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EP0463123A1 - 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane derivatives, pharmaceutical compositions containing them and their use for the removal of toxic metal ions and radioactive isotopes from the living organism - Google Patents

1,4,10,13-tetraoxa-7,16-diazacyclooctadecane derivatives, pharmaceutical compositions containing them and their use for the removal of toxic metal ions and radioactive isotopes from the living organism

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Publication number
EP0463123A1
EP0463123A1 EP90916523A EP90916523A EP0463123A1 EP 0463123 A1 EP0463123 A1 EP 0463123A1 EP 90916523 A EP90916523 A EP 90916523A EP 90916523 A EP90916523 A EP 90916523A EP 0463123 A1 EP0463123 A1 EP 0463123A1
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EP
European Patent Office
Prior art keywords
hydrogen
formula
metal
group
tetraoxa
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90916523A
Other languages
German (de)
English (en)
French (fr)
Inventor
József EMRI
Béla Györi
Zoltán KOVACS
Ernö BRÜCHER
László B. SZTANYIK
László VARGA
Ödön KIRALY
Béla KANYAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ORSZAGOS "FREDERIC JOLIOT-CURIE" SUGARBIOLOGIA ES SUGAREGESZSEGUGYI KUTATO INTEZET
Kossuth Lajos Tudomanyegyetem
Original Assignee
ORSZAGOS "FREDERIC JOLIOT-CURIE" SUGARBIOLOGIA ES SUGAREGESZSEGUGYI KUTATO INTEZET
Kossuth Lajos Tudomanyegyetem
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Filing date
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Application filed by ORSZAGOS "FREDERIC JOLIOT-CURIE" SUGARBIOLOGIA ES SUGAREGESZSEGUGYI KUTATO INTEZET, Kossuth Lajos Tudomanyegyetem filed Critical ORSZAGOS "FREDERIC JOLIOT-CURIE" SUGARBIOLOGIA ES SUGAREGESZSEGUGYI KUTATO INTEZET
Publication of EP0463123A1 publication Critical patent/EP0463123A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/08—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and more than one oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to partially novel 1,4,10,13-tetraoxa- -7,16-diazacyclooctadecane derivatives and the use of such com ⁇ pounds for the decorporation of metal ions, mainly radioactive isotopes damaging the living organism. More particularly, the invention relates to metal complexes, salts and double salts of l,4,10,13-tetraoxa-7,16-diazacyclooctadeca ⁇ e derivatives of the formula (I)
  • Q 1 and Q 2 mean hydrogen or a group of the formula (III).
  • R substituents independently represent hydrogen, a C ⁇ _5 straight or branched chain alkyl group, a C 2 _5 straight or branched chain alkenyl group, phenyl or phenyl-C- ⁇ alkyl group, the two latter ones optionally being substituted on their aro ⁇ matic part by one or more halogen(s), C- ⁇ alkyl, C- ⁇ alk- oxy, cyano or ⁇ itro group(s), with the proviso that at least one of Q-'- and Q 2 is other than hydrogen;
  • M and N independently from each other, stand for hydrogen or an alkaline metal, alkaline earth metal or optionally substi ⁇ tuted ammonium ion; m, ⁇ and p are integers each being equal to the charge of N, M or
  • the compounds of the formula (I) are used mainly as intermediates.
  • the compounds of the formula (I) are capable to form a stable complex with radioactive metal ions, above all with radio ⁇ active strontium and cerium being present in the blood circula ⁇ tion and extracellular space, and then to be eliminated.
  • the present invention relates to com ⁇ pounds of the formula (I), wherein 0- and Q 2 mean hydrogen or a group of the formula (III), with the proviso that at least one of them is other than hydrogen; and in the groups of the formula (III) the R substituents independently mean hydrogen, a C]__5 straight or branched chain alkyl group, a C 2 _5 straight or branched chain alkenyl group, phenyl or phenyl-C ⁇ . ⁇ alkyl group, the two latter ones optionally being substituted on their aro ⁇ matic part by one or more halog ⁇ n(s), C ⁇ alkyl, ⁇ _5al - oxy, cyano or nitro group(s);
  • M and N independently from each other, stand for hydrogen or an alkaline metal, alkaline earth metal or optionally substi ⁇ tuted ammonium ion; m, ⁇ and p are integers each being equal to the charge of N, M or
  • R as a Cj ⁇ alkyl group may be of straight or branched chain such as a methyl, ethyl, n-propyl, isopropyl, ⁇ -butyl, sec-butyl, tert-bu- tyl, ⁇ -pentyl or isopentyl group, preferably a methyl or ethyl group;
  • R as a C2_5alkenyl group may be e.g. a vinyl or propenyl group;
  • R as group may contain one of the alkyl moieties defined above, preferably a methyl group.
  • Me as an alkaline metal ion means preferably sodium or potassium ion; Me as an alkaline earth metal ion preferably stands for calcium or magnesium ion; and Me as a transition metal ion may be e.g. the ion of a metal belonging to the 3d, 4d or 5d group, preferably iro ⁇ (II) (ferrous) or zinc ions.
  • M and N as al- kaline metal or alkaline earth metal ions are preferably the above ions; whereas the optionally substituted ammonium ion con ⁇ tains 1,2,3 or 4 above-identified alkyl, phenyl or phe ⁇ ylalkyl group(s) (supposed that no steric hindrance occurs). Due to their toxicity, the compounds containing a tetramethylammonium ion, cannot be used for administering into a living organism.
  • radioactive isotopes such as iodi ⁇ e-131 ( 131 I), stro ⁇ tium-89 and -90 ( 89 Sr and 90 Sr) as well as cesiu - 134 and -137 ( 1 4 Cs and 137 Cs) and cerium-141 and -144 ( 141 Ce and l 44 Ce) may get into the atmosphere /see e.g. in: Nuclear and Radiochemistry", John Wiley and Sons, pages 158 to 166 (1981/.
  • strontium After the radioactive contamination, strontium begins to be built in to the bones in several hours, and there is no more pos ⁇ sibility to elinimate (decorporate) the strontium deposited from the organism. Thus, the protection against radioactive strontium is particularly problematic.
  • the only possible way of protection is to inhibit the fixation of strontium to the tissues, above all to bone tissues by introducing a suitable strontium-specific complexing agent to the organism, thus binding in a stable form the isotope occuring in the blood circulation or extracellular space and decorporating it from the organism.
  • a suitable strontium-specific complexing agent to the organism, thus binding in a stable form the isotope occuring in the blood circulation or extracellular space and decorporating it from the organism.
  • the solving of this problem is made more difficult thereby that the calcium complexes of complexing agents known from the literature, e.g. ethylenediaminetetraacetic acid or diethylene- triaminepe ⁇ taacetic acid, are substantially more stable than
  • the mechanism of complex formation is in this case dif ⁇ ferent from that of the earlier known complexing agents as due to the structure of the new complex forming molecule, the metal ions get to holes with well-defined sizes and therefore, the stability of the complex formed essentially depends on the size of the
  • the ligand proved to be highly toxic /W.H. M ⁇ ller: Naturwiss. 31_, 248 (1970); W.H. M ⁇ ller and W.A. M ⁇ ller: Naturwiss. ⁇ , 455 (1974); W.H. M ⁇ ller et al.: Naturwiss. 6£, 96 (1977); J. K ⁇ ajfl et al.: 12th Ann. Meeting of ESRB, Budapest (1976); 3. Batsch et al.: Nukleonika 23_, 305 (1978)/.
  • the pharmaceutical compositions containing the compounds of the formula (I) as active ingredients can be prevented and thereby severe health injuries induced by the radiation load of the organism can be avoided or diminished.
  • the lithium salt thus prepared can be used in the form of a composition being useful for enhancing the solubility of barium sulfate in the petroleum industry.
  • the corresponding tetrasodium salt is also mentioned in the same specification although it is not described in a specific example.
  • the double salt of the tetrasodium salt with sodium bromide as well as the therapeutic utility of this double salt have been published in the Hungarian patent application No. 2614/89.
  • the water-soluble salts and complexes of the compounds of the formula (I), wherein M and N stand for hydrogen or an alkaline metal or alkaline earth metal ion and Me means an alkaline earth metal ion can be synthetized also by reacting l,4,10,13-tetraoxa-7,16-diazacyclo ⁇ ctadeca ⁇ e with a 2-halodicarb- oxylic acid of formula (II) preferably with 2-bromomalo ⁇ ic acid in an aqueous medium at a pH of 6 to 13 in the presence of the alkaline metal or alkaline earth metal hydroxide corresponding to the salt to be prepared.
  • the complexes of formula (I), wherein q is 1, can be obtain ⁇ ed by reacting an alkaline metal salt of the formula (I), wherein q is 0 and M as well as N stand for alkaline metal ions, prefer- ably the tetrasodium salt, with an equivalent amount of a complex-forming metal halide, suitably metal chloride.
  • the elimination was studied on radioactive isotopes intro ⁇ quizzed in various rooutes to various sites, e.g. to the blood cir ⁇ culation, abdominal cavity, lungs, muscles or subcutaneous con- nective tissue of the experimental animals.
  • the compound increas ⁇ ing the elimination of the isotopes was administered daily once or two times in the form of an injection, powder or liquid aerosol or plaster to the organism of the experimental animals. Thereafter, whole body activity measurements were performed and - Q -
  • the compounds of formula (I) can be converted to pharmaceu ⁇ tical compositions by using the common carriers and other auxili- ary materials in a known manner.
  • the useful carriers, excipients, disintegrating, binding and other additive materials are de ⁇ scribed in detail in a number of relating handbooks.
  • the investigations on the effectivity of the compounds of Examples 1 to 16 showed that, after administration, the active ingredient was absorbed and exerted a decorporating effect either in the form of an i ⁇ jectable solution or in the form of a sub- lingual tablet, dragde, capsule, e ⁇ tero-solvent tablet, powder or liquid aerosol or transdermal plaster.
  • the effective dose was found to be 1.0 to 200 /umol/kg of body-weight, preferably 10 to 100 /umol/kg of body-weight, which was administered in one or more portions, preferably in two subdoses.
  • compositions containing the compounds of formula (I) as active ingredient are useful also for the preven ⁇ tion of building-in to the organism of metal ions being harmful to the living organism.
  • Example 1 Preparation of N,N'-bis(dicarboxymethyl)-l,4,10,13-tetraoxa-7,16- -diazacyclooctadecane tetrasodium salt a) 2.74 g (14.98 mmol) of 2-bromomalonic acid are neutral ⁇ ized in 1.0 ml of water by adding sodium hydroxide solution of 7.410 mole/litre concentration in the presence of phenolphthalein indicator.
  • the extract is evaporated to dry ⁇ ess, 10 to 15 ml of petro ⁇ leum ether are added and after filtration the precipitate is dried in a stream of nitrogen. 2.27 g (4.82 mmol) of the product obtained containing 13.3% by weight of sodium bromide (inter ⁇ mediate) are used in the next manufacturing production batch.
  • the identifying data of the intermediate are as follows: 1 H-NMR spectrum (200 MHz, D 2 0, ⁇ Tppm): 3.87 (IH, s); 3.67 (18H, m); 2.78-2.92 (8H, m).
  • the residue of the methylene chloride extract is extracted with 60 ml of anhydrous ethanol until the extract is practically free from solid material.
  • the residue of the extraction is dissolved in 6 to 7 ml of water and after adding sodium bromide it is evaporated to dry ⁇ ess and dried. Thereafter, it is extracted by using 30 ml of anhydrous ethanol as described above. The two ethanolic extracts are combined and evaporated to dry ⁇ ess to give 4.89 g of double salt containing 2.71 moles of sodium bromide. The yield is 94.1% calculated for the macrocycle used.
  • the identifying data for the double salt are as follows: IR spectrum (KBr, cm -1 ): 2950, 2868 (m, ⁇ c _ H ); 1605 (vs,
  • Example 1 The process described in Example 1 is followed by using 2.84 g (15.54 mmol) of 2-bromomalo ⁇ ic acid, 2,02 g (4.11 mmol) of N- dicarboxymethyl-l,4,10,13-tetraoxa-7,16-diazacyclooctadecane di ⁇ sodium salt containing 16.87% by weight of sodium bromide and 2.01 g (7.66 mmol) of l,4,10,13-tetraoxa-7,16-diazacycloocta- deca ⁇ e, except that the reaction mixture is maintained at 50°C and the sodium hydroxide is portionwise added during 10 hours.
  • the amount of monosubstituted intermediate obtained by extraction with methylene chloride is 2.17 g (4.41 mmol) and contains sodium bromide in an amount of 16.93% by weight.
  • the product weighes 3.92 g, the yield is 96.5% calculated for the macrocycle used.
  • the product contains 1.6% by weight of disodium hydroxymalonate.
  • Example 3 Preparation of N,N'-bis(dicarboxymethyl)-l,4,10,13-tetraoxa-7,16- -diazacyclooctadecane tetrapotassiu salt a) After neutralizing 1.32 g (7.22 mmol) of 2-bromomalonic acid in 1.0 ml of water by adding potassium hydroxide solution of 5.760 mole/litre concentration in the presence of phenolphthalein indicator, 1.25 g (4.77 mmol) of l,4,10,13-tetraoxa-7,16-diaza- cyclooctadecane are added.
  • the reaction mixture is heated at 50°G for 26 hours while adding an equivalent amount of potassium hydr ⁇ oxide solution of 5.760 mole/litre concentration in portions. After evaporating the reaction mixture the solid residue is dried under reduced pressure and then extracted with a total of 20 ml of methylene chloride in several portions. After evaporation the residue is dried to give 0.35 g (1.73 mmol) of N-dicarboxymethyl- -l,4,10,13-tetraoxa-7,16-diazacyclooctadecane dipotassium salt containing 16.7% by weight of potassium bromide (intermediate). This product can be used in a next manufacturing batch.
  • the residue of the methylene chloride extraction is extracted with 60 ml of anhydrous ethanol and after evaporation of the extract the residue is dried to give 2.18 g of product, i.e. a yield of 94.0% calculated for the macrocycle used.
  • the product is a double salt formed with potassium bromide which contains 29.97% by weight of potassium bromide.
  • Example 4 The process described in Example 4 is followed by using 0,92 g (1.65 mmol) of product obtained according to Example 1 b) and 0.24 g (1.65 mmol) of calcium chloride dihydrate to give 1.08 g (98.2%) of title product containing 17.57% by weight of sodium chloride.
  • Example 6 Preparation of N , N ' -bis(dicarboxymethyl ) -1 , 4 , 10 , 13-tetraoxa-7 ,16- -diazacyclooctadeca ⁇ e calcium complex disodium salt containing disodium hydroxymalonate and sodium chloride After neutralizing 3.44 g (18.825 mmol) of 2-bromomalo ⁇ ic acid in 1.0 ml of water by adding sodium hydroxide solution of 8.360 mole/litre concentration in the presence of phenolphthalein indicator, 2.010 g (7.65 mmol) of l,4,10,13-tetraoxa-7,16-diaza- cyclooctadeca ⁇ e are added.
  • the reaction mixture is heated at 30 to 45°C for 43 to 4G hours while adding sodium hydroxide solution (1.83 ml) required to form the disubstituted compound. There ⁇ after, the reaction mixture is maintained at 60°C for 22 to 25 hours while portionwise adding sodium hydroxide solution in an amount required to hydrolyze the u ⁇ reacted 2-bromomalonate. After termination of the reaction the solution is evaporated, then Example 1 b) is followed to obtain 4.720 g of dry crude product containing 12.0% by weight of disodium alonate and practically no sodium bromide.
  • the crude product may be worked up in any of the following two ways: a) The crude product is dissolved in a mixture of 3.0 ml of water and 7.5 ml of calcium chloride solution of 1.000 mole/litre concentration. 12.0 ml of 99.7% by volume ethanol and 0.85 ml of calcium chloride are added to the above solution under stirring, then the ethanol content of the solution is adjusted to 90% by volume by adding 105 ml of 99.7% by volume ethanol.
  • the product contains 13.2% by weight of sodium chloride, 7.35% by weight of water and a negligible amount of disodium
  • a pure chic ide-free product can be prepared by extraction with anhydrous ethanol.
  • Example 8 Preparation of N, '-bis(dicarboxymethyl)-l, ,10,13-tetraoxa-7,16- -diazacyclooctadecane calcium complex calcium salt After neutralizing 1.743 g (9.53 mmol) of 2-bromomalonic acid in 2.0 ml of water by adding calcium hydroxide in portions in the presence of phenolphthalein indicator, 1.000 g (3.01 mmol) of l,4,10,13-tetraoxa-7,16-diazacyclooctadeca ⁇ e is added.
  • the reaction mixture is heated at 40, 45 and finally at 50°C for a total of 72 hours, then the reaction mixture is heated at 60°C for 24 hours while portionswise adding 0.85 g (11.47 mmol) of calcium hydroxide under vigorous stirring. Then, the precipitate (the major part of which is calcium hydroxymalonate) is filtered off and washed with 4 to 5 ml of water in 3 portions. The combined filtrate is evaporated under reduced pressure and then 2x35 ml of methylene chloride are distilled off from the evaporation residue to obtain a solid product which is dried at 75 to 85° under reduced pressure. In this way the title product is obtained in a yield of 2.710 g (89.7%) with a calcium bromide content of 31.5% by weight.
  • Example 4 The process described in Example 4 is followed by using 0.735 g (1.32 mmol) of product prepared according to Example 1 b) and 0.180 g (1.32 mmol) of anhydrous zinc chloride to give 0.89 g (97.5%) of title product containing 16.92% by weight of sodium chloride.
  • the mixture is stirred at 55 to 60°C for 30 minutes, then evaporated.
  • the dry residue is extracted in several portions with a total volume of 25 to 30 ml of methylene dichloride. After evaporating the extract, the residue is treated with ether and the solid precipitate is filtered off.
  • the material remaining after the extraction with ether contains also a little amount of 1,4,10,13— etraoxa-7,16-diazacyclooctadecane which can be removed by dissolving the product in methylene dichloride and precipitating by ether.
  • the ethanolic extract is evaporated to dry ⁇ ess under reduced pressure and dried to give 1.323 g (83.0%) of the double salt formed with 2.06 moles of sodium bromide.
  • a sodium bromide-free product can be obtained from the double salt by extraction with 96% by volume of ethanol as described in Example 1 b) to give 0.532 g (54.5%) of the title product.
  • Example 12 The process described in Example 12 is followed by using 1.608 g (7.62 mmol) of 2-bromoethylmalonic acid and 1.000 g (3.81 mmol) of 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane to give 0.517 g (26.2%) of N-(l,l'-dicarboxypropyl)-l,4,10,13-tetraoxa- -7,16-diazacyclooctadecane disodium salt containing 15.61% by weight of sodium bromide.
  • the title double salt containing 3.10 moles of sodium bromide is obtained in a yield of 0.475 g (52.7%) by using 0.517 g (1.00 mmol) of the above intermediate containing 15.61% by weight of sodium bromide and 0.229 g (1.20 mmol) of 2-bromo- alonic acid.
  • 1 H-NMR spectrum of the title double salt (200 MHz, D 2 0, cTppm) : 3.88 (IH, s); 3.67 (16H, m); 2.91 (4H, t); 2.86 (4H, t); 1.84 (2H, q); 0.88 (3H, t).
  • Example 14 Preparation of N-dicarboxymethyl-N'-(benzyl-dicarboxymethyl)- 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane tetrasodium salt containing disodium hydroxymalonate
  • the process described in Example 12 is followed, except that the reaction is carried out in a water/etha ⁇ ol mixture of 1:1 volume ratio by using 2.081 g (7.62 mmol) of 2-bromo-2-be ⁇ zylma- lonic acid and 1.000 g (3.81 mmol) of 1,4,10,13-tetraoxa-7,16-di ⁇ azacyclooctadecane to obtain 0.372 g (17.4%) of N-(benzyl-dicarb- oxymethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane disodium salt containing 11.21% by weight of sodium bromid
  • the title double salt containing 0.42 mole of disodium hydr- oxymalo ⁇ ate is obtained by using 0.372 g (0.662 mmol) of the above intermediate containing 11.21% by weight of sodium bromide and 0.161 g (0.880 mmol) of 2-bromomalo ⁇ ic acid.
  • For obtaining the product first an extraction with methylene chloride and then extraction with abs. ethanol are carried out to give the title salt in a yield of 0.432 g (91.4%).
  • the mixture Before termination of the reaction, the mixture is heated at 55 to 60°C for 30 minutes and then evaporated.
  • the dry residue is extracted in several portions with .a total of 45 to 50 ml of methylene chloride.
  • the extract is evaporated, the residue is treated with ether, the precipitate is filtered off and dried. In this way 2.08 g (4.29 mmol) of intermediate containing 14.0% by weight of sodium bromide are recovered which can be used in a next manufacturing batch.
  • the solid material remaining after the extraction with methylene chloride is dried at 75 to 80°C under reduced pressure.
  • Example 15 The process described in Example 15 is followed; by carrying out the reaction with 0.362 g (1.324 mmol) of 2-bromo-2-benzylma- lonic acid and 0.372 g (0.662 mmol) of onosubstituted interme ⁇ diate containing 11.21% by weight of sodium bromide in a water/ethanol mixture of 1:1 volume ratio, a double salt contain ⁇ ing 4.2 moles of sodium bromide is obtained in a yield of 0.085 g (11.1%).
  • the acute toxicity values of the products prepared according to Examples 1 to 16 were determined on laboratory mice and rats in the following manner. Solutions containing the compounds in various concentrations were prepared by using physiological saline solution or glucose solution of 5% by weight concentration and the active agents were administered in various concentrations into the blood circulation of the animals by injecting them slowly during 3 to 5 minutes. Groups consisting of 6 to 10 animals (Swiss mice and Wistar rats of both sexes) each were used for the various dose levels. Thereafter, the animals were observed for 30 days. The LD5 Q /3 Q value (i.e. the dose causing the death of 50% of the experimental animals within 30 days) was determined from the number of animals died during this period by using probit analysis /D.3. Fi ⁇ ey: Probit Analysis (2nd ed.) Cambridge University Press (1952)/. These values expressed in mmol/kg of body-weight for the active agents according to the invention are summarized in column (B) of Table 1. Table 1
  • radioactive isotope elimination-increasing effects of compounds prepared according to Examples 1 to 16 were compared on Swiss mice as described hereinafter.
  • the animals of the treated groups were intra ⁇ venously (i.v.) given the active agent used in an amount to achieve a concentration of 50 to 100 /umol/kg of body-weight in the animal organism for each treatment.
  • the animals of the con ⁇ trol groups were similarly treated with the carrier (sterile phy- siological saline or glucose solution of 5% by weight concentra ⁇ tion) without active agent.
  • the amount of radioactivity introduced to the animal organ ⁇ ism was determined immediately after administration of the iso ⁇ tope, then these measurements were repeated daily or in every two or three days in a device constructed for the purpose of whole- body measurements on small animals.
  • the counts observed were related to the starting activity value of the zero (0) day and a so-called retention/time correlation was obtained by considering the activity retained in the organism.
  • the change of activity of the animal organism in the time is illustrated in Figure 1 where the time (in days) elapsed after the treatment is shown on the abscissa and the whole-body retention as percentage is plotted on the ordinate.
  • Example 20 The effect of compounds according to the invention on the elimination of isotopes after administration into the blood cir ⁇ culation, abdominal cavity or subcutaneous connective tissue have been described in Example 17 to 19. From the viewpoint of human therapy and even more of the effective and rapid protection of a greater population it was important to justify that the compounds according to the invention are useful to decorporate internal radioisotope contaminations also by other routes of administra ⁇ tion.
  • Wistar rats were used for this purpose.
  • radiostrontium was administered into the abdominal cavity of the animals and after 60 minutes the active agent according to the invention was given through the rachea into the lungs.
  • the compounds indicated in Table 1 with an El value above 100 were used as active agents.
  • the whole-body activ ⁇ ities were measured for 30 days. It turned out on evaluation of the whole-body retention curves, plotted in the usual manner, that the active agents according to the invention exerted a good effect on the elimination after inhalation in a powder or liquid aerosol form.
  • the retention of 91% measured in the control ani ⁇ mals was diminished to 15% on the first day, and became lower than 10% on the 3rd day in the treated animals.
  • An F factor value of 7.9 and El value of 164 (c.f. Table 1) were found which sup ⁇ ported the above statements.
  • the active agents according to the invention can be used also in the form of pharmaceutical compositions such as subli ⁇ gual tablet, supposi- tory, ent ⁇ rosolvent dragee or capsule or transdermal plaster.

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EP90916523A 1990-01-16 1990-11-07 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane derivatives, pharmaceutical compositions containing them and their use for the removal of toxic metal ions and radioactive isotopes from the living organism Withdrawn EP0463123A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU90145A HU210667B (hu) 1990-01-16 1990-01-16 Eljárás N,N'-bisz(dikarboxi-metil)-1,4,10,13-tetraoxa-7,16-diaza-ciklooktadekán-származékok sói és komplexei és a vegyületeket tartalmazó gyógyászati készítmények előállítására
HU14590 1990-01-16

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EP0463123A1 true EP0463123A1 (en) 1992-01-02

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EP90916523A Withdrawn EP0463123A1 (en) 1990-01-16 1990-11-07 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane derivatives, pharmaceutical compositions containing them and their use for the removal of toxic metal ions and radioactive isotopes from the living organism

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EP (1) EP0463123A1 (hu)
JP (1) JPH04505626A (hu)
KR (1) KR970009042B1 (hu)
AU (1) AU645507B2 (hu)
CA (1) CA2048627A1 (hu)
HU (2) HU210667B (hu)
IN (1) IN171733B (hu)
RU (1) RU2060256C1 (hu)
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WO (1) WO1991010655A1 (hu)

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WO1992005804A1 (en) * 1990-09-27 1992-04-16 Brunswick Corporation Chelating agents
HUP1100731A2 (en) * 2011-12-30 2013-06-28 Stratoxer S Kft Complex forming compounds
EA201201241A1 (ru) * 2012-06-19 2013-12-30 Елена Владимировна ОРЛОВА БИОБЕЗОПАСНЫЙ НАНОКОМПОЗИТНЫЙ ПОЛИМЕРНЫЙ СОРБЕНТ ДЛЯ СЕЛЕКТИВНОГО СВЯЗЫВАНИЯ ИЗОТОПОВ Sr И Cs ИЗ ЖИДКИХ СРЕД И СЫРЬЕВАЯ СМЕСЬ ДЛЯ ЕГО ИЗГОТОВЛЕНИЯ

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US4190462A (en) * 1978-07-04 1980-02-26 Shell Oil Company Dissolving barium sulfate scale with aqueous solutions of salts of carboxymethyl monocyclic macrocyclic polyamines
US4597903A (en) * 1984-08-21 1986-07-01 University Of Maryland Process for the direct preparation of N,N-disubstituted derivatives for 4,13-diaza-18-crown-6
JPS61263964A (ja) * 1985-05-17 1986-11-21 Terumo Corp 新規クラウン（チオ）エ−テルおよびその製造方法

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HU900145D0 (en) 1990-03-28
HUT73493A (en) 1996-08-28
UA35547C2 (uk) 2001-04-16
RU2060256C1 (ru) 1996-05-20
AU6711690A (en) 1991-08-05
CA2048627A1 (en) 1991-07-17
HU210667B (hu) 1998-03-30
IN171733B (hu) 1992-12-26
KR920701184A (ko) 1992-08-11
WO1991010655A1 (en) 1991-07-25
KR970009042B1 (ko) 1997-06-03
AU645507B2 (en) 1994-01-20
HU9502769D0 (en) 1995-11-28
JPH04505626A (ja) 1992-10-01

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