JPH04505626A - 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane derivatives, pharmaceutical compositions containing them and their use for the removal of toxic metal ions and radioisotopes from living organisms - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 1.4.10.13-tetraoxa-716-cyazanekurook decane palpitations , those ions from A-; Theirs The present invention provides a partially novel 1,4,10.13-tetraoxa-7,16-cyazashi Clooctadecane derivatives and metal ions that damage living organisms, especially radioactive isotopes Concerning the use of such compounds for the separation of. More specifically, the present invention includes: The following formula (1) [In the formula, Q' and C2 are hydrogen or the following formula (■): (In the formula, the R substituents are independently , hydrogen, C+-S straight chain or branched alkyl group, C2-3 straight chain or branched chain chain alkenyl group, phenyl or phenyl-C3-5 alkyl group, the latter The two groups optionally contain one or i number of halogens, C Cl-5 alkyl, Cl-5 alkoxy, cyano or nitro substituted ), where at least one of Ql and C2 is hydrogen other than; Me represents an alkali metal or alkaline earth metal or transition metal ion; q is O or 1: M and N are, independently of each other, hydrogen or an alkali metal, an alkaline earth metal, or optionally substituted ammonium ions; m, n and p are integers equal to the charge of N, M or Me, respectively; S and r are each independently 0, 1.2.3 or 4, provided that (i) r, s and q are not O at the same time: and (ii) the number of hydrogens in M or N is 0.1 or 2] 1,4.10.13-tetraoxa- Metal complexes, salts and double salts of 7,16-cyazacyclooctadecane derivatives and the same The present invention relates to a pharmaceutical composition containing a compound of the present invention.

From the compound of formula (1), a compound containing hydrogen as Q' and C2 can be used as an intermediate. Mainly used. When administered into living organisms, the compounds of formula (I) will be novel whether or not radioactive metal ions, especially radiation present in the blood circulation and extracellular space. can form stable complexes with strontium and cerium, and may be excluded.

From the compounds of formula (1), new compounds contain a group of formula (III), where each R is other than hydrogen; or q is 1 if R is hydrogen; Furthermore, when q is O, M and N are other than sodium or lithium ions. It is.

Therefore, on the one hand, the present invention relates to a compound of formula (1), where Ql and C2 are hydrogen or a group of formula (III), provided that at least one of them is a group other than hydrogen. and the R substituents are independently hydrogen, a straight or branched chain of Cl-5; alkyl group, C2-3 straight chain or branched alkenyl group, phenyl or phenyl group Nyl-CI-S alkyl group, the latter two groups being one or more halogens, alkyl of CI-5, alkyl of Cl-3 on the aromatic moiety of substituted with an xy, cyano or nitro group; Me represents an alkali metal or alkaline earth metal or transition metal ion; q is 0 or 1; M and N are, independently of each other, hydrogen or an alkali metal, an alkaline earth metal, or optionally substituted ammonium ions; m, n and p are integers each equal to the charge of N, M or Me; S and r are each independently 0.1.2.3 or 4, provided that (i) r, s and q are not 0 at the same time; (ii) the number of hydrogens in M or N is 0.1 or 2; (ii) q is 1 when R is hydrogen; and (iv) M and When q is O, N is other than sodium or lithium ion.

Regarding the substituents of formula (1), R as a Cl-5 alkyl group may be straight-chain or branched. chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , 5ec-butyl, tert-butyl, n-pentyl or isopentyl group, preferred or a methyl or ethyl group, and R as a zcX-S alkenyl group may be is a vinyl or propenyl group; R as a phenyl-Cl-S alkyl group is It may contain one of the alkyl moieties mentioned above, preferably a methyl group.

Me as an alkali metal ion is preferably a sodium or potassium ion Me as an alkaline earth metal ion preferably represents calcium or represents magnesium; and Me as transition metal ion is, for example, 3d.

Ions of metals belonging to groups 4d or 5d, preferably iron(II) (ferrous) or It is a lead ion. M and N as alkali metal or alkaline earth metal ions Preferred are the above ions; however, optionally substituted ammonium ions 1, 2, 3 or 4 alkyl, phenyl or phenyl as identified above Containing alkyl groups (assuming no steric hindrance occurs), due to their toxicity, Compounds containing tetramethylammonium ions should not be used for administration to living organisms. cannot be used.

Due to a nuclear explosion or nuclear reactor disaster, highly dangerous radioactive isotopes, e.g. Iodine-131 (item 1), Strontium-89 and -90 ("Sr and 905 r) and cesium-134- and -137 (“’Cs and +2’FC8) and Cerium-141 and -144 (“’Ce and +44Ce) are released into the atmosphere It is known that ("Nuclear and Radio chemist ry’+John Wiley and 5ons+ pages 158-166 ( (1981)].

These isotopes can enter the lungs through inhalation or through ingestion of contaminated food or fluids. If it gets into the blood circulation or lymphatic system after absorption into the gastrointestinal tract or through the skin, When they occur, they are deposited and accumulated in tissues, and finally, they can cause serious health problems. Lead to harm ((”Su+wsary Report on the Po5t A cident Revfew Meeting on the Cherno byl Accident' 5afety 5eries No, 75. IA EA, Vienna (1986)).

After radioactive contamination, strontium begins to accumulate in bones within a few hours and is precipitated from living organisms. There is no possibility to exclude (remove) the attached strontium, therefore radiation Protection against strontium is particularly problematic.

The only possible method of protection is the fixation of strontium in tissues, especially bone tissue, Introducing a suitable strontium-specific complexing agent into the product and thus the blood circulation or extracellular Combining isotopes existing in space in an appropriate form and eliminating them from living organisms It is to prevent it by.

The solution to this problem is to use complexing agents known from the literature, such as ethylenediaminete Calcium complexes of triacetic acid or diethylenetriaminebentaacetic acid are substantially made more difficult by being more stable than these strontium complexes. (A, Catsch:’Radioactive Metal Mobiliz ation in Medicine’.

Charles C, Thomas version, Springfield, l1lino is (1964); 8, Catsch: “Dekorporierving r adioaktiver and 5tabiler Metallionen ″, Therapeutische Grundlagen, Th1en+ig , Murich edition (1968); A.

Ca tsch: “Removal of Transuranium El es+ent by Chelating Agents”, :Diagnos is and Treatment o: Incorporated Rad ionuclides, IAEA Publication No. STI/P UB/411. IAEA, ν1enna+, page 295 (1976)).

New possibilities for the study of crown ether and cryptand type molecules It has been recognized through synthesis. That is, in this case, the mechanism of complex formation is a new complex. Because of the structure of the body-forming molecules, metal ions obtain well-defined sized holes and Therefore, the stability of the complex formed depends substantially on the size of the metal ion. This is different from the mechanism of complexing agents known so far.

The first convincing result is that the stability constant is several times higher than that of the calcium complex. 4゜7.13,16,2i24-hexaoxane to form a strontium complex. During research on sar-1,10-diazabicyclo(8,8,8)-hexacosane Coordination Chemistry of Macr cyclic Cowpounds”, GJ, Melson edition, Plenum Press (1979)), however, this compound was not tested in animal experiments. The complex formed with the ligand outside the organism by using Since then, it has been studied together with Gantt, a radioactive strontium that does not dissociate in living organisms. There was no evidence that the complex could be removed from living organisms as a stable complex. It was done. Furthermore, the ligand was found to be highly toxic (W, H, Mii ller: Naturwiss, 57, 248 (1970); W, H, M'1 Jller and W. A. Miller: Naturwiss.

61.455 (1974); W. H. Muller et al.: Naturwi ss, 64.96 (1977); J.

Knaj tl etc.: 12th Ann, Meeting of ESRB, Budapest (1976); J.

Batsch et al.: Nukleonika 23.305 (1978)].

Compounds of formula (I) (when q is 0 are salts and when q is 1 are complexes) body) are harmful to the organism and affect the blood circulation and extracellular space of the organism. radioactive strontium and cesium, mainly obtained from living organisms. It has specific complexing properties that allow for the binding and exclusion of ions.

Administration of a pharmaceutical composition containing a compound of formula (I) as an active ingredient to a human or animal This prevents the deposition of radioactive strontium into the tissue area and This avoids severe health damage induced by radiation burden in living organisms. , or can be reduced.

F, de Jongna means N,N'-bis(dicarboxymethyl)-1,4, 10,13-tetraoxa-7,16-cyazacyclooctadecanetetralithium A method for preparing mu salts has been published (Rec, Trav, Chim, Pays-Bas 102.164 (1983)) o According to this method, the corresponding cryptand is ester derivatives reacted with methyl 2-bromomalonate and obtained was hydrolyzed and the lithium salt was obtained with a yield of less than 15%. British patent number 2 ．． According to No. 024,822, the lithium salt thus prepared is In the form of a composition that is useful for increasing the solubility of barium sulfate in the petroleum industry can be used.

Its corresponding tetrasodium salt is also mentioned in the same specification, but only However, it is not mentioned in any particular example.

The double salt of tetrasodium salt and sodium bromate and the therapeutic utility of this double salt It is published in Hungarian Patent No. 2614189.

Formula (I) of the present invention (wherein Q', Q'', R, Me, M, N.

The complex and water-soluble salt of (■): [wherein R is as defined above and X is halogen, preferably bromine] the corresponding halogenated dicarboxylic acid represented by or a reactive derivative thereof, Suitably ester and 1.4.10.13-tetraoxa-7,16-cyazacyc rooctadecane in an organic solvent and then the thus obtained The obtained product is treated with a strong base, such as hydroxide, or with a strong base and Mixing hydroxides or salts of complex-forming metals, preferably halides, in appropriate proportions can be prepared based on the above reaction by hydrolysis with a compound.

On the other hand, formula (■) [wherein M and N are hydrogen, alkali metals, or alkaline earth metals] ion and Me represents an alkaline earth metal ion] Water-soluble salts and complexes of compounds include 1,4,10.13-tetraoxa-7,16- cyazacyclooctadecane and a 2-halodicarboxylic acid of formula (II), preferably 2 - bromomalonic acid and an alkali metal or alkali salt corresponding to the salt to be prepared. It can also be synthesized by reacting in the presence of an earth metal hydroxide.

A complex of formula (■) [wherein q is 1] is a complex of formula (■) [wherein q is 0 and its and M and N are alkali metal ions, preferably an alkali metal salt of The complexing metal halide with the sodium salt is reacted, suitably with a corresponding amount of metal chloride. It can be obtained by responding.

Clearance of metal ions that damage living organisms as they rise The effect of the compound of formula (II) of the present invention is shown in 5wlss mice of both sexes and - Using radioactive strontium or cesium ions for 1 star rats It was investigated by.

connective tissue in various areas, such as the blood circulation, abdominal cavity, lungs, muscles or subcutaneous tissue of laboratory animals; Exclusion was studied for radioisotopes introduced by various routes. isotopic Elimination-enhancing compounds can be administered to laboratory animals by injection, in the form of powder or liquid aerosols or salves. It was administered once or twice daily. Afterwards, whole body activity is measured and A residual curve was taken and then compared with the results obtained for the control group.

The resulting residue curves were analyzed on a computer. “Nonlinear Regression by the Code of BMDP-3R” (B M Kano 5 statistical Software Manual, UCLA+L osAngeles, 1990. Chief Ed.

W. J. Dixon) computer software was used for this purpose. was used. that the curve can be described by a decreasing exponential function of two components; can be mentioned from the obtained results. Two types of data characterize its effectiveness. calculated for. The data for one of these shows an increase in exclusion with respect to the control. , and means an increase in isotopic exclusion under the effect of the test compound with respect to untreated animals. It was a so-called F factor (see (C) in Table 1).

For exemplary comparisons of the compounds of the invention, additional characteristic data, the so-called EI value is given, and this value, together with the acute toxicity value (LD, .7.., harmless, ■), Increasing the degree of isotope exclusion as a percentage with respect to the control group (effectiveness, E) (See (D) in Table 1). EI value is therapeutic ratio (safety finger) numbers) are not mathematically identical, but it often It shows a certain activity.

Radioactive strontium has been detected in the bones of animals treated with the active compounds of the invention. It seems to be an important experimental observation that no ~10% residual activity was found in the soft parts and liver of the animals, whereas the control The major portion (65-70%) of the residual percentage measured in animals was bone.

Similar results can be obtained by administering test compounds to organisms by different routes. Ta.

The outstanding effectiveness is shown by the formula (■) [where Q' and Q2 are the same and R is water] It was found that this was shown by the compound [representing the element ]. Of these compounds, N, N'-bis(dicarboxymethyl)-1,4,10,13-tetrao The disodium salt of xa-7,16-diazacyclooctadecane calcium complex is particularly showed a remarkable effect on The importance of the effective compounds of formula (I) is due to their This is further evidenced by the favorable therapeutic ratio. Its low toxicity and high elimination For efficacy, the calcium complex disodium salts mentioned above are particularly preferred. .

The compounds of formula (1) can be prepared using customary carriers and other auxiliaries in a known manner. It can be converted into a pharmaceutical composition by

Useful carriers, excipients, disintegrators, binders and other additives include many related This is explained in detail in the handbook.

Studies on the effectiveness of the compounds of Examples 1-16 have shown that after administration, the active ingredient is Liquid or sublingual tablets, dragees, capsules, enteral vehicle tablets, powder or liquid aerosols or In the form of a transdermal ointment, it was shown to be absorbed and affect the degradative effect. Yes The effective dose is 1.0 to 200 μmol/kg body weight, preferably 1o to 100 μmol/k g body weight, and this is divided into l or several times; preferably It is administered in two doses.

Pharmaceutical compositions containing a compound of formula (1) as an active ingredient may also be harmful to living organisms. It is also useful for preventing the accumulation of metal ions in living organisms.

The invention is illustrated in more detail by the following non-limiting example.

anus N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa- Preparation of 7,16-diazacyclooctadecanetetrasodium salt a) 2.74 g (14.98 mmol) of 2-bromomalonic acid was added to phenolphtyl Sodium hydroxide solution with a concentration of 7,410 mol/2 in the presence of a rhein indicator. By adding water 1. Neutralize in Od. Next, the odor obtained in the above reaction is N-dicarboxymethyl-1,4,10, containing 14.10% by weight of sodium 13-tetraoxa-7,16-diazacyclooctadecane disodium salt 1. 75g (3,69mmol) (intermediate); then 1.4,10.13-tetraoxy 1.95 g (7.43 mmol) of sar-7,16-cyazacyclooctadecane, Add to the solution. The reaction mixture was 7°410 mol/! Sodium hydroxide at a concentration of While adding 2.02 d (14.98 mmol) of thorium solution in O, ld portions, 6 Maintain at 0°C for 10-11 hours. After stopping the reaction, filter the solution if necessary. , sodium bromide was added, then evaporated and dried under reduced pressure, and a total of 20 ~2. ! Extract in several portions with lid methylene chloride.

The extract was evaporated to dryness, 10-50 m petroleum ether was added and the filtered Afterwards, the precipitate is dried in nitrogen vapor. Contains 13.3% by weight of sodium bromide. 2.27 g (4.82 mmol) of the product (intermediate) obtained by Muso was prepared in the following manner. Use for batches.

The identification data of the intermediate is as follows: 'H-NMR7! , vector (20 0MHz, DzO, δppm): 3°87 (IH, s); 3.67 (18H, m); 2.78-2°92 (8H, m).

the residue of the methylene chloride extract until the extract is substantially free of solid matter; Up to 60jd of absolute ethanol! Extract by. The residue of the extraction is washed with 6-7 ml of water. d and after addition of sodium bromide it was evaporated to dryness and Let dry. It was then treated as above using 30d of absolute ethanol. Extract. The two ethanolic extracts were combined and evaporated to dryness, sodium bromide 489 g of double salt containing 2.71 moles of lithium are obtained. The yield is based on the macrocycle used It is 94.1% when calculated for objects.

The identification data for the double salt are as follows: IR spectrum (KBr, CI-'): 2950, 2868 (m.

rC-H); 1605 (vs, Tcoo/as); 1430 Not identified Other characteristics except frequency: 1350 (s), 1320 (s), 1095 ( s), 928 (w).

'H-NMR spectrum (200MHz, DtO, δppm): 4.0 0 (2H, s); 3.70 (8H, s); 3.63 (8H, t); 2.92 (8H, t).

b) Sodium bromide is removed from the double salt by extraction with 95% ethanol 50d do. Dry the extraction residue and remove the ethanol under reduced pressure, 3.22 g of product is obtained.

The yield, calculated on the macrocycle used, is 93.2%.

The identification data of the product is as follows: 'H-NMR spectrum (200MH z, DzO, δppm): 3.95 (2H, s); 3.64 (8H , s); 3.60 (8H, t); 2.85 (8H, t).

IIC-NMR spectrum (50MHz, DzO, δppa+): 1 79.95 (dan = ○) i76.45 (N once H (Coo) z); 71.66 and and 70.84 (0Hz); 54. os (N once Hz). .

father-in-law N,N’-bis(dicarboxymethylene) containing disodium hydroxymalonate )-1,4,10,13-tetraoxa-7,16-diazacyclooctadeca Preparation of Ntetra sodium salt According to the method described in Example 1, 2.84 g of 2-bromomalonic acid (15,54 mmol), N-dicarboxymethyl-1 containing 16.87% by weight of sodium bromide ,4,10,13-tetraoxa-7,16-diazacyclooctadecandinato 2.02 g of lithium salt (1 mmol of 4,I) and 1,4.10゜13-tetrao Xa-7,16-diazacyclooctadecane 2, Olg (7,66 mmol) with the exception that the reaction mixture was maintained at 50°C and sodium hydroxide was Dropped over 0 minutes. One substitution obtained by extraction with methylene chloride The amount of intermediate is 2.17 g (4.41 mmol) and 16.93% by weight Contains sodium bromide in amounts.

The weight of the product is 3.92 g and the yield is calculated for the macrocycle used. The total is 96.5%. The product is disodium hydroxymalonate 1.6 Including weight %.

) [-NMR spectrum of the product (200 MHz, D, O.

δppm+) corresponds to that of the product of Example 1, except that the resonance signal is also , which appears as 4,31(S), which is characteristic of hydroxymalonate.

■Lord N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa- Preparation of 7,16-diazacyclooctadecanetetrapotassium salt a) 5.760 mol/! in the presence of phenolphthalein indicator. hydroxylation at a concentration of By addition of potassium solution, water 1. 1.32 g of 2-bromomalonic acid in Od ( After neutralizing the solution of 1,4.10.13-tetraoxa-7 ゜Add 1.25 g (4.77 mmol) of 16-cyazacyclooctadecane . The reaction mixture was diluted with an equal volume of potassium hydroxide solution having a concentration of 5760 mol/2. Heat at 50° C. for 26 hours with gradual addition. After evaporating the reaction mixture , the solid residue was dried under reduced pressure, and then a total of 2011 dl of methyl chloride was added. Extract several times with glass. After evaporation, the residue was dried and dissolved in potassium bromide 16. N-dicarboxymethyl-1,4,10,13-tetraoxa- containing 7% by weight 7,16-diazacyclooctadecane dipotassium salt (intermediate) 0.85g (1 , 73 mmol). This product can be used for the next production batch.

The residue of the methylene chloride extraction was extracted with 60 d of absolute ethanol and its After evaporation of the extract, the residue was dried to obtain 2.18 g of product, i.e. The rate is 94.0% calculated for the macrocycle used.

The product is a double salt formed by potassium bromide and potassium bromide 29 ．． Contains 97% by weight.

'H-NMR spectrum of intermediate (200 MHz, DtO.

δppm): 3.86 (LH, s); 3.63 (16H, m); 2.89 (4H, t); 2.78 (4H, m).

IH-NMR spectrum of double salt formed by potassium bromide (200MHz , D20. δppm): 3. 99 (2H, s); 3.69 (8H, s); 3.63 (8H, t); 2.86 (8H, t).

b) a pure, potassium bromide-free product obtained as described above; 1.16 g of fresh product, i.e. the yield is 75.6% calculated on the macrocycle used. It is.

'H-NMR spectrum of the title product (200 MHz, DzO1δppm+ ): 4. 00 (2H, wide S); 3.70 (8H.

wide s); 3.65 (8H, wide) i2.8B (8H, wide).

! 1( N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa- Preparation of 7,16-diazacyclooctadecane magnesium complex disodium salt Water 2. Magnesium chloride pentahydrate dissolved in Od'@! J0.30g (1,4 6 mmol) of the product prepared in Example 1b) in 30 d of water (1,4 6 mmol). After 30 minutes, the solution was evaporated under reduced pressure and The residue was dried and the title product containing 17.99% of sodium chloride at 0.0°C was obtained. 93 g (97.8%) are obtained.

IH-NMR spectrum of the title product (200 MHz, in the presence of NaOD) DtO, δl3I) 11): 4. 00 (2H, s); 3.67 (8 H, s); 3.62 (8H, wide); 2.88 (8H2 wide).

"C-NMR spectrum (50MHz, DtO, δppm): 179 ．． 71 (dan = O); 71. ss and 71.05 (0Hz); 54.51 (N once H2).

Note: Due to duratylium substitution, cH(Coo)! The resonance signal of is absent. .

■Engineer N,N'-bis(dicarboxymethyl)-1,4,10, containing sodium chloride 13-tetraoxa-7,16-diazacyclooctadecane calcium complex dina Preparation of thorium salts According to the method described in Example 4, the product obtained in Example 1b) 0 ．． 92 g (1,65 mmol) and 0.24 g (1,65 mmol) of sodium chloride dihydrate 65 mmol) and 1.0% of the title product containing 17.57% by weight of sodium chloride. 8 g (98.2%) are obtained.

) f-NMR spectrum of the product (200 MHz, DzO.

δppm+): 3. 90 (4H, wide); 3.53 (14H, wide): 2.92 (4H, fusion t); 2.72 (4H, fusion t).

"C-NMR spectrum (50MH2, DtO, δppm): 179.2 3 (dan = O); 82.38 (dan H (COOh); 71.62 (0 once Hz ); 55.63 (N once H2).

N,N'-bis (containing disodium hydroxymalonate and sodium chloride) dicarboxymethyl)-1,4,10゜13-tetraoxa-7,16-diaza Preparation of cyclooctadecane calcium complex disodium salt Sodium hydroxide at a concentration of 8.360 mol/2 in the presence of a phenolphthalein indicator. 2-bromomalonic acid 3.4 in water 1.0 by adding thorium solution After neutralizing the 4g (18,825mmol) solution, 1,4,10.13-tetra Oxa-7, Erogiazacyclooctadecane 2.010g (7.65mmol) Add. Add the reaction mixture to the amount of water needed to form the disubstituted compound. 43-4 at 30-45 °C while adding sodium oxide solution (1,83d) Heat for 8 hours. Then, the reaction mixture was added with unreacted 2-bromomalonate. While adding dropwise the amount of sodium hydroxide solution required for water splitting, After stopping the reaction, the solution was evaporated and then Example 1b) Accordingly, 20 g of disodium malonate containing 12.0% by weight are obtained. So The crude product of is treated in one of two ways: a) The crude product is mixed with water 3. Sodium chloride solution with a concentration of Od and 1.000 mol/2 Dissolve the mixture in 7.5 m of liquid. 99°7% ethanol 12.0m and potassium chloride Add 0.85 m of lucium to the above solution while stirring and then The alcohol content is 99.7% ethanol 105M+1! With the addition of Adjust to product %. Stir the resulting suspension vigorously for 30-60 minutes while heating. and after filtering the solid precipitate, the filtrate was evaporated under reduced pressure and the semi-dry product The material was dried under reduced pressure at 75-85°C, containing 14.0% by weight of sodium chloride and 4.48 g of the title product containing 1.08% by weight of disodium hydroxymalonate (90.6%).

The 'H-NMR spectrum (200MHz+Dzo+δppm) of the product is shown in Example 5. However, the resonance signal also corresponds to that of the product of hydroxymalonate. It appears at 4.31 ppm (IH, s), which is the characteristic of .

b) Treat the crude product as described under a) above. However, calcium chloride After the addition of the first portion (7,50d) of the solution, a concentration of 1.000 mol/2 An additional portion of 3.10d of calcium chloride solution was added to the reaction mixture and the mixture was The ethanol content is 114a+1! 90 bodies by adding volume % and the product was dried under a stream of nitrogen to remove the calcium complex. In addition to the sodium salt, 19.5 mol% of the calcium salt of the calcium complex (macrocycle 5.00 g (94°9%) of product containing Ru.

The product contains 13.2% by weight of sodium chloride, 7.35% by weight of water and negligible amounts. Contains disodium hydroxymalonate.

IH-NMR spectrum of the product (200 MHz, DgO.

δppm) corresponds to that of the product of Example 5.

■Engineer N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa- Preparation of 7,16-thiazacyclooctadecane calcium diammonium Water 0.5r11.0.998mol/2 calcium chloride solution 2°04M1 and no 30 d of water-ethanol and 0.55 d of the tetrasodium salt obtained according to example 1b) Add 4 g (1,000 mmol). Reduce the solution to about 1/3 of its original volume Evaporate the anhydrous ethanol and reduce the ethanol concentration of the solution to 95-96 vol. Add in sufficient amount to adjust to %. Then warm up the solution and stir for 30 minutes. Stir, filter the precipitated sodium chloride and wash with absolute ethanol. . To the combined filtrate was added 0.554 g (1,000 mmol) of tetrasodium salt. and 0.214 g (4,000 mmol) of ammonium chloride and then water were added to the solid Add in an amount that will dissolve the substance. After evaporation of the solution, the residue was dissolved in water at 75-80 °C under reduced pressure. standard containing 19.91% by weight of sodium chloride and 7.33% by weight of water. 1.452 g (98.1%) of the product are obtained. Pure, chloride-free production can be prepared by extraction with absolute ethanol.

1H-NMR spectrum of the product without chloride and containing sodium chloride (200MH2, DzO, δppm): 3.

90 (4H, wide m); 3.73 (14H, wide m); 2°92 (4H, wide t); 2.72 (4H, wide t).

Five l N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa- Preparation of 7,16-diazacyclooctadecane calcium complex calcium salt Calcium hydroxide is added in small portions in the presence of a phenolphthalein indicator. By water 2. 1.743g of 2-bromomalonic acid (9,53mmol) in Od. After neutralizing 1,4,10,13-tetraoxa-7,16-thiazasic 1.000 g (3.81 mmol) of looctadecane are added.

The reaction mixture was heated at 40.45 and finally 50°C for a total of 72 hours and then While vigorously stirring the reaction mixture, add 0.85 g of calcium hydroxide (11, 47 mmol) was added dropwise while heating at 60° C. for 24 hours. Next, the precipitate (the main part of which is calcium hydroxymalonate) is filtered, and water 4-5 Wash 3 times with d. The combined filtrates are evaporated under reduced pressure and then chlorinated Tyrene 2X35d was distilled from its evaporation residue and dried at 75-85°C under reduced pressure. A solid product is obtained which is dried. , in this procedure the title product (calcium bromide) 31.5% by weight of Si) with a yield of 2.710 g (89.7%).

IH-NMR spectrum of the product (200 MHz, D, O.

δppm) is identical to that of the product prepared according to Example 5.

■R spectrum (KBr, C11-'): 2920.2880 (m, IC- H); 1615 (vs, ycoo/as); 1450 (rrBcoo /s).

Other features excluding frequencies that are not identified: 1355.1290 (m), 1250 (m), 1085 (vs), 950 (m).

five lords N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa- Preparation of 7,16-cyazacyclooctadecane iron(II) complex disodium salt Product prepared according to example 1b) according to the method described in example 4 0.141 g (1,35 mmol) and ferrous chloride tetrahydrate 0.268 g (1,35 mmol) ). However, during its preparation, the oxidation of ferrous ions to ferric ions This is prevented by using a nitrogen atmosphere. In this way, sodium chloride In a yield of 0.835 g (91.0%) of the title product containing 17.16% by weight of can get.

The 'H-NMR spectrum of the product was evaluated for the presence of paramagnetic ferrous ions. It can't be done.

IR spectrum (KBr, CI-'): 2910.2880 (m, yC-H ); 1630 (vs, 7coo/as); 1400 (s, 7coo /s).

Other features excluding unidentified frequencies: 1355 (m), 1330 (m), 1 100 (s), 930 (m).

■1 stand N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa- 7. Preparation of IC-diazacyclooctadecane zinc complex disodium salt Product prepared according to example 1b) according to the method described in example 4 0.735 g (1,32 mmol) and anhydrous zinc chloride 0.180 g (1,32 mmol) 0.89 g of the title product containing 16.92% by weight of sodium chloride (97, 5%).

'H-NMR spectrum (200MHz, DzO, δppm): 3.6-4 ．． 2 (18H, wide t-band system); 3. to (8H1 wide t).

M1 top N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa- Preparation of 7,16-diazacyclooctadecane trisodium salt Example 1b 1.72 ml of a hydrochloric acid solution with a concentration of 1.048 mol/Il in 5° OId of water ) of 1°000 g (1,804 mmol) of the tetrasodium salt obtained according to solution under cooling (0-5 °C), the solution is then evaporated, and the residue is Water-free by using methylene and then dried at 60°C under reduced pressure. 1.069 g of the title product containing 9.5% by weight of sodium chloride (96,7 %).

'H-NMR spectrum (200MHz, DzO, δppm): 4.1 B (2H, s); 3.79 (16H, m, wide); 3°29 (8H, wide S ).

The spectrum of the product in the presence of Na0D and taken in O is shown in example 1b) Match the given spectrum.

IR spectrum (KBr, am-'): 2940.2850 (m, 7C-H ); 1655.1605 (vs, Icoo/as); 1440 (m, r coo/s).

Other characteristics excluding unidentified frequencies: 1345 (S), 1320 (s), 1120 (s), 1100 (s); 93ON-dicarboxymethyl-N'- (1,1'-dicarboxyethyl)-1,4,10,13-tetraoxa-7, Preparation of 16-diazacyclooctadecanetetrasodium salt phenolphthalei sodium hydroxide solution with a concentration of 8.360 mol/2 in the presence of an indicator. 3.00 bromomethylmalonic acid in 0.5 d of water by addition at 5°C. After neutralizing the solution of 3 g (15,25 mmol), 1.4.10.13-tetra Oxa-7,16-cyazacyclooctadecane 2.000g (7,62mmol ) is added. The solution was converted into a sodium hydroxide solution with a concentration of 8.360 mol/l. 8-10 days at 20-25℃ while dropping 1.82ml (15.25mmol) maintain for a while. After stopping the reaction, the mixture was stirred at 55-60 °C for 30 min and then Evaporate. The dry residue was extracted in several portions with a total of 25-30 d of methylene chloride. put out

After evaporation of the extract, the residue is treated with ether and the solid precipitate is filtered. do. The material remaining after extraction with ether also contains a small amount of 1.4.10.1 Contains 3-tetraoxa-7,16-diazacyclooctadecane, which produces removed by dissolving the substance in methylene chloride and precipitating with ether. can be removed. In this way, a purified product containing 13.81% by weight of sodium bromide N-(1,1'-dicarboxyethyl)-1,4,10,13-tetraoxy Sur-7,16-diazacyclooctadecane disodium salt (intermediate) at 1.3 A yield of 90 g (37.2%) is obtained.

After evaporation of the ether extract, pure 1,4,10.13-tetraoxa-7,16 - Recover 1.159 g of cyazacyclooctadecane. Therefore, the actual yield of the reaction The rate corresponds to 38.5%.

IH-NMR spectrum of intermediate (200 MHz, DzO.

δppm): 3. 66 (16H, m); 2. 82 (4H, t); 2 ．． 72 C4H, t); 1.36 (3H, s).

By using the above intermediates, disubstituted derivatives are obtained as follows.

Sodium hydroxide at a concentration of 8,360 mol/l in the presence of phenolphthalein indicator 0.4 2-bromomalonic acid in 0.5 d of water by adding a solution of After neutralizing 83 g (2.64 mmol) of the solution, 13.81 parts by weight of sodium bromide % of the above intermediate was added, and then the reaction The mixture was dissolved in a sodium hydroxide solution with a concentration of 8.360 mol/2 0.32 IIN ( 2,64 mmol) at 30-45°C for 7 hours, and 50-60°C. After stopping the reaction, the solution is evaporated and the residue is dried under reduced pressure for 7 hours. Dry at 5-80°C. After extraction of the dry residue with absolute ethanol, its The ethanolic extract was evaporated to dryness under reduced pressure and treated with 2.06 moles of sodium bromide. 1.323 g (83.0%) of the double salt formed with

The sodium bromide-free product was purified with ethanol as described in Example 1b). can be obtained from the double salt by extraction with 96% by volume of the title product (0.5% of the title product 32g (54.5%)).

? J[17)'H-NMR and IR spectra are substantially similar to those of the title product. is the same as

IR spectrum (KBr, C!l-'): 2960.2870 (m, rC- H); 1645.1600 (vs, ycoo/as); 1405.14 40 (m, rcoo/s).

Remove unidentified frequencies (other features: 1355 (s), 1315 (s), 1095 (s), 930 (m).

'H-NMR spectrum (200MHz, DzO, δppn+): 3. 89 (IH, s); 3.68 (16H, m); 2.92 (4H, t); 2. 78 (4H, t); 1.41 (3H, s).

V low 1 N-dicarboxymethyl-N'-(1,1'-dicarboxypropyl)-1,4 ,10,13-tetraoxa-7,16-diazacyclooctadecanetetranate Preparation of sodium salt bromide double salt Following the method of Example 12, 1.608 g of 2-bromoethylmalonic acid (7,62 m mole) and 1.4,10.13-tetraoxa-7,16-thiazacycloocta Using 1.000 g (3.81 mmol) of decane, 15.61 weight of sodium bromide % containing N-(1,1'-dicarboxypropyl)-1,4,10,13-tetra Oxa-7,16-diazacyclooctadecane disodium salt 0.511g ( 26.2%).

After evaporation of the ether extract, 1.4.10.13-tetraoxa-7,16-sia 0.508 g of cyclooctadecane is recovered. Therefore, the actual yield is 53.3 %.

'H-NMR spectrum of intermediate (200MHz, DzO.

δppm): 3.68 (16H, m); 2.88 (4H, t); 2.82 (4H, t); 1.84 (2H, (1); 0.90-(3H, t).

The title double salt containing 3.10 moles of sodium bromide was converted into 15.61 moles of sodium bromide. % and the above intermediate containing 0.229 g (1,20 mmol) of 2-bromomalonic acid By using 0.517g (1°00mmol), 0.475g (5 2.7%) yield.

'H-NMR spectrum of the title double salt (200MH2, DzO.

δppm+): 3.88 (LH, s); 3.67 (16H, m); 2.91 (4H, t);2. ．． 86 (4H, t); 1,84 (2H, q); 0.8 8 (3H, t).

calligraphy N-dicarboxymethyl-N'-(base) containing disodium hydroxymalonate dicarboxymethyl)-1,4゜10.13-tetraoxa-7,1 Preparation of 6-diazacyclooctadecanetetrasodium salt Follow the method described in Example 12. However, the reaction is 2-bromo-2-benzyl malo 2.081 g (7.62 mmol) of phosphoric acid and 4,10.13-tetraoxa -7,16-cyazacyclooctadecane 1.000g (3.81mmol) was used. carried out in a 1=1 volume ratio mixture of water:ethanol by , N-(benzyl-dicarboxymethyl) containing 11.21% by weight of sodium bromide )-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane 0.372 g (17.4%) of disodium salt (intermediate) are obtained.

After evaporation of the ether extract, 1,4,10.13-tetraoxa-7,16-silane 0.714 g of azacyclooctadecane is recovered. Therefore, the actual yield is 60 ．． It becomes 9%.

'H-NMR spectrum of intermediate (200 MHz, DzO.

δppm+) near, 45 (2H, d); 7.29 (3H, m); 3°68 (12H, m); 3.57 (4H, t); 3.47 (2H, s); 2.78 (8H, m).

The title double salt containing 0.42 mol of disodium hydroxymalone) was added to sodium bromide. 11.21% by weight of aluminum and 0.161g of 2-bromomalonic acid (0,880mmol) By using 0.372 g (0,662 mmol) of the above intermediate containing get it. To obtain the product, first extraction with methylene chloride followed by Extraction with water and ethanol was carried out and the title salt was extracted with a yield of 0.432 (91.4%). obtained in quantity.

'H-NMR spectrum of the title product (200MH2, DiO1δppm): 7.43 (2H, d); 7.29 (3H, m); 3.90 (LH, s) ;3.64 (16H, wide);3.34 (2H,s);2.91 (4H, t); 2.80 (4H.

N,N'-bis(1,1'-dicarboxyethyl)-1,4゜10.13-te Preparation of traoxa-7,16-diazacyclooctadecanetetrasodium salt Sodium hydroxide at a concentration of 8.360 mol/i in the presence of phenolphthalein indicator. Bromomethyl dissolved in 1.0+d of water by addition of thorium solution at 0-5°C After neutralizing a solution of 3.11 g (14.79 mmol) of malonic acid, sodium bromide N-(1,1'-dicarboxyethyl)-1,4,10, containing 18.6% by weight; 13-tetraoxa-7,16-diazacyclooctadecane disodium salt 3. 52 g (6,565 mmol) (intermediate) was added and the reaction mixture was then ．． 1.77 d of sodium hydroxide solution with a concentration of 360 mol/2 (14°79 m-T :jLz) is maintained at 20-25°C for 12 days. of reaction Before stopping, heat the mixture at 55-60"C for 30 minutes and then evaporate. . The dry residue is extracted in portions with a total of 45-50 ml of methylene chloride. . The extract was evaporated, the residue treated with ether, the precipitate filtered and Let dry. In this procedure, a medium containing 14.0% by weight of sodium bromide was used. 2.08 g (4.29 mmol) of intermediate was recovered, which was used for the next manufacturing batch. can be done.

The solid material remaining after extraction with methylene chloride is dried at 75-80 °C under reduced pressure. Let it dry. After extraction of the dry residue with absolute ethanol 55-6°d, The tanol extract was evaporated to dryness under reduced pressure and dried, sodium bromide 3.90 g of double salt containing 78.2% by weight (22.2%) are obtained.

The yield calculated for the intermediates used in the reaction is 64.3%. be.

Double salt (7)'H-NMR vector (200MHz, Dz 0, 6pp m): 3-67 (8H, s); 3.64 (8H, t); 2゜73 ( 8H, t); 1.36 (6H, s).

The sodium bromide-free product was added to ethanol 9 as described in Example 1b). 3.90 g of double salt containing 2% by weight of sodium bromide for 7 days by extraction with 6% by volume Get from. In this procedure, 0.489 g (57.5%) of the title product were obtained. It will be done.

After evaporation and drying and repeated extraction with absolute ethanol, sodium bromide A double salt containing 80-90% by weight is obtained from a filtrate containing 96% by weight of ethanol. child The double salt of can be used in the next manufacturing batch.

[Metallic acid (7)'H-NMR spectrum (200MHz, DzO1δp ps+): 3.70 (16H, wide m); 2.71 (8H.

Fusion t); 1.34 (6H, wide S).

■1 day N,N'-bis(benzyl-dicarboxymethyl)-1,4°10.13-tet Laoxa-7,16-diazacyclooctadecanetetrasodium salt sodium salt Following the method described in Preparation Example 15 of Promide Double Salt; 1:1 water:ethanol A monosubstituted intermediate containing 11.21% by weight of sodium bromide in a mixture of volume ratios 0.372g (0,662mmol) and 2-bromo-2-benzylmalonic acid 0 ．． By carrying out the reaction of 362 g (1,324 mmol) of sodium bromide A double salt containing 4.2 mol of mole is obtained with a yield of 0.085 g (11.1%).

0.296 g of intermediate containing 11.21% by weight of sodium bromide is recovered. Therefore, The calculated yield for the intermediate used in the reaction is 54.2%.

'H-NMR spectrum of the title product (200MHz, DzO2δppm) : 7.64 (4H, d); 7.45 (6H, m); 3.65 (12H, m); 3,52 (4H, t); 3.31 (4H, s); 2.68 (8H, t ).

Morning low L The acute toxicity values of the products prepared according to Examples 1-16 were determined by the following means: determined for mice and rats.

Solutions containing the compounds at various concentrations were added to physiological saline or glucosuria at a concentration of 5% by weight. the active agent for 3 to 5 minutes. was administered at various concentrations into the blood circulation of the animal by injecting it into the animal's blood circulation. .

From 6-10 animals (5w1ss mice and Wista, r rats of both sexes) Each group was used for various dosage levels. Then the animal Observed for 30 days. L　D　s. 7. . (i.e. within 30 days 7H analysis (D, J, Finn ey: Probit Analysis (2nd edition) Cambridge Un By using the iversity Press (1952)), this period This was determined from the number of animals that died during the period. in mmol/kg body weight for the active agent of the invention These values expressed are summarized in column (B) of Table 1.

Table 1 Characteristic data of the products of the invention 1/a　O,3271,85,40 1/b O, 3792, 89, 66 20,3683,311,10 3/a O, 3332, 312, 30 3/b　O,2721,78,90 40,2112,37,30 52.5 or more 3.7 145.00 6/a 3.0 or more 3.9 158.006/b 3.0 or more 4.2 16 0.007 2.5 or more 1.7 65.00 8 1.5 or more 1.6 58.00 9 0.250 1.7 8.25 10 0.091 2.3 3.20 11 0.111 2.6 2.90 12 0.305 1.5 7.90 13 0.302 2.1 13.3014 0.422 1.4 7.60 15 0.450 1.3 6.80 16 0.470 1.3 7.10 Kuniro Kame The radioisotope exclusion enhancement effects of the compounds prepared according to Examples 1 to 16 will be described hereafter. Comparisons were made against 5w1ss mice as described.

37-74 KBq (1-2 μCi) of active radioactive strontium (Sr85) Cj! z) or radioactive cesium (Ce-144CIlz), respectively, into the animal's abdomen. injection into the cavity, which was then administered to treatment groups of 5-10 animals each. divided. 30-60 minutes after isotope administration, animals in that treatment group receive their individual treatment. used in animals to reach concentrations of 50-100 μmol/kg body weight for The active agent was administered intravenously (i,v,). Control group animals received active agent carrier (sterile saline or glucose at a concentration of 5% by weight) solution).

The amount of radioactivity introduced into the animal is determined immediately after administration of the isotope and then these Measurements are configured for whole body measurements on small animals, daily or every 2 or 3 days. repeated with the same equipment. The observed counts are at the starting activity value on day zero (0). related, and the so-called residue/time interaction takes into account the residual activity in the organism. It can be obtained by The changes in animal activity over time are shown in Figure 1, where The time (days) that has passed since treatment is shown on the horizontal axis, and the residual rate of the whole body is plotted on the vertical axis. will be cut. Elimination rate of 5r-85 administered intraperitoneally in control animals is slow: 1 day Their activity is only 15% within 4 days, 25% within 4 days and 30% within 7 days. was eliminated from the animal, and its elimination became −1 slower at later times. contrast Generally, 40% were introduced within 1 day, 65% within 4 days, and 67% within 7 days. The radioactivity was increased in one dose with 100 μmol/kg of activator prepared according to Example 13. After treatment, the animal was expelled. Even better results were obtained with the product prepared according to Example 5. 81°84 and 85%, respectively, within the above period. Emission values were given. Based on the analysis performed in the above manner, the residual curve is a two-component It was mentioned that it could be explained by a decreasing exponential function. Regarding the product of the above example The F-factor and EI values are summarized in Table 1 (C) and (D), respectively.

It is clear that the effectiveness of various scavengers varies greatly, especially based on EI values. It is. Therefore, an excluder with an EI value of 0-5 is weak and an EI value of 5-50 is weak. An excluder with an EI value of 50-100 is considered good. and those with an EI value of 100 or above have been shown to be superior. It will be done.

■1 main a) The systemic residue curve shown in Figure 2 shows the intraperitoneal ( i, P,) After administration, the release agent was introduced into the lungs of Wtstar rats through the trachea. Radioactive strontium is treated with solvent only, indicating the elimination of radioactive strontium. The pattern of the top curve in Figure 2 indicates that there was a low degree of exclusion from the treated control animals. can be found. More than 30-35% of the initial activity was eliminated in the days following internal contamination. I couldn't. In contrast, the systemic loading dose is 50 μmol/kg body weight of the present invention. In the group treated once (middle curve) with the product in the amount or treated In the group treated twice at 3-hour intervals within one day after treatment (lower curve), 9 0% (measured based on control) to 20%, significantly reduced. isotope rapid Elimination lasted several days after treatment and was 94-96 in the twice-treated group. % and reached 88-90% in the once treated group. radioactive stolons of animals treated with the active agent of the invention and killed at the end of the experiment. It is an important experimental result that little or nothing could be detected in bone.

Residual activity of 5-10%, measured as systemic residue, is found in animal cartilage and liver. and the major portion (65-70%) of the residual rate found in controls is composed of bones. It was. A similar advantageous result is obtained when the compounds of the invention are administered intravenously or subcutaneously to the connective tissue. obtained by giving.

b) If the compounds of the invention that enhance isotopic exclusion are removed from animals by other radioactive metals, It was used to eliminate um-144 (belongs to the group of rare earth elements).

In this experiment, Ce144C introduced into the lungs of female Wistar rats f* elimination after a single administration or after repeated treatments at 24-hour intervals. (Figure 3) as a function of time.

The results obtained indicate that the compounds of the invention are released with relatively low solubility in body fluids. It has been shown that it can be conveniently used for the removal of radioactive compounds from the lungs. experimental At the end, i.e. on day 300, 40% of the introduced starting activity is present in the control animals. However, 14% was treated with the activator of the present invention once i, p.

were detected in the treatment group; and systemic residual rates increased by 60 minutes after isotope administration. and then decreased to 5.6% by 24 hours based on the effect of treatment with the active agent. . Abrupt at the beginning of the systemic residual curve in the treated group, but later delayed The pattern is probably due to solubility relationships of radioactive contaminant compounds and exclusion properties of metal complexes. It's for a reason.

l standing of the present invention for isotope elimination after administration into the blood circulation, peritoneal cavity or subcutaneous connective tissue. The effects of the compounds have been described in Examples 17-19. treatment of humans and even populations. From the point of view of effective and rapid protection, the compounds of the invention may be administered by other routes. It is important to justify the usefulness of eliminating internal radioisotope contamination. It was important.

Wistar rats were used for this purpose. During the test portion, radioactive Strontium is administered intraperitoneally to the animal and 60 minutes later the active agent of the invention is administered. given to the lungs through the trachea. Chemicals shown in Table 1 with an EI value of 100 or more compound was used as the activator. After that, whole body activity was measured for 30 days. The active agent of the invention has a good effect on elimination after inhalation in powder or liquid aerosol form. Based on evaluation of whole-body residual curves plotted in the usual manner, It turned out that it was. The 91% residue rate measured in control animals was higher than that in treated animals. It was reduced to 1.5% on the first day, and below 10% on the third day. 7.・ The F-factor value of 9 and the EI value of 164 (see Table 1) support the above explanation. It was found that

The possibility of absorption of the active agents of the invention from epithelial surfaces was investigated in additional experiments. . Hair was removed from the skin 3X3C11 on the back of the rat. in the lungs of anesthetized animals After administering radioactive strontium through the trachea, whole body activity was measured, and then Apply the active agent solution onto the previously cleared and cleaned area of the back skin. It was applied in Areas containing activators can be adhesively imparted with their isotopic transfer effects. can be estimated from daily measurements of whole body activity. Considering all measurements, An F-factor value of 2°5 and a Fl value of 105-110 were obtained.

Based on the above experimental results, the active agents of the present invention may also be used in pharmaceutical compositions, such as sublingual tablets. It can be used in the form of tablets, suppositories, enterically soluble dragees or capsules, or transdermal salves.

Fl to IJRE I 0 4 8 12 16 20 2+1 28 Days after processing FIGURE 2 u　4　(3121620242R32Pl!Number of days after international search report 1AIs, @a□, -m9. 11 seasons pcτ/monnit)/fX cuff 0

Claims (10)

[Claims] 1. The following formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Q1 and Q2 are hydrogen or the following Formula (III): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R substituent are independently hydrogen, C1-5 straight or branched alkyl group, C2-5 straight chain chain or branched alkenyl group, phenyl or phenyl-C1-5 alkyl group; and the latter two groups may optionally contain one or more groups on their aromatic moieties. Halogen, C1-5 alkyl, C1-5 alkoxy, cyano or nitro group A group represented by One is other than hydrogen; Me represents an alkali metal or alkaline earth metal or transition metal ion; q is 0 or 1; M and N are, independently of each other, hydrogen or an alkali metal, an alkaline earth metal, or optionally substituted ammonium ions; m, n and p are integers equal to the charge of N, M or Me, respectively; s and r are each independently 0, 1, 2, 3 or 4, provided that (i) r, s and q are not 0 at the same time; (ii) the number of hydrogens in M or N is 0, 1 or 2; can be; (iii) q is 1 when R is hydrogen; and (iv) M and N are When q is 0, a compound other than sodium or lithium ion] Compound. 2. Claim 1, wherein Q1 and Q2 are the same and R is hydrogen. Compounds listed. 3. N,N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxy Cir-7,16-diazacyclooctadecane calcium complex disodium salt. 4. Composition useful for eliminating metal ions, mainly radioactive isotopes, that are harmful to living organisms A substance with the following formula (I): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, Q1 and Q2 are hydrogen or the following formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (wherein R substituents are independently hydrogen, C1-5 straight or branched chain alkyl group, C2-5 straight chain or branched alkenyl group, phenyl or phenyl group Nyl-C1-5 alkyl group, and the latter two groups are, in some cases, on the aromatic moiety of one or more halogens, C1-5 alkyl, C1-5 alkyl (substituted by xy, cyano or nitro group), with the proviso that At least one of Q1 and Q2 is other than hydrogen; Me represents an alkali metal or alkaline earth metal or transition metal ion; q is 0 or 1; M and N are, independently of each other, hydrogen or an alkali metal, an alkaline earth metal, or optionally substituted ammonium ions; m, n and p are integers equal to the charge of N, M or Me, respectively; s and r are each independently 0, 1, 2, 3 or 4, provided that (i) r, s and q are not 0 at the same time; and (ii) the number of hydrogens in M or N is 0, 1 or 2). A composition consisting of 5. Tablets, dragees, capsules, suppositories, injection solutions, powders or aerosols or transdermal salves 5. A composition according to claim 4 characterized by a pharmaceutical form. 6. As an active ingredient, the formula (I) (wherein Q1 and Q2 are the same and R is 6. A composition according to claim 4 or 5, comprising a compound (hydrogen). 7. N,N'-bis(dicarboxymethyl)-1,4,10,1 as active ingredient 3-tetraoxa-7,16-diazacyclooctadecane calcium complex dinate 6. The composition according to claim 4 or 5, comprising a lithium salt. 8. In order to eliminate metal ions, mainly radioactive isotopes, that are harmful to living things, the following General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Q1 and Q2 are hydrogen or the following Formula (III): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R substituent are independently hydrogen, C1-5 straight or branched alkyl group, C2-5 straight chain chain or branched alkenyl group, phenyl or phenyl-C1-5 alkyl group; and the latter two groups may optionally contain one or more groups on their aromatic moieties. Halogen, C1-5 alkyl, C1-5 alkoxy, cyano or nitro group A group represented by One is other than hydrogen; Me represents an alkali metal or alkaline earth metal or transition metal ion; q is 0 or 1; M and N are, independently of each other, hydrogen or an alkali metal, an alkaline earth metal, or optionally substituted ammonium ions; m, n and p are integers equal to the charge of N, M or Me, respectively; s and r are each independently 0, 1, 2, 3 or 4, provided that (i) r, s and q are not 0 at the same time; and (ii) the number of hydrogens in M or N is 0, 1 or 2]. 9. Formula (I ) (wherein Q1 and Q2 are the same and R is hydrogen) . 10. To eliminate metal ions, mainly radioactive isotopes, that are harmful to living things, N, N'-bis(dicarboxymethyl)-1,4,10,13-tetraoxa-7, Use of 16-diazacyclooctadecane calcium complex disodium salt.