DE2118219A1 - New X-ray contrast medium - Google Patents

Description

3-acetamido-5-hydroxyaeei; amido-2, ¹ A- , 6-tri.iodobenzoic acid of the formula I

§OGH Π

o ^ '■■; "■" - .. Y I. : R = OH II : E = H ^ -NC-CH ₀ -R
HO III OCH 3 π ι
OH

is from Larsen et al. (J.Am.Cheia.Soc. £ 8, 3210-16 (1.956)) was first synthesized and examined for its suitability as an X-ray contrast medium. The value for the intravenous LD [-q in ¹ mouse was 8.5-0 ,? g / kg * found had the contrast also tested hydroxyl-3,5-di-acetamido-2, ^z (-, 6-trij odbenzoe the Forniel II acid almost twice as expensive LDt-Q from 13.4 to 0, 68 g / kg. While II became an important commercial preparation, the hydroxy compound I has understandably not been mentioned in the literature for radiological purposes since then.

It has now surprisingly been found that the hydroxy compound I in the form of their concentrated aqueous solution with physiologically compatible bases for intravenous use on humans has an excellent general tolerance. It is quickly excreted in the urine and does not cry any harmful

209844/1152

Vor.il> 'ifid: H «nn-Jürni'ri I luuutnn · Karl OUo MiHolsIonncItoiil VoralUotulor tins Auf & lchtnrat« r Dr, jur. HduariJ v. Schwart / koppon 1 Bot A C5, MiitloroiraOo 170-175 Dr. rur. mil. Oorlmrd Kiinpn ■ Dr.-In;). Hotol V / l! .- ul SIIz <! w Cosnllorhalt: Uurlln and ncnjkoraen Poslf & cJi EO

ORIGINAt INSPECTED

"²;" 2ΤΊ82Τ9: -.

the influence on the ficre or the liver. Her. Impact, " on the circulatory system. is particularly small, - like experiments on dogs:

revealed. During-connection II .the, contraction force ders. . . =. Cardiac muscle somewhat diminished for some time, shows compound I; this ef fect, not. but increases, rather see the systoli ... -; Pressure slightly above the initial value. This means for patients with a poor ■■■ heart - so-called relative insufficiency, which occurs when sitting down and not exercising - or with a certain weakness of the heart muscle, one ins Weight falling progress. Because of their special tissue compatibility it is also suitable for sngiographic examination techniques.

The methoxy compound III already known from the German Auslegeschrift 1,129,260 shows an equally favorable toxicity, in the rat, but causes, as our own experiments have shown, a: severe disturbance of the circulatory system in dogs and humans. Also, inso- so far was the favorable pharmacological effect of I didn't expect it. . . .

The invention accordingly relates to new X-ray contrast media containing 3 - A ■ cetalIlido-5-hydroxyacetamido-2,4-, 6-triiodobenzoic acid and their water-soluble salts with physiologically compatible bases.

Examples of physiologically acceptable bases are

- 3 -2 0 9 8 4 4/113 2

• ^ fiifi .. - BADORfGINAL.

SCHERING. AG - 3 -

Consider: caustic soda, ίί -methyl gl'iin η ml η, Κ, Ν-dimethylglucamine, Ethanolamine, Diethanolamine, Ilorpholine, etc. III To a certain extent, alkali can also be replaced by alkaline earth, such as calcium and magnesium hydroxide. Mixtures of the salts can also be used.

The synthesis of I according to the methods described by LARSEIT et al. (J.AiruChem. Soc. 78 , 3210-16 (1956) and corresponding US Pat. No. 3,076,024) gives the compound I in a 5-step process. Yield of 7 _? 5 % of theory. 3-Amino-5-nitrobeiizoesäui ^> e is successively hydroxyacetylated, reduced, iodinated, acetylated and saponified.- If the reaction sequence of acetylation and hydroxyacetylation is reversed, so we can, as we found, compound I over the 5 steps in over 70% yield can be obtained. For this purpose, the method of HOEY et al. Was used for the hydroxyacetylation of the iodine compound. (J.Hed.Chem. 6, 24 (1963)) "which works with lower fatty acid chlorides in dimethylacetainide", transferred for the first time to acetoxyactyl chloride.

2098U / 1 1 3 2

SAD

Example 1 . ''

A suspension of 60 g of 3-acetamido-5-amino-2,4 _} S-triJodenbenzoic acid monohydrate in 180 ml of dimethylacetamide is added dropwise with 27 ml of acetoxyacetyl chloride while cooling with ice and then stirring is continued for 18 hours without cooling mixture was diluted with 1 liter of water and ■ for saponification of Acetoxyacetyln: roup on the Dnmpfbnd carefully with concentrated sodium hydroxide solution (a total etv ^r a.

65

The pH 8-10 is treated for one hour. Finally, the title compound is precipitated with hydrochloric acid under ice-cooling and filtered off with suction after stirring overnight E = 78% d- ⁶¹ "theory of 5-acetamido-5-hydroxyacetamido-2,4,6-triiodobenzoic acid dihydrate with a melting point of 2-54 ° C. (with decomposition).

Example 2

3-Acetamido-5-hydroxyacetaraido-2,4, o-tri ^ odenbenzoic acid dihydrate, a solution of 28.3 g of acetoxyacetic acid in 50 ml of dimethylformamide is added dropwise with 17.4 ml of thionyl chloride and after one hour with a solution of 59 g of 3-acetamido-5-amino-2,4,6-trijöd-benzoic acid-I ^/ ionohydrate were added to 50 ml of dimethylformamide. The batch, which is stirred overnight at room temperature, is then diluted with 300 ml of water and saponified and purified as in Example 1. Yield: 49.5 g ^r; 73% of theory 3-acetamido-5-hydroxyacetamido-2,4,6-triiodobenzoic acid dihydrate with a melting point of ? .5 <\ ° C (with decomposition). 209844 / '1132 _ ₅ _

BATH ORIGINAL

Example 3

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

3-acetaraido-5-hydroxyacetamido-2, 4-, 6-trij od-

benzoic acid ·. 525.0 g

N-methyl-glucamine 153.5 S

Disodium edetate _ 0.1 g

Double distilled water to 1000 ml

The solution is filled into ampoules or ilultivials and Sterilized at 120 ° G. It contains 300 mg iodine / ml. ·

example M-

Preparation of a ready-to-use mixed saline solution: 3-acetamido-5-hydroxyacetamido-2,4,6-triiodobenzoic acid 628.8 g

K-methyl glucamine 163.3 g

Caustic Soda ■. 6.4 g

Disodium edetate 0.1 g

Double distilled water to 1000 ml

• The solution is filled into ampoules or multivials and sterilized ^{at 120 0 G.} It contains 380 mg iodine / ml.

209044/1132

K.-

Claims (1)

, SGHERING AG. · -Β - ■ godfather, nt claimsclie 1.) X-ray contrast media, containing I-acetamido - ^ - hydroxyacetamido-2,4-, 6-triiodobenzoic acid "related to their
water-soluble salts with physiologically compatible bases. 2 “) X-ray contrast medium according to claim 1, containing the Sodium, calcium, H-methylglucamine or ethano1amine salt; of 3-acetamido ~ 5-hydroxyacetamido-2, ^z ! -, 6-triiodrjenzoic acid. 4/1132