JPS5834447B2 - Scintilography reagent and its manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is to provide a scintillographic reagent which is a chelate of a dialkyl acetanilide derivative of iminodiacetic acid and a radioactive metal, and a method for producing the same.

The products of the invention are intended for intravenous administration in medical diagnosis, in particular in diagnosis of the bile ducts.

A known method for preparing scintillographic reagents, N-alkyl acetanilide derivatives of iminodiacetic acid chelated with a radioactive metal, disclosed in U.S. Pat. - It consists of treating 6-dimethylaniline with chloroacetyl chloride at a temperature of 10° C. and then with a solution of sodium acetate.

Shake this mixture for 30 minutes.

The precipitate that forms is dissolved in benzene diethylamine solution and the resulting solution is warmed for several hours under a water circulating condenser.

The diethylamine hydrochloride is then separated and the solution is extracted using hydrochloric acid.

The extraction phase is made alkaline and then extracted with ether.

The obtained ether solution is distilled and the distillation product is ω-
Chloro-2,6-dinitylacetanilide is obtained.

The yield in this method is 70%.

Further, this ω-chloro-2,6-ethylacetanilide and sodium salt of iminodiacetic acid are dissolved in 75% alcohol.

The mixture is heated for about 2 days under a water circulating condenser, and the dry precipitate after evaporation of the solvent is dissolved in water and extracted twice with ether.

After removing the ether extract, hydrochloric acid is added until the pH is approximately 3.2 and the resulting precipitate is crystallized from water.

The derivative of iminodiacetic acid thus produced is dissolved again in water and a 1N solution of stannous chloride in hydrochloric acid is added, followed by the addition of sodium hydroxide to adjust the pH value to approximately 5.5.

The solution is then clarified through a sterile strainer, lyophilized and stored in sterile ampoules under nitrogen or filled under reduced pressure.

Immediately before intravenous administration, sterilize the
Add the c solution to the derivative of iminodiacetic acid.

The shelf life of the scintillographic paper drug prepared by this method is 2 hours.

Also, Swiss Patent No. 607920 (Japanese Unexamined Patent Publication No. 52-148
No. 629), a known method for producing scintillographic reagents is disclosed in US Pat. In this method, an aniline derivative having a lower alkyl group as a substituent is dissolved in anhydrous acetone.

Separately, chloroacetyl chloride is cooled in ice water and a solution of the above derivative is gradually added dropwise in an amount of 15 moles of chloride/13 moles of derivative.

The solution is mixed for 30 minutes at a temperature increasing from 2°C to 12°C.

The acetone is then replenished, an appropriate amount of ice-cold water is added, the mixture is mixed again, and a solution of hydrochloric acid in acetone is added to the reaction mixture.

After mixing for 15 minutes, the precipitate is filtered once, washed twice with copious amounts of hydrochloric acid, and dried.

The dry product A, a derivative of ω-chloroacetanilide, is crystallized from 50-80% ethanol.

Dissolve iminodiacetic acid in an aqueous solution of soda lye, add sodium carbonate, and heat to 7°C.
A solution of product A in absolute ethanol heated to a temperature of 6
Add to the above mixture, being careful not to drop the temperature below 5°C.

The reaction mixture is heated to 80° C. under a water circulating condenser during the 12 hour reaction.

A small amount of distilled water at a temperature of 45° C. is then added and the ethanol is evaporated under reduced pressure.

The residual liquid is filtered once, then homogeneously dispersed in water, filtered once again, and washed with water.

Dilute the first solution with water and gradually add hydrochloric acid until the pH value becomes 1.5-2.

The precipitate, designated product B, is filtered once and washed twice with hydrochloric acid.

After 1 filtration, the product is dissolved in soda lye until a pH value of 8-8.5 is obtained, this clear solution is mixed with acetone and treated with hydrochloric acid with vigorous mixing until a pH of about 2.0 is obtained. Make acidic.

Finally, the crystal product B was washed twice with dilute hydrochloric acid and once with water.
The mixture is filtered and dried under reduced pressure.

In the final stage of scintillography reagent preparation, at the second, fourth and/or sixth carbon atom of the aromatic ring,
Product B is a dicarboxylic acid substituted with at least 2 lower alkyl groups having at least 3 carbon atoms
is chelated with a radioactive metal, specifically pertechnetate-99m.

Scintilographic reagents prepared in this manner can be used for 0.5 to 2 hours after chelation and for up to 6 hours.
Suitable for injection up to an hour.

To facilitate the application of this reagent, the dicarboxylic acid, product B, is prepared by specifically adding 100 to 200 μg of stannous chloride in IN hydrochloric acid to 820 to 25 η of the product. Convert to the water-soluble sodium salt of this acid, adjust the pH value to 5.5-5.7, inject the salt into sterile ampoules, lyophilize and store under nitrogen, and before injection ~2 hours before, maximum 6 hours before chelation with 99 m Tc.

A chelate of a radioactive metal and a dialkyl acetanilide derivative of iminodiacetic acid, the alkyl group of the derivative;
The scintillographic reagent according to the invention, in which the CH groups are preferably located on the second and fourth carbon atoms of the aromatic ring, unexpectedly improves the radiochemical durability and the biological and scintillographic outcomes. As a result of experiments and inspections, it has become clear that

Changes in the substituents of 99 m Tc/acetanilide iminodiacetate have a significant impact on biological effects.

The chelate of 2,4-dimethylacetanilide iminodiacetate according to the invention is disclosed in the above-mentioned Swiss Patent No. 60799.
Chelate of (2,6-dinitylacetanilide)-iminodiacetic acid (trade name HIDA), which is specifically disclosed in No. 0
Despite their structural similarities, differences were observed in their liver and bile properties.

This difference seems to be based on differences in stereochemical structure.

After injection in patients with good liver function, 2.5.10.
Comparing the dynamic scintillography images obtained by the chelate of the present invention after 15, 20 and 45 minutes with those obtained by the above HIDA, the liver bile passage time is faster and the liver extraction efficiency is superior.

Maximum hepatic absorption is 5-15 minutes for HIDA and 1-12 minutes for the chelates of the invention.

Common fillings in the hepatic duct, biliary duct, hepatic duct, gallbladder and the appearance of early activity in the duodenum are 15% for HIDA.
~30 minutes, and for the chelates of the invention 13-2
It is 0 minutes.

The diagnostic utility of the chelates of the invention was reported by the Oncology Society of Warsaw on the Boland Symposium on Nuclear Drugs, and its application was demonstrated in the diagnosis of various liver disease causes, in the differentiation of "cold" lesions in the liver, and is crucial in distinguishing between cancerous and non-cancerous liver lesions.

The present invention provides another method for making scintillographic reagents.

The method of the invention consists in dissolving a derivative of aniline having alkyl groups, preferably CH3, on the second and fourth carbon atoms of the aromatic ring in acetic acid at room temperature, adding chloroacetyl chloride with vigorous mixing, and adding chloroacetyl chloride at 4°C. The components include maintaining the temperature at C for several hours.

Pour the reaction mixture into ice water.

The precipitate was crystallized from alcohol and also on a postcrystalization base.
) in water and recovering an additional amount of precipitate, the total yield is 80-82%.

The ω-chloroacetanilide thus produced is dissolved in dilute alcohol together with the sodium salt of iminodiacetic acid.

The mixture is heated under a water circulation cooler for several hours.

After evaporating the solvent, the dry precipitate is dissolved in water and the pH of the aqueous solution is adjusted to about 2.5 after separation of unreacted components.

After dissolving the precipitate in absolute ethanol, separating off the unreacted components and evaporating the solvent, the derivative of iminodiacetic acid is purified by precipitation from water at a pH of about 2.5.

Yield is 25-35%. Furthermore, the formed sodium salt of the derivative of iminodiacetic acid is dissolved in water and, if desired, a solution of stannous chloride in hydrochloric acid is added to adjust the pH value to 4-6, depending on the radiometal to be chelated.

The solution is then passed through a sterile strainer and lyophilized before being stored in sterile ampoules placed in nitrogen or filled under vacuum.

at least half an hour before the intravenous injection)
A sterile solution of 99mTc or other radioactive metal is added to the derivative of iminodiacetic acid.

The durability of the scintillography reagent according to the present invention is 24
It's time.

The present invention will be described in detail below with reference to examples.

Example: To 0,12 moles of 2,4-dimethylaniline dissolved in acetic acid, 0.13 moles of chloroacetyl chloride was added at room temperature and the components were mixed vigorously for 5 to 10 minutes.

The reaction mixture was kept at a temperature of 4° C. for 3-4 hours and then poured into ice water.

The precipitate was dried and crystallized from ethanol.

An additional amount of precipitate was recovered from the post-crystalline base after dissolving it in water, resulting in a total yield of 19.4f, i.e.
It was 82%.

40 mmol of ω-chloro-2,4-dimethylacetanilide thus obtained were dissolved together with 40 mmol of the sodium salt of iminodiacetic acid in 250 ml of dilute ethanol.

The volume ratio of water to ethanol was 1:1.2.

The mixture was heated on a water bath under a water circulating condenser for 6 hours.

After evaporating the solvent, the dry residue was dissolved in water, unreacted components were separated, and the pH of the aqueous solution was adjusted to about 2.5 using hydrochloric acid.

The derivative of iminodiacetic acid was purified from the aqueous solution after dissolving the precipitate in absolute ethanol and evaporating the solvent.

The yield was about 30%.

Furthermore, 1 μ of the generated sodium salt of N-(2,4-dimethylphenyl-carbamylmethyl)-iminodiacetic acid was added to 0.
0 dissolved in 1rrLl of water and dissolved in 1N hydrochloric acid,
Add 0.021n9 of stannous chloride and add 0.021n9 of stannous chloride. The pH was adjusted to about 4 by adding IN sodium hydroxide solution.

After thorough mixing and incubation for 15 minutes, 0.5 ml of Beltechnete (Beltechnet) with a radioactivity of 1 mC1 was added.

Packard apparatus
Chelate persistence was determined using high-pressure one-paper electrophoresis combined with radiation chromatography detection according to (2009).

For biological and scintillographic testing, N-
Prepare 101v samples of the sodium salt of (2,4-dimethylphenylcarbamylmethyl)-iminodiacetic acid, add 0.21r19 stannous chloride dissolved in IN hydrochloric acid to each sample, pass through a sterile sieve, and transfer to BelTechnet. )9
10W 1 g of the sodium salt of the acid after adding a sterile solution of 9mTc and performing scintillographic examinations at least every 30 minutes, or adding 0.2 rv of stannous chloride.
Samples were removed, lyophilized, and stored for several months at 4° C. in sterile ampoules placed in nitrogen.

Claims (1)

[Scope of Claims] 1. A scintillography reagent comprising a chelate of a dialkyl acetanilide derivative of iminodiacetic acid and a radioactive metal, wherein the alkyl group of the derivative is a CH3 group, and the alkyl group of the derivative is a CH3 group, and the alkyl group of the derivative is a CH3 group, and A scintillography reagent characterized by the following. 2 Dissolve the aniline derivative in acetic acid, mix with chloroacetyl chloride, and then crystallize; crystallize the separated precipitate from alcohol, re-collect an additional amount of the acetanilide derivative in the post-crystal, and convert it to the sodium salt of iminodiacetic acid. and dilute alcohol, then warm this solution under a water circulation condenser, evaporate the solvent, then dissolve the dry residue, separate the unreacted components, and remove the remaining solution. The pH value is adjusted with hydrochloric acid; the precipitate is subsequently dissolved, the solvent is evaporated and the derivative of iminodiacetic acid is purified by precipitation from water or a 25% solution of sodium acetate; If desired, a solution of stannous chloride in hydrochloric acid is added and the pH value is adjusted again; the solution is then passed through a sterile strainer, lyophilized and stored in sterile ampoules, and In the method for producing a reagent for synterography, which is a chelate of a dialkylacedoanitri derivative of iminodiacetic acid and a radioactive metal, which comprises finally chelating with a radioactive metal, the step of dissolving 2,4-dimethylaniline in acetic acid is performed. A method characterized by: The reaction of 32,4-dimethylaniline with chloroacetyl chloride was carried out in acetic acid at room temperature to automatically generate ω-chloro-2,4-dimethylacetanilide, and the derivative was purified by washing with acetic acid and ethanol. reaction of the derivative with the sodium salt of iminodiacetic acid in a ratio of 1 mol of derivative/1 mol of acid for 6 hours, and finally, immediately after separation of the unreacted components, the pH value of the solution is reduced to approx. 2. The method according to claim 2, characterized in that the temperature is adjusted to 2.5.