SK168990A3 - Diagnostic agent - Google Patents

Abstract

Diagnosis-reagent compsn. labellable with 99m-Tc, comprises: (a) a metal salt adduct of an isonitrile ether of formula CN-R-0R (II) opt. in combination with 0.03-1.0 pts.wt. of a reducing agent; (b) 0.5-5 pts.wt. of an antioxidant; (c) at least 10 pts.wt. of a saccharide and/or an amine acid of formula H2N-(CH2)n-C00H (III); and (d) enough buffer to set the pH to 4-6 when the compsn. is dissolved in water. R = 2-8C alkylene, opt. substd. by halo, phenyl or halophenyl; R1 = 1-4C alkyl; n = 1-4; All pt.wt. values are based on wt. of adduct.

Description

Diagnostic device

Technical field

The invention relates to a diagnostic composition suitable for labeling ^99m Tc based on a metal salt adduct and an isocyanate.

BACKGROUND OF THE INVENTION

It is known in the art that the isocyanate salts of the isocyanethers in the form of complexes of the general formula I [(CN-R-OR ') ₆ ^m Tc] ⁺ 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, particularly in the detection of myocardial disorders. For this purpose, salts or complexes of C1-C4 alkyl isocyanotechnium (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. J. Nucl. Med. 12, 219 (1986); J. Nucl. Med. 27, 404 (1986).

These labeled salts or complexes are prepared by reacting the corresponding isocyanether of formula II

CN-R-OR '(II), in which R and R' are as defined above, with a technetium salt or complex thereof, wherein the technetium ^99m Tc is contained in an oxidation stage of greater than 1, the reaction being carried out in the presence of a reducing agent (see U.S. Patent No. 4,452,774). This patent also discloses a compound for the preparation of a complex of formula I. The compound 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 disadvantage 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 resulting isocyanate ether metal salt adducts 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 preparing the radiodiagnostic complex, the composition of the above published European patent applications is reacted, as in the prior art, with a salt or technetium complex containing ^99m Tc technetium in an oxidation state of greater than 1. This reaction is carried out in an aqueous environment at elevated temperatures. temperature.

The above-described procedures described in EP-A no. 183 5S5 and no. 233 368, the above-mentioned difficulties in handling and storing said composition can be overcome. A disadvantage, however, is that if a diagnostic composition comprising a reducing agent and an adduct of isocyanate ether and a metal salt reacts with an ion source of ^99m Tc, a radiodiagnostic complex is obtained with unsuitable stability. This is attributable to the fact that the isocyanether ligands bound to the ^99m Tc ion decompose relatively rapidly, and so, several hours after the preparation of the radiodiagnostic complex, the amount of radioactive ion-bearing ligands is insufficient to perform the diagnostic measurement.

It is an object of the present invention to provide a diagnostic means which, when reacted with a ^99ra Tc ion source, ^does not form a radiodiagnostic complex of unstable nature, but rather to produce a radiodiagnostic complex of stable nature over a long working time. considerably delayed.

SUMMARY OF THE INVENTION

According to the invention it has been found that these requirements are met by the diagnostic composition of a known composition comprising an adduct izokyanoéter-metal salt and a reducing agent, which is complemented by a protective colloid formed by the saccharide and / or amino; __ acid of formula H ₂ N- (CH _{2) n} COOH, wherein n is an integer from 1 to 4, together with a buffer and an antioxidant.

Principle of a ^99m Tc Labeling Diagnostic Tool Containing an Adduct of a Metal Salt and an Isocyanether of 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 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 based on the weight of the adduct according to the 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 isocyanate ether metal salt adduct present in this diagnostic composition of the invention may be the same as in the above-cited European patent applications cited above. Of these, Cu (I) -tetrafluoroborate adducts of the isocyanethers of 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 above-cited documents.

Any reducing agent commonly used to reduce ^99m Tc in an oxidation stage of greater than 1 may be used as the reducing agent. For example, stannous chloride dihydrate, stannous tartrate, stannous citrate, stannous gluconate, stannous fluoride, stannous aprotinin and stannous pyrophosphate can be mentioned.

The diagnostic composition according to the invention contains as buffer a substance which, in the reaction carried out with an ion source of ^99m Tc, adjusts the pH of the aqueous reaction medium to 4 to 6, preferably to 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 scalding of the solution used for radiodiagnostic purposes, further increasing the solubility of the low-soluble isocyanether-ether salt adducts in water.

The diagnostic composition according to 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 exhibit 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.

Under the combined influence of the carbohydrate, buffer and antioxidant present in the diagnostic composition of the invention, the stability of the radiodiagnostic complex obtained by reaction with the ^99m Tc ion significantly increases. According to the measurements made by the present inventors, it has been found that in this way the stability is increased at least three-fold compared to a radiodiagnostic complex prepared from a prior art diagnostic composition containing only a reducing agent and an isocyananoether-metal 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 together prior to mixing (e.g. grinding) prior to mixing.

If the diagnostic composition of the invention comprises at least one poorly water-soluble component (such as a poorly soluble isocyanether-ether 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 as such or in the form of an aqueous solution, and the mixture obtained is lyophilized. These operations are carried out in an oxygen-free atmosphere.

The ^99m Tc radio-diagnostic complex may be prepared from a diagnostic composition of the invention by the method described, for example, in the cited patents, for example by the procedures of EP-A 183 555 and 233 308.

The isocyanethers of formula (II) used as precursors in the preparation of the adducts of the isocyanoether-metal 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 compounds of formula (II) which are simpler, employing fewer process steps, achieving higher yields under milder reaction conditions, and / or using readily available starting materials. These procedures can be summarized as follows:

(a) the cyano compound of formula HO-R '' - CN wherein R '' is a straight or branched chain alkylene group having 1 to 7 carbon atoms, which is optionally substituted by halogen, phenyl or halophenyl, is reacted with an alkylating agent of general 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 by a complex metal hydride, the amine of formula

R'OR-NH ₂ where R and R 'are as defined above, is formylized with formic acid and the obtained formyl compound is dehydrated;

(b) reacting a compound of formula R '' = CH ₂ wherein R '' is as defined above, with an alcohol of formula R'-OH wherein R 'is as defined above, in the presence of mercuric acetate, whereby the obtained compound of formula

R'O-R-HgOAc wherein R and R 'are as defined above and Ac is acetate, is reacted with an alkali metal halide of formula

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

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

R'O-R-Hal wherein R, R 'and Hal are as defined above,

I is reacted with silver cyanide and the compound of formula I obtained

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

The advantage of process (a) is that it provides an intermediate of formula R'OR-NH _{2 in a} simpler manner and in a higher yield than 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 a lower alkanecarboxylic acid, such as a reactive formic acid derivative, for the formylation of an amine of the formula R 10 -R-NH ₂ . 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 exemplary embodiments.

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 of 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 (CDC1 _3): 1.05 (6H, 2CH _3), 1.8 (4H, CH 2 _Z), 3.45 (ΙΗ, ΟΗ).

Thereafter, the mixture containing 56.5 g (0.5 mol) of 2-hydroxy-2-ethylbutyroocyanate obtained above, 24 g (0.75 mol) of absolute methanol and 68.1 g (0.5 mol) of anhydrous zinc chloride was stirred for 6 hours. hours at 60 ° C. The reaction mixture thus obtained was left

I was cooled at 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 (52% yield) of 2-methoxy-2-ethylbutyrocyanate, b.p. 147 ° C, were 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 a process of this embodiment, a 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. 73.0 g of 2-methoxyisobutyrocyanate (74% yield) were obtained. 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

I

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 (CDC1 _3): 0.99 (3H, _CH3), 1.45 (3H, _CH3), 1.74 to 1.79 (2H, _CH2), 3.37 (3H, _OCH3).

Example 4

Preparation of 2-methoxyisobutylamine

According to the present embodiment with 20.9 mixture g (0,55 mol) of lithium aluminum hydride 600 ml of dry and diethyl ether stirred under a nitrogen atmosphere cooled to below 20 C, and ^E to the solution under cooling was added dropwise a mixture comprising 49.5 g (0.5 mol) of 2-methoxyisobutyrocyanate and 100 ml of dry diethyl ether. Thereafter, 35 ml of 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 i

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. In this way, 45.3 g of 2-methoxyisobutylamine were obtained (yield 88%).

Boiling point: 58 ° C (16 kPa).

NMR (CDCl): 1.13 (6H, 2 CH _3), 1.82 (2H, _NH2), 2.62 (2H, CH _2),

3.19 (3H, _OCH3).

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 ml of water was added dropwise under cooling. 5 g (0.5 mol) of 2-methylisobutyrocyanate and 150 ml of dry diethyl ether. The mixture thus obtained was stirred for a further 30 minutes and then 35 ml of a 10% strength 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 (CDC1 _3): 0.61 (3H, _CH3), 0.85 (3H, _CH3), 1.13 (2H, NH _2),

1.29 (2H, _CH2), 2.41 (2H, _CH2), 2.92 (3H, _OCH3).

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% 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 was added dropwise thereto while cooling, followed by 35 ml of water. 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 (CDC1 _3): 0.78 (6H, 2 CH _3), 1.04 (2H, _NH2), 1.35 (4H, ₂ CH2), 2.31 (2H, _CH2), 2.82 ( 3H, OCH ₃ ).

Example 7

Preparation of 2-methoxybutylformamide

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 in an 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 _a ), 3.12 (2H, CH ₂ ), 3.27 (3H, OCH ₃ ), 6.56 (ΙΗ, ΝΗ), 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, corresponding 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. In this way, 60.4 g of crude 2-methoxy-2-methylbutylformamide were obtained (yield 99%). This material was sufficiently pure for the next operation (dehydration).

Example 9

Preparation of 2-methoxy-2-ethylbutylformamide

According to this embodiment, a mixture comprising 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 under autoclave at 0.8 for 24 hours. bar. The remaining ethyl formate and ethanol formed were evaporated. 33.1 g of crude 2-methoxy-2-ethylbutylformamide (yield 99%) are obtained. This material was sufficiently pure to carry out the next operation (dehydration).

Example 10

Preparation of 2-methoxyisobutylisocyanate

In the method of this example 76.7 g (0.5 mole) phosphorous oxychloride with stirring and cooling to 0 ^and C added dropwise to a mixture of 52.4 g of 2-metoxyizobutylformamidu (0.4 mol), 101.2 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 (CDC1 _3): 01.24 (6H, 2 CH _3), 3.23 (3H, _OCH3), 3.35 (2H, _CH2).

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)

YJ 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 (CDC1 _3): 0/72 (3H, _CH3), 0.94 (3H, _CH3), 2.37 (2H, CH _2),

3.12 (3H, _OCH3), 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-methyl-2-ethylbutylisocyanate were obtained (yield 73%).

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-ethoxyisobutyrocyanide was obtained (yield 83%).

Boiling point: 124 ° C.

Example 14

Preparation of 2-n-propoxyisobutyrocyanate

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

Boiling point: 129 ° C.

Example 15

Preparation of 2-isopropoxyisobutyrocyanate

According to this embodiment, the same procedure was followed

In the same manner as 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-isopropoxyisobutyrocyanate were 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 (93% yield) were obtained.

Boiling point: 62 ° C (16 kPa).

Example 17

Preparation of 2-n-propoxyisobutylamine

This 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 were obtained (yield 90%).

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-isopropoxyisobutyrocyanate (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 obtained.

Example 21

Preparation of 2-isopropoxyisobutylformamide

The procedure of this Example was carried out 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. 40.64 g of 2-ethoxyisobutylisocyanate were obtained (yield 80%).

Boiling point: 67 ° C (3 kPa).

Example 23

Preparation of 2-n-propoxybutyrate from cyano

The procedure of Example 10 was followed except that 63.6 g of 2-n-propoxyisobutylformamide (0.4 mol) was used in place of 2-methoxyisobutylformamide. 44.0 g of 2-n-propoxyisobutylisocyanate (yield 78%) were prepared according to the procedure.

Boiling point: 69 ° C (3 kPa).

Example 24

Preparation of 2-isopropoxybutyl from cyano

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

In this embodiment, a solution containing 2.47 g of copper (I) 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-methoxyisobutyl. of cyanide (0.1 mol). The mixture was then held at 0 ° C for two hours, the crystals formed being 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 (CDCl ₃ ): 1.24 (6H, 2CH ₃ ), 3.23 (3H, OCH ₃ ), 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 (I) 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 12.7 g with cooling and stirring. 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 (CDCl ₃ ): 0.72 (3H, CH ₃ ), 0.94 (3H, CH ₃ ), 2.37 (2H, CH ₂ ),

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 (I) 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 14 ml with cooling and stirring. 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 off, washed with water and a small amount of alcohol and then dried. 11.6 g of a pale yellow crystalline substance are obtained in this way (yield 65%).

NMR (CDC1 _3): 0.85 (6H, 2 CH _3), 2.14 (4H, ₂ CH2), 2.91 (3H, _OCH3), 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. 12.78 g of an adduct of 2-ethoxyisobutylisocyanate and copper tetrafluoroborate (78% yield) were obtained.

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

Example 31

Preparation of the diagnostic device

According to this example, a diagnostic composition of the following composition was prepared: 2-methoxyisobutylisocyanate adduct 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 by the same prepared

Following the procedure of Example 31, the diagnostic composition was: adduct of 2-methoxy-2-methylbutylisocyanate and copper tetrafluoroborate disodium phosphate decahydrate

0.50 mg 1.2 mg

glucose 12.0 mg L-cysteine hydrochloride 0.54 mg stannous chloride dihydrate 0.03 mg.

Example 33

Preparation of the diagnostic device

According to this embodiment, the same procedure was carried out as in Example 31, with a diagnostic composition having the following composition:

2-Methoxy-2-ethylbutylisocyanate adduct a

copper tetrafluoroborate 0 55 mg disodium phosphate decahydrate 1 2 mg glucose 12 0 mg L-cysteine hydrochloride 0 54 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:

2-methoxyisobutylisocyanate adduct a

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.

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:

2-methoxy-2-methylbutylisocyanate adduct a

copper tetrafluoroborate 0.50 mg sodium citrate dihydrate 1.2 mg maltose 12.0 mg L-cysteine hydrochloride 0.45 mg stannous chloride dihydrate 0.03 mg.

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:

2-Methoxy-2-ethylbutylisocyanate adduct a

tetrafluoroborate 0.55 mg sodium citrate dihydrate 1.2 mg maltose 12.0 mg L-cysteine hydrochloride 0.45 mg stannous chloride dihydrate 0.03 mg.

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:

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

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-methylbutylisocyanate and cuprous tetrafluoroborate 0.50 mg glycine 0.3 mg inositol 12.0 mg α-mercaptopropionylglycine 0.3 mg stannous chloride dihydrate 0.03 mg.

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:

2-Methoxy-2-ethylbutylisocyanate and cuprous tetrafluoroborate adduct 0.55 mg glycine 0.3 mg inositol 12.0 mg α-mercaptopropionylglycine 0.3 mg stannous chloride dihydrate 0.03 mg.

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:

2-methoxyisobutylisocyanate and cuprous tetrafluoroborate adduct 0.5 mg sodium phosphate dibasic decahydrate 5.2 mg glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg stannous chloride dihydrate 0.3 mg.

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-methylbutylisocyanate and copper tetrafluoroborate 0.5 mg sodium phosphate dibasic decahydrate 5.2 mg glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg t

stannous chloride dihydrate 0.3 mg.

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 copper tetrafluoroborate adduct 0.5 mg sodium phosphate dibasic decahydrate 5.2 mg glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg stannous chloride dihydrate 0.3 mg.

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:

2-methoxyisobutylisocyanate and copper tetrafluoroborate adduct 0.25 mg 2-methoxy-2-methylbutylisocyanate and copper tetrafluoroborate adduct 0.25 mg sodium phosphate dibasic decahydrate 5.2 mg glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg stannous chloride dihydrate 0.3 mg.

Example 44

Preparation of the diagnostic device

In this embodiment, §a proceeded in the same manner as in Example 31, wherein a diagnostic composition having the following composition was prepared:

adduct of 2-ethoxyisobutyl isocyanate and copper tetrafluoroborate 0.5 mg sodium phosphate dibasic decahydrate 5.2 mg glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg stannous chloride dihydrate 0.3 mg.

Example 45

Preparation of the diagnostic device

According to this embodiment, the same procedure was carried out as in Example 31, with a diagnostic composition having the following composition:

2-ethoxyisobutylisocyanate and copper tetrafluoroborate adduct 0.25 mg 2-methoxyisobutylisocyanate and copper tetrafluoroborate adduct 0.25 mg sodium phosphate dibasic decahydrate 5.2 mg glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg stannous chloride dihydrate 0.3 mg.

Example 46

Preparation of the diagnostic device

In the same manner as in Example 31, a diagnostic composition of the following composition was prepared:

adduct of 2-n-propoxyisobutyl isocyanate and tetrafluoroborate 0.5 mg sodium phosphate dibasic decahydrate 5.2 mg glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg stannous chloride dihydrate 0.3 mg.

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-isopropoxyisobutyl isocyanate and copper tetrafluoroborate 0.5 mg sodium phosphate dibasic decahydrate 5.2 mg glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg stannous chloride dihydrate 0.3 mg.

Example 48

Diagnostic device stability test

The stability of the composition of the invention was investigated, wherein the diagnostic composition described in Examples 31-33 was reacted in an aqueous medium with 2.0 mL of ^99m Tc-pertechnetate (activity: 370-1110 Mbq). This reaction was carried out for 10 minutes on a steam bath.

Samples were periodically sampled from the obtained radiodiagnostic complexes and the content of the ^99m Tcisocyanoether complex, which was 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 fat-soluble ^99m Tc-isocyanether complex was expressed as a percentage of the starting amount in each sample. The results are shown in the following table. I.

Table I

^99m Tc-isocyanoether 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 ^99m Tc diagnostic reagent containing an adduct of a metal salt and an isocyanate of 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 '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, 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, based on the amount of adduct, and a buffer in an amount necessary to achieve a pH between 4 and 6 when the composition is dissolved in water.