HUT73493A - Salts and complexes of n,n`-bis(dicarboxy-methyl)-1,4,10,13-tetraoxa-7,16-diaza-cyclooctadekane derivatives, ad pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to partially novel metal complexes, salts and double salts of 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane compounds of formula (I), wherein Q<1> and Q<2> mean hydrogen or a group of formula (III), in the groups of formula (III) the R substituents independently represent hydrogen, a C1-5 straight or branched chain alkyl group, a C2-5 straight or branched chain alkenyl group, phenyl or phenyl-C1-5alkyl group, the two latter ones optionally being substituted on their aromatic part by one or more halogen(s), C1-5alkyl, C1-5alkoxy, cyano or nitro group(s), with the proviso that at least one of Q<1> and Q<2> is other than hydrogen; Me stands for an alkaline metal or alkaline earth metal or transition metal ion; q is 0 or 1; M and N, independently from each other, stand for hydrogen or an alkaline metal, alkaline earth metal or optionally substituted ammonium ion; m, n and p are integers each being equal to the charge of M, N or Me, respectively; s and r are, independently from each other, 0, 1, 2, 3 or 4, with the proviso that (i) r, s and q cannot simultaneously be 0; and (ii) the number of hydrogens in the meaning of M or N may be 0, 1 or 2, as well as pharmaceutical compositions containing these compounds. The compounds and compositions according to the invention can be used for the decorporation of metal ions, mainly radioactive isotopes such as radioactive strontium or cerium being harmful to the living organism. The active agents according to the invention exert their effects either in intravenous or local, transdermal or rectal route of administration.

Description

This invention relates to novel N, N'-bis (dicarboxymethyl) -

Water soluble salts and complexes of 1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane and its derivatives and pharmaceutical compositions containing the compounds. In the formula

R is hydrogen, C 1-5 straight or branched alkyl or benzyl,

M and N are the same or different and may be hydrogen, an alkali metal or alkaline earth metal or ammonium ion, and Me is a transition metal, preferably an iron or zinc or alkaline earth metal, preferably magnesium or calcium, m and η 1 or 2, p 1, 2 or 3 , q is 0 or 1, s and r are 0, 1 or 2 with the proviso that the number of hydrogen atoms is 0, 1 or 2 and with the proviso that if q = 1 then s and r cannot be 0 or 2 at the same time and with the proviso that when q = 0, then M and N cannot be an alkaline earth metal or ammonium ion, and when q is 0 and each R is hydrogen, then M and N cannot be the same as sodium or lithium.

The present invention also relates to pharmaceutical compositions for enhancing the elimination of radioactive metal isotopes of the compound of formula (I) as active ingredient in water.

The compounds of formula (I) possess specific complexing properties which enable them to bind and remove from the body radioactive strontium and cerium in the bloodstream and in the extracellular space of the organism. The use of parenteral pharmaceutical formulations containing the active compounds of formula (I) as an active ingredient will prevent the deposition of radioactive strontium in the tissue compartments and thereby reduce or prevent serious damage to health caused by exposure to the body.

It is known that radioactive isotopes that are extremely dangerous in the event of a nuclear explosion or nuclear reactor catastrophe can be released into the atmosphere · Such as iodine 1J1, strontium 89 and 90 »cesium 1J4 and 1J7, and cerium 141 and 144 ·

If these isotopes enter the bloodstream or lymphatic system by inhalation or by ingestion of food or fluid into the digestive tract or through the skin, they will be deposited and accumulate in the lungs, resulting in serious health damage.

Protection against radioactive stronclum is particularly problematic because after a few hours of radioactive contamination strontium starts to be incorporated into the bones and it is not possible to remove already deposited stronclum from the body ·

The only way to control this is to prevent strontium from integrating into tissues, particularly bone tissue, by delivering a suitable strontium-specific complexing agent to the

> · · The isotope in the extracellular space is bound and extracted from the body in a stable complex.

The problem is solved by the fact that, in the case of complexing agents known in the art, such as ethylenediaminetetra-acetic acid or diethylenetriaminepentaacetic acid, calcium complexes are substantially more stable than strontium complexes.

There was a new opportunity for the praise by producing the crown ether and crypt type molecules discovered in the late 1960s, since the mechanism of complexation differs from the complexing properties of previously known ligands by introducing metal ions into wells of well-defined size, the stability of the complex depends primarily on the size of the metal ion.

The first promising result was obtained from the study of 4,7,13,16,21,2 * -hexaoxa-1,1'-diazabicyclo £ 5.8.87hexacosan, which has a stability constant of its strontium complex several orders of magnitude higher than that of its calcium complex. (Coordination Chemistry of Macrocyclic Compounds, Ed. GA Maison, Plenum Beess, 1979). However, when tested in animal experiments, they could only demonstrate that dissociation of the ligand bound and administered outside the body to the radioactive metal did not occur, but did not provide evidence that the radioactive strontium present in the test animals was stable in the ligand complex. can be extracted from the body (Naturwiss. 52, 248 (1970), 61, 455 (1974) | 64, 96 (1977)).

It is an object of the present invention to provide a ligand with a specific complexing property which forms a stable complex with radioactive strontium in the bloodstream and extracellular space and is cleared.

from the body.

Surprisingly, it has been found that the formula (I)! water-soluble salts and complexes - wherein R, Me, M and N are as defined above, and m, n, p, q, r and s are as above capable of binding and greatly enhancing the clearance of radioactive strontium or cerium under in vivo conditions from the body.

The importance of the above compounds is enhanced by the fact that their therapeutic efficacy is very favorable.

For the preparation of the tetralithium salt of N, N '-bis (dicarboxymethyl) -1,4,10,13-tetraoxa-7,16 diazacyclooctadecane tetralithium, a method was described by F. de Jong et al., Recl. Trav. Chim. Pays. -Bas 102, 164 (1983), according to which the corresponding cryptand was reacted with 2-bromo-malonic acid methyl ester to hydrolyze the resulting ester derivative to the lithium salt in only 15% yield. The lithium salt thus prepared is used in the petroleum industry in the form of a composition suitable for increasing the solubility of barium sulfate according to British Patent No. 2,024,822.

The compound described in Example VI of the Shell Patent (GB 2 024 822) is not the same as the compound we want to protect because the malonyl group in the disclosed method is 1,10-diaza-4,7,13,16-tetraoxycyclooctadecane forms an acid amide compound. The so-called solubility of barium sulfate is indicated for the compound. effectiveness

• · ·· ·:.

• · · · · ·

- 6 gi is very low, and an unrealistically high amount of halogen is reported for the compound obtained after the acidification and in a subsequent publication by the inventors [P. de Jong et al., Recl. Trav. Chim. Pays-Bas (JR Neth. Chem. Soc.) 102 (3) 164-73 (1983)] also confirms that the compound of Shell patent does not correspond to bis (dicarboxymethyl). -1, 10-diaza-4,7,13,16-tetraoxa-cyclooctadecane tetralithium salt composition.

In our experiments, the water-soluble salts and complexes of formula (I) can be prepared in a higher yield and simpler, in one step, by reacting a strong base or ammonium ion corresponding to the desired salt in an aqueous medium at a pH of 6-13. in the presence of 1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane and / or the dialkali metal salt of N- (dicarboxy-R-methyl) -1,4,10,13tetraoxa-7,16-diaza-cyclooctadecane wherein R is above, the solution is evaporated and the reaction product is isolated with anhydrous alcohol, if desired, to obtain the pure tetraalkali metal salts, i.e., dialkali hydroxylmalonate and alkali bromide, in 90-98% by volume ethanol or 92-99.5% by volume. extraction with% methanol or, if desired, converting the tetraalkali metal salt to an acid salt or, if desired, a salt of the complexing metals to an aqueous solution of the resulting tetraalkali metal salt. and the alkali metal salt of the resulting complex • · <»·

optionally converted to another salt.

The reaction product obtained in the first step, in addition to the target product, the metal bromide corresponding to the desired salt and, depending on the reaction temperature and the molar ratio of reactants, the hydroxyl malonate and the monosubstituted derivative (N- dicarboxymethyl) -1,4,10,13-tetraoxyl 7,16diaza-cyclooctadecane disodium).

When the reaction is carried out at 80 ° C and an excess of 2-bromo malonic acid is used to complete the conversion, the reaction product does not contain a monosubstituted derivative, but the hydroxy malonate content is so high that it is difficult to prepare the target product in pure form. can be achieved at a fairly low yield. (For example, the yield of the tetrasodium salt, which is complexed in the next step, is 55-60%).

One way to reduce the formation of hydroxy malonic acid is to use a lower reaction temperature. It has been found that the rate of reaction of the macrocycle with 2-bromomalonate is lower than the rate of hydrolysis of 2-bromomalonate using a lower reaction temperature. However, lowering the reaction temperature is naturally accompanied by an increase in the reaction time. This is most easily compensated for by increasing the concentration of the reactants, which is largely achieved by carrying out the reaction with a concentrated solution, for example 7-8 molar.

• · »· •. · · · ·« · «·. :.:. ··; ·;

Alternatively, an excess of 2-bromo-malonic acid may be used instead of an excess of macrocycle, whereby a significant amount of N- (dicarboxymethyl)

1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane (MMK) is also formed. The latter can be easily removed from the product by extraction with dichloromethane and used in the next batch to provide an excess of macrocycle.

The fact that the monosubstituted product is easily separable by dichloromethane extraction allows the preparation of a mixed R-malonyl disubstituted product in which one of R is hydrogen. Namely, when the 1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane is reacted with the disodium salt of bromo-R-malonic acid and the product obtained by evaporation of the solution by dichloromethane extraction, the monosubstituted reaction product is isolated and the bromo reacting to give the corresponding mixed disubstituted product. (Examples 11, 12 and 14).

If the reaction is carried out as described above at 40-70 ° C, preferably 40-60 ° C, the macrocyclic excess of 10-40 mol%, preferably 20-25 mol%, based on the compound of the formula II is used, preferably partially or wholly in the form of the monosubstituted derivative, the reaction product contains much less hydroxy malonate, from which the target product may be readily isolated. By using the excess macrocycle and the lower reaction temperature, the reaction yield is 92-97% for continuous production.

αχ

In a preferred embodiment of the process according to the invention, 1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane is reacted with 2-bromo-malonate so that

2-Bromo-malonic acid is dissolved in water, neutralized to pH 9-11 with a concentrated solution of sodium hydroxide, preferably 7.5 mol, and an amount of macrocycle equivalent to 2-bromo-malonic acid and 10-40 mol%, preferably 20-25 mol%, are added. excess macrocycle, preferably in the form of the disodium salt of the monosubstituted derivative. The reaction mixture was maintained at 50-55 ° C for 10-11 hours while maintaining the pH between 9-11 by addition of additional sodium hydroxide solution. After completion of the reaction, the mixture was evaporated. The reaction product thus obtained, in addition to the tetrasodium salt, which is subsequently complexed, contains a small amount of hydroxalmalonate and the disodium salt of N- (dicarboxymethyl) -1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane and sodium bromide.

In our attempts to purify the reaction product, it has surprisingly been found that dichloromethane extraction of the monosubstituted derivative and anhydrous ethanol separation of the tetrasodium salt from the hydroxy malonate can be carried out only in the presence of a sufficient amount of sodium bromide. Therefore, before the reaction mixture was concentrated, sodium bromide was added to the solution, followed by extraction with dichloromethane. (From the dichloromethane extract, the disodium salt of the monosubstituted derivative is recovered and used in the next batch.)

Reaction product purified by dichloromethane extraction · «* · ··»

Dry, dissolve in a little water and add enough sodium bromide to bring the sodium bromide content to 55-60% of the tetrasodium salt and then evaporate. The residue was extracted with anhydrous ethanol from the 2-hydroxy malonate together with the major part of the sodium bromide, the tetrasodium salt.

The production of the sodium bromide-free tetrasodium salt was also made possible by the surprising discovery that the tetrasodium salt in 9098% by volume, preferably 95% by volume of ethanol and 92-99.5% by volume of methanol, preferably 98% by volume it is no longer soluble, but sodium bromide is freely soluble and can be removed from the tetrasodium salt (Example 1).

If the reaction product contains up to 2% by weight of hydroxymalonic acid, the yield of the above process variant can be further improved and substantially simplified due to the absence of each purification step (Example 2).

This simpler method of preparation is also important because the effect of different formulations of hydroxy malonate on the clearance of radioactive strontium was practically the same as that of the pure hydroxy malonate-free formulation.

Similarly, the tetrakalium or dicalcium salt can be obtained.

In another embodiment, the tetrasodium or tetrakalium salt is first prepared, and then the other salts or complexes are prepared.

One or two equivalents of acid, preferably hydrochloric acid, is added to the tetrasodium or potassium salt to give a solution of the acid salt which is concentrated in vacuo to give the corresponding stable solid acid (Example 10).

The complexes are prepared by adding aqueous solutions of the chlorides of the complexing metals, for example, chlorides of alkaline earth or transition metals (MgCl2 / CaCl2 etc., FeCl2, ZnCl2 etc.) to aqueous solution of the tetrasodium or tetrakalium salt (4) and Examples 9 and 9). Examples of transition metals include: chromium (III), manganese (II), iron (II), cobalt (II), nickel (II), copper (II), zinc (II), preferably iron (II). ) - or a zinc (II) atom. The sodium or potassium complex salt thus obtained may be converted into another complex salt, such as an ammonium complex salt (Example 16).

The compounds thus prepared are metal complexes of the sodium or potassium salts, depending on the starting salt, which also contain sodium or potassium chlorides which do not affect the action of the preparation (Examples 4-6).

The clearance effect of the tetrakalium salt and disodium salts of magnesium, calcium and zinc complexes in animal studies was found to be equal or better than that of the pure tetranodium salt.

• · · ·

Example 1

Ν, Ν'-Bis (dicarboxymethyl) -1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane tetrasodium salt (Na4DMK)

2.74 g (14.98 mmol) of 2-bromo-malonic acid salt are dissolved in 2.0 cm ^{3 of} water and neutralized with 7.41 moles / dm ³ sodium hydroxide solution with phenolphthalein indicator. To the solution was then added N-dicarboxymethyl-1,4,10,13-tetraoxa-7,16-diazacycloocta-decane disodium salt (1.75 g, 3.69 mmol) containing 14.10% sodium bromide. (Na2MMK) obtained in the previous reaction followed by 1.95 g (7.43 mmol) of 1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane (Kryptofix 22, Merek). The reaction mixture was heated at 60 ° C for 10 to 11 hours while 2.02 ^cm3, 7.41 mol / dm ³ solution of sodium hydroxide (14.98 mmol) was added during the first 7 hours, 0.1 cm ³ in portions, making sure the mixture has a pH between 9 and 11. After completion of the reaction, the solution is filtered if necessary, sodium bromide (3.51 g, 34.1 mmol) is added, evaporated, dried in vacuo and extracted with several portions of dichloromethane (20-25 cm ³ ). The extract was evaporated to dryness to 10-15 cm ³ of petroleum ether was added, filtered and the filter cake was dried in a nitrogen stream. The material thus obtained (2.27 g, 4.83 mmol) containing 13.3% by weight of sodium bromide was used for the next batch.

The residue from the dichloromethane extraction is extracted with 60 cm ^{3 of} anhydrous ethanol until the extract is substantially free of solids. The extraction residue is dissolved in 6-7 cm ^{3 of} water, and enough sodium bromide is added to bring the sodium bromide content to 55-60% by weight and then to dryness.

- 13 steamed and dried. It is then extracted with 30 cm ^{3 of} anhydrous ethanol as above. The two ethanol extracts were combined and evaporated to dryness.

• · · ·

The intermediate thus obtained had Na ^ DMK.2.71 NaBr composition weight 4.89 g.

IR spectrum (KBr, οϋΛ) δ 295θ, 2868 (m, 0) 1605 ( ^vs »C00 / as ^ ^{? 1450} COO / s ^ *

Other typical but unidentified frequencies »

1350 (s), 1320 (s), 1095 (s), 928 (w).

NTfR spectrum (200 MHz, <T, ppm) in Dg0: 4.00 (2H, s), 3.70 (8H, s), 3.63 (8H, t), 2.92 (8H, t) .

The intermediate product is approx. Extract with 50 cm <3> of 95% ethanol until the solids content of the extract is practically negligible. The extraction residue was dried under a stream of nitrogen and kept under vacuum at 40 to 50 ° C until the alcohol content was removed.

Weight of product (Na2 DMK): 3.22 g.

Yield (Ka.sub.2 TMK + NagMMK): 5.49 g (93.2%).

The product contains negligible content of disodium hydroxyl malonate, the content of sodium bromide is negligible,

Na ^ DMK Identification:

EMR Spectrum (200 MHz, ppm in D ₂ O: 3.95 (2H,

s), 3.64 (8H, s), 3.60 (8H, 2.85 (θΗ, t)).

¹⁵ C NMR (50 MHz, J -1, ppm) in DgC: 179.95 (0 = 0),

76.45 (N-CH / C00 / ₂ ), 71.66 and 70.84 (0-0¾), 54.06 (N-OH2).

ID:

Nuclear Magnetic Resonance Spectrum (200 MHz, ppm) in D ₂ O:

Example 2

Containing less than 2% of disodium hydroxymalonate containing N, N'-bis (dicarboxymethyl) -1,4,10,13-traoxa-7,16-diaza-cil 0 0k ta de khan-1 e tr the sodium tr i urn salt

-45 «·

2.84 g (15x5 * mmol) of 2-bromomalonic acid, 2.02 g (4.11 mmol) of NagMMK containing 16.87% sodium bromide and 2.01 g

7.66 mmol) using Kryptofix 22 was carried out as described in Example 1, except that the reaction mixture was kept at 50 ° C, with 15.54 mmol of sodium hydroxide (2.10 cm 2).

7.41 mol / dnr solution) was added over 10 hours, and after completion of the reaction (22 hours), 4.66 g (45.29 mmol) of sodium bromide was added. The amount of monosubstituted tablecloth obtained by dichloromethane extraction was 2.17 g (4.41 mmol) and the sodium bromide content was 16.95%. The remainder of the dichloromethane extraction is extracted with 60 cm <3> of 95% v / v ethanol until the solids content of this extract is practically negligible. The extraction residue was dried and alcohol-free as described in Example 1.

The product weighed 5.92 g.

Yield (Na ^ DMK + Na ^ MMK): 96.5% ·

The product contains 1.6% sodium hydroxide and negligible sodium bromide ·

The NMR spectrum (200 MHz, ppm) of DgO-bane is consistent with that of Example 1, but also exhibits the 4.51 (s) resonance signal, which is a characteristic of hydroxy malonate.

• · · ·

-IC • · · · · · · · · · · · · · · · · · · · · · · · ···

Example 3

Ν, Ν'-Bis (dicarboxymethyl) -1,4,10,10-tetraoxa-7,16-diaza-cyclooctadecane tetrakalium salt (K 2 -DMK)

1.52 g (7.22 µmol) of 2-bromo-D-malonic acid are dissolved in 1 cm @ 2 of water and neutralized with 5.7θ mol / mol potassium hydroxide solution in the presence of phenolphthalein, followed by addition of 1.25 g (4.77). mrnól) Kryptofix 22. The reaction mixture is kept at 50 ° C for 26 hours while the equivalent of (1.25 cm 2) potassium pulp H ⁹ θ 'is added in portions over a period of 12 hours.

Hydroxide solution / · The reaction mixture is evaporated, the solid is dried under vacuum, and the mixture is extracted with 20 ml portions of dichloromethane. The extract is evaporated and dried. The r.sup- (dicarboxymethyl) -1,4,10,13-tetraoxa-7,16-diazacyclooctedecane dipotassium salt (0.85 g, 1.73 mmol) containing 16.7% potassium bromide was obtained. (K ^ iX) can be used for the following batch batch. The residue from the dichloromethane extraction is extracted with 60 cwr of anhydrous ethanol until the extract is substantially free of solids * The extract is evaporated and dried.

Product weight: 2.18 g.

Yield (K 2 DLK + 1 HMM): 94.0%.

The product contains negligible dipotassium hydroxamic malonate and 29.97% potassium bromide ·

-π ~ • · «··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·„ „„ C

HMR spectrum (200 MHz, J ~, ppm) in Dg O: 3.99 (2Ηs),

3.69 (8H, s), 3.63 (8H, t), 2.86 (8H, t).

Extraction of the material obtained above with 97% v / v ethanol to give a pure potassium bromide-free product.

The product (K 2 -LKK) weighed 1.16 g.

Yield (K ₄ DMK + K 4 WK): 75.6%.

Nuclear Magnetic Resonance Spectrum (200 MHz, ppm) in Dg0: 4.00 (2H, bs), 3.7θ (8H, bs), 3.65 (8H, bs),

2.88 (8H, broad).

.Kjoélda

Sodium chloride-containing disodium salt of N, I'P-bis (dicarboxymethyl) -1,4,10,13-tra oxe-7? 16-di-8-dicycloocta de khan magnesium co mplex (NagDMKMg)

NaCl2 (0.81 g, 1.46 mmol) was dissolved in 3.0 water and a solution of magnesium chloride hexahydrate (0.30 g, 1.46 mmol) in water (2.0 cm2) was added. After half an hour, the solution was concentrated in vacuo and dried.

Yield: 0.93 g (97-8%).

The product contains 17.99% sodium chloride.

1 H NMR spectrum (200 MHz, cT, ppm) in Dg0 in the presence of NaOD: 4.00 (2H, s), 3.67 (8H, s), 3.62 (8H, broad), 2.83 (8H, broad) ).

NUR spectrum (50 MHz, ppm) in DgO: 179.71 (0 = 0),

71.88 and 71.05 (O-CHg), 54.51 (N-CHg) (lack of CH / COO / g resonance signal due to deuteration) ·

5 «Example

Sodium chloride-containing N, N'-bistdicarboxymethyl) -1,4,10,13-tetraoxa-7,16-diaza-cyclooct8decane calcium complex disodium salt (NagDMECa)

-48 • · • ♦ ···· «· ···· · · ·· · ·

X

Using 0.92 g (1.65 mmol) of Na2 DMK and 0.24 g (1.65 mmol) of calcium chloride dihydrate, the product is prepared as described in Example A ·

Yield: 1.08 g (98.2%).

The product had a sodium chloride content of 17.57% w / w. HMR spectrum (200 L HI2, <T, ppm) in DgO: 5.9θ (4H, broad), 5.75 (14H, broad), 2.92 ( 4H, merged triplet),

2.72 (4H, fused triplet).

Example 6

Disodium salt of ója, Ν'-bis (dicarboxymethyl) -1,4,10,15-tetraoxa-7,16-diazacyclooctadecane zinc complex containing sodium chloride (NagBMKZn)

The product was prepared as described in Example 4 using 0.755 g (1.52 mmol) of Na2 DMK and 0.180 g (1.52 mmol) of anhydrous zinc chloride.

Yield: 0.89 g (97.5%) ·

The product contains sodium chloride 16.92% by weight ·

NMR (200 MHz, _t, J = ppm) DGO was: 5.6 to 4.2 (18H, broad band systems), 5.10 (8H, br) · "Example?

N, N * -bis (dicarboxymethyl) -1,4,10,15-tetraoxa-7? 16-diaza- containing 0 to 10% disodium hydroxynallonate and 15 to 16% sodium chloride. cyclooctadecane-k81oium complex disodium salt (Na ₂ DMKCa)

2-Bromo-malonic acid (5.44 g, 18.825 mmol) was dissolved in water (1.0 cm 2) and neutralized with sodium hydroxide (8.56 mol / dm 2) with phenolphthalein indicator. Then, 2,010 g (7.65 mmol) of 1,4,10,15-tetraoxa-7,16-diaza-cyclooctadecane was added. The reaction mixture was held at 5θ-4 · 5 ^ο 0-οη for 45-48 hours, · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «· ·

19 while adding the amount of alkali (1.83 cm ³ ) required to form Na ⁴ OH. Subsequently, the reaction mixture is kept at 60 ° C for 22-25 hours and the basic amount (pH 9-11) necessary for the hydrolysis of the unreacted 2-bromomalonate is added in portions. After completion of the reaction, the reaction mixture was added dropwise to boiling anhydrous ethanol (150 cm ^{3) with} vigorous stirring and the solution was refluxed for a further 2-3 hours. The precipitated solid is filtered off and the filtrate is extracted until the extract is no longer solid. The product was dried to give 4.728 g of a dry crude product containing 12.0% by weight of disodium malonate and essentially no sodium bromide. The crude product can be processed in the following ways:

(a) The crude product is dissolved in a mixture of 3.0 cm ^{3 of} water and 7.5 cm ^{3 of a} solution of calcium chloride 1.000 mol / dm ³ . While stirring, 12.0 cm ^{3 of} 99.7% ethanol and 8.85 cm ^{3 of} calcium chloride solution were added to the solution, followed by the addition of 105 cm ^{3 of} 99.7% ethanol to 90% alcohol by volume. set. The resulting slurry was stirred vigorously for 1 hour with heating, then the precipitated solid was filtered off and the filtrate was evaporated. After evaporation of the alcohol, the mixture is concentrated under vacuum in a vacuum. 30 cm @ 3 of dichloromethane are distilled off from the semi-dry material and the product is dried under vacuum at 75-5 ° C.

Product weight: 4.48 g.

Yield (Na ₂ DMKCa): 90.6%.

The product contains 14.0% sodium chloride and 1.08% disodium hydroxyl malonate.

The NMR spectrum of the product (200 MHz, J ”, ppm) in DgO is the same as that of the product obtained in (e) above.

t) The crude product is treated according to a) except that after addition of the first portion of this calcium chloride solution (7.5θ cm 2), a long time solution of calcium carbonate 3 x 1 ° 1,000 mol / dm 2 is added. the reaction mixture is brought to 90% by volume with the addition of 114 cm @ 3 of ethanol and the product is dried under a stream of nitrogen.

Product weight: 5> 00 g.

Yield (Na ₂ DMKCa + CaDKIKCa): 94.9%.

In addition to the calcium complex disodium salt (Na ₂ CMKCa), the product also contains 19.5 mole% of the calcium complex calcium chloride (CaDMKCa) in all macrocycles. The product contains 13.2% by weight of sodium chloride, the water content is 7> 35% by weight, the content of disodium hydroxyammonone is negligible ·

The NMR spectrum of the product (200 MHz, _C- T, ppm) in D2O is consistent with that of Example 5.

♦ 4 · »

Example 8

Calcium Bromide Containing Calcium Salt of N, N * -bis (Dicarboxymethyl) -1,4,10,15- ^ tra 2x2-7,16-Diaza-Cyclooctadecane-Calcium Complex (CaLLiECa)

1.743 g (9.53 mmol) of 2-bromo-malonic acid are dissolved in 2.0 cc of water and neutralized by addition of calcium hydroxide in portions with phenolphthalein as an indicator. Then, 1,000 g (3.81 mmol) of 1,4,4,10,15-tetraoxa-7,16-diazacyclooctadacane was added. The reaction mixture was heated at 40 ° C, 45 ° C and finally 5 ° C for 72 hours, and the temperature was maintained at 60 ° C for a further 24 hours while stirring with 0.85 ° C (11.47 mmol) in portions. aluminum hydroxide is added.

The precipitate containing mostly calcium hydroxamic malonate was then filtered off and washed with water (4-5 cm @ 3) in 5 portions. The combined filtrates were evaporated in vacuo, the residue was evaporated to remove 55 dichloromethane as a solid, filtered through dichloromethane and washed with dichloromethane. The product was first dried under a stream of nitrogen and then dried in vacuo at 75-85 ° C.

The product weighs 2,710 g.

Yield (CaDMZCe) r 39.7% ♦

Λ The product also contains 51.5% Calcium Bromide.

The NMR spectrum (200 MHz, ppm) of the product in O is identical to that of the product prepared in Example 5.

IR (KBr, cm ^"1) 2920 i, 2880 (m,% _ _Η)" 16155 (v, ^ _{COO / as),} 1450 (m, COO 0 / R) * ^{E b} 3y® characteristic but nein identified frequencies: 1555 »1290 (π), I25O (m), 1035 (vs), 95θ (a) · • * · *

-22Ό Example ₉

Sodium chloride-containing disodium salt of N, N'-bis (dicarboxymethyl) -1,4,10,13-tetraoxa-7β-dlaz0-cyclooctadecane iron (II) complex (NagDMKFe)

0.747 g (1.55 mmol) of Na2 DMK and 0.268 g (1.55 mmol) of iron (H) chloride tetrahydrate were prepared as described in Example ·, except under nitrogen atmosphere. prevent oxidation of iron (II) ions to iron (III) ions ·

Product Weight * 0.855 g ·

Yield (NSgDMKFe): 91.0%.

The product contains 17.16% sodium chloride ·

Due to the presence of paramagnetic iron (II) ion

NME spectrum cannot be evaluated.

IR spectrum (KBr, cm -1): 2910, 2880 (m, * 1650 (v, 1), _{coo / aa} ), 1400 ( ^s )% oo / _a ) · Other characteristic but not identified frequencies: 1555 (m) , 1550 (m), 1100 (s), 950 (m).

10 «Example

Sodium chloride-containing Ν, Ν'-bis (dicarboxymethyl) -1,4,10,15-traoxa-7,16-diaza-cyclooctadecane trisodium trihydrogen salt (Na2H4MK)

NaCl DMK (1.000 g, 1.804 mmol) was dissolved in water (5.0 mL) and hydrochloric acid (1.72 cm3, 1.048 mol / dm2) was added under cooling (0-5). The solution was evaporated and the residue was dried over dichloromethane and dried in vacuo. Dry at 60 ° C.

Yield: 1.069 g (96.7%) · Sodium chloride content: 9.5% · NMR spectrum (200 MHz, ppm) in DgO: 4.18 (2H, s), 5.79 (16H, m) , broad), 3.29 (8H, s, broad).

The NMR spectrum of the product in DgO in the presence of NaOD is the same as that of Na2DMK in Example 1.

IR spectrum (KBr, cm -1) δ 2940, 2850 (m, 1655,

1605 (vs, ϋ coo / as ^ · ¹⁴⁴⁰ (“» ^ COO / s ^ · ^E 5 ^éb Typical but not identified frequencies: 134-5 (s), 1320 (s), 1120 (s), 1100 ( s), 950 (m).

Example '44 · N- (Dicarboxymethyl) -N '- (1,1'-dicarboxyethyl) -1,4,10,13-tetraX8-7,16-diaza-cyclooctadecane tetrasodium salt (Na Bromomethylmalonic acid (5.003 g, 15.25 mmol) was dissolved in water (0.5 cm 2) and neutralized with cold (0-5 ° C) sodium hydroxide (8.36 M) in the presence of phenolphthalein. 1,4,000,10,13-tetraoxa-7,16-di-cyclooctadecane (2.000 g, 7.82 mmol) was then added and the solution was heated at 20-25 ° C for 8-10 days. 1.82 cm3 (15.25 mmol) of sodium hydroxide solution (8.36 M) was added in portions. After completion of the reaction, the reaction mixture was stirred for half an hour at 55-60 ° C, and the solution was concentrated. The dry residue is extracted with several portions of 25-30 cm @ 3 of chloromethane. The extract is evaporated, precipitated with ether and the solid is filtered off and the filtrate is then extracted several times. The residue after ether extraction is small 1,4,10,13 apos; -bis-7,16-diaza-cyclo-24-

It also contains octadecane which is purified by dissolving in dichloromethane and precipitating with ether. The material thus purified was 15.81% by weight of sodium bromide containing N- (1,1'-dicarboxyethyl) -1,4,10,15-tetraoxa-7,16-diaza-cyclooctadecane disodium salt (Na ₂ MMeK). ·

Yield: 1.590 g (57 x 2%).

After evaporation of the ether extract, 1.159 g of pure 1,4,4,10,15-tetraoxa-7,16-diaza-cyclooctane decane is recovered, yielding an actual reaction yield of 88.5%.

Na ₂ MMeK Identification:

Nuclear Magnetic Resonance Spectrum (200 MHz, ppm) in D2O: δ = 66 (16H, m), 2.52 (4H, t), 2.72 (4H, t), 1.56 (JH, s).

NegMMeK can be used to obtain the disubstituted product as follows:

Dissolve 8.485 g (2.64 mmol) of 2-bromo-malonic acid in 0.5 cm @ 2 of water and neutralize with 8.56 M sodium hydroxide in the presence of phenolphthalein. Na ₂ MMeK (1.002 g, 2.04 mmol) containing 15 to 81% sodium bromide was added and the reaction mixture was stirred at 50-45 ° C for 72 hours and at 50-60 ° C for 24 hours. while the reaction mixture was added in portions to 0.52 cm3 (2.64 mmol) of sodium hydroxide (8.6 Moles / dm). After completion of the reaction, sodium bromide (0.50 g) was added to the reaction mixture, the solution was evaporated and the residue was concentrated in vacuo at 75-8 ° C. The dry material was extracted with 50-35 cm <3> of anhydrous ethanol. The alcoholic extract was evaporated to dryness in vacuo and taken up to give Na 2 DMeMK.2.06 NaBr.

Yield (Na2 DMeMK.2.06 NaBr): 1.523 g (85.0%).

Extracting 1.525 g Na ^ DMeMK.2.06 NaBr with 96 vol% ethanol in the same manner as in Example 1 gave 0.552 g of sodium.

-25ium bromide-free material can be obtained ·

Efficiency of sodium bromide inactivation: 54.5% ·

Na ^ pMeMK.2,06 NaBr and Na ^ BMeMK bromide-IR and ¹ H NMR data are practically identical ·

IR (KBr, cm ^{- '1)} "2960" 2870 (m, 0 c-IP * 1600 (vs, HCOO / as ^' ^LZG) 5, ^lW) (® · GOO / s ^ · ^{Other Μ} 1θπι20> but unidentified frequencies: 1355 (s), 1315 (s), 1095 (s), 930 (m).

¹ H NMR Spectrum (200 MHz, J, ppm) D ^{2 O} δ b ^: 3 »θ 9 (1H,

a), 3.68 (16H, m), 2.92 (4H, t), 2.78 (4H, t), 1.41 (3H, a).

Example 42

Sodium bromide-containing N- (dicarboxymethyl) -N- (1,1'-dicarboxopropyl) -1,4,10,13-tetra oxa-7? 16-diaza-cyclooctane decane tetrasodium salt (Na ^ DEtMK)

In the same manner as in Example 11, 1.61 g (7.62 mmol) of 2-bromoethylmalonic acid and 1.000 g (3.4 θ1 nanol) of tetraoxadiazacyclooctedecane containing 15.61% by weight of Na ₂ MEtK- we produce.

Yield (NagMEtK): 0.517 g (26.2%) ·

Concentration of the ether extract yielded 0.508 g of tetraoxadiazacyclooctane, yielding an effective yield of 53.3%.

¹ H NMR (200 MHz, J ^- , ppm) in D 20 O: 3.68 (16H, m), 2.88 (4H, t), 1.84 (2H, q), 0.90 ( 3H, t).

Use of NagMetK (0.517 g, 1.00 mmol) containing 15.61% sodium bromide and 0.229 g (1.20 nmol) of 2-bromo-malonic acid gave Na 2 DEtMK.3.10 NaBr.

Yield (Na2 DEtMK.3.10 NaBr): 0.475 g (52.7%).

¹ H NMR (200 MHz, ppm) of the product in DgO:

3.88 (1H, s), 3.67 (16H, m), 2.91 (4H, t), 2.86 (4H, t), 1.84 (2H, q), 0.88 (3H) , t).

~ ZC-

Example 15

N, N * -Bis (1,1'-dicarboxyethyl) -1,4,10,13-tetraoxa / M

-7,16-di8za-cyclooctadecane tetrasodium salt (Na ^ DMe → K)

3.11 g (14.79 mmol) of bromomethylmalonic acid 1.0 cm? dissolved in water and neutralized with cold (0-5 ° C) sodium hydroxide solution (8.36 M, dt / N) in the presence of phenolphthalein. (3.52 g, 6.565 mmol)

Na2MMeK (18.6% by weight) was added and the reaction mixture was heated at 20-25 ° C for 10-12 days while being treated in portions with 1.77 cm 2 (14.79 moles) of 8.36 moles sodium hydroxide solution is added. Before the reaction was complete, the reaction mixture was heated at 55-60 ° C for half an hour and then the solution was evaporated. The stem was extracted with several portions of dichloromethane (45-50 cm 2), the extract was evaporated, precipitated with ether, filtered off and dried. The thus recovered, containing 2.08 g (4.29 mmol) of 14.0% sodium bromide

M

NagMMeK is used for the next batch.

The solid remaining after extraction of the dichloro-methane was dried under vacuum at 75-θΟ ° 0-οη. The dry residue was extracted with anhydrous ethanol (55-60 cm). The alcoholic extract was evaporated to dryness in vacuo, dried and so on

3.9 g of Na 2 CO 3 containing 78.2% HaBr are obtained. Yield: 3.9θ 8 (22.2%).

/THE

The yield used for the reaction was 64.3% ·

The product had a HMR spectrum (200 MHz, J, ppm) in DgO

3.67 (8H, e), 3.64 (8H, t), 2.75 (8H, t), 1.36 (6H, s).

M

Extraction of 3.90 g of Na 2 DMegK (78.2% by weight) with DMFK (96% by volume) afforded sodium bromide-free material as in Example 1.

The weight of the product is 0.489 g.

Efficiency of sodium bromide depletion 57.5% ·

After concentration from the 96% ethanol filtrate and evaporation and drying, 80-90% sodium is added by anhydrous ethanol extraction. Ife ^ DMegK containing bromide is used and is used in the next batch.

Sodium Bromide-Free Na ^MMDEGK NMR (200 MHz, ppn) DantO-bane 3.70 (16H, bm), 2.71 (8H, fused t), 1.34 · (6H, broad s) ).

Example 15

N- (dicarboxymethyl) -N ^, N '- (benzyldicarboxynatyl) -1,4,10,13-tetraoxa-7,16-diazacyclooctedecane trisodium salt containing NaHCO3 )

Following the procedure of Example 13, except that the reaction was carried out in 5θ% aqueous ethanol, 2.081 g (7.62 mmol) of 2-bromobenzylmalonic acid and 1,000 g (3.81 mmol) of 1,4 11.21% NagMBzK containing sodium, sodium bromide was prepared from 1,10,13-tetraoxa-7,16-diazaacyclooctadecane.

Yield (Ha ₂ MBzK): 0.372 g (17.4%).

Concentration of the ether extract gave 0.714 g of 1,4,10,13-tetraoxyl-7,16-diaza-cycloctoctadecane as an effective yield; 60.9% ·

Nuclear Magnetic Resonance Spectrum (200 MHz, _t ), ppm in DgO:

7.45 (2H, d), 7.29 (3H, w), 3.68 (12H, m), 3.57 (4H, t), 3.47 (2H, a), 2.78 (8H) , m).

Using NaMBzK (0.372 g, 0.662 mmol) containing 11.21% sodium bromide and 0.161 g (0.880 mmol) of 2-bromomalonic acid, Na ₂ DB ₂ MCM 0.42 Na ₂ H0-M was prepared. The product is first isolated by dichloromethane extraction,

* · We'll do an absolute ethanol extracol *

Yield (Na ₄ DBzMK.0.42 NgO-H) 0.432 g (91.4%).

Nuclear Magnetic Resonance Spectrum (200 MHz, J, ppm) DgO

7.45 (2H, d), 7.29 (5H, m), 5.90 (1H, s), 5.64 (16H, m, broad) 3, J4 (2H, s), 2.91 (4H, t), 2.80 (4H, t).

Example 15

Sodium bromide-containing N, N'-bis (benzyldicarboxymethyl) -1,4,10,13-tra oxa-7,16-diaza-cyclooctadecane trisodium salt (Na 2 DBZgK)

In the same manner as in Example 13, the reaction was carried out in a 50 W water booth using 0.362 g (1.324 mmol) of 2-bromobenzylmalonic acid and 0.372 g (0.662 mmol) of 11.21% sodium bromide in Na 2 DBZgK.4.2 NaBr is obtained.

Yield (Na ₄ DBz ₂ K.4.2 NaBr): 0.085 g (11.1%).

The reaction yields 0.296 g of ItegMBzK containing 11.21% sodium bromide, yielding 54.2% of NagMBzK used in the reaction,

NMR (200 MHz, cT, ppm) of the product in DgO:

7.64 (4H, d), 7.45 (6H, m), 3.65 (12H, m), 3.52 (4H, t), 3.31 (40, s), 2.68 (8H) t).

-29IG · velcla

N, N '-Bis (dicarboxymethyl) -1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane calcium complex diammonium salt ([NH4] 2DMKCa)

To 554 g (1.000 mmol) of the sodium bicarbonate salt obtained in Example 1b was added 0.5 cm of water and 2.04 cm of 0.998 molar calcium chloride solution followed by 30 cm of anhydrous ethanol. The solution was diluted with ca. one third of the solvent was evaporated and anhydrous ethanol was added to make the solution 95-96% by volume with respect to ethanol. The solution was heated and stirred for half an hour, the precipitated sodium chloride was filtered off and washed with anhydrous alcohol. To the combined filtrate was added 0.554 g (1.000 mmol) of the tetrasodium salt and 0.214 g (4.000 mmol) of ammonium chloride followed by water until a homogeneous solution was obtained. The resulting solution was evaporated and the residue was dried under vacuum at 70-80 ° C.

Yield: 1.452 g (98.1%).

The product contains 19.91% by weight of sodium chloride and 7.33% by weight of water which can be extracted with anhydrous ethanol to give a chloride-free material.

The chloride-free product and the sodium chloride-containing product had the same NMR (200 MHz, δ, ppm) in δ20: 3.90 (4H, broad m), 3.73 (14H, broad m), 2.92 (4H, broad t), 2.72 (4H, broad t).

Example 17

1-13. For example, the acute toxicity of cheye products was determined in laboratory animals (mouse, rat). In the assay, the compounds were diluted in various concentrations with physiological saline or 5% glucose solution, and the active compounds were administered in increasing concentrations by slow injection into the bloodstream of the animals for 5 to 5 minutes. There were 6-10 animals (Swiss mice of both sexes and Wistar rats) in each concentration group. The animals were then observed for 5θ days. During this time, half-lethal dose (LD ^ q / ^ q) was determined by probit analysis (D.J. Finney's Probit Analysis / 2nd ed. / Cambridge University Press, 1952) of the number of animals killed.

Table 1

The number of the example Identification of the reaction product ^see 50/30 mmol / kg First Na ₄ DMK-0.76 NaBr 0.327 First Well ₄ DMK 0.379 Second Well ₄ DMK .368 5th Na ₄ DMKCa «2 NaCl Above 2.5 4th Na ₂ DMKMg-2 NaCl 0.211 6th Na ₂ DMKZn «2 NaCl 0.091 Third K ₄ DMK-2.2 KBr 0.333 4th K ₄ DMK 0.272 10th Na ₂ DMKFe * 2 NaCl 0,250 8th CaDMKCa · CaBr ₂ Above 1.5 5th Na ₂ DMKCa-2 NaCl Above 2.5 12th Well ₄ DEtMK 0.302 7a. 1.1% by volume of Na ₂ H0-M in tartrate. Na ₂ DMKCa-21.58 NaCl Above 3.0 7b. Na _1/8 DMKCa _1/2 «l, 44 NaCl Above 3.0 11th Na ₄ DMeMK · 2.06 NaBr 0.105 10th Na ₃ HDMK »NaCl 0.111 16th [NH ₄ ] ₂ DMKCa Above 2.5

Example 18

1-14. The compounds of the invention prepared by the methods described in Examples 1 to 9 have the effect of enhancing the radioactive isotope clearance

Swiss mice were compared. In examinations, it is like: · · · · · · · · · · · · · · · · · · · · · · · ·

32 animals were injected intraperitoneally with radioactive strontium (Sr-85Cl2) or radioactive cerium (Ce-144Cl3) in an amount of 37-74 kBq (1-2 μ-Ci). The animals were then divided into treatment groups (5-10 animals per group). 30-60 minutes after administration of the isotope, the drug was injected into the bloodstream (intravenous route, i.v.) of the treated group to give a compound concentration of 50-100 μιηόΐ / kg body weight per administration. The animals in the control groups were treated in the same way with the drug-free vehicle (sterile physiological saline or 5% glucose solution).

The amount of radioactivity administered to the animals immediately after administration of the isotope was determined and repeated every one to three days after administration of the active ingredient, usually for 28-30 days in a dedicated animal whole body measuring apparatus. The counts obtained were compared with the initial activity values at day 0 and a retention time relationship was obtained from the amount of activity retained (retinalized) in the body. Figure 2 shows the temporal change in animal body activity. The abscissa of the figure shows the radioactive strontium depletion activity of Na4? ETtMK and Na2DMKCa * 2 NaCl measured in days after treatment in Swiss mice, as a percentage of whole body retention on ordinate. As seen, the clearance of Sr-85 into the abdominal cavity of control animals is slow. Only 15% left in one day, 25% in 4 days slat, and 7% in 7 days · In later times, the elimination is even longer. In contrast, 40%, 65% and 67% of the activity was administered to Na ^ DEtMK (100 µmol / kg) within 1 day after a single treatment. Even more favorable results were obtained for NagDMKCa.S HeCl treatment. Quantities emptied during those times! 81%, 84% and 85%. Analyzing the retention curves obtained in the usual way, it was found that they can be described by a two-fold decreasing exponential function. indicates increased clearance (how many times more isotopes are excreted from untreated animals) and the other is the HA values from the efficacy and safety (LD ^ q) data. As you can see, the effectiveness of different decorculating agents, especially on HA values, is quite different from each other. · In our opinion, 0-5 HAs are weak, 5-50 are moderate, 50-100 are good, and over 100 are excellent. · be considered

Data listed in Table 2 are values relative to controls ·

Table 2

Labeling of the reaction product F IF Na ₄ DMK-0.76 NaBr co rH 5.40 Well ₄ DMK 2.8 9.66 Well ₄ DMK 3.3 n, i Na ₄ DMKCa «2 NaCl 3.7 145 Na ₄ DMKMg-2 NaCl 2.3 7.3 Na ₄ DMKZn-2 NaCl 2.3 3.2 K ₄ DMK «2.2 KBr 2.3 12.3 K ₄ DMK 1.7 8.98 Na ₂ DMKFe «2 NaCl 1.7 8.25 CaDMKCa-1.4 CaBr ₂ 1.6 58 Na ₂ DMKCa-NaCl 4.9 155 Well ₄ DEtMK 2.1 13.3 1.1% Na ₂ HO-M in tartrate Na ₂ DMKCa · 1.58 NaCl 3.9 158 Na _1/8 DMKCa _lz 2 * l / 44 NaCl 4.2 160 Na ₄ DMeMK · 2.06 NaBr 2.2 2.3 Na ₃ HDMK-NaCl 2.6 2.9 [NH ₄ ] ₂ DMKCa 1.7 65.00

• · · ·

-35- ..........

Example 49

the)

The whole body retention curves in Fig. 5 · show the clearance of radioactive strontium injected into the lungs of Wistar rats after intraperitoneal administration of NagDMKCa.S Ne Cl in the abdominal cavity (i.p.) of these animals.

In animal experiments, Wistar female rats weighing 230-250 g were used. The radioactive strontium (Sr-85, at a dose of 1-2 uCi) was administered to the lungs of the animals via the trachea, and after 60 minutes the test compound (vehicle for control) was injected intraperitoneally. The potential to remove radioactive material from the lungs is highlighted because this mode of delivery of these radioisotopes to the body is very common and until now there is no way to treat this type of internal contamination. Following the administration of the isotope, whole-body radioactivity was determined in a dedicated nuclear counting device. After administration of the clearance agent, the activity measurement was repeated daily or every third day. The duration of the experiment was 30-52 days. Activity values obtained after administration of the isotope were considered as the initial isotopeic load, designated 100% whole body retention. Further measured data were expressed as a percentage.

From the upper curve in the figure, it is clear that control animals treated with solvent alone have a small amount of radioactive strontium excretion. In the days following internal contamination, only 50-35% of the initial activity leaves the body. In contrast to Kz, the de-

group (50 μιηόΐ / kg) in a single treatment group (center curve), but also in animals treated twice at 3 hour intervals (lower curve), the whole body load was significantly reduced as early as Day 1 after treatment, from 90% in the control group. To 20%. In the days following treatment, rapid depletion of isotope continues, reaching 88-90% in the once-treated group and 94-96% in the double-dose formulation. Also important is the fact that little or no radioactive strontium could be detected in the bones of animals killed at the end of the study in the drug-treated groups. Residual activity of 5-10% of whole body retention was found in the soft parts of the animals and liver, while the majority of retention (65-70%) in the control body was incorporated into bone. Similarly favorable results were obtained when the decorculating agent was administered intravenously or into subcutaneous connective tissue.

b) Our isotope depletion enhancing compounds have been tested for the removal of radioactive metals other than radio-tritium, in particular cerium-144 from the group of rare metals. The whole-body retention curve in Figure 4 is an illustration of the clearance of radioactive cerium: Ce-144C13 into the lungs of Wistar female females with Na2DMKCa2NaCl repeated once and 24 hours apart.

ip treatment, depending on the treatment time. The results obtained demonstrate that the test compounds can also be advantageously used to remove this relatively poorly soluble radioactive compound in body fluids. At the end of the experiment, on day 30, the initial activity was administered

• ·

- 40% of the 37 volumes remained in the control animals, whereas the active substance i.p. 14% in the once treated group, 60 minutes after the isotope injection, and

-38 '

After one hour of treatment with the active ingredient again, whole body retention was reduced to 5.6%. Whole-body retention curves for the treated groups are initially steep, but their prolonged run is likely due to the solubility, curve, and clearance of 8 metal complexes of the pollutant.

.20. example

The? - <9. Examples 1 to 4 describe the effects of this new decorculating compound on isotope depletion following administration to the circulatory system, abdominal cavity, or subcutaneous connective tissue. From a human medical point of view, and more particularly for the effective and rapid protection of a larger population, it was important to clarify whether the formulations are suitable for the removal of internal radioactive contamination by other routes. Wistar rats were used for this purpose in animal experiments. In one portion of the studies, the animals were administered radiostraction to the abdominal cavity and, after 60 minutes, received the active ingredient in their trachea into their lungs, in a series of formulations in Table 2 above 100 HA. Whole body activity measurements were then performed for $ 0 days. Whole-body retention curves were constructed as described above and evaluated to show that the formulations have a very good elimination efficiency after inhalation in powder or liquid aerosol form. The retention of 91% in the control decreased to 15% on day 1 and did not reach 10% on day J. Factor F in Table 2 was 7.9, and HA was 164, confirming our previous statements.

In further experiments, the epithelium of the

-33 ·· ···· The potential for absorption from the cat was examined · The rats were depilated on the epidermis (cm). In anesthetized animals, radioactive strontium was injected through the trachea into the lungs and whole body activity was measured. Subsequently, the active ingredient was applied to the surface of the backwash and dissolved in a cleaned state. The affected area was then covered with a wound dressing patch. Daily whole-body activity measurements showed that the formulation exerts its isotope-mobilizing effect through the skin. Considering all measurement points, values of 2.5 for F and 105 to 110 for HA were obtained. It seems, therefore, that this therapeutic practice may also include treatments in the form of transmucosal (tongue-loaded tablet), suppository or enteric-coated tablets.

Claims (2)

PATENT CLAIMS Water-soluble salts and complexes of N, N'-bis (dicarboxymethyl) -1,4,10,13-tetraoxa-7,16diaza-cyclooctadecane and derivatives thereof, having the formula: R is hydrogen, C 1-5 straight or branched alkyl or benzyl, M and N are the same or different and may be hydrogen, an alkali metal or alkaline earth metal or ammonium ion, and Me is a transition metal, preferably an iron or zinc or alkaline earth metal, preferably magnesium or calcium, m and η 1 or 2, p 1, 2 or 3 , q 0 or q 1, s and r 0, 1 or 2 with the proviso that the number of hydrogen atoms is 0, 1 or 2 and with the proviso that if q = 1 then s and r cannot be 0 or 2 at the same time and with the proviso that when q = 0, then M and N cannot be an alkaline earth metal or anonium ion, and if q is 0 and each R is hydrogen, then M and N cannot be the same as sodium or lithium. Pharmaceutical compositions, characterized in that they contain, as active ingredient, compounds of the formula I in which the substituents are as defined above.