DE2118219B2 - New X-ray contrast medium - Google Patents

Description

J
\ I. COOH N —C — CH, -R / H Jv I. i! R = Κλ H O HjC-C- R = ) Il R = j O I: OH II: H III: OCH; J
/ \

is from Larsen et al. (J. Am. Chem. Soc. 78, 3210-16 [1956]) was first synthesized and examined for its suitability as an X-ray contrast medium. As a value for the intravenous LDm in the mouse was 8.5 ± 0.7 g / kg found. In contrast, the hydroxyl-free 3,5-di-acetamido-2,4,6-triiodobenzoic acid which was also tested had formula II an LD »of 13.4 ± 0.68 g / kg, which is almost twice as favorable. During II became a significant As a commercial preparation, the hydroxy compound I is understandably useful for radiological purposes has not been mentioned in the literature since then.

It has now been found, surprisingly, that the hydroxy compound I was concentrated in the form of it aqueous solutions with physiologically compatible bases for intravenous use on the human level Excellent general tolerance. It is quickly excreted in the urine and shows no harmful effects on the kidneys or liver. their effect on the circulatory system is particularly low, as tests on dogs have shown. While compound II the contraction force of the The heart muscle is somewhat diminished for some time

ίο Compound I does not have this effect, but rather increases it the systolic pressure slightly above the initial value This means for patients with little resilience Hearts - so-called relative insufficiency, which occurs even when sitting down and not exercising - or with a certain cardiac insufficiency a significant progress because of their special Tissue compatibility, it is also suitable for angiographic examination techniques.

The one from the German Auslegeschrift 1129 260 already known methoxy compound III shows an equally favorable toxicity in the rat, caused but, as our own experiments have shown, a severe disturbance of the circulatory system in dogs and humans. Also in this respect was So the favorable pharmacological effect of I not to be expected.

The superiority of the compound I according to the invention over the methoxy compound III was by a comparative circulation analysis demon-ίο striert Both connections were in the form of their Methylglucamine salts used in aqueous solution

The hemodynamic analyzes were carried out on beagle dogs owned by Schering's own breed The effect on the circulatory system after injection of the solution of compound I was compared with that effect caused by the injection of the solution of compound III. The dose was 4 ml / kg Body weight of a solution adjusted to 300 mg J / ml is deliberately kept large in order to avoid pharmacological

• to see effects to be able to determine. These are in essentially between the first 30 seconds and the 2nd minute after the end of the intravenous injection. Within This is the time when the vast majority of incidents also occur in diagnostic applications.

Table 1

Maximum deflection of the hemodynamic parameters in the 30th second and further Course in the 1st and 2nd minute after the end of the injection

parameter

Measurement results related to the exit value set equal to 100
Meglium salt solution of 1 Meglium salt solution of III

Maximum I. Min. 2. Min. Maximum I. Min. 2. Min.

Systol. pressure
Endodiastole. pressure
Pressure amplitude
Heart rate
Heart stroke volume
Heart-Zcit-Volume
Total peripheral resistance

From Table 1 it can be seen that the systolic, Above all, however, the clinically more important end-diastolic pressure declines. The pressure loss after the injection of the

71 88 98 75 86 93 47 75 86 33 68 86 24 13th 12th 38 18th 17th 82 88 94 78 87 91 375 230 210 630 315 155 325 195 190 520 270 160 18th 39 44 IO 30th 56

Solution of I is lower and also increased again more quickly than that after the injection of III. the Pressure amplitude does not increase with connection I.

to the same extent as with connection UI, one The heart rate shows a similar tendency. The stroke volume remains at one after the injection of I. Increase of 275 within physiological limits. On the other hand, it increases by after the injection of III the substantial amount of 530. Nevertheless, the total peripheral resistance at II falls to 10% of the Starting value from; with I, on the other hand, despite the smaller increase in stroke volume, only to 18%. That Cardiac output shows a similar trend. the Circulatory changes after injection of I are nowhere near as extreme and much more balanced than after Injection of III.

The superiority of the compound I according to the invention over the Methoxy compound HI in influencing the circulatory system.

The invention accordingly relates to new X-ray contrast media containing S-acetamido-S-hydroxyacetamido-2A6-triiodobenzoic acid and their water-soluble salts with physiologically compatible bases.

Examples of physiologically acceptable bases are into consideration: caustic soda, N-methylglucamine, Ν, Ν-dimethylglucamine, ethanolamine, diethanolamine, Morphoün, etc. To a certain extent, one can also use alkali by alkaline earth, such as calcium and Magnesium hydroxide.

Mixtures of the salts can also be used.

The synthesis of I according to the Larsen et al. (J. Am. Chem. Soc 78, 3210-16 [1956] and corresponding US Pat. No. 3,076,024) delivers the compound I in a 5-hour process in a yield of 73% <ler Tuarie. It will 3-Amino-5-nitrobenzoic acid - successively hydroxyacetylated, reduced, iodized, acetylated and saponified. Will the reaction sequence of acetylation and hydroxyacetylation can be reversed, as we have found. link I can be obtained over the 5 stages in over 70% yield. This was done for the hydroxyacetylation the iodine compound, the method of Hoey et al. (J. Med. Chem. 6, 24 [1963J, that with lower Fatty acid chlorides in dimethylacetamide works, first transferred to acetoxyacetyl chloride.

example 1

3-Acetamido-5-hydroxyacetamido-2,4,6-triiodobenzoic acid dihydrate

on the steam bath carefully with concentrated sodium hydroxide solution (approx. 65 ml in total) at pH 8-10 Treated for hour. Finally, under ice cooling the title compound precipitated with hydrochloric acid and filtered off overnight after tubes through a

Purification of the crude product from methanol

isolated ammonium salt, dissolve in water and reapply

Cases with hydrochloric acid are 53 g - 78% of theory S-Acetamido-S-hydroxyacetamido - ^. E-trijodbeiJUoe-

in acid dihydrate with a melting point of 254 ° C (with decomposition) obtain.

Example 2

A suspension of
triiodobenzoic acid monohydrate in 180 ml of dimethylacetamide is admixed dropwise with 27 ml of acetoxyacetyl chloride while cooling with ice and stirring, and then stirring is continued for 18 hours without cooling. The reaction mixture is then diluted with 1 liter of water and, in order to saponify the acetoxyacetyl group, 3-acetamido-5-hydroxyacetamido-2,4,6-triiodobenzoic acid dihydrate

A solution of 283 g of acetoxyacetic acid in 50 ml Dimethylformamide is added dropwise with 17.4 ml of thionyl chloride and after one hour with ice-cooling a solution of 59 g of 3-acetamido-5-amino-2,4,6-triiodo-benzoic acid monohydrate in 50 ml of dimethylformamide added overnight at room temperature further stirred batch is then diluted with 300 ml of water and saponified as in Example 1 and purified Yield: 493 g = 75% of theory S-Acetamido-S-hydroxyacetamido ^ Ae-triiodobenzoic acid dihydrate melting point 254 ° C (with decomposition).

J ₀ formulation example 3

Preparation of a ready-to-use methylglucamine salt solution:

3-acetam ido-5- hydroxyacetam ido-

2,4,6-triiodobenzoic acid 525.0 g

'' N-methyl-glucamine 1533 g

Disodium edetate 0.1 g Double distilled water to 1000 ml

The solution is filled into ampoules or w Multivials and sterilized at 120 ⁰ C. It contains 300 mg iodine / ml.

Formulation example 4
Preparation of a ready-to-use mixed saline solution:

S-acetamido-S-hydroxyacetamido-

2,4,6-triiodobenzoic acid 628.8 g

N-methyl-glucamine 163Jg Caustic soda 6.4 g Disodium edetate 0.1 g Double distilled water to 1000 ml

The solution is filled into vials or Multivials and sterilized at 12O ⁰ C. It contains 380 mg iodine / ml.

Claims (2)

Patent claims: 1. X-ray contrast medium containing 3-acetamido-5-hydroxyacetamido-2,4,6-triiodobenzoic acid or their water-soluble salts with physiologically compatible bases. 2. X-ray contrast medium according to claim 1, containing the sodium, calcium, N-methylglucamine or ethanolamine salt of S-acetamido-S-hydroxyacetamido-2,4,6-triiodobenzoic acid. S-Acetamido-S-hydroxyacetamido - ^. E-triiodobenzoic acid the formula