CA1048536A - X-ray contrast agents - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) of the formula

Description

1C~48536 This invention relates to new X-ray contrast agents.
The present invention provides 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) of the formula COOH COOH

~NH-CO-(CH2-O-CH2~ 3-CO-NH~

and physiologically tolerable salts thereof with bases.
The invention also provides an X-ray contrast preparation ` which comprises (as a radio-opa~ue substance) 3,6,9-trioxaunde-cane-l,ll-dioyl-bis-(3-carboxy 2,4,6-triiodo-anilide) or a physiologically tolerable salt thereof with bases, in admixture or conjunction with a physiologically tolerable carrier. The preparation may contain one, two or more of the compounds of the present invention.
Physiologically tolerable salts with bases include both metal salts, for example, sodium, lithium and magnesium salts, and amine salts, preferably glucamine, ~ methylglucamine, M,N-dimethylglucamine, ethanolamine, diethanolamine and morpholinesalts. Mixtures of the salts may also be used.
The salts are preferably used as parenteral bile contrast agents.
Among the numerous com~ounds hitherto proposed for intra-venous cholegraphy only members of the following general formula have to our knowledge attained practical importance:-COOH COOH

NH-CO-X--CO-N~

. . .

:

1~48S3f~
Thus, the compounds in which X = (C~I2)4 (Iodipamide -German Patent No. 936,928) and in which X = CH2-O-CH2 (Ioglycamide - German Patent No. 962,698) have been available in commerce for a long time.
Other members of this general formula have been des-cribed in which X = CH2-CH2-(O-CH2-CH2)3 in German Patent Publica-tion No. 1,922,57~, and in which X = CH2-CH2-(O-CH2-CH2)4 in German Patent Publication No. 1,937,211.
The ever increasing need for more efficient radiological diagnosis in the case of severely injured patients having reduced liver performance imposes high requirements both on the tolerability of the contrast agent, in order to avoid severe and very severe incidents, and also on its property of being transported rapidly and in high concentration through the liver in the bile, in order to enable good radiograms to be obtained also in pathological cases.
, It has now been found that 3,6,9-trioxaundecane-1,11-. , .
dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) (both in the free . and in the form of physiologically tolerable salts thereof with . 20 bases) combines the required properties in a high degree.

In the following tables, the compound A of the present invention is compared with the known compounds B, C, D and E.

A: 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide).

B: 4,7,10-trioxatridecane-1,13-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide).

German Patent Publication No. 1,922,578.

C: 4,7,10,13-tetraoxahexadecane-1,16-dioyl-bis-(3-carboxy-

2,4,6-triiodo-anilide). ;

~erman Patent Publication No. 1,937,211.

D: Adipinoyl-bis-(3-carboxy-2,4,6-triiodo-anilide).

(Iodipamide).

German Patent No. 936,928.

104~53~
E: Diglycolyl-bis-(3-carbaxy-2,4,6-triiodo-anilide).

(Ioglycamide).

German Patent No. 962,698 Table 1 Toxicity (LD50) on rats after intravenous application of methylglucamine salt solutions of the test compound.

Injection rate: 0.8 ml/min. Statistical evaluation by the probitanalysis.

Compound LD50 Reliable rangeToxicity relative __ Sg Iodine/kg)__ (95%)to a (p C0.05) :-A 6.19 5.46 - 7.29 B ~.9 C 5.36 4.85 - 5.79 +
D 2.97 2.51 - 3.52 +
E 4.51 3.21 - 5.70 +

As seen by the data of Table 1, compound A of this inven-tion is less toxic than the prior art compounds.
Table 2 The elimination of the compounds in the dog after the intravenous injection of solutions of the methylglucamine salt.

; Dose Compound sile (% of dose) Urine (% of dose) (Mg of acid/kg) up to 1 hr. 48 hrs. up to 48 hrs.
p. appl. p. appl.
:
100 mg A 6] 87 13 10.5 55 22 300 mg A 34 79 20 . .

~, ~ ,: . , ~, :
. .

~8536 Table 2 shows that compound A of the present invention , with regard to separation by way of the bile is superior to the ' , substances used for comparison. The amount separated with the bile and the rate of separation are increased as compared with the substances used for comparison.
By means of the Valzelli test, after cisternal applica-tion and after injection into the A. carotis comm., there was tested the neural tolerability for cholescyst-cholangiography in the rat:
lOTable 3 Neural tolerability i Method ED50 A C D E

Valzelli mg I/kg rat 6.4 2.92 6.35 4.83 Reliable range (5.0- (1.56- (5.11- (2.73-7.8) 3.96) 7.44) 6.68) Cisternal mg I/kg rat 2.21 l.l9 1.07 1.98 Reliable range(1.53- (0.16- (0.54- (0.65-

3.53) 7.24) 1.83) 117.46) A.carotis g I/kg rat 2.06 1.65 1.55 1.82 Reliable range(1.69- (0.93- (0.87- (1.34_ 2.50) 1.97) 1.83) 2.13) .. . . _ _ .

From Table 3 it will be seen that compound A of the present invention, especially with regard to its cisternal and cerebral tolerability, is distinctly superior to the known compounds.
The new radio-opaque substance A is therefore suitable, especially in the form of concentrated a~ueous solutions of the physiologically tolerable salts thereof with bases, for injec-tion preparations for visualization of the bile.
There may be used solutions containing approximately 5 to 45%, and preferably approximately 10 to 30%, by weight of 1~4~53~
combined iodine. The amount of the salt (or the total amount of the salts if more than one salt is present) contained in such salt solutions is accordingly an amount that is equivalent to an amount of 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) within the range of from approximately 10 to 90 grams, preferably 20 to 60 grams, per 100 ml.
The present invention further provides a process for ,, producing 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) or a physiologically tolerable salt thereof - 10 with a base, wherein 3-amino-2,4,6-triiodo-benzoic acid is reacted with a reactive derivative of 3,6,9-trioxaundecane-1,11-diacid and, if desired, any resulting 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) is converted into a physiologically tolerable salt thereof with a base and/or any resulting salt of 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) is converted into the free com-pound.
The reactive derivatives of the 3,6,9-trioxaundecane-l,ll-diacid include especially acid halides or mixed anhydrides.
The reaction is carried out in a polar solvent, for example, chlorobenzene, dioxane, dimethylacetamide, dimethylfor- -mamide or acetonitrile, at temperatures of 0 to 150C, and preferably 20 to 120C.
The new compounds of the present invention may be brought with, for example, the additives normally used in ~alenism into a form suitable for intravenous application.
he following examples illustrate the invention:-Example 1 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide).

16~g85~
; (a) Condensation in dimethylacetamide To a suspension of 51.5 g of anhydrous 3-amino-2,4,6-triiodo-benzoic acid (0.1 mole) in 100 ml of dimethylacetamide , were slowly added dropwise, while stirring, 15.5 g of 3,6,9-trioxaundecane diacid dichloride (0.06 mole), during which the temperature gradually rose to about 50C and the whole passed into solution. After being stirred overnight, the solution was added dropwise to 1 litre of a 0.28N solution of sodium hydrox-ide, and then 200 ml of 2N hydrochloric acid were cautiously added. The precipitate was filtered with suction, washed with water and dried. The yield was practically quantitative.
(b) Condensation_in dloxane 15.5 g of 3,6,9-trioxaundecane diacid dichloride were added dropwise at about 95C to a solution of 51.5 g of anhydrous 3-amino-2,4,6-triiodo-benzoic acid in 52 ml of anhydrous dioxane.
After further stirring and heating for 3 hours, the solution was cooled, stirred dropwise into 500 ml of a 0.4N solution of sodium hydroxide, and further worked up as described under paragraph (a). The yield was practically quantitative.
(c) Purification To the crude product obtained as described under para-graph (a) or (b) in 300 ml of methanol was slowly added a quantity (about 15 ml) of a 12N solution of sodium hvdroxide such that a test portion diluted with water had a pH of 8-9.
~fter stirring the mixture overnight, the sodium salt of 3,6,9-trioxaundecane-l,ll-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) which crystallized was filtered with suction, washed with metha-nol and dried.
Yield: 92 g (90~ of the theoretical yield).
A solution of the salt in 900 ml of water was treated with active carbon, and concentrated hydrochloric acid was added 1~4~53t;
until the pH was 1. The precipitate was filtered with suction, washed with water, and dried at 50C.
The yield of pure 3,6,9-trioxaundecane-1,11-dio l-bis-(3-carboxy-2,4,6-triiodo-anilide) was 80 g (80% of the theore-tical yield). The substance melted at 175C with sintering.
The 3,6,9-trioxaundecane-1,11-diacid re~uired as inter-mediate product can be prepared by oxidizing tetraethylene gly-col with nitric acid in a manner similar to that described in British Patent No. 639,491. The oily acid can be purified by isolation of the dicyclohexylamine salt or by distillation of the dimethyl ester (B-P-6 Torr = 175-130C). The synthesis of 3,6,9-trioxaundecane diacid dichloride may be carried out either in accordance with German Patent Publication No. 2,028,556 in ben-zene with oxalyl chloride or more easily with thionyl chloride in toluene. After distilling the solvent, the desired dicarbox-ylic acid dichloride remains.
Example 2 The preparation of a methylglucamine salt solution ready for use:

3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide~287 g N-methylglucamine 92 g ~ -Disodium edetate 0.1 g Bi-disti~led water to make1000 ml The solution was packaged into ampoules or multi-phials and sterilized at 120C. They contained 180 mg of iodine per ml.
Example 3 The preparation of a mixed salt solution ready for use:

3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide)446.8 g N-methylglucamine 75.5 g Caustic soda 13.9 g . .

1~)4~53~
: .
Disodium edetate 0.1 g Bi-distilled water to make lO00 ml The solution was packaged into ampoules or multi-phials and sterilized at 120C. They contained 280 mg of iodine per ml.
Example 4 Production of a ready for use sodium salt solution:
3,6,9-trioxaundecane-l,ll-dioyl-bis-(3-carboxy-2,4,6-triiodoanilide) 79.84 g Sodium hydroxide 5.25 g Disodium edetate 0.1 g Bi-distilled water to make lO00 ml The solution is placed in ampoules or multi-phials and sterilized at 120C. The solution contains 50 mg of iodine per ml.

' ~,

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) or a physiologically tolerable salt thereof with a base comprising the step of react-ing 3-amino-2,a,6-triiodobenzoic acid with an acid halide or mixed anhydride of 3,6,9-trioxaundecane-1,11-diacid.

2. A process according to claim 1, wherein any 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxv-2,4,6-triiodo-anilide) is converted into a physiologically tolerable salt thereof with a base.

3. A process according to claim 1, wherein any result-iny salt of 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) is converted into the free compound.

4. A process according to claim 1, 2 or 3, wherein the reaction is carried out at a temperature of 20 to 120°C.

5. A process according to claim 1, wherein 3,6,9-triox-aundecane diacid dichloride is reacted with anhydrous 3-amino 2,4,6-triiodo-benzoic acid to produce 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide).

6. A process according to claim 5, wherein the reaction is effected in a polar solvent.

7. A process according to claim 6, wherein said solvent is dimethylacetamide or dioxane.

8. A process according to claim 5, wherein the product is reacted with sodium hydroxide to produce the sodium salt thereof.

9. 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) of a physiologically acceptable salt thereof with a base whenever prepared or produced by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.