction through 6 h after irradiation also shows that the effect is implemented by enhancing the repair of sublethal radiation damage. No radiomodification drugs when administered 4 h before irradiation, at 6 h after irradiation virtually eliminates its implementation through the body irradiated animal-type enhance tissue recovery. An attempt to explain radiomodification action of drugs through the mechanism of the oxygen effect" untenable, due to celebrate efficacy when administered after exposure and depends on the condition of stem cells in the bone marrow and intestine.

In the experiment in the application of the inventive compounds in a dose of 10 mg/kg in 15 min after each fraction at five times the dose fractionation, which shows the possibility of increasing the effectiveness of therapy (see table. 8) feed=1,16-1,19.

The data show the effectiveness of the drug at low doses. Given the low toxicity of drugs and considerable latitude t is I the General formula I with long-term (chronic) exposure to low dose.

After analyzing the data, you can come to the following conclusions:

The claimed compounds are a new class of compounds with Adomavicius action. Radiomodification action is carried out both during and after irradiation and fundamentally distinguishes the proposed connections from known radioprotectors, the effectiveness of which is only a problem when introducing them before irradiation.

The mechanism of action of the proposed compounds or their metabolites in mammals is carried out by increasing levels of reparations sublethal radiation damage stem cells of the intestine and bone marrow of irradiated animals. Thus the value radiomodification effect does not depend on the radiation dose in the range of from 4.0 to 10.0 G (survival curves in control and experience are parallel).

A significant difference radiomodifying actions proposed connections from known radioprotectors is almost constant and its value is within the range of doses from 10.0 to 80.0 mg/kg (PID=1,1). This allows you to apply a low, distant from toxicity dose preparations on their basis and creates the opportunity for multiple primenenii.

All these differences make for a promising application of the proposed compounds for the prevention and treatment of radiation damage in animals and humans, as when fractionated irradiation can improve feed.

Therapeutic efficacy of drugs used currently in radiology, falls fractionation of the radiation dose and is virtually absent in the application of ultra-low doses. The effect of the application of the proposed compounds increases with the number of fractions of radiation.

The proposed method for obtaining the claimed compounds is carried out as follows. Compounds of General formula II is subjected to interaction with palladium dichloride when the stoichiometric ratio of the components, using standard equipment. For this purpose a portion of the compounds of General formula II is mixed with the sample of palladium dichloride and the mixture was incubated until complete interaction of initial reagents at a temperature of 30-80aboutC. the temperature of the reaction mixture should not exceed 80aboutIn order for the reaction proceeded in the right direction without decomposition of the reaction products. If the temperature is less than 30aboutFrom the source to the sediment, using traditional methods.

Obtained in the form of crystals of the target product is dried and analyze methods of elemental analysis, IR spectroscopy and other commonly used methods. The yield of the target product is 88.2-97,5% of theoretical calculated on the entered palladium.

P R I m e R 1. The addition of palladium dichloride and 1.00 g (5,64 mmol) dissolved in 10 ml of water, acidified with 0.2 ml of 10 N. HCl, the solution is filtered in a flat-bottomed flask with a volume of 50 ml. of this solution is poured filtered solution of 2.21 g (11,28 mmol) 1-(4-nitrophenyl)-2-methylaminoethanol in 10 ml of 2 N. HCl. Almost immediately falls crystalline precipitate of the product. The reaction mixture was incubated for 1 h with stirring at a temperature of 30-40aboutWith and filtered at room temperature. The precipitate is dried in a drying Cabinet at a temperature of 60aboutC at atmospheric pressure to constant weight.

Get the compound of formula I, where X1=H; Y=p-NO2; X2=OH; X3=H; R2=CH3.

Output 3,20 g, representing 88.3% of theoretical introduced into the reaction palladium.

For C18H26N4O6PdCl4composition calculated %: Pd 16,56; Cl Representing 22.06; N 8,12.

Found, %: Pd 16,5 is Noah 0.2 ml of 10 N. HCl, the solution is filtered in a flat-bottomed flask with a volume of 50 ml. of this solution is poured filtered solution of 3.16 g (12.7 mmol) of 1-(4-nitrophenyl-2-aminopropane-1,3-diol hydrochloride dissolved in 20 ml of water. The resulting mixture is heated with stirring on a water bath at a temperature of 80aboutWith almost dry. The residue is poured 25 ml of water and evaporated to a minimum volume (this operation is repeated twice). When cooled receive a crystalline substance, which is dried in a drying Cabinet at a temperature of 60aboutC at atmospheric pressure until constant weight.

Get the compound of formula I, where X1=H; Y=p-NO2; X2=OH; R2=H; X3= CH2OH.

The output of 4.00 g, which comprises 93.5% of theoretical introduced into the reaction palladium.

For the composition of C9H12N2O4PdCl4calculated %: Pd 15,77; Cl 21,02; N 8,30.

Found, %: Pd 15,96; Cl 20,97; N Of 8.37.

P R I m e R 3. The addition of palladium dichloride 0,99 g (to 5.35 mmol) was dissolved in 30 ml of water, acidified with 0.2 ml of 10 N. HCl, the solution is filtered in a flat-bottomed flask with a volume of 100 ml. of this solution is poured filtered solution 2,42 g (11.1 mmol) of the hydrochloride of 2-(3-hydroxyphenyl)-2-ethylaminoethanol in 20 ml of water. Received Bhima. To the residue is poured 25 ml of water and evaporated almost to dryness (this operation is repeated twice). Upon cooling, get a thick crystalline precipitate, which is dried in a drying Cabinet at a temperature of 60aboutC at atmospheric pressure to constant weight.

Get the compound of formula I, where X1=H; Y=m-OH; X2=OH; X3=H; R2=C2H5.

The output of 3.00 g, which is 88.2% of theoretical calculated on the entered palladium.

For the composition of C20H32O4N2PdCl4calculated, %: Pd 17,37; Cl 23,15; N 4,57.

Found, %: Pd 18,24; Cl 24,56; N 4,90.

P R I m e R 4. The addition of palladium dichloride of 0.44 g (2.5 mmol) is dissolved in 30 ml of water, acidified with 0.2 ml of 10 N. HCl, the solution is filtered in a flat-bottomed flask with a volume of 100 ml. of this solution is poured filtered solution of 1.07 g (5 mmol) of the hydrochloride of 2-phenyl-1-methylaminopropane-2-ol in 20 ml of water. The resulting mixture was evaporated at periodic stirring in a water bath at a temperature of 60aboutWith up to minimum volume. The solution is cooled and the resulting crystalline precipitate is filtered off and dried in a drying Cabinet at a temperature of 60aboutC at atmospheric pressure to constant weight.

Get soy is 93% of theoretical, calculated on the entered palladium.

For the composition of C20H32O2N2PdCl4calculated, %: Pd 18,32; Cl 24,42; N of 4.83.

Found, %: Pd 18,58; Cl 24,83; N 4,82.

1. Compounds of palladium and derivatives aromatic amines of General formula

(NH2R1R2)2PdCl4< / BR>
where

R1=

R2= CH3C2H5;

Y IS H, OH, NO2;

X1= H, OH;

X2= OH, CH3;

X3- H, CH3CH2OH;

except for the case when Y = X1- H, X3= R2- CH3X2= OH.

2. The method of obtaining compounds based on palladium and derivatives aromatic amines of General formula

(NH2R1R2)2PdCl4,

where

< / BR>
R2= CH3C2H5;

Y = H, OH, NO2;

X1= H, OH;

X2= OH, CH3;

X3= H, CH3CH2OH;

except for the case when Y = X1- H, X3H = R2- CH3H2- OH,

characterized in that the compound of General formula

(NH2R1R2)Cl

where R1and R2have the specified values,

subjected to interaction with palladium dichloride when the stoichiometric ratio of the components at a temperature of

 

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