SK279625B6 - Diagnostic agent - Google Patents

Abstract

There is disclosed a diagnostic agent for 99mTc indication based on an adduct of metal salt and isocyanoether, or based on a mixture of these adducts. Said agent contains a reducer; 0.5 - 5 weight parts of antioxidant, in respect to the weight of the adduct; 10 weight parts of saccharine and/or aminoacid of formula H2N-(CH2)n-COOH, wherein n is a whole number from 1 to 4, in respect to the weight of the adduct; and a puffer in an amount satisfactory to obtain pH value between 4 and 6 when said agent is dissolved in water. The agent is used for the purpose of isotopic radio-diagnostic method, especially for diagnosing myocardial disorders.

Description

Technical field

The invention relates to a diagnostic composition suitable for marking 99 m-R _{c to} b _A2E metal salt adduct and izokyanoéteru.

BACKGROUND OF THE INVENTION

It is known from the prior art that the technetium salts of isocyanethers in the form of complexes of formula (I) [(CN-R-OR ') g 99mT _c + a- (I) in which

R is a straight or branched chain alkylene group having 2 to 8 carbon atoms to which is optionally attached a substituent selected from the group consisting of halogens, phenyl or halophenyl,

R 'is a straight or branched chain alkyl group having 1 to 4 carbon atoms,

A ^- represents a monovalent anion or one equivalent of a multivalent anion, and can be advantageously used for isotopic diagnosis, especially in the detection of myocardial disorders. For this purpose, salts or complexes of C1-C4 alkylisocyanotechnonium (I) cations are most commonly used, for example, reference is made to: Int. J. Nucl. Med. Biol. 11,225 (1984); J. Nucl. Med. 25, 1350 (1984); Eur. Nucl. Med. 12, 219 (1986); J. Nucl. Med. 27, 404 (1986).

These labeled salts or complexes are prepared by reacting an appropriate isocyanether of formula (II)

CN-R-OR '(II) in which R and R' as defined above, with a salt of technetium or a complex in which the technetium 99my _C in the oxidation step above 1, wherein the reaction is performed in the presence of a reducing agents (see U.S. Patent No. 4,452,774). Said patent also describes a compound for the preparation of a complex of formula (I). This is an isocyanether of formula (II) and a reducing agent.

A disadvantage of the composition described in U.S. Pat. No. 4,452,774 is difficult to handle and store since most of the isocyanethers of formula (II) are volatile.

Further, European patent no. EP-A 183 555 according to which the drawback of the volatile nature of isocyanethers is eliminated by treating the isocyanethers of the formula (II) with an orbital metal salt 3d and using the isocyanether-metal salt adducts used in the composition instead of the isocyanethers themselves. In addition to the adduct, the composition also contains a reducing agent. In EP-A patent no. 183 555 discloses the use of Zn, Cd, Hg, Ga, In, TI, Sn, Pb and Bi salts, while the use of Cu, Mo, Pd, Co, Ni, Cr and Rh salts is disclosed in U.S. Pat. EP-A 233 368. It is stated in both patents that the second ion is not critical and, moreover, a metal complex can be used instead of metal salts.

In the preparation of the complex is radiodiagnostic composition of those disclosed by European patent applications have reacted, similarly to prior known processes, a salt or complex of technetium, comprising technetium 99mp _seminar oxidation state of greater than 1. The reaction is carried out in aqueous medium at an elevated temperature .

According to the procedures described in EP-A no. 183 555 and no. 233 368, the aforementioned difficulties arising from the handling and storage of said composition can be eliminated. The disadvantage is the fact that, when a diagnostic composition that contains a reducing agent · adduct izokyanoéteru and a metal salt, is reacted with a source _of ion 99my _C s ₃ | <radiodiagnostic _{and the} complex compound of unsuitable stability. This has to be attributed to the fact that izokyanoéterové ligand bound to the ion 99mf _{C rather} quickly decompose, so for some hours after the preparation of the radiodiagnostic agent complex, the amount of ligands bearing radioactive ion insufficient for performing a scan measurement.

The invention aims to find such a diagnostic agent that would be the reaction of the source ion 99mT _c did not form radiodiagnostic complex is unstable character, but rather to form a radiodiagnostic complex substance stable character during long working hours, which means, by which the decomposition izokyanoéterových ligands considerably delayed.

SUMMARY OF THE INVENTION

According to the present invention, it has been found that a diagnostic composition of known composition comprising an isocyananoether-metal salt adduct and a reducing agent is added which is supplemented with a protective colloid formed by a saccharide and / or an amino acid of the formula H2N- (CH2) n -COOH, an integer from 1 to 4, together with a buffer and an antioxidant.

Principle of a 99mp _c Labeling Diagnostic Agent Containing an Adduct of a Metal Salt and an Isocyanate of Formula (II)

CN - R - OR '(II), wherein R represents a straight or branched chain alkylene group having 2 to 8 carbon atoms, optionally with a substituent selected from the group consisting of halogen atoms, phenyl or halophenyl, and

R 'is a straight or branched chain alkyl group having 1 to 4 carbon atoms, or a mixture of such adducts and 0.03 to 1.0 parts by weight of a reducing agent according to the weight of the adduct of the present invention, further comprising 0 , 5 to 5 parts by weight of an antioxidant, based on the weight of the adduct, of at least 10 parts by weight of a carbohydrate and / or amino acid of the formula

H 2 N- (CH 2) _n -COOH, wherein n is an integer from 1 to 4, and a buffer in an amount necessary to achieve a pH between 4 and 6 when the composition is dissolved in water.

In a preferred embodiment, the diagnostic composition of the invention comprises glycine as said amino acid.

The isocyanether ether metal salt adduct present in this diagnostic composition of the invention may be the same as in the cited published European patent applications. Of these, Cu (I) -tetrafluoroborate adducts of isocyanethers of general formula (II) are particularly preferred. The term isocyanether ether metal salt adduct also includes within its scope adducts formed with the metal complexes described in the cited documents.

As the reducing agent used may be any substance commonly used for the reduction of ions 99my _seminar oxidation state of greater than 1. In that connection, there can be mentioned, for example, stannous chloride dihydrate, stannous tartrate, stannous citrate, stannous gluconate, stannous fluoride, aprotinin, stannous pyrophosphate and stannous.

The diagnostic composition of the invention contains, as a buffer substance which, in the reaction by performing the ion source 99nrr _c adjusting the pH of the aqueous reaction mixture to 4 to 6, preferably 4.5 to 5.5. Examples of buffers useful for this purpose include sodium citrate, sodium pyrophosphate, glycine, potassium phthalates and sodium phthalate.

Examples of carbohydrates present in the diagnostic composition of the invention include mannitol, glucose, inositol, dextrose and maltose. These substances play the role of protective colloids and thus prevent scaling of the solution used for radiodiagnostic purposes, further increasing the water solubility of the sparingly soluble isocyanether-ether salt adducts.

The diagnostic composition of the invention may contain, for example, penicillamine, cysteine, α-mercaptopropionylglycine, dithiothreitol, glutathione and / or ascorbic acid as an antioxidant. Most of these antioxidants, such as penicillamine, cysteine, α-mercaptopropionylglycine, dithiothreitol, glutathione, also have radioprotective effects. These substances are excreted by the liver and kidneys together with the radioactive substance, and thus the radioactive load of the patient can be greatly suppressed in the isotopic diagnostic test. If the antioxidant used does not have a radioprotective effect (such as ascorbic acid is such an antioxidant), then it is preferable to add some radioprotective agent to the diagnostic agent.

The combined effects of the sugar, a buffer and an antioxidant, present in the diagnostic composition of the invention significantly increases the stability of radiodiagnostic complex of the product by treatment with the ion 99 m _[C according to measurements made by the authors of the present invention, it has been found that in this way increasing the stability of at least 3-fold compared to a radio-diagnostic complex prepared from a prior art diagnostic composition containing only a reducing agent and an isocyananoether-metal salt adduct.

The diagnostic composition according to the invention can be prepared in a very simple manner by mixing the individual components. If desired, the ingredients may be powdered or mixed prior to mixing (eg grinding) prior to mixing.

If the diagnostic composition of the invention comprises at least one low water soluble component (such as a poorly soluble isocyanether ether metal salt adduct), the composition is preferably prepared as follows: the low water soluble component is dissolved in an organic solvent, the other components are added to the solution thus obtained, either alone or in the form of an aqueous solution, and the resulting mixture is lyophilized. These operations are carried out in an oxygen-free atmosphere.

Radioactive imaging agent for complete labeling 99m-p _cm Trademark be _much of a diagnostic composition of the invention prepared as described for example in references cited above, for example according to EP-A 183 555 and 233,308th

The isocyanethers of formula (II) used as precursors in the preparation of the adducts of the isocyanether-ether salt present in the diagnostic composition of the invention can be prepared by known methods, such as the process of EP-A 233 308 and the references cited therein. However, it is also possible to use other processes for the preparation of the compounds of formula (II) which are simpler, with fewer process steps, higher yields under milder reaction conditions, and / or more readily available starting materials. These procedures can be summarized as follows:

(a) a cyano compound of the formula

HO-R -CN, wherein R is a straight or branched chain alkylene group having 1 to 7 carbon atoms, optionally substituted by halogen, phenyl or halophenyl, is reacted with an alkylating agent of the formula

R '-X, wherein R' is as defined above and X is halogen or hydroxy, in the presence of a Lewis acid catalyst, the compound of formula (I) thus obtained

R'O-R-CN, where R 'and R are as defined above, is reduced with a complex metal hydride, the amine of formula

RO-R-NH2, where R and R 'are as defined above, is formylized with formic acid and the obtained formyl compound is dehydrated;

(b) a compound of formula

R = CH 2, wherein R is as defined above, is reacted with an alcohol of formula

R'-OH, wherein R 'is as hereinbefore defined, in the presence of mercuric acetate, the compound of the formula

R'OR-HgOAc, where R and R ¹ are as defined above and Ac is acetate, is reacted with an alkali halide of formula

Alk-Hal, where Alk is an alkali metal atom and Hal is a halogen having an atomic mass greater than 36, the obtained compound of formula

R'O-R-Hg-Hal, where R, R 'and Hal are as defined above, are reacted with a halogen of the formula Hal 2, wherein Hal is as defined and the compound of the formula obtained

R'O-R-Hal, where R, R 'and Hal are as hereinbefore defined, are reacted with silver cyanide to give the compound of formula

R'O-R-NC. Ag-Hal, where R, R 'and Hal are as previously defined, is treated with an alkali cyanide.

The advantage of process (a) is that it provides an intermediate of formula RO-R-NH 2 in a simpler manner and in a higher yield than the prior art processes, thus also increasing the overall yield of the process. The advantage of process (b) is the use of readily available raw materials and the reaction process carried out under mild reaction conditions.

In the first step of process (a), for example, zinc chloride or aluminum chloride can be used as the Lewis acid catalyst. The complex metal hydride representing the reducing agent used in the second step may be, for example, lithium aluminum hydride or sodium borohydride. It is preferred to use lower alkyl formates or mixed formic anhydride and lower alkanecarboxylic acid, such as a reactive formic acid derivative, to formylate an amine of formula RO-R-NH2. The last step of the series of reactions is dehydration, which may be carried out with a conventional dehydrating agent such as diphosgene, phosphorus oxychloride, phosphorus trichloride or thionyl chloride in the presence of an organic base such as pyridine, diisopropylamine or triethylamine.

DETAILED DESCRIPTION OF THE INVENTION

The diagnostic composition of the present invention, its preparation, properties and characteristics, and the preparation of starting materials will be illustrated in the following by specific examples which illustrate the invention in more detail without limiting it to the examples.

Example 1

Preparation of 2-methoxy-2-ethylbutyroocyanate

In this embodiment, 145 mL of water and 46.0 g (0.94 mol) of sodium cyanide were charged to a flask equipped with an HCN absorber, stirrer, thermometer, and dropping funnel. To this solution was then added 86.0 g (1.0 mol) of diethyl ketone, followed by dropwise addition of 252 ml of a 40% strength by weight aqueous sulfuric acid solution while cooling the flask with ice at a temperature ranging from 5 to 10 ° C. The mixture was then stirred at a temperature ranging from 5 to 10 ° C for an additional 30 minutes. Then the phases were separated and the separated aqueous phase was washed twice with 100 ml of diethyl ether. The washed phases were combined with the organic phase, the organic solution was dried over anhydrous sodium sulfate, and then the diethyl ether was evaporated and the residue was distilled under reduced pressure. 78.0 g of 2-hydroxy-2-ethylbutyroocyanate (yield 69%) were obtained.

Boiling point: 116.5 ° C (5 kPa).

NMR (CDCl 3): 1.05 (6H, 2CH 3), 1.8 (4H, 2CH 2), 3.45 (1H, OH). Thereafter, the mixture containing 56.5 g (0.5 mol) of 2-hydroxy-2-ethylbutyrocyanate obtained by the above process, 24 g (0.75 mol) of absolute methanol and 68.1 g (0.5 mol) of anhydrous zinc chloride was stirred. 6 hours at 60 ° C. The reaction mixture thus obtained was allowed to cool to room temperature, and then 100 ml of water and 100 ml of diethyl ether were added. The phases were separated and the organic phase was washed four times with 30 ml of water and the aqueous phase was washed four times with 30 ml of diethyl ether. The organic phases were combined, dried over sodium sulfate, and then the diethyl ether was evaporated and the residue was distilled. 33.0 g (yield 52%) of 2-methoxy-2-ethylbutyrocyanide with a boiling point of 147 ° C are obtained.

NMR (CDCl 3): 0.96 (6H, 2CH ₃ ), 1.76 (4H, 2CH ₂ ), 3.36 (3H, OCH 3).

Example 2

Preparation of 2-methoxyisobutyrocyanide

In an embodiment, the mixture containing 85 g (1.0 mol) of acetone-cyanohydrin, 48 g (1.5 mol) of absolute methanol and 136.2 g (1.0 mol) of anhydrous zinc chloride was stirred for 4 hours at temperature 60 ° C. The reaction mixture thus obtained was cooled to room temperature, and then 200 ml of water and 200 ml of diethyl ether were added. The resulting phases were separated and the organic phase was washed four times with 50 ml of water and the aqueous phase was washed four times with 50 ml of diethyl ether. The ether phases were then combined, dried over sodium sulfate, then the solvent was evaporated and the residue was distilled. In this way, 73.0 g of 2-methoxyisobutyrocyanone were obtained (yield 74%). Boiling point: 117 ° C.

NMR (CDCl 3): 1.48 (6H, 2CH ₃ ), 3.33 (3H, OCH 3).

Example 3

Preparation of 2-methoxy-2-methylbutyrocyanate

In the process of this example, a mixture containing 99 g (1.0 mol) of 2-hydroxy-2-methylbutyrocyanate, 48 g (1.5 mol) of absolute methanol and 136.2 g (1.0 mol) of anhydrous zinc chloride was stirred 5 hours at 60 ° C. The reaction mixture thus obtained was cooled to room temperature, and then 200 ml of water and 200 ml of diethyl ether were added. The phases thus obtained were separated, the organic phase was washed four times with 50 ml of water and the aqueous phase was washed four times with 50 ml of diethyl ether. The organic solutions thus formed were combined, dried over sodium sulfate, the diethyl ether was evaporated and the residue distilled. This procedure afforded 61.0 g of 2-methoxy-2-methylbutyroocyanate (yield 54%).

Boiling point: 135 ° C.

NMR (CDCl3): 0.99 (3H, CH3), 1.45 (3H, CH3), 1.74 to 1.79 (2H, _CH2), 3.37 (3H, OCH 3).

Example 4

Preparation of 2-methoxyisobutylamine

According to this embodiment, the mixture containing 20.9 g (0.55 mol) of lithium aluminum hydride and 600 ml of dry diethyl ether was cooled to below 20 ° C under stirring under nitrogen, and to this solution was added dropwise a mixture containing 49, 5 g (0.5 mol) of 2-methoxyisobutyrocyanate and 100 ml of dry diethyl ether. Thereafter, 35 ml of a 10% by weight aqueous sodium hydroxide solution was added dropwise to the mixture, followed by 70 ml of water. The white precipitate thus formed was removed by filtration and then washed three times with 50 ml of diethyl ether. The filtrate and washings were combined and the resulting solution was dried over sodium sulfate, then the solvent was evaporated and the residue was distilled under reduced pressure. 45.3 g of 2-methoxyisobutylamine (88% yield) were obtained. Boiling point: 58 ° C (16 kPa).

NMR (CDCl 3): 1.13 (6H, 2CH 3), 1.82 (2H, NH ₂ ), 2.62 (2H, CH ₂ ), 3.19 (3H, OCH 3).

Example 5

Preparation of 2-methoxy-2-methylbutylamine

In a procedure of this example, a mixture containing 20.9 g (0.55 mol) of lithium aluminum hydride and 600 ml of dry diethyl ether was cooled to below 20 ° C under stirring under nitrogen, and then a mixture containing 56.5 g (0.5 mol) of 2-methylisobutyrocyanate and 150 ml of dry diethyl ether. The mixture thus obtained was stirred for an additional 30 minutes, and then 35 ml of a 10% by weight aqueous sodium hydroxide solution was added to the mixture, followed by 70 ml of water. A white precipitate was formed, which was filtered off and washed three times with 50 ml of diethyl ether. The filtrate and washings were combined, dried over sodium sulfate, and the ether was evaporated and the residue was distilled under reduced pressure. 52.6 g of 2-methoxy-2-methylbutylamine (90% yield) were obtained.

Boiling point: 76 ° C (13 kPa).

NMR (CDCl 3): 0.61 (3H, CH 3), 0.85 (3H, CH 3), 1.13 (2H, NH ₂ ), 1.29 (2H, CH ₂ ), 2.41 (2H, CH) ₂ ), 2.92 (3H, OCH 3).

Example 6

Preparation of 2-methoxy-2-ethylbutylamine

In the process of this example, a mixture containing 10.5 g (0.275 mol) of lithium aluminum hydride and 300 ml of dry diethyl ether was cooled to below 20 ° C under stirring under nitrogen, then a mixture containing 31 ml of water was added dropwise to the mixture. 75 g (0.25 mol) of 2-methoxy-2-ethylisobutyrocyanate and 50 ml of dry diethyl ether. The mixture was stirred at room temperature for 30 minutes, and then 18 ml of 10% sodium hydroxide solution and then 35 ml of water were added dropwise to the mixture while cooling. A white precipitate was formed, which was filtered off and washed three times with 25 ml of diethyl ether. The filtrate and washings were combined and dried over anhydrous sodium sulfate, then the ether was evaporated and the residue was distilled under reduced pressure. 29.5 g of 2-methoxy-2-ethylbutylamine (90% yield) were prepared by this procedure.

Boiling point: 94 ° C (13 kPa). NMR (CDCl 3): 0.78 (6H, 2CH ₃ ), 1.04 (2H, NH ₂ ), 1.35 (4H, 2 CH ₂ ), 2.31 (2H, CH ₂ ), 2.82 (3H, OCH 3).

Example 7

Preparation of 2-methoxyisobutylformamide

According to this embodiment, a mixture containing 43.2 g of 2-methoxyisobutylamine (0.42 mol) and 200 ml of ethyl formate (184.6 g, i.e. six times the stoichiometric amount) was boiled under autoclave at a pressure of 0.8 MPa for 16 hours.

The remaining ethyl formate and ethanol formed were evaporated. This gave 55.0 g of crude 2-methoxyisobutylformamide (yield 99%). This material was sufficiently pure to carry out the next operation (dehydration).

NMR (CDCl 3): 1.18 (6H, 2CH ₃ ), 3.12 (2H, CH ₂ ), 3.27 (3H, OCH 3), 6.66 (1H, NH), 8.18 (1H, HCO).

Example 8

Preparation of 2-methoxy-2-methylbutylformamide

According to this embodiment, a mixture containing 49.14 g (0.42 mol) of 2-methoxy-2-methylbutylamine and 200 ml of ethyl formate (184.6 g, equivalent to six times the stoichiometric amount) was boiled for 20 hours in an autoclave at 0. 8 MPa. The remaining ethyl formate and ethanol formed were evaporated. 60.4 g of crude 2-methoxy-2-methylbutylformamide (yield 99%) were obtained. This material was sufficiently pure for the next operation (dehydration).

Example 9

Preparation of 2-methoxy-2-ethylbutylformamide

In this embodiment, a mixture containing 27.5 g of 2-methoxy-2-ethylbutylamine (0.21 mol) and 100 ml of ethyl formate (92.3 g, equivalent to six times the stoichiometric amount) was boiled for 24 hours in an autoclave at 0. 8 MPa. The remaining ethyl formate and ethanol formed were evaporated. 33.1 g of crude 2-methoxy-2-ethylbutylformamide (yield 99%) were obtained. This material was sufficiently pure to carry out the next operation (dehydration).

Example 10

Preparation of 2-methoxyisobutylisocyanate

In the process of this example, 76.7 g (0.5 mol) of phosphorus oxychloride was added dropwise to a mixture of 52.4 g of 2-methoxyisobutylformamide (0.4 mol), 101.2 with stirring and cooling to 0 ° C. g (1 mol) of diisopropylamine and 300 ml of dichloromethane. A solution containing 75 g of sodium carbonate in 300 ml of water was then added to the mixture. The phases were separated, the aqueous phase was washed three times with 100 ml of dichloromethane and the organic phase was washed three times with 150 ml of water. The organic solutions were then combined, dried over sodium sulfate and the solvent was evaporated. The residue was distilled under reduced pressure. 35.2 g of 2-methoxyisobutylisocyanate were obtained (yield 78%). Boiling point: 64 ° C (3 kPa).

NMR (CDCl 3): 1.24 (6H, 2CH 3), 3.23 (3H, OCH 3), 3.35 (2H, CH ₂ ).

SK 279625 Β6

Example 11

Preparation of 2-methoxy-2-methylbutylisocyanate

According to this embodiment, 76.6 g (0.5 mol) of phosphorus oxychloride was added dropwise to a stirred and cooled mixture containing 58 g of 2-methoxy-2-methylbutylformamide (0.4 mol), 101.2 g (1 mol) of diisopropylamine and 300 mL of dichloromethane at 2 ° C. A solution containing 75 g of sodium carbonate in 300 ml of water was then added dropwise to the mixture while cooling. The phases were separated and separated, the aqueous phase was washed three times with 100 ml of dichloromethane and the organic phase was washed three times with 150 ml of water. The organic solutions were combined, dried over sodium sulfate, the solvent was evaporated and the residue was distilled under reduced pressure. According to this embodiment, 38.1 g of 2-methoxy-2-methylbutylisocyanate was obtained (yield 75%).

Boiling point: 75 ° C (3 kPa).

NMR (CDCl3): 0.72 (3H, CH3), 0.94 (3H, CH3), 2.37 (2H, _CH2), 3.12 (3H, OCH 3), 3.28 (2H, _CH2 ).

Example 12

Preparation of 2-methoxy-2-ethylbutylisocyanate

In this procedure, 38.35 g (0.5 mol) of phosphorus oxychloride was added dropwise to a stirred and cooled mixture containing 31.8 g (0.2 mol) of 2-methoxy-2-ethylbutylformamide, 50.6 g (0%). 5 mol) of diisopropylamine and 150 ml of dichloromethane at 4 ° C. A solution containing 38 g of sodium carbonate in 150 ml of water was then added dropwise to the mixture while cooling. The phases were separated, the aqueous phase was washed three times with 50 ml of dichloromethane and the organic phase was washed three times with 80 ml of water. The organic phases obtained were combined, dried over sodium sulphate and the solvent was evaporated, and the residue was distilled under reduced pressure. 20.6 g of 2-methoxy-2-ethylbutylisocyanate (yield 73%) were obtained.

Boiling point: 87 ° C (3 kPa).

NMR (CDCl 3): 0.85 (6H, 2CH ₃ ), 2.14 (4H, 2CH ₂ ), 2.91 (3H, OCH 3), 3.17 (2H, CH ₂ ).

Example 13

Preparation of 2-ethoxyisobutyrocyanide

The procedure of Example 2 was followed except that 69 g of absolute ethanol (1.5 mol) was used instead of absolute methanol. According to this embodiment, 94 g of 2-ethoxyisobutyrocyanate was obtained (yield 83%). Boiling point: 124 ° C.

Example 14

Preparation of 2-n-propoxyisobutyrocyanate

The procedure was as described in Example 2 except that 99 g of absolute n-propanol (1.5 mol) was used instead of absolute methanol. 102.9 g of 2-n-propoxyisobutyrocyanone were obtained (yield 81%).

Boiling point: 129 ° C.

Example 15

Preparation of 2-isopropoxyisobutyrocyanate

The procedure was as described in Example 2 except that 99 g of absolute isopropanol (1.5 mol) was used instead of absolute methanol. In this way, 97.8 g of 2-isopropoxyisobutyrocyanone was obtained (yield 77%).

Boiling point: 127 ° C.

Example 16

Preparation of 2-ethoxyisobutylamine

The procedure was as in Example 4 except that 56.5 g of 2-ethoxyisobutyrocyanide (0.5 mol) was used instead of 2-methoxyisobutyrocyanide. 54.4 g of 2-ethoxyisobutylamine were obtained (yield 93%). Boiling point: 62 ° C (16 kPa).

Example 17

Preparation of 2-n-propoxyisobutylamine

The procedure was carried out in the same manner as in Example 4 except that 63.5 g of 2-n-propoxyisobutyrocyanate (0.5 mol) was used instead of 2-methoxyisobutyrocyanide. 58.9 g of 2-n-propoxyisobutylamine (90% yield) were obtained. Boiling point: 66 ° C (16 kPa).

Example 18

Preparation of 2-isopropoxyisobutylamine

The procedure was as in Example 4 except that 63.5 g of 2-isopropoxyisobutyrocyanide (0.5 mol) was used instead of 2-methoxyisobutyrocyanide. 57.0 g of 2-isopropoxyisobutylamine were obtained (yield 87%). Boiling point: 65 ° C (16 kPa).

Example 19

Preparation of 2-ethoxyisobutylformamide

The procedure was as in Example 7 except that 49.14 g of 2-ethoxyisobutylamine (0.42 mol) was used instead of 2-methoxyisobutylamine. According to this embodiment, 60.29 g of 2-ethoxyisobutylformamide (yield 99%) were obtained.

Example 20

Preparation of 2-n-propoxyisobutylformamide

The procedure of Example 7 was followed except that 55.02 g of 2-n-propoxyisobutylamine (0.42 mol) was used instead of 2-methoxyisobutylamine. 66.11 g of 2-n-propoxyisobutylformamide (yield 99%) were thus obtained.

Example 21

Preparation of 2-isopropoxyisobutylformamide

The procedure was as in Example 7 except that 55.02 g of 2-isopropoxyisobutylamine (0.42 mol) was used instead of 2-methoxyisobutylamine. 66.11 g of 2-isopropoxyisobutylformamide were obtained (yield 99%).

Example 22

Preparation of 2-ethoxyisobutylisocyanate

The procedure of Example 10 was followed except that 58.0 g of 2-ethoxyisobutylformamide (0.4 mol) was used in place of 2-methoxyisobutylformamide. In this way 40.64 g of 2-ethoxyisobutylisocyanate (yield 80%) was obtained. Boiling point: 67 ° C (3 kPa).

Example 23

Preparation of 2-n-propoxyisobutylisocyanate

The procedure was carried out as in Example 10 except that 63.6 g of 2-n-propoxyisobutylformamide (0.4 mol) were used instead of 2-methoxyisobutylformamide. 44.0 g of 2-n-propoxyisobutylisocyanate was prepared (yield 78%).

Boiling point: 69 ° C (3 kPa).

Example 24

Preparation of 2-isopropoxyisobutylisocyanate

The procedure was carried out in the same manner as in Example 10 except that 63.6 g of 2-isopropoxyisobutylformamide (0.4 mol) was used instead of 2-methoxyisobutylformamide. 43.4 g of 2-isopropoxyisobutylisocyanate (77% yield) were prepared according to the procedure.

Boiling point: 67 ° C (3 kPa).

Example 25

Preparation of copper 2-methoxyisobutylisocyanetetrafluoroborate adduct

According to this embodiment, a solution containing 2.47 g of copper (II) chloride (0.025 mol) and 2.65 g of sodium tetrafluoroborate (0.025 mol) in 60 ml of a 1 mol / liter aqueous hydrochloric acid solution was added to 11.3 g of 2- methoxyisobutylisocyanate (0.1 mol). The mixture was then held at 0 ° C for two hours, whereupon the crystals formed were filtered off, washed with water and a small amount of alcohol, and then dried. 10.5 g of white crystalline product were obtained (yield 70%).

NMR (CDC1 _3): 1.24 (6H, 2 CH _3), 3.23 (3H, _OCH3), 3.35 (2H, CH 2).

Example 26

Preparation of 2-methoxy-2-methylbutylisocyanate and copper tetrafluoroborate adduct

According to this embodiment, a solution containing 2.47 g of copper chloride (0.025 mol) and 2.65 g of sodium tetrafluoroborate (0.025 mol) in 60 ml of a 1 mol / liter aqueous hydrochloric acid solution was added to 12 ml with cooling and stirring. 7 g of 2-methoxy-2-methylbutylisocyanate (0.1 mol). The mixture was then kept at 0 ° C for two hours, then the separated crystals were filtered off, washed with water and a small amount of alcohol, and then dried. 11.8 g of a pale yellow crystalline substance are obtained (yield 72%).

NMR (CDC1 _3): 0.72 (3H, _CH3), 0.94 (3H, _CH3), 2.37 (2H, _CH2), 3.12 (3H, _OCH3), 3.28 ( 2H, _CH2).

Example 27

Preparation of 2-methoxy-2-ethylbutylisocyanate and copper tetrafluoroborate adduct

To this example, a solution containing 2.47 g of copper (II) chloride (0.025 mol) and 2.65 g of sodium tetrafluoroborate (0.025 mol) in 60 ml of a 1 mol / liter aqueous hydrochloric acid solution was added with cooling and stirring. to 14.1 g of 2-methoxy-2-ethylbutylisocyanate (0.1 mol). The mixture was kept at 0 ° C for two hours, then the separated crystals were filtered, washed with water and a small amount of alcohol, and then dried. 11.6 g of a pale yellow crystalline substance are obtained (yield 65%).

NMR (CDC1 _3): 0.85 (6H, 2 CH _3), 2.14 (4H, ₂ CH2), 2.91 (3H, OCH 3), 3.17 (2H, _CH2).

Example 28

Preparation of adduct of 2-ethoxyisobutylisocyanate and copper tetrafluoroborate

The procedure of Example 25 was followed except that 12.7 g of 2-ethoxyisobutylisocyanate (0.1 mol) was used in place of 2-methoxyisobutylisocyanate. In this way 12.78 g of 2-ethoxyisobutylisocyanate and copper tetrafluoroborate adduct were obtained (yield 78%)

Example 29

Preparation of 2-n-propoxyisobutylisocyanate and copper tetrafluoroborate adduct

The procedure was as in Example 25 except that 14.1 g of 2-n-propoxyisobutylisocyanate (0.1 mol) was used instead of 2-methoxyisobutylisocyanate. 12.49 g of an adduct of 2-n-propoxyisobutylisocyanate and copper tetrafluoroborate were obtained (yield 70%).

Example 30

Preparation of adduct of 2-isopropoxyisobutylisocyanate and copper tetrafluoroborate

The procedure was as in Example 25 except that 14.1 g of 2-isopropoxyisobutylisocyanate (0.1 mol) was used instead of 2-methoxyisobutylisocyanate. 12.85 g of an adduct of 2-isopropoxyisobutylisocyanate and copper tetrafluoroborate were obtained according to the procedure of this example (yield 72%).

Example 31

Preparation of the diagnostic device

According to this example, a diagnostic composition of the following composition was prepared:

adduct of 2-methoxyisobutyl isocyanate and copper tetrafluoroborate 0.43 mg sodium pyrophosphate decahydrate 1.2 mg glucose 12.0 mg

L-cysteine hydrochloride 0.54 mg stannous chloride dihydrate 0.03 mg

To prepare this diagnostic agent, the adduct was dissolved in nitrogen saturated ethanol and an aqueous solution of the other ingredients was added to the ethanolic solution. All of these operations were performed under a nitrogen atmosphere. The resulting solution was filled into vials of 1 ml and the contents of the vials were lyophilized.

Example 32

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

adduct of 2-methoxy-2-methylbutylisocyanate and copper tetrafluoroborate 0.50mg sodium diphosphate decahydrate 1.2 mg glucose 12.0mg

L-cysteine hydrochloride 0.54mg stannous chloride dihydrate 0.03mg.

adduct of 2-methoxyisobutylisocyanate and copper tetrafluoroborate 0.45 mg glycine 0.3 mg inositol 12.0 mg α-mercaptopropionylglycine 0.3 mg stannous chloride dihydrate 0.03 mg.

Example 33

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

Example 38

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

adduct of 2-methoxy-2-ethylbutylisocyanate and copper tetrafluoroborate 0.55mg sodium diphosphate decahydrate 1.2 mg glucose 12.0 mg

L-cysteine hydrochloride 0.54mg stannous chloride dihydrate 0.03mg.

adduct of 2-methoxy-2-methylbutylisocyanate and copper tetrafluoroborate 0.50 mg glycine 0.3 mg inositol 12.0 mg α-mercaptopropionylglycine 0.3 mg stannous chloride dihydrate 0.03 mg.

Example 34

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

Example 39

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

adduct of 2-methoxyisobutylisocyanate and copper tetrafluoroborate 0.45 mg sodium citrate dihydrate 1.2 mg maltose 12.0 mg

L-cysteine hydrochloride 0.43 mg stannous chloride dihydrate 0.03 mg.

adduct of 2-methoxy-2-ethylbutylisocyanate and copper tetrafluoroborate 0.55 mg glycine 0.3 mg inositol 12.0 mg α-mercaptopropionylglycine 0.3 mg stannous chloride dihydrate 0.03 mg.

Example 35

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

Example 40

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

adduct of 2-methoxy-2-methylbutylisocyanate and copper tetrafluoroborate 0.50mg sodium citrate dihydrate 1.2mg maltose 12.0mg

L-cysteine hydrochloride 0.45mg stannous chloride dihydrate 0.03mg.

adduct of 2-methoxyisobutyl isocyanate and copper tetrafluoroborate 0.5mg sodium diphosphate decahydrate 5.2mg glycine 16.0mg

L-cysteine hydrochloride 2,0mg stannous chloride dihydrate 0,3mg

Example 36

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

Example 41

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

adduct of 2-methoxy-2-ethylbutylisocyanate and copper tetrafluoroborate 0.55 mg sodium citrate dihydrate 1.2 mg maltose 12.0mg

L-cysteine hydrochloride 0.45 mg stannous chloride dihydrate 0.03 mg.

2-methoxy-2-methylbutylisocyanate and copper tetrafluoroborate adduct 0.5mg sodium diphosphate decahydrate 5.2mg glycine 16.0mg

L-cysteine hydrochloride 2,0mg stannous chloride dihydrate 0,3mg.

Example 37

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

Example 42

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

2-methoxy-2-ethylbutylisocyanate and cuprous tetrafluoroborate adduct 0.5mg sodium diphosphate decahydrate 5.2mg glycine 16.0mg

L-cysteine hydrochloride 2,0mg tin (II) chloride dihydrate 0,3mg.

Example 43

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

Example 47

Preparation of the diagnostic device

This procedure was carried out in the same manner as in Example 31, with a diagnostic composition having the following composition:

adduct of 2-isopropoxyisobutylisocyanate and cuprous tetrafluoroborate 0.5mg sodium diphosphate decahydrate 5.2mg glycine 16.0mg

L-cysteine hydrochloride 2,0mg tin (II) chloride dihydrate 0,3mg.

2-methoxyisobutylisocyanate adduct a copper tetrafluoroborate 0.25 mg adduct of 2-methoxy-2-methylbutylisocyanate and copper tetrafluoroborate 0.25 mg disodium phosphate decahydrate 5,2 mg glycine 16.0 mg L-cysteine hydrochloride 2.0 mg tin (II) chloride dihydrate 0.3 mg. Example 44 Preparation of the diagnostic device This procedure was carried out in the same manner as in Example 31, whereby a diastate was prepared. gnostic agent of the following composition: 2-ethoxyisobutylisocyanate and cuprous tetrafluoroborate adduct 0.5 mg disodium phosphate decahydrate 5,2 mg glycine 16.0 mg L-cysteine hydrochloride 2.0 mg tin (II) chloride dihydrate 0.3 mg. Example 45 Preparation of the diagnostic device This procedure was carried out in the same manner as in Example 31, whereby a diastate was prepared. gnostic agent of the following composition: 2-ethoxyisobutylisocyanate and cuprous tetrafluoroborate adduct 0.25 mg 2-methoxyisobutylisocyanate and cuprous tetrafluoroborate adduct 0.25 mg disodium phosphate decahydrate 5,2 mg glycine 16.0 mg L-cysteine hydrochloride 2.0 mg tin (II) chloride dihydrate 0.3 mg. Example 46 Preparation of the diagnostic device The same procedure was followed as in Example 31, wherein according to 1 : ohto example the diagnostic means of the following ZENIT: an adduct of 2-n-propoxyisobutylisocyanate and copper tetrafluoroborate 0.5 mg disodium phosphate decahydrate 5,2 mg glycine 16.0 mg L-eysteínhydrochlorid 2.0 mg tin (II) chloride dihydrate 0.3 mg.

Example 48

Diagnostic device stability test

This example examined the stability of the composition of the invention, the diagnostic composition described in Examples 31-33 was treated in aqueous medium with 2.0 ml 99 m p _c -pertechnctátu (activity: 370-1110 MBq). This reaction was carried out for 10 minutes on a steam bath.

Samples were periodically sampled from the obtained radioiodiagnostic complexes and the content of the 99mp _c- isocyanether complex, which is fat-soluble, was chromatographically determined. Chromatographic analyzes were performed under the following conditions:

adsorbent A: silica gel plate 2.5 x 20 cm, eluent: ethanol, adsorbent B: aluminum oxide plate 2.5 x 20 cm, eluent: ethanol.

The content of the 99nrr _cis -isocyanate complex, which is fat-soluble, was expressed as a percentage of the starting amount in each sample. The results are shown in the following table. I.

Table I

99mTc -isocyanate ether complex, fat solubility,%

temporal Example 31 Example 32 Example 33 interval A B A B A B 15 minutes 98.9 99.1 98.6 99.0 98.4 98.6 1 hour 98.6 98.8 98.3 98.8 98.2 98.5 2 hours 98.5 98.6 98.2 98.7 98.1 98.3 3 Hours 98.3 98.3 98.0 98.4 98.0 98.3 8 hours 98.8 98.2 97.3 98.3 97.2 98.1 24 hours 94.7 96.0 94.4 95.4 95.3 95.7

Claims (1)

PATENT CLAIMS Diagnostic reagent for labeling 99mf _c containing an adduct of a metal salt and an isocyanate of the general formula (II) CN-R-OR '(II) in which R represents a straight or branched chain alkylene group having 2 to 8 carbon atoms, optionally with a substituent which may be a halogen, a phenyl group or a halophenyl group, and R 1 is a straight or branched chain alkyl group having 1 to 4 carbon atoms, or a mixture of these adducts and 0.03 to 1.0 parts by weight of a reducing agent, based on the weight of the adduct, characterized in that it contains 0.5 to 5 parts by weight of the antioxidant, based on the weight of the adduct, of at least 10 parts by weight of the carbohydrate and / or amino acid of the formula H 2 N- (CH 2) _n -COOH, wherein n is an integer from 1 to 4, based on the amount of adduct, and a buffer in an amount necessary to achieve a pH in the range of 4 to 6 when the composition is dissolved in water.