The method of obtaining complexes of transition metals

 

(57) Abstract:

Usage: as radiopharmaceutical products or in the synthesis of radiopharmaceutical products. Entity: an improved way of obtaining complexes of transition metals selected from the group of:99mTe186Re ,188Re containing nitride group: M-N, where M is Tc,186Re,188Re . Reagent 1: compound of the transition metal pertechnetate or perinat alkali metal or ammonium. Reagent 2.: the first ligand - postsin General formula where R1, R2, R3- same or different and denote phenyl, which may be substituted by CN, sulphonate group, a lower alkyl which may be substituted by cyano. Reaction conditions: reagent 1 is subjected to interaction with the first ligand is a phosphine of the formula 1: where R1, R2, R3- same or different and denote phenyl, which may be substituted by cyano group, a sulphonate group and the second ligand is a nitrogen - containing compound selected from the compounds of formula II where R4is hydrogen, lower alkyl, R5lowest alkylthiomethyl, where Z Is O,S, R H, lower alkyl, NH2or Z is NH, R is H or COR , where R is lower alkoxy, lower alkyl, furyl, oxetanyl or soy the azide of an alkali metal, or ammonium , and, if necessary, with the third ligand from the group of compounds of the formula where R8- R9- , (CH2)2NH2or halide-di-lower alkylphosphonate, or hydrohalogen of mercaptoquinoline, in aqueous solution at a molar ratio of nitrogen-containing ligand to the peroxide compound is 1: 10-9- 10-4. 1 C.p. f-crystals, 3 tables.

The invention relates to methods for transition metal complexes that can be used as radiopharmaceutical products as such or in the synthesis of new radiopharmaceutical products.

More specifically, the invention relates to the production of nutrigenomics transition metal M selected from the99mTc 186Re and188Re containing the group MN, where M stands for99mTc 186Re and188Re.

These complexes of transition radioactive metals are used as pharmaceutical products for radiodiagnosis and radiotherapy.

A method of obtaining radiopharmaceutical products based on complexes of technetium - 99m containing the group (Tc N)2+(see J. Chem.Soc. Dalton. Trans. 1981, pp. 1798-1801), which consists in the interaction of the compounds of formula R+M. However, this method is long, as mentioned source includes at least three stages. In addition, this method does not guarantee the sterility and apyrogenicity of the obtained product.

From the document Isotopenpraxis, 1981, pages 174-175 is also known interaction pertechnitat99mTC sodium with ligands, for example, triphenylphosphine and diclorhidrato hydrazine; carried out in an organic solvent, such as benzene, ether, acetone. However, as returned by this method the complex is not pharmaceutically suitable product, and is used as a catalyst for the reduction reaction of elemental nitrogen into ammonia.

The purpose of the invention is to develop a more simple way of obtaining complexes of radioactive metals with obtaining sterile and pyrogen-free pharmaceutically suitable product.

This goal is achieved by the proposed method to obtain nutrigenomics transition metal selected from the group of:99mTc186Re and188Re, which lies in the interaction of peroxy compounds of the transition metal with the appropriate ligand and characterized in that the peroxide compound is transient the action with the first ligand is a phosphine of General formula I

PR2where R1, R2, R3- same or different denote phenyl, possibly substituted by cyano or sulfonic group, and lower alkyl, possibly substituted by cyano, and with the second ligand is a nitrogen - containing compound selected from the group: azide of alkali metal or ammonium, and the compounds of formula II:

H2N-N where R4is hydrogen, lower alkyl,

R5is hydrogen, lower alkylthiomethyl, group:

CHR , where Z means oxygen atom or sulfur,

R" is hydrogen, lower alkyl, NH2or Z signifies NH, R" is hydrogen or -- COR"', where R"' is lower alkoxygroup, lower alkyl, furyl, oxetanyl; or the compounds of formula III

R7-CH= N-N where R4- has the above meanings;

R6lowest alkylthiomethyl,

R7oksifenil, pyridyl, and, if necessary, with the third ligand selected from the group of compounds of the formula

C-C where R8= R9means C(CH3)2SH, (CH2)2NH2; or hydrohalogen di-lower alkylphosphonate or hydrohalogen of mercaptoquinoline, in aqueous solution at a molar ratio of nitrogen-containing ligand to the peroxide compound is equal to 1:(10-9- 10-4).

For prakticheskoj is respectfully in aqueous solution, and then, after adjusting the pH to a desired value by using acid or alkali, add the required amount of peroxide compound of the transition metal, for example, pertechnitat technetium 99m. The reaction is carried out at room temperature or at a temperature higher by 50 to 100aboutC. Temperature and pH value depends on the type of the second ligand. Typically operate at pH below 4.

The resulting product is suitable for use as a radiopharmaceutical product in therapy or diagnosis. To obtain nutrigenomics with enhanced tropism for certain organs of the human body obtained nutrigenomics technetium subjected exchange reaction with the third ligand.

This exchange reaction can be carried out simultaneously, preferably in aqueous solution with formation of nutrigenomics by the interaction of all components: peroxide compounds transition metal, the first ligand, the second ligand and second ligand, which is used as the organic compound with the nucleophilic group, a monoclonal antibody or antibody fragment.

It is possible to conduct the reaction in two stages: the first stage carried out Predoctoral ligands, and in the second stage, the interaction of the product obtained in the first stage, with the third ligand selected from the monoclonal antibodies or fragments of antibodies, also preferably in aqueous solution.

This exchange reaction can be carried out in an alcohol or water-alcohol solution; you can also first and second stage in various solutions, for example, the first phase in an aqueous solution, and the second phase - in alcoholic or aqueous-alcoholic solution or Vice versa.

Organic ligands with nucleophilic groups can be very diverse. For example, it is possible to use amines, thiols, thioethers, oximes, phosphines, and polyfunctional ligands of type polyaminopropyl.

For implementing the method in a hospital setting it is enough to position the kit comprising a first vial containing a first ligand phosphine type, and a second vial containing the second nitrogen-containing ligand.

Mix the contents of two vials and add, for example, a solution of sarahnet alkali metal or ammonium. The first and second ligand can be respectively in the first and second vials in liquid form or in liofilizirovannom.

In n the removed solution of peroxide compounds transition metal, for example, pertechnitat or perrenate for receiving radiopharmaceutical product.

As mentioned above, you can use the complex transition metal obtained from the first and second ligand, as an intermediate product to obtain further another nutrigenomics transition metal by exchange reaction with the third ligand is a monoclonal antibody or antibody fragment.

The product resulting from this reaction can also be used as such as a radiopharmaceutical product or for the diagnosis or therapy. In this case, a kit for preparing a radiopharmaceutical product may include a third vial containing a third organic ligand with nucleophilic groups, a monoclonal antibody or antibody fragment.

P R I m e R 1. In penitsillinovy vial injected with 0.4 ml of a solution containing 210-2mol/l (2.5 mg/ml) S-methyldithiocarbamate (second ligand) in ethanol, and then 0.2 ml of a solution containing 210-2mol/l (5 mg/ml) of triphenylphosphine (first ligand) in ethanol, and 0.1 ml of 1 N. chlorotalonil acid. Then add 0.5 to 1 ml pertechnitat sodium (Tc-99m), (10-6- 10-11

P R I m e R s 2-13. Work according to the method of example 1 and obtained from the ligand listed in table.1 nutrigenomics technetium, entering into the vial 510-3- 110-2mmol second ligand, 410-3mmol first ligand and 0.1 ml of 1 N. HCl and then adding 0.5 to 1 ml pertechnitat sodium.

Chromatographic analysis of the products shows that we are talking about nitrido complexes containing the center TCN.

P R I m e R 14. In penicillin vial injected with 0.4 ml of an alcohol solution of the second ligand, consisting of a solution with a concentration of 2.5 mg/ml (1.1 x x10-2mol/l) S-methyl-beta-N-(2-hydroxyphenyl) methylenecyclobutane in ethanol, 0.2 ml of a solution containing 5 mg/l (210-2mol/l) of triphenylphosphine (first ligand) in ethanol and 0.1 ml of a 1 N. chlorotalonil acid.

Then add 0.5-1 ml of sterile solution pertechnitat sodium (technetium - 99m), the corresponding radioactivity from 18 Bq M to 3.7 GBq (0.5 to 100 mG), then heat the flask at 80aboutC for 30 minutes

Chromatographic analysis in a thin layer in the opposite phase, using as solvent a mixture of methanol, acetonitrile, and then it is carbonated is her group TcN.

P R I m e R s 15-22. Repeat the procedure of example 14, but with the first and second ligands are listed in table. 2, entering into the vial 110-2- 310-3mmol second ligand, 410-3mmol first ligand and 0.1 ml of 1 N HCl and then adding 0.5 to 1 ml pertechnitat sodium Tc-99m. At the end of the operation, the resulting product is subjected to chronographie in a thin layer, which indicates that the complex contains a group TN and that phosphine is an integral part of the received complex.

P R I m e R 23. Working as described in example 1, but using as the second ligand 4-methyl-3-thiosemicarbazide formula

CH3-NH--NH-NH2Chromatographic analysis of the product shows that the resulting complex is nutrigenomics technetium and that it contains triphenylphosphine.

P R I m e R 24. In this example, followed by the method of example 14, but using as the second ligand aminoacetonitrile formula

H2N--NH-N= H2-NH2< / BR>
Chromatographic analysis in a thin layer shows that the resulting complex is nutrigenomics technetium.

P R I m e R 25. In this example, is injected into the vial with 1 ml of a solution containing 510-3mol/l alpha-N-methyl-S-methyl-beta-N - (2-gidrol-phosphino)ethane of the formula:

(CH3)2P-CH2-CH2-P(CH3)2and 0.1 ml of 1 N. chlorotalonil acid. Then add 0.5 ml of sterile solution pertechnitat sodium (Tc-99m) vial and heated at 80aboutC for 30 minutes

Get nutrigenomics technetium containing a first ligand-based diphosphine.

P R I m e R 26. Work the same as in example 25, but using a solution containing 510-3mol/l bis(1,2-dificil-phosphine)ethane and the solution 510-3mol/l alpha-N-methyl-S-methyl-beta-N - (2-hydroxy - phenyl) methylenecyclobutane.

Get nutrigenomics technetium containing diphosphinic ligand.

P R I m e R 27. In this example, preparing a complex of rhenium-186, entering into the vial penicillin type 7 mmol of triphenylphosphine and 2 mmol of alpha-N-methyl-S-methyl-beta-N - (2-hydroxyphenyl) methylenecyclobutane in an alcohol solution and 5 mmol of 1 N. chlorotalonil acid. Then enter 1 mmol of perrenate sodium and carried out at 40aboutC for 30 minutes

Get nutrigenomics rhenium with output above 90%. In the following examples use nutrigenomics technetium obtained in the previous examples for other complexes of technetium used as a diagnostic cont what about the complex of technetium with the third ligand, which is the compound 1,1-(1,2-atendimento (bis-(2-methyl-2-propanethiol) formula

C To the contents of the bottle obtained in example 14, add 0.2 ml of a solution containing 410-2mol/l of 1,1'-(1,2-tenderlionne)-bis(2-methyl-2-propanethiol) in ethanol.

Bring the pH to 9.5 by adding 0.5 ml of buffer solution, carbonate/bicarbonate concentration of 0.5 M and heat the bottle up to 80aboutC for 30 minutes

The resulting product analyzed by chromatography in thin layer using silica gel and a solvent mixture of ethanol, chloroform and benzene (2: 2: 1). The location of the chromatographic spots corresponds to nutrigenomics technetium containing group TcN; Rf = 0,44 (silicon oxide, ethanol/chloroform/benzene).

Comparative example 1.

Interact solution of 1,1'-(1,2-tenderlionne) bis-(2-methyl-2-propanethiol) pertechnitat sodium (Tc-99m) in the presence of chloride of tin. Get diaminopimelate Ecotechnie that analyze thin-layer chromatography under the same conditions as the product in example 27.

The location of the chromatographic spots obtained complex of technetium center (TSS)3+different from the location of these spots nitri is Holocene other nutrigenomics technetium, on the basis of the products obtained in examples 1, 2 and 16-21 and using as the third ligand compound 1,1'-(1,2-tenderlionne)-bis-(2-methyl-2-propanethiol).

In all cases receive nutrigenomics technetium containing the third ligand. Rf = 0,44 (silicon oxide, ethanol/chloroform/benzene).

P R I m e R 37. Work similarly to the method of example 28 to obtain a new complex of technetium from the product obtained in example 1, but using as the third ligand solution containing 610-2mol/l of tetrataenia formula

< / BR>
Get a new nutrigenomics technetium containing as a ligand tetrathionate Rf = 0,61 (cellulose, ethanol, ammonium acetate).

The purity of the obtained product was determined by thin-layer chromatography using cellulose and solvent-based ethanol-ammonium acetate 0.15 M ratio (4:3).

P R I m e R s 38-45. Follow the procedure of example 37, by adding to the product obtained in examples 2, 14, 16-21 0.2 ml of a solution containing 610-2mol/l Tetra - asoundconf.

In all cases receive nutrigenomics technetium containing the ligand tetrathionate. Rf = 0,61 (cellulose, ethanol, ammonium acetate).

P R I m e R 46. To stereomate bis(1,2-dimethylphosphino)ethane (DMPE). Bring the pH to 10 by adding 0.5 ml of buffer solution of bicarbonate/carbonate with a concentration of 0.5 mol/l and carry out the reaction at 80aboutC for 30 minutes

The resulting product analyzed by thin-layer chromatography (cellulose; solvent - ethanol - ammonium acetate, 0,015 M; 4:3). The analysis confirms the receipt of nutrigenomics technetium containing the third ligand. Rf = 0.75 in (cellulose, ethanol, ammonium acetate).

So chromatographic spots related to this complex differ from those obtained with the known complex of technetium with formulas

99mTcCl2DMPA2+and 99mTcO2DMPA2+< / BR>
P R I m e R 47. Obtaining complex99mTc N containing 8-mercaptoquinoline.

A. Obtaining an intermediate product.

In the vial penicillin-type injected with 0.2 ml of a solution containing 7,710-2mol/l (5 mg/ml) of sodium azide in water, and then 0.5 ml of a solution containing 5,210-3mol/l (1 mg/ml) of Tris(2-cyanoethyl)-phosphine in water.

Then add 0,5-5 ml pertechnitat sodium (99mTc) and conducting the reaction at 80aboutC for 30 min or at 100aboutC for 15 minutes

B. Receiving target complera carbonate-sodium bicarbonate concentration of 0.5 mol/l to pH 9.0 and 0.4 ml of solution, containing 510-2mol/l hydrochloride 8-mercaptoquinoline (10 mg/ml) in ethanol.

The reaction is carried out for 15 min at 100aboutC, 30 min at 80aboutC or 60 min at room temperature.

Radiochemical purity of the obtained complex was determined by chromatography in thin layer using silica gel and a solvent mixture of ethanol, chloroform, toluene and ammonium acetate (0.5 M) in the ratio 6:3:3: 1.

The resulting complex has a Rf = 0.95, and while99mTcO4- indicator Rf = 0,5.

Radio purity above 95%.

P R I m e R 48. Obtaining antibodies, labeled intermediate complex TN.

a) Obtaining an intermediate product.

In the vial penicillin-type injected with 0.4 ml of a solution containing 210-2mol/l (2.7 mg/ml) S-methyl-N-methyldithiocarbamate in the water, and then 0.5 ml of a solution containing 5,210-3mol/l Tris(2-cyanoethyl)phosphine in water and 0.1 ml and 1 N. chlorotalonil acid. Then add 0.5 to 5 ml, pertechnitat sodium (99mTC) and conducting the reaction at 80aboutC for 30 min or at 100aboutC for 15 minutes

b) Obtaining labeled antibodies.

The contents of practical anti-ACE (anti-antigen, carcinoembryonic), the pre-treated mercaptoethylamine for activation of sulfhydryl groups in a buffer solution of 0.1 M phosphate with a pH of 7.0.

The reaction proceeds for 30 min at 35aboutC.

Radiochemical purity determined by chromatographic method by filtration through a gel column TSK type G 3000 SW (0,75 x 30 cm) using phosphate tampon 0.1 M pH 7.0 at a speed of 1 ml/min was recorded Simultaneously radioactivity and absorption capacity of the sample.

95% elyuirovaniya radioactivity detected between 7 and 7.8 ml, and the designated number of99mTCO4with 12 ml is less than 5%.

P R I m e R s 49-55. In these examples, we study the properties of the complexes obtained in examples 2, 14, 17, 21, 28, 37 and 47, by bearsdley in male rats breed Sprague Dawley weighing 200+20, For this purpose, rats, shot by pentobarbital, enter the product dose from 3.7 q to 10 q (1-2,7).

Animals wortlaut after 5 min after administration of the product. Authorities seized washed and measure their radioactivity on scintigraphically the counter.

The results are shown in table.3. The results are expressed as percentages of induced reactivity detected the.

The METHOD of OBTAINING COMPLEXES of TRANSITION METALS selected from the group99mT186Re ,188Re containing nitride group of the General formula where M is Tc , 186Re ,188Re possessing radiopharmaceutical properties, the interaction of peroxy compounds of the transition metal with the appropriate ligand, characterized in that the peroxide compound of the transition metal used pertechnetate or perinat alkali metal or ammonium, which is subjected to interaction with the first ligand is a phosphine of General formula

< / BR>
where R1, R2, R3the same or different, is a phenyl which may be substituted by CN, sulphonate group, a lower alkyl which may be substituted by cyano,

and with the second ligand is a nitrogen - containing compound selected from the compounds of General formula

< / BR>
where R4is hydrogen, lower alkyl;

R5is hydrogen, lower alkylthiomethyl, where Z Is O, S; R" is hydrogen, lower alkyl, NH2or Z is NH, R" is hydrogen or COR"', where R"' is lower alkoxy, lower alkyl, furyl, oxyphenyl,

or compounds of General formula

< / BR>
where R4has the specified values;

R6lowest alkylthiomethyl;

R7oksifenil,s compounds of General formula

< / BR>
where R8= R9- C(CH3)2SH, (CH2)2NH2< / BR>
or hydrohalogen di-lower alkylphosphonate, or hydrohalogen of mercaptoquinoline, in aqueous solution at a molar ratio of nitrogen-containing ligand and peroxide of 1 : 10-9- 10-4.

2. The method according to p. 1, wherein the first ligand using triphenylphosphine or diethylphosphine.

Priority signs

15.11.88 first ligand is a phosphine, in which R1and/or R2is phenyl or alkyl substituted by CN-group, the second ligand - azide of alkali metal or ammonium, the third ligand - hydrogenogenic of mercaptoquinoline.

09.05.88 - all other values specified in the formula.

 

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