Derivatives 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane that have the property to eliminate radioactive isotopes from a living organism, and a pharmaceutical composition for the excretion of radioactive isotopes

 

(57) Abstract:

Use: for removing damaging living organisms metal ions, especially radioactive isotopes. The invention relates to a partially new metal complexes, salts and double salts of 1, 4, 10, 13-tetraoxa-7, 16-diazacyclooctadecane connections first formula given in the claims, have the property to eliminate radioactive isotopes from a living organism, as well as to pharmaceutical compositions containing compounds of the indicated formula. 6 C. p. F.-ly, 3 ill., table 1.

The invention relates to a partially new derived 1,4,10-13-tetraoxa-7,16-diazacyclooctadecane and use of such compounds for removal from organisms of metal ions, especially radioactive isotopes, providing a striking effect. In particular, the invention relates to metal complexes, salts and double salts 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane derivatives of formula (1)

M Q1-QNms+where Q1and Q2hydrogen or a group with the General formula (2)

-R

In the group with the formula 2 R can be hydrogen, straight or branched C1-5alkiline group, straight or again in the last two groups, if necessary, may be substituted on the aromatic component by one or more halogen, WITH1-5alkyl, C1-5alkoxy, cyano - or nitro group, provided that at least Q1or Q2is not hydrogen. Me represents an alkali metal or alkaline rare earth metal, or transition metal ion; q is 0 or 1; M and N independently of one another represent hydrogen or alkali metal, alkaline rare earth metal or, if necessary, substituted ammonium ion; and m, n and p are equivalent charges, respectively, N, M or IU; S and r independently from each other 0, 1, 2, 3, or 4, provided that r, s and q at the same time cannot be 0 and the number of hydrogen atoms in M and N may be 0, 1 or 2.

The invention relates also to pharmaceutical compositions based on these compounds.

From among compounds with the formula (1) compounds containing as Q1and Q2hydrogen, used primarily as a derivative.

When introduced into the body of the compounds of formula (1) regardless of whether new or not they are capable of forming stable complexes with ions of radioactive metals, primarily with radioactive strontium and cesium present in the blood and extracellular space, which are then excreted. Moviedom, or, if R represents hydrogen, q is 1. In other words, these compounds are complexes in which M and N, in addition, differ from sodium or lithium, if q is 0.

Thus, on the one hand, the invention relates to compounds of formula (1) in which Q1and Q2is hydrogen or a group of formula (2), provided that at least one of them is not hydrogen in the groups of formula (2) as R can be hydrogen, C1-5Alchemilla group with a straight or branched chain, WITH2-5Alchemilla group with a straight or branched chain, phenyl or phenyl WITH1-5alkyl group, with the latter two can be, if necessary, replaced by an aromatic component by one or more halogen, C2-5alkyl, C1-5alkoxy, cyano - or nitro groups. Me represents an alkali metal or alkaline rare earth metal, or transition metal ion; q is 0 or 1; M and N independently of one another represent hydrogen, alkali metal, alkaline rare earth metal or, if necessary, substituted ammonium ion, m, n and p are equivalent charges, respectively, N, M or IU; s and r independently from each other 0, 1, 2, and 3 or 4 when sloviplast a 1, if R is represented by hydrogen, and M and N are not ions of sodium or lithium, if q is 0.

Among the substituents in the compounds with formula (1) R as1-5alkyl groups may be represented by a straight or branched chain such as methyl, ethyl, n-sawn, ISO-propyl, n-butilkoi, second-butilkoi, tert-butilkoi, n-Pintilei or isopentyl group, preferably a methyl or ethyl group. R as2-5alkenylphenol group can be, in particular, presents vinyl or propenyloxy group, and R as phenyl WITH1-5the alkyl groups may contain one of the above alkyl chains, preferably methyl.

IU as an alkali metal ion should preferably be presented ions of sodium or potassium, as ion alkaline earth metal ions of calcium or magnesium, and as the transition metal ion is an ion of a metal belonging to the third, fourth or fifth group, preferably a divalent ion of iron or zinc. M and N as ions of alkali or alkaline earth metal preferably presents the above ions, whereas the substituted ammonium ion contains 1, 2, 3 or 4 is x difficulty). Compounds containing ion chetyrekhmernogo ammonium, cannot be used for introduction into living organisms because of their toxicity.

It is known that nuclear explosions or accidents at nuclear reactors in the atmosphere come extremely dangerous radioactive isotopes such as iodine-131 (131I), strontium-89 and 90 (89Sr and90Sr) and cesium-134 and 137 (134Cs and137Cs) and cerium-141 and 144 (141CE and144CE) (see, for example, Nuclear and Radiochemistry, John Willy and Jons, 1981, PP. 158-166). When getting these isotopes into the lungs during breathing or digestive tract from contaminated food and liquids, as well as in the blood and the lymphatic system as a result of resorbtive through the skin they are deposited and accumulate in the tissues, which, ultimately, leads to serious health consequences (see Summary Report on the Post Recident Review Meting on the Chernobyl Quident, Safety Series N 75, IAEA, Vienna, 1986).

In the case of radiation poisoning strontium after a few hours found in bone tissue, and its removal from the body is not possible. This makes it extremely difficult task of protecting the body from radioactive strontium.

The only possibility of such protection is to prevent vibracoustic specific complexes with strontium. In this way are binding isotope that is present in the blood or the extracellular space, in a stable form and its excretion from the body.

The solution to this problem is complicated by the fact that described in the literature complexing compounds, such as Ethylenediamine-chetyrehchastnaya acid or diethylenetriaminepentaacetic acid form with calcium significantly more stable complexes than with strontium (A. Catsch Radioative Metal Mobilization in Medicine, Ed. Charles C. Thomas, Springfield, Illinois, 1964; A. Catsch Dekorporierung radioaktiver und stabiler Mettallionen, Therapeutische Grundlagen, Ed. Thiemig, Munich, 1968; A. Catsch Removal of Transuranium Elements by Chelating Agents m: Diagnosis and Treatment of Incorporated Radionuclides, IAEA Publication N ST1/PUB/411, IAEA, Vienna, 1976, p.295).

New prospects for research in this direction has been opened after synthesis of createrow and Cryptologic molecules. In this case, the mechanism of complex formation differs from previously known, because the structure of the new complexidade molecules metal ions Localita in cells of a specific size, and therefore the stability of the complexes depends primarily on the size of this type ions.

First encouraging results were obtained from the research 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo higher than that of its complex with calcium (see Coordination Chemistry of Macrocychie, Compounds Ed. G. A. Melson, Plenum Press, 1979). However, in the study of this compound in animal experiments failed to prove only that formed outside the body complex with legenday not subjected to dissociation after its introduction into the body. At the same time, data were not collected about the possibility of removing radioactive strontium from the body in the form of a stable complex with legenday. In addition, ligand proved to be extremely toxic (W. H. Muller, Naturwiss, 57, 2248, 1970; W. H. Muller and W. A. Muller, Naturwiss, 61, 455, 1974; W. H. Muller et al; Naturwiss, 64, 96, 1977; J. Knajfe et al, 12th Ann. Meeting of ESRB, Budapest, 1976; J. Batsch et al. Nukleonika, 23, 305, 1978).

The compounds of formula (1), a salt in the case of q equal to 0, and when q is 1, have a specific complexing properties that allow them to bind and remove metal ions, dangerous for the body, especially radioactive strontium and cerium, which penetrate into a living body and enter the blood stream and/or the extracellular space. When administered to a human or animal pharmaceutical compositions containing the compounds of formula (1) as active ingredients, it is possible to prevent accumulation in the tissues of radioactive strontium, which in turn allows F. de Jond et al, proposed a way to obtain the N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane in the form chetyrehluchevoy salt (Rec. Trav. Chim. Pays-Bas, 102, 164, 1983). In accordance with the methodology required cryptand reacts with methyl-2-bromomalonate and the resulting ether derivative is hydrolyzed to the formation of the lithium salt with the release of not more than 15 According to the United Kingdom patent N 2024822 thus obtained lithium salt may be used in the form of a composition to increase the solubility of barium sulfate in the petroleum industry. In the same description contains a mention of the relevant chetyrehmetrovoy salt, although its use is not described in specific examples. Double salt chetyrehmetrovoy salt with sodium bromide, and the suitability of such double salts for therapeutic applications described in the application for the Hungarian patent N 2614/89.

Soluble salts and complexes of formula (1) according to the invention, in which Q1, Q2, R, Me, M, N, m, n, p, s, r and q are defined above, can be obtained by analogy with the procedure outlined in the preceding exposition of the reaction involving the interaction of the corresponding halogenosilanes dicarboxylic acid of the formula (3)

X - DG is with 1,4,10,13-tetraoxa-7,16-disallowance Dean in the environment of an organic solvent with subsequent hydrolysis of the thus obtained product of a strong base, for example sodium hydroxide, or a mixture (in the required molar ratio) of a strong base with a hydroxide or salt, preferably a halide, complexing metal.

Another way water-soluble salts and complexes of the compounds with formula (1) in which M and N is represented by hydrogen or ions of alkaline or alkaline earth metals, and IU ion alkaline earth metal, can also be synthesized through the reaction between 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane and 2-Gloversville acid of the formula (3), preferably 2-bromomalonate acid, in aqueous medium with a pH of 6 to 13 in the presence of a hydroxide of alkali or alkaline earth metal, a corresponding salt, you want to get.

Compounds with formula (1) in which q is 1, can be obtained by reaction of the alkali metal salt of formula (1) in which q is 0, and M as well as N are alkali metal ions, preferably chetyrehmetrovoy salt with an equivalent amount of the complexing metal halide (valid chloride of the metal).

The effect of the compounds of formula (1) according to the invention, which is manifested in the increased excretion of metal ions, parahydrogen strontium or cerium.

The removal of radioisotopes studied after their introduction in different ways in different tissues and parts of the body, in particular in the bloodstream, the abdominal cavity, lungs, muscles or subcutaneous connective tissue of experimental animals. Connection, facilitating the excretion of radioactive isotopes, was administered daily once or twice a day by injection, in the form of powder, liquid, aerosol or patch. After this was determined by the total radioactivity of the body and received delay curves, which are then compared with the same parameters obtained in control animals.

Curves delays were analyzed using computer, using for this purpose the program, known as Nonlinear Regression by the Code of BMDP-3R(BMDP Statistical Software Manual, UCLA, Los Angeles, 1990, Chief Editor, W, J. Dixon). On the basis of the obtained results we can conclude that the curves describes two descending exponential function. To calculate the efficiency used two indicators. One of them served the so-called F-factor describing the increased excretion of radioactivity in comparison with observed in control animals, which reflects an increase in the excretion of the radioisotope under the influence astroimages).

For a more visual comparison of the characteristics of the compounds that are the subject of the invention are the so-called indicators E1, which was obtained by multiplying the intensity of excretion of the radioisotope in the percentage observed in the control group (efficiency (E) and indicator of acute toxicity (LD50/30harmless, 1), shown in column D of table. Although the indicator E1 digital expression and not identical to the index of therapeutic security connection, it is in all cases characterized by weak or high activity of the tested product.

An important experimental result is considered no defined using method was used to radioactive strontium in the bones of animals that were administered the active compound according to the invention. In soft tissues and liver of animals of residual radioactivity accounted for 5-10% of the total delay, whereas the control animals the main part of the delay was due to the accumulation of radioactivity in the bones (65 to 70).

Similar results were obtained by different routes of administration of the test compounds in the animal body. It is shown that very high efficiency had connected the race. From among these compounds are especially remarkable properties possessed N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-calc avicoles, double Sol. The value of highly effective compounds with the formula (1) is due to their very good indicators of therapeutic security. The above disodium salt of calcium is particularly preferred due to its low toxicity and ability to enhance the removal of radioactive isotopes from a living organism.

Compounds with formula (1) can be used in the composition of medicines in combination with conventional carriers and other well-known auxiliary materials. Suitable for this purpose, the media and other additives are described in detail in numerous manuals on the matter.

To study the efficacy of the compounds described in examples 1 to 16, showed that after their introduction is the absorption of the active ingredient, which then provides the excretion of radioactive isotopes. The introduction is carried out as part of injectable solutions or in the form of tablets placed under the tongue, pills, capsules, tablets for oral administration, powders, liquid aerosols and skin bandages. E. one or more parts of this total dosage, preferably in the form of two subnotebook.

Drugs, containing as active ingredient the compounds of formula (1), suitable to prevent the accumulation of in vivo harmful metal ions.

P R I m e R 1. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia-salcoatitan, Terentieva salt.

a) to 2.74 g (14,98 mmol) 2-bromomalonate neutralize acid in 1 ml of water, adding a solution of sodium hydroxide at a concentration of 7,410 mol/l in the presence of phenolphthalein indicator. Then, the resulting mixture was added 1.75 g (3,69 mmol) N-dicarboxyethyl-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane (disodium salt) containing 14,10 wt. sodium bromide (intermediate) obtained in the preceding reaction, and 1.95 g (7,43 mmol) 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane. The reaction mixture is left at 60aboutWith 10-11 hours, adding to it a solution of sodium hydroxide at a concentration of 7,410 mol/l (14,98 mmol) in portions of 0.1 ml total 2,02 ml After completion of the reaction the mixture is optionally filtered off add sodium bromide, evaporated, dried under reduced pressure and extracted with several portions of methylene chloride, the total amount is about ether, and obtained after filtration the precipitate is dried in a stream of nitrogen. of 2.27 g (4,82 mmol) thus obtained product containing 13.3 wt. sodium bromide (intermediate), used in the production of the next batch of the desired product.

Identification indicators intermediate:1H-NMR spectrum (200 MHz, D2O), parts/million): a 3.87 (1H, S), 3,67 (18H, m), 2,78 of 2.92 (8H, m).

The residue formed after extraction with methylene chloride, extracted with 60 ml of anhydrous ethanol up until the extract is virtually no solid material. The residue after the final extraction plant in 6 to 7 ml of water and after adding sodium bromide evaporated and dried to a dry residue. The latter is extracted with 30 ml of anhydrous ethanol, as described above. Both ethanol extracts are combined and evaporated to a dry residue, which contains 4,89 g of a double salt, which has 22,71 mol of sodium bromide. The output for the macrocycle is 94,1% of the material. The residue after the final extraction plant in 6 to 7 ml of water and after adding sodium bromide evaporated and dried to a dry residue. The latter is extracted with 30 ml of anhydrous ethanol, as described above. Both ethanol extracts are combined and evaporated to samogo the macrocycle is 94,1%

Identification performance for double salts: IR spectrum (KBr, cm-1): 2950, 2868 (m, CH), 1605 (VS, COO/as), 1430 (m, COO/S). Other characteristic, but not identified frequency: 1350 (S), 1320 (S), 1095 (S), 928 (W).1H-NMR spectrum (200 MHz, D2Oh, parts/million): 54,00 (2H,S) 3,70 (8H, S), 3,63 (8H, t), of 2.92 (8H, t).

b) sodium Bromide is removed from the double salt by extraction with 50 ml of 95% (by weight) of ethanol. The resulting residue is dried and freed from ethanol by evaporation under reduced pressure with the formation 3,22 g of the final product. The output for this macrocycle is 93.2

Identification performance for last:1H-NMR spectrum (200 MHz, D2Oh, parts/million): 3,95 (2H, s), to 3.64 (8H, s), of 3.60 (8H, t), 2,85 (8H, t).13C-NMR spectrum (50 MHz, D2Oh, parts/million): 179,95 (C 0), 76,45 (N-CH-(COO)2), 71,66 and 70,84 (O-CH2), 54,06 (N-CH2).

P R I m m e R 2. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia-selloutica, Terentieva salt containing disodium oxomalonate.

In accordance with the procedure described in example 1,2,84 g (15,54 mmol) 2-bromomalonate acid, 2,02 g (4,11 mmol) N-dicarboxyethyl-1,4,10,13-tetraoxa-7, 16-diazacyclooctadecane disodium salt containing 16,87 wt. sodium bromide and a 2.01 g (7,66 mmol) 1,4,10,1 Crookes separate sodium are added in several portions over 10 hours As a result of extraction with methylene chloride receive one-deputizing derived 2.17 g (to 4.41 mmol). It contains 16,93 wt. sodium bromide. The weight of the final product to 3.92 g, yield of 96.5 (if the calculation used the macrocycle). The product contains 1.6 wt. disodium of oxomalonate.

Range1H-NMR (200 MHz, D2Oh, parts/million) corresponds to the spectrum of the product obtained in example 1, except that it also gives a resonant signal at 4, 31 (S), which is typical for oxomalonate.

P R I m e R 3. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia-selloutica, tetracylines salt.

a) of 1.32 g (7.22 mmol) of 2-bromomalonate neutralize acid in 1 ml of water, adding a solution of potassium hydroxide at a concentration of 5,760 mol in the presence of phenolphthalein indicator. In the thus obtained solution is added to 1.25 g (4.77 mmol) 1,4,10,13-tetraoxa-7,16-dieselloks-Dean. The reaction mixture is heated to 50aboutC for 26 h, adding portions equivalent quantity of a solution of potassium hydroxide at a concentration of 5,760 mol/L. After evaporation of the mixture of the solid residue is dried under reduced pressure, and then extracted with methylene chloride total volume of 20 ml in a number of techniques. PEFC is Kadena, Pikalevo salt containing 16.7 wt. potassium bromide (intermediate). This product can be used to prepare the next batch of the desired product.

The residue after extraction with methylene chloride is extracted with 60 ml of anhydrous ethanol and after evaporation of the solution, the residue is dried with the formation of 2.18 g of the desired product, i.e., the output 94 when calculating used on the macrocycle.

The product is a double salt with potassium bromide, which contains 29,97 wt. bromide of potassium.

1H-NMR spectrum of the intermediate (200 MHz, D2Oh, parts/million): 3,86 (1H, S) 3,63 (16H, m), 2,89 (4H, t), 2,78 (4H, m).

1H-NMR spectrum of the double salts formed by calcium bromide (200 MHz, D2Oh, parts/million): 3,99 (2H, s), of 3.69 (8H, s), 2.63 in (8H, t), 2,86 (8H, t).

b) Clean, free from potassium bromide, the product can be obtained as described above using about 97. of ethanol. The result is of 1.16 g of the desired product, i.e. the output of 75.6 when terms used macrocycle.

1H-NMR-spectrum of the desired product (200 MHz, D2Oh, parts/million): 4,00 (2H, broad s), 3,70 (8H, broad s), the 3.65 (8H, broad), 2,88 (8H, broad).

P R I m e R 4. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-TA magnesium chloride, diluted in 2 ml of water, add the solution containing 0,81 g (of 1.46 mmol) of the product obtained as described in example 1B, 3 ml of water. After 30 min, the solution was evaporated under reduced pressure and the residue is dried with the formation of 0.93 g (of 97.8) of the desired product containing 17.99 wt. sodium chloride.

1H-NMR spectrum of the final product (200 MHz, D2In the presence of NaOD, parts/million): 4,00 (2H, s), to 3.67 (8H, s), 3,62 (8H, broad), 2,88 (8H, broad).13H-NMR spectrum (50 MHz, D2Oh, ppm): 179,71 (C=O) 71,88 and 71,05 (O-CH2), 54,51 (N-CH2).

Note: resonance signal CH(COO)2missing from deuteranomaly.

P R I m e R 5. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia-selloutica-cal of leukoplakia, disodium salt containing sodium chloride.

Use the process described in example 4, from 0.92 g (of 1.65 mmol) of the product obtained in accordance with example 1B, and 0.25 g (of 1.65 mmol) digigrade of calcium chloride, which gives 1,08 g (of 98.2) of the desired product containing 17,57 wt. sodium chloride.

1H-NMR spectrum of the product (200 MHz, D2Oh, parts/million): 3,90 (4H, broad), 3,53 (14N, broad), of 2.92 (4H, coalescence t) of 2.72 (4H, coalescence t).13C-NMR spectrum (50 MHz, D<, the values of N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia-selloutica-cal of leukoplakia, disodium salt containing the disodium oxomalonate and sodium chloride.

3,44 g (18,825 mmol) 2-bromomalonate neutralize acid in 1 ml of water, adding a solution of sodium hydroxide at a concentration of 8,360 mol/l in the presence of phenolphthalein indicator. Then add 2,010 g (of 7.65 mmol) 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane. The reaction transition mixture is heated at 30 to 45aboutWith over 43 48 hours, adding to 1.83 ml solution of sodium hydroxide, which is required for the formation of disubstituted compounds. After the reaction, the mixture is left on 22 25 h at 60aboutWith adding separate portions of a solution of sodium hydroxide in quantities necessary for the hydrolysis of unreacted 2-bromomalonate. Upon completion of the reaction solution is evaporated and then act as described in example 1 b, with 4,720 g of dry crude product, which contains 12 wt. disodium of malonate and contains almost no sodium bromide. Then the obtained product is used to implement one of the following procedures.

(a) the Crude product is dissolved in a mixture of 3 ml of water and 7.5 ml of calcium chloride solution having a concentration of 1000 mol/L. Add 12 ml (99,7 about.) ethanol and 0,85 ml of calcium chloride with continuous on the Yu vigorously stirred for 30 to 60 min when heated, then filter out the solids, the filtrate is evaporated under reduced pressure and half the dry product continue to dry at 75 85aboutC and reduced pressure to obtain 4,48 g (90,6) of the desired substance containing 14 wt. sodium chloride and 1.08 wt. disodium of oxomalonate.

1H-NMR spectrum of the obtained compound (200 MHz, D2Oh, parts/million) corresponds to the spectrum of the product obtained in example 5, except that the resonant signal also appears at or 4.31 parts/million (1H, S), which is typical for oxomalonate.

b) Repeat the procedure described in section a), with the difference that after adding the first portion of calcium chloride solution (7,50 ml) was added another portion of the volume of 3.10 ml with a concentration of calcium chloride 1000 mol/L. the Content of ethanol in the reaction mixture is brought to about 90. adding 114 ml of ethanol, after which the product is dried in a stream of nitrogen to obtain substances 5 g (94,9), which contains a 19.5 mol. calcium salts calcium complex (based on the overall macrocycle), and the disodium salt of calcium complex. The final product contains up to 13.2 wt. sodium chloride, 7,35 wt. water and minor amounts of disodium oxime is, who must register in example 5.

P R I m e R 7. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia-selloutica-cal of ciidamada.

0.5 ml of water, 2,04 ml calcium concentration is 0.998 mol/l and then 30 ml of anhydrous ethanol is added to 0,554 g (1000 mmol) of Terentieva salts obtained in accordance with example 1 b. The solution is evaporated to approximately one-third the original volume and the remaining number of added ethanol in an amount sufficient to bring its concentration in the solution to 95 96 about. Then the solution is heated, stirred for 30 min, usageprice sodium chloride is filtered off and washed with anhydrous ethanol. To the combined filtrate add 0,554 g (1000 mmol) of Terentieva salt and 0,214 g (4000 mmol) of ammonium chloride and then water in a quantity sufficient to dissolve the solid material. After evaporation of the solution, the residue is dehydrated by heating at 75-80aboutC and reduced pressure, to education 1,452 g (98,1%) of the desired product containing of 19.91 wt. sodium chloride and 7,33 wt. water. Cleared chloride final product is obtained by further purification of anhydrous ethanol.

1H-NMR spectra free from chloride and soteriades the broad t), of 2.72 (4H, broad t).

P R I m e R 8. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia-selloutica-cal of leukoplakia, calcium salt.

After neutralization 2,743 g (at 9.53 mmol) 2-bromomalonate acid in 2 ml of water by adding separate portions of calcium hydroxide in the presence of phenolphthalein indicator to the solution so obtained is introduced 1000 g (3,81 mmol) 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane. The reaction mixture is heated at 40, 45 and, finally, 50aboutWith over a total of 72 h, and then to 60aboutC for 24 h with the addition of separate portions of 0.85 g (11,47 mmol) of calcium hydroxide under conditions of vigorous mixing. After that, the sediment, the bulk of which is oxymoronic calcium, filtered and washed with three portions of water for 4 to 5 ml each. The combined filtrate evaporated under reduced pressure, the resulting residue is twice distilled in 35 ml of methylene-chloride, getting a solid product, which is dried at 75-85aboutC and reduced pressure. Thus, get the desired substance 2,710 g with a yield of 89.7

1H-NMR-spectrum of this compound (200 MHz, D2Oh, parts/million) is identical to the spectrum of the product obtained as described by frequency: 1355, 1290 (m), 1250 (m), 1085 (vs), 950 (m).

P R I m e R 9. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia-selloutica-jelly Zist(II) complex, disodium salt.

Use the process described in example 4, 0,747 g (1.35 mmol) of the product obtained in accordance with section b) of example 1, and 0,268 g (1.35 mmol) chloride tetrahydrate iron. In contrast to the previously described procedure, the oxidation of divalent iron to trivalent prevent, carrying out the reaction in a nitrogen atmosphere. With this way we obtain the desired compound with a yield of 91 in number 0,835 g when the content of sodium chloride 17,16 wt.

1H-NMR spectrum of the final product cannot be defined due to the presence of paramagnetic iron ions. IR spectrum (KBr, cm-1): 2910, 2880 (m, C-H), 1630 (vs, COO/as), 1400 (s, COO/s). Other characteristic, but not identified frequency: 1355 (m), 1330 (m), 1100 (s), 930 (m).

P R I m e R 10. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16 - diazacyclooctadecane-zinc complex, disodium salt.

Use 0,735 g (1,32 mmol) of the product obtained as described in example 1 b, and 0,180 g (1,32 mmol) of anhydrous zinc chloride, of which according to the method shown in example 4, receive 0, the Tr (200 MHz, D2Oh, parts/million): 3,6 4,2 (N, wide band system t) 3,10 (8H, broad t).

P R I m e R 11. Obtaining N,N'-bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-dia - selloutica, traintravel salt.

1,72 ml of hydrochloric acid at a concentration of 1,048 mol/l are added to a solution of 1000 g (1,804 mol) of Terentieva salt, obtained as described in example 1 b, in 5 ml of water in the cooling conditions (0 to 5aboutC). After this, the solution evaporated, the residue is dehydrated methylene-chloride and dried at 60aboutC and reduced pressure to obtain 1,069 g of the final product with the release 96,7 containing 9.5 wt. sodium chloride.

1H-NMR spectrum (200 MHz, D2Oh, parts/million): 4,18 (2H, s), 3,79 (S, broad m), 3,29 (8H, broad s). Product spectrum in the D2In the presence of NaOD corresponds to the range shown in example 1 b. IR spectrum (KBr, cm-1): 2940, 22850 (m, C-H), 1655, 1605 (vs, COO/as), 1400 (m. COO/s). Other characteristic, but unidentified frequency: 1345 (s), 1320 (s), 1120 (s), 1100 (s), 930 (m).

P R I m e R 12. Obtaining N-dicarboxyethyl-N'-(1,1-dicarboxyethyl)-1,4,10,13-tetraoxa-7,16-desacyl outernational salt.

After neutralization 3,003 g (15,25 mmol) of bromeilles acid in 0.5 ml of water by addition of a solution hydrokit 2000 g (7.62 mmol) 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane. The mixture is left for 8-10 Nam at 20-25aboutWith adding portions to 1.82 ml (15,25 mmol) of sodium hydroxide concentration 8,360 mol/L. Upon completion of the reaction the mixture is stirred for 30 min at 55 60aboutWith, and then evaporated. The dry residue is extracted with several portions of methylene-chloride total 25 30 ml. After evaporation of the extract, the residue is treated with ether and the solid precipitate filtered off. The remaining material after extraction with ether) contains a small amount of 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, which you can remove, diluting the product of methylene-chloride and precipitating with ether. In this way we obtain a purified N-(1,1-dicarboxyethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, disodium salt containing 13,81 wt. sodium bromide (intermediate). The yield of the final product is 1,390 g (37,2%).

After evaporation of the ether extract get 1,159 g purified 2,4,10,13-tetraoxa-7,16-diazacyclooctadecane. Thus, the final output of the product reaches a 38.5

1H-NMR spectrum of the intermediate (200 MHz, D2Oh, parts/million) 3,66 (16H, m), 2,82 (4H, t), of 2.72 (4H, t), of 1.36 (3H, s).

1H-NMR spectrum (200 MHz, D2Oh, parts/million): 4,18 (2H, s), 3,79 (S, broad m), 3,29 (8H, broad s). the m-1): 2940, 2850 (m, C-H), 1655, 1605 (vs, COO/as), 1400 (m. COO/s). Other characteristic, but unidentified frequency: 1345 (s), 1320 (s), 1120 (s), 1100 (s), 930 (m).

P R I m e R 12. Obtaining N-dicarboxyethyl-N'-(1,1-dicarboxyethyl)-1,4,10,13-the - trioxa-7,16-diazacyclooctadecane, Terentieva salt.

After neutralization 3,003 g (15,25 mmol) of bromeilles acid in 0.5 ml of water by adding sodium hydroxide at a concentration of 8,360 mol/l at 0, 5aboutIn the presence of phenolphthalein indicator to the solution was added 2000 g (7.62 mmol) 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane. The mixture is left for 8-10 Nam at 20-25aboutWith adding portions to 1.82 ml (15,25 mmol) of sodium hydroxide concentration 8,360 mol/L. Upon completion of the reaction the mixture is stirred for 30 min at 55 60aboutWith, and then evaporated. The dry residue is extracted with several portions of methylene-chloride total 25 30 ml. After evaporation of the extract, the residue is treated with ether and the solid precipitate filtered off. The remaining material after extraction with ether) contains a small amount of 1,4,10,13-tetraoxa-7,16-disallowance-decane, which you can remove, diluting the product of methylene-chloride and precipitating with ether. In this way we obtain a purified N-(1,1-dicarboxylate the go). The yield of the final product is 1,390 g (37,2%).

After evaporation of the ether extract get 1,159 g purified 2,4,10,13-tetraoxa-7,16-diazacyclooctadecane. Thus, the final output of the product reaches a 38.5

1H-NMR spectrum of the intermediate (200 MHz, D2Oh, parts/million) 3,66 (16H, m), 2,82 (4H, t), of 2.72 (4H, t), of 1.36 (3H, s).

Using this intermediate connection get disubstituted derivative by the method described below.

After neutralization 0,483 g (2,64 mmol) 2-bromomalonate acid in 0.5 ml of water by adding sodium hydroxide at a concentration of 8,360 mol/l in the presence of phenolphthalein indicator added 1,002 g (2.04 mmol) of the above intermediate compounds containing 13,81 wt. sodium bromide. Then the reaction mixture was left for 72 h at 30-45aboutWith and then for a further 24 h at 50-60aboutWith adding in portions of 0.32 ml (2,64 mmol) of sodium hydroxide in a concentration of 8,360 mol/L. Upon completion of the reaction solution is evaporated and the residue is dried at 75 80aboutC and reduced pressure. The dry residue is extracted with anhydrous ethanol, the ethanol extract was evaporated to dryness under reduced pressure and dried with education 1,323 g of a double salt, cdxtract double salts 96. ethanol as described in example 1 b. The result is 0,532 g of the desired substance with a yield of 54.5

1H-NMR and IR spectra of the double salt is almost identical spectra chetyrehmetrovoy salt. IR spectrum (KBr, cm-1): 2960, 2870 (m, C-H), 1645, 1600 (vs, COO/as), 1405, 1440 (m. COO/s). Other characteristic, but unidentified frequency: 1355 (s), 1315 (s), 10995 (s), 930 (m).1H-NMR spectrum (200 MHz, D2Oh, parts/million): the 3.89 (1H, s), 3,68 (16H, m), of 2.92 (4H, t), 2,78 (4H, t), of 1.41 (3H, s).

P R I m e p 13. Obtaining N-dicarboxyethyl-N'-(1,1-dicarboxylate)-1,4,10,13-tetraoxa-7,16-diesel katerinastrieby salts, double salts of sodium bromide.

Obtaining carried out according to the method described in example 12, using 1,608 g (7.62 mmol) of 2-bromoethylamine acid and 1000 g (3,81 mmol) 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane that gives 0,517 g of N-(1,1-dicarboxylate)-1,4,10,13-Tetra-oxa-7,16-diazacyclooctadecane, disodium salt, which contains 15,61 wt. sodium bromide. After evaporation of the ether extract get 0,508 g 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane. Thus, the true yield of the desired product is 53.3 per

1H-NMR spectrum of the intermediate (200 MHz, D2O parts/million): 3,68 (16H, m), is 2.88 (4H, t), 2,82 (4H, t), of 1.84 (2H, q), of 0.90 (3H, t).

Search double the 0 mmol) of the above intermediate compound, containing 15,61 wt. sodium bromide and 0,229 g (1.20 mmol) of 2-bromomalonate acid.

1H-NMR spectrum of the desired double salts (200 MHz, D2Oh, parts/million), 3,88 (1H, s), 3,67 (16H, m), 2.91 in (4H, t), of 2.86 (4H, t), of 1.84 (2H, q) to 0.88 (3H, t).

P R I m e R 14. Obtaining N-dicarboxyethyl-N'-(benzyl-dicarboxyethyl)-1,4,10, 13-tetraoxa-7,16-diazacyclooctadecane, chetyrehmetrovoy salt containing disodium oxomalonate.

Use the procedure described in example 12 with the difference that the reaction is carried out in a mixture of water with ethanol (1:1), which add 2,081 g (7.62 mmol) of 2-bromo-2-benzylmalonate acid and 1000 g (3,81 mmol) 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane. In this way receive 0,372 g of N-(benzyl-dicarboxyethyl)-1,4,10,13-tetraoxa-7,16-disallowance-decane containing 11,21 wt. sodium bromide (intermediate) output 17,4 After evaporation of the ether extract get 0,714 g 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane. Thus, the true yield of up to 60.9% of

1H-NMR spectrum of the intermediate (200 MHz, D2Oh, parts/million): was 7.45 (2H, d), 7,29 (3H, m), 3,68 (12H, m), of 3.57 (4H, t), 3,47 (2H, s), 2,78 (8H, m).

The desired double salt containing 0.42 mol of disodium oxomalonate, get, using 0,372 g (to 0.662 mmol) of the above is the final product first, the extraction is carried out in the methylene-chloride, and then absolute ethanol, giving 0,432 g of the desired salt with access to 91.4

1H-NMR spectrum of the final product (200 MHz, D2Oh, parts/million): the 7.43 (2H, d), 7,29 (3H, m), 3,90 (1H, s) to 3.64 (16H, broad), to 3.34 (2H, s), 2.91 in (4H, t), 2,80 (4H, t).

P R I m e R 15. Obtaining N,N'-bis(1,1-dicarboxyethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, chetyrehmetrovoy salt.

After neutralization of 3.11 g (14,79 mmol) of bromeilles acid and diluted to 1 ml by adding sodium hydroxide at a concentration of 8,360 mol/l at 0, 5aboutIn the presence of phenolphthalein indicator added to 3.52 g (6,565 mmol) of N-(1,1-dicarboxyethyl)1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, disodium salt containing at 18.6 wt. sodium bromide (intermediate). Then the reaction mixture is heated to 20 25aboutWith and leave for 10-12 Nam, adding portions 1.77m (14,79 mmol) of sodium hydroxide in a concentration of 8,360 mol/L. Before termination of the reaction mixture for 30 min heated at 55 60aboutWith and evaporated. The dry residue is extracted with several portions of methylene-chloride total 45 50 ml. of the Extract evaporated, the residue is treated with ether, the precipitate is filtered off and dried. In this way gain of 2.08 g (4,29 mmol) intermediate compound, with the="ptx2">

The solid material remaining after extraction with methylene chloride, dried at 75-80aboutC and reduced pressure. After extraction of solids 55 60 ml of anhydrous ethanol, the obtained extract was evaporated to a dry residue under reduced pressure and dried to education 3,90 g of a double salt containing 78,2 wt. sodium bromide at the exit of 22.2 Estimated yield of the intermediate product used in the reaction, is 64.3

1H-NMR-spectrum of a double salt (200 MHz, D2Oh, parts/million): to 3.67 (8H, s), to 3.64 (8H, t), 2,73 (8H, t), of 1.36 (6H, s).

The product does not contain sodium bromide, obtained from 3,90 g of a double salt containing 78,2 wt. bromide of sodium, which is extracted with 96. ethanol as described in example 1 b. This way we obtain a 0,489 g of the desired product with a yield of 57.5

After evaporation, drying and re-extraction with anhydrous ethanol get a double salt containing 80 to 90 wt. sodium bromide (from the filtrate with 96% ethanol). This double salt can be used to obtain the next batch of product.

1H-NMR-spectrum of the desired product (200 MHz, D2Oh, parts/million): 3,70 (S, broad m), 2,71 (8H, coalescence t) 1,34 (6N, extended s).

P R I m e R 16. Obtaining N,N'-bis(benzyl-d CLASS="ptx2">

Use the procedure described in example 15. The reaction is carried out with 0,362 g (1,324 mmol) 2-bromo-2-benzylmalonate acid and 0,372 g (to 0.662 mmol) one-deputizing intermediate compounds containing 11,21 wt. sodium bromide in a mixture of ethanol with water at a volume ratio of 1:1. In this way receive of 0.085 g of a double salt containing 4.2 mol of bromide of sodium, with the release of 11.1%

During the described procedures have 0,296 g of the intermediate product, which contains 11,21 wt. sodium bromide. Thus, the estimated yield for the reaction intermediate product is 54,2%

1H-NMR spectrum of the desired compound (200 MHz, D2Oh, parts/million): to 7.64 (4H, d), was 7.45 (6H, m), 3,65 (12H, m), 3,65 (12H, m), 3,52 (4H, t), and 3.31 (4H, s), 2,68 (8H, t).

P R I m e R 17. Rates of acute toxicity of the products obtained according to examples 1 to 16, were determined in laboratory mice and rats by the following method.

Solutions containing test compounds at various concentrations were prepared on the basis of physiological saline or 5% (by weight) glucose solution. Active compounds in different concentrations were injected into the bloodstream of animals, using for this purpose slow for 3 to 5 min, injection. To test each dodania for the animals continued for 30 days. Indicators LD 50/30, i.e., the dose that causes the death of 50 animals for 30 days, was determined by the number of deaths during this period, mice and rats using probit analysis as described by D. J. Finney (Probit Analysis, Ind ed. Cambridge University Press, 1952). These indicators are expressed in mmol/kg of body weight. The results of the evaluation of the toxicity of the compounds obtained according to the invention, are summarized in the column In the table.

The table shows the main characteristics of the products according to the invention.

P R I m e R 18. The described method of evaluation stimulating action of the compounds obtained according to examples 1 to 16, on the removal of radioactive isotopes from the body of mice.

In the abdominal cavity of the animals were injected radioactive strontium (85SrCl2) or cerium (144eCl3with activity from 37 to 74 kBq (1 2 µci). Then the animals were divided into groups of 5 0 individuals each. After 30 to 60 min after the injection of radioisotopes one group of animals was intravenously injectively active compound in a quantity providing its concentration in the body 50 to 100 µmol/kg body weight. Animals of the control group was similarly injected media (sterile saline solution or 5% glucose solution), not containing a TEC is PA, and then repeated the measurements on a daily or every two or three days in a special apparatus, designed to establish the content of radioactivity in the body of small animals. The results were compared with the background activity at day 0 and was calculated the so-called delay time, setting its correlation with the duration of the period after the introduction of the radioisotope. Changes in the content of radioactivity in animals over time (in days) is shown in Fig.1, in which the ordinate delayed delay introduced radioactivity (as a percentage of the initial amount), and the abscissa the period after the introduction of radioactivity. It is evident from Fig.1 shows that the rate of excretion of strontium-85 after its introduction into the abdominal cavity of the animals of the control group was low: during the first day were derived only 15 for 4 DN 25 and over 7 DN 30 total amount of radioactivity. In subsequent excretion rate had slowed. On the other hand, after a single injection of active compound, obtained as described in example 13, in a dose of 100 μmol/kg for the first day was warmed to 40 the total amount of radioactivity within 4 DN 65 and over 7 Nam 67 Even more impressive result is within a specified time was in this case respectively 81, 84 and 85% On the basis of statistical analysis of the above method, it was found that the curves of delay active compounds according to the invention describes a two descending exponential function. The factors E and indicators E1, characterizing the products obtained according to the invention, presented in columns C and D of table. Obviously, the effectiveness of individual drugs with regard to their stimulating effect on the excretion of radioactivity from the body of experimental animals is significantly different, especially if based evaluation on indicators E1. Connection with figure E1 between 0 and 5, are poorly active connection performance of E1 from 5 to 50 can be estimated with an average efficiency and connection with the performance of E1 from 50 to 100 or higher, must be regarded as highly effective for this purpose drugs.

P R I m e R 19.

a) delay Curves of radioactivity is shown in Fig.2, illustrate the removal of radioactive strontium, which was introduced nutritarian in the lungs of rats Wistar after intra-abdominal injection of the compound described in example 6b. The nature of the upper curve in Fig.2 witness who was claravale solvent, not containing the test compound. For several days after radioactive contamination from the body displayed no more than 30 35 initial amount of radioactivity. At the same time, the level of radioactive contamination of the organism as a whole has decreased from 90 (control) to 20 animals, which were injected once with 50 µmol/kg body weight of the compounds according to the invention (middle curve) or who have entered it twice during the day after contamination with 3-hour intervals (lower curve). Fast removal of radioisotope continued throughout the observation period and reached 88 90 single administration of the drug and up to 94 96 after his double injection. It is important to emphasize that during the experiment the radioactive strontium was practically absent in the bone tissue of animals, which was introduced one of the compounds according to the invention (according to the survey after slaughter at the end of the experiment). Residual radioactivity in the soft tissues and the liver was 5-10% whereas in the control the main part of the label (65 of 70) was retained in the bones. Similar results were obtained by intravenous injection of the test compounds or their introduction into the subcutaneous connective tissue.

144CeCl3after its introduction in the lungs of female rats line Westar as a function of time elapsed after a single dose or after repeated injections with an interval of 24 h (see Fig.3). The results obtained show that the compounds according to the invention can be used to enhance the excretion of radioactive materials with relatively poor solubility in biological fluids (light pollution). By the end of the experiment, i.e., 30 days, control animals in the lungs remained until 40 initial amount of radioactivity, whereas in animals treated with a single intraperitoneal injection of one of the active compounds of the invention, this indicator did not exceed 14 Total delay of radioactivity under the influence of the tested compounds after 60 min decreased to 5.6 and continued to decrease over the next day. Her sharp decline at the beginning of the experiment and the slowdown in later terms were, apparently, due to the nature of the solubility of the radioactive contaminant material and features elimination in the composition ke radioisotopes after injection into the bloodstream, the abdominal cavity and subcutaneous connective tissue. From the point of view of therapeutic efficacy in humans and, more importantly, from the point of view of quick and effective protection of the large continents of the population seemed important to show that the compounds according to the invention can be used to accelerate the removal of radioactive isotopes and other ways of their introduction into the organism. To this end, experiments were carried out on rats line Wistar. Parts of animals, radioactive strontium was injected into the abdominal cavity, and after 60 minutes they nutritarian entered active compounds obtained according to the invention. As such compounds used drugs with indicator E1 over 100, which are shown in the table. After injection for 30 days was determined by the total radioactivity of the body of rats. In the analysis of delay curves of radioactivity was found that in case of construction of a conventional connection method according to the invention had a high efficiency from the point of view of elimination of the label after inhalation in the form of a powder or aerosol. Animals from the control delay has reached 91 and rats who were administered the drug according to the invention, it is the first day was reduced to 15 and on the third day the CLASS="ptx2">

In additional experiments explored the possibility of adsorption of active compounds according to the invention with the surface of epithelial tissues. On the back of rats shaved a plot size of 3 x 3 see After the introduction of their lungs vnutritraheinogo way radioactive strontium (under anesthesia) was determined by the General level of radioactivity in the body. After this, the solution of the compounds according to the invention was applied on the prepared skin area and was closed the last sticky patch. On the basis of daily measurements of total radioactivity levels in the body is determined that the connection according to the invention had the ability to enhance the excretion of radioactivity and the effects through the skin. Based on the results of the measurements were calculated factor F and the indicator E1, which was equal respectively 105 and 110.

The experimental results show that the active compounds obtained according to the invention, can be used in the composition of medicines in tablet form for placing under the tongue, candles, soluble in the digestive tract, pills, capsules or skin patch.

1. Derivatives 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane formula I1-C5-alkyl straight or branched chain, phenyl, phenyl-C1-C5-alkyl;

Me Mg, Ca, Fe (II), Zn; M N Na, K;

g 0,1;

z and s 1,2,

or M and N together Ca; z and s 0, provided that g 0, then M N Na, or g, z, s cannot simultaneously equal to 0.

2. Connection on p. 1, where Q1and Q2identical; R is hydrogen.

3. Connection on p. 1, have the property to eliminate radioactive isotopes from a living organism.

4. Connection PP. 1 and 2, with the property that output radioactive isotopes from a living organism.

5. N,N-Bis(dicarboximide)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane complex, disodium salt under item 1.

6. Connection on p. 5, have the property to eliminate radioactive isotopes from a living organism.

7. Pharmaceutical composition for the excretion of radioactive isotopes, including the active agent and a carrier, wherein the active means it contains compounds on p. 1 in an effective amount.

 

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