FI58589C - ROENTGENCONTRASTMELEL INNEHAOLLANDE 3,6,9-TRIOXIUNDEKAN-1,11-DIOYL-BIS- (3-CARBOXY-2,4,6-TRIJOD-ANILID) ELLER SALT DAERAV OCH FOERFARANDE FOER FRAMSTAELLNING AV DETTA - Google Patents

Description

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Patent · och reglsteretyreleen '' AmMcm uthgd och utUkrHtm pubUurad 28.11.80 (32) (33) (31) «Tuoik * u» —Wj »rd priority 0li. 02.74

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2405652.8 (71) Schering Aktiengesellschaft, Berlin / Bergkamen, DE; Miillerstrasse 170-178, D-l Berlin 65, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Heinrich Pfeiffer, Berlin, Ulrich Speck, Berlin, Karl Heinz Kolb,

Hamburg, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (74) Oy Kolster Ab (54) 3,6,9-trioxyundecane-1,1,-diioyl-bis- (3-carboxy-2,4,6-triiodanilide) or an X-ray contrast agent containing salts thereof and a process for its preparation - X-ray contrast media containing 3,6,9-trioxydundecane-1,1-diioyl-bis- (3'-carboxy-2,4,6-triiodanilide) or a mixture thereof for the purposes of this Regulation

The invention relates to an X-ray contrast agent containing 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,4,6-triiodanilide) having the formula

C00H C00H

/ S-, HH-CO- (CH2-O-CH2) -CO-NK2,

J J

or salts thereof with physiologically acceptable bases.

The invention further relates to a method for preparing such an X-ray contrast agent.

2 58589

Suitable salts with physiologically acceptable bases are both metal salts, such as sodium, lithium and magnesium salts, and amine salts, in particular glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, diethanolamine or morpholine. Salt mixtures can also be used.

The salts are preferably used as parenteral bile contrast agents. Of the many compounds hitherto presented for intravenous bile imaging, only those of the following formula have acquired practical significance.

COOH COOH

l ^ oT Tojf

NH-CO-X-CO-NH

J J

Compounds with X = (CH 2) ^ (Iodopamid - DBP 936 928) and with X = CH 2 -O-CH 2 (iodlycamide - DBP 962 698) have been used for a long time.

Other members of the general formula had X = CH 2 -CH 2 -10-CH 2 -CH 2) in German Application 1,922,578 and X = C 1 -C 6 -CH 2 -CO-CH 2 -CH 2) in German Application 1,937,211.

The need for more in-depth radiological diagnostics in severely severely injured patients with hepatic impairment places high demands on both the suitability of the contrast agent to avoid difficult and most difficult complications and its ability to pass rapidly and in high concentrations through the liver into the bile.

It was found that 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxyoxy-2,6,6-triiodanilide) largely combined these required properties.

The following tables compare the invented compound A with the known compounds B, C, D and E.

A: 3,6,9-Trioxyundecane-1,11-diioyl-bis- (3-carboxy-2, 1,6-triiodanilide) B: k, 7,10-trioxytridecane-1,13-diioyl-bis - (3-carboxy-2,6-triiodanide)

German Application Publication 1,922,578.

3,58589 ° C: 1+, 7,10,13-tetraoxyhexadecane-1,16-diyl-bis- (3'-carboxy-2,1,6-triiodanilide)

German application publication 1 937 211.

D: Adipinoyl-bis- (3-carboxy-2,6,6-triiodanilide); (Iodopamide) D3p 936928 E: Diglycoloyl-bis- (3-carboxy-2,6,6-triiodanilide); (Joglycamide) DBF 962 698.

table 1

Toxicity (LD ^ q) in rats after application of intravenous methylglucamine saline. Injection rate 0.8 ml / min. Statistical limits and significance were performed by probit analysis.

Compound (LD - g iodine / kg) Statistical Significance to A limits (95%) (p <0.05) A 6.19 5, U6 - 7.29 B k, 9 C 5.36 U, 85 - 5.79 + D 2.97 2.51 - 3.52 + E U.51 3.21 - 5.70 +

The data in Table 1 show that the invented Compound A is the least toxic substance.

Table 2

Elimination of the compound in dogs after intravenous injection of methylglucamine saline.

Dose mg Compound Bile {% dose- U8 hours Urine (% of dose) acid / kg) 1 hour U8 hours after dose 100 mg A 61 87 13 58 83 9 C 61 89 9 51 85 8 D 31 66 5 37 81 10 E 28 58 2h 10.5 55 22 300 mg A 3U 79 20 33 70 31 C 19 U5 U9 23 51 Uo E 19 58 33 10 U8 Uit >> 58589

Table 2 shows that the invented compound A is superior to the reference substances in terms of biliary excretion. The rate of biliary excretion and the rate of excretion are set against the reference compounds.

The Valzelli test, after application to the neck and injection into A. carotis comm., Examined the neural suitability for the imaging of the gallbladder and bile ducts in the rat:

Table 3

Nervous system fit

Method ED, -q A C D E

Valzelli mg J / kg rat 6, h 2.92 6.35 * +, 83 reliability (5.0-7.8) O »56-3 * 96) (5» 11 * 7, * + * +) (2.73-6.68) range

Neck mg J / kg rat 2.21 1.19 1.0? 1.98 confidence- (1.53-3.53) (0.16-7.2 * +) (0.5 ^ -1.83) (0.65-117, ½) range A. carotis g J / kg rat 2.06 1.65 1.55 1.82 reliability (1.69-2.50) (0.93-1.97) (0.87-1.83) (1.3 * + -2.13) range

It can be seen from Table 3 that the invented compound A is clearly superior to the known compounds, especially in the cisternal and cerebral sense.

The new contrast agent A is therefore particularly suitable in the form of a concentrated aqueous saline solution for injection in bile imaging.

Solutions of about 5 ~ * + 5% *, preferably about 10-30% iodine bound, can be prepared. Such saline solutions uniformly contain about 10-90 g per 100 ml, preferably 20-60 g of 3,6,9-trioxyundecane-1,11-dioyl-bis- (3-carboxy-2,3 *, 6-triiodanilide) .

The process for preparing a novel X-ray contrast agent according to the invention is characterized in that 3-amino-2, * +, 6-triiodobenzoic acid is reacted in a polar solvent with a reactive derivative of 3,6,9-trioxyundecane-1,11-diacid at a temperature of 0-150 ° C and the resulting 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,3 *, 6-triiodanilide) are salified with a physiologically acceptable base to a suitable form for intravenous administration.

Suitable reactive derivatives of 3,6,9-trioxyundecane-1,11-diacid are, in particular, acid halides or mixed anhydrides.

5,58589

The reaction is carried out in a polar solvent such as chlorobenzene, dioxane, dimethylacetamide, dimethylformamide or acetonitrile at a temperature between 0 ° C and 150 ° C, preferably 20-120 ° C.

Example 1 3,6,9-Trioxyundecane-1,11-dioyl-tis- (3-carboxy-2 th, β-triiodo anilide) a) Condensation in dimethylacetamide

To a suspension of 51 to 5 g of anhydrous 3-amino-2,1 +, 6-triiodobenzoic acid (0.1 M) in 100 ml of dimethylacetamide is slowly added dropwise with stirring for 15 s 5 g of 3,6,9-trioxyundecanoic acid dichloride ( θ, θ6 M), whereupon the temperature gradually rises to about 50 ° C and everything dissolves. After stirring overnight, the solution is added to 1 liter of 0.28 N sodium hydroxide and finally 200 ml of 2N hydrochloric acid are carefully added. The precipitate is filtered off with suction, washed with water and dried. The yield is practically quantitative.

b) Condensation in dioxane

To a solution of 51> 5 g of anhydrous 3-amino-2,2,6-triiodobenzoic acid in 52 ml of anhydrous dioxane is added dropwise at about 95 ° C 15.5 g of 3.6.9-trioxyundecanoic acid dichloride. Stirring and heating are continued for 3 hours, after which the solution is cooled, stirred dropwise in 500 ml of 0.1+ N sodium hydroxide and continued according to (a). The yield is practically quantitative.

c) Cleaning

The crude product from a) or b) is slowly combined in 300 ml of methanol with an amount of 12 N sodium hydroxide (about 15 ml) to give a pH of 8-9 when diluted with water. After stirring overnight, the crystallized sodium salt of 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,1 +, 6-triiodanilide) is filtered off, washed with methanol and dried. Yield: 92 g (90% of theory).

The salt dissolved in 900 ml of water is treated with activated carbon and concentrated hydrochloric acid is added until the pH is 1. The precipitate is filtered off with suction, washed with water and dried at 50 ° C. Yield of pure 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,1 +, 6-triiodanilide): 80 g (80% of theory). The substance melts at 175 ° C by sintering.

The intermediate 3,6,9-trioxyundecane-1,11-diacid required as an intermediate can be prepared by oxidation with nitric acid from tetraethylene glycol analogous to Brit. Pat. 639 for 1 + 91. Purification of the oily acid is possible by isolating the cyclohexylamine salts or by distilling off the dimethyl esters (kpg -torr = 175-180 ° C).

The synthesis of 3,6.9-trioxyundecanoic acid dichloride can be performed in either DOS

According to 2,928,556 in benzene with oxalyl chloride or more simply with s 58589 thionyl chloride in toluene. When the solvent is distilled off, the desired dicarboxylic acid dichloride remains.

Example 2 Preparation of a ready-to-use methylglucamic acid solution: 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,1,6-triiodanilide) 287 g N-methylglucamine 92 g

Disodium edetate 0.1 g

Double distilled water ad 1000 ml

The solution is placed in ampoules or vials and sterilized at 120 ° C. It contains 180 mg of iodine / ml.

Example 3 Preparation of ready-to-use mixed salt solution: 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,6,6-triiodanilide) -6.8 g N-methylglucamine 75.5 g

Sodium hydroxide 13.9 g

Disodium edetate 0.1 g

Double distilled water ad 1000 ml

The solution is placed in ampoules or vials and sterilized at 120 ° C. It contains 280 mg of iodine / ml.

Example h Preparation of ready-to-use sodium salt solution: 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,1 * 6-triiodanilide) 79.8 g

Sodium hydroxide 5.25 g

Disodium edetate 0.1 g

Double distilled water ad 1000 ml

The solution is placed in ampoules or vials and sterilized at 120 ° C. It contains 50 mg of iodine / ml.

Claims (5)

X-ray contrast agent, characterized in that it contains 3,6,9 "trioxyundecane-1,1'-allyl-bis- (3-carboxy-2, k, 6-triiodanilide) or its salts with physiologically acceptable bases as shading agents . X-ray contrast agent according to Claim 1, characterized in that it contains, as a shading agent, the N-methylglucamine salt of 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,6,6-tridiananilide). X-ray contrast agent according to Claim 1, characterized in that it contains, as a shading agent, the sodium salt of 3,6,9 'trioxyundecane-1,11-diyl-bis- (3'-carboxy-2,6,6-triiodanilide). X-ray contrast agent according to Claim 1, characterized in that it contains 3,6,9-trioxyundecane-1,11-dioyl-bis- (3-carboxy-2, k, 6-triiodanilide) N-methylglucamine and sodium salt as shading agents . X-ray contrast agent according to Claim 1, characterized in that it contains 3,6,9-trioxyundecane-1,11-diyl-bis- (3-carboxy-2,6,6-triiodanilide) N-methylglucamine and / or or in an aqueous solution of a sodium salt having a concentration of about 10-90 g, preferably 20-60 g. Process for the preparation of an X-ray contrast agent according to one of the preceding claims, characterized in that 3-amino-2,6-triiodobenzoic acid is reacted in a polar solvent with a reactive derivative of 3,6,9 "trioxy-undecane-1,11-diacid. at 0-150 ° C and the resulting 3, 6,9 "trioxyundecane-1,11-dioyl-bis- (3" carboxy-2,6-triiodanilide) is salified with a physiologically acceptable base into a suitable form for intravenous administration .