Derivatives of 2,4,6-triiodo-isophthalic acid, processes for their synthesis and X-ray contrasting materials containing these

Compounds for use in non-ionic X-ray contrasting materials having the formula ##STR1## in which (H0).sub.2-3 alkyl is 1,3-dihydroxyisopropyl, 2,3-dihydroxypropyl or 1,3-dihydroxy-2-hydroxymethylisopropyl, PA1 R is hydrogen or methyl, and PA1 R.sub.1 is an alkyl residue with 1 to 5 carbon atoms. These compounds possess high water-solubility as well as excellent stability against hydrolysis. Methods for preparation and use of the compounds are also disclosed.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to novel, readily water-soluble 
5-(N-alkyl-.alpha.-hydroxyacyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-( 
hydroxyalkyl-amides) suitable for use as X-ray contrast agents. 
2. Description of the Prior Art 
5-Acylamino-2,4,6-triiodo-isophthalic acid diamides and their use in X-ray 
contrasting materials are disclosed in Swiss Pat. No. 544,551. They 
contain only simple, unsubstituted aliphatic acyl groups, usually acetyl 
groups. Some representatives of this group, which contain carbohydrate 
residues, are readily water-soluble, for example, the 
3-acetylamino-5-N-methyl-acetylamino-2,4,6-triiodo-benzoyl-glucosamine, 
which has become known under the non-proprietary name of METRIZAMIDE. In 
this connection, see also compound No. 11 of U.S. Pat. No. 3,701,711, 
British Pat. No. 1,321,591, Swiss Pat. No. 554,551, Austrian Pat. No. 
318,134 and German Offenlegungsschrift No. 2,031,724, as well as 
publications by T. Almen, S. Salvesen, K. Golman: Acta Radiologia Suppl. 
335 (1973), 1-13, 233-75, 312-38. 
One of the disadvantages with this compound is that it is difficult to 
obtain. This is because it is present in the form of a mixture of isomers 
and it is practically impossible to isolate the individual isomers, and 
primarily because it has relatively little stability in aqueous solutions. 
This makes the handling of the material difficult and significantly limits 
its usefulness. 
The 
1-5-.alpha.-hydroxypropionylamino-2,4,6-triiodophthalic-acid-bis-(1,3-dihy 
droxyisopropylamide) represents an advance over this compound and has 
become known under the non-proprietary name of IOPAMIDOL. In this 
connection, see German Pat. No. 2,547,789, British Pat. No. 1,472,050, 
U.S. Pat. No. 4,001,323 and the article by Felder et al., IL FARMACO, Ed. 
Sc. 32, 835-844 (1977). It is distinguished by an essentially simpler 
structure, by higher stability, by a lower viscosity of its concentrated 
aqueous solutions and by being more easily isolated. The toxicity of this 
compound is very low. 
Recently, two additional derivatives of 
5-acylamino-2,4,6-triiodo-isophthalic acid, namely, 
5-(N-2-hydroxyethylacetyl-amino)-2,4,6-triiodoisophthalic-acid-bis-(2,3-di 
hydroxypropylamide) and 
5-(N-2,3-dihydroxypropyl-acetylamino)-2,4,6-triiodoisophthalic-acid-bis-(2 
,3-dihydroxypropylamide), which have similar properties, were disclosed in 
Belgian patent 855,850. They are derived from the slightly water-soluble 
5-acetylamino-2,4,6-triiodoisophthalic-acid-bis-(2,3-dihydroxypropylamide) 
, the water solubility of which is 1% (w/v) at 20.degree.-40.degree. C. It 
is therefore not surprising that some pertinent isomers are insoluble in 
water and therefore, practically unusable (see, for example, Belgian Pat. 
No. 855,850, pages 21-22). 
The developments in recent years have clearly shown that it is extremely 
difficult and only infrequently possible to find compounds which have the 
properties required for use in nonionic X-ray contrasting materials. These 
properties are a true water solubility sufficient for producing stable, 
that is, not supersaturated, concentrated solutions, maximum general and 
neurotropic tolerance, minimum osmolality, slight viscosity, maximum 
stability towards hydrolytic effects and a sufficiently simple structure 
to make the synthesis economical as well as to simplify the isolation and 
purification. 
SUMMARY OF THE INVENTION 
We have discovered a select group of novel compounds which possess these 
properties and a simple method for preparing these compounds. More 
particularly, the compounds of the present invention have the formula 
##STR2## 
in which 
(HO).sub.2-3 alkyl represents 1,3-dihydroxyisopropyl, 2,3-dihydroxypropyl 
or 1,3-dihydroxy-2-hydroxymethylisopropyl, 
R represents hydrogen or methyl; and 
R.sub.1 represents an alkyl residue with 1 to 5 carbon atoms, of which 
methyl, ethyl and propyl are preferred. 
These compounds simultaneously possess high water solubility which reaches 
absolute peak values in some instances, optimum tolerance and relatively 
slight osmolalities, as well as high stability towards hydrolytic 
influences, and the good stability of the starting materials, which are 
not alkylated at the aromatic nitrogen atom and on which they are based. 
This enhanced stability towards hydrolytic influences is important for 
preventing even the trace formation of free aromatic amines to avoid any 
possible cytotoxic effect of these amines in conjunction with X-rays. In 
this connection, see A. Norman et al., Radiology 129, 199-203 (October 
1978). 
The compounds of the present invention are prepared by alkylation of 
5-.alpha.-hydroxyacylamino-2,4,6-triiodo-isophthalic-acid-bis-(dihydroxy-p 
ropylamide) of the general formula (III) 
##STR3## 
at the aromatic nitrogen in an alkaline medium by reaction with alkylating 
agents of the general formula (IV) 
EQU R.sub.1 --X (IV) 
in which 
R and R.sub.1 in formulas (III) and (IV) have the meaning defined 
hereinbefore, and 
X represents a halogen atom, iodine, bromine or chlorine or a sulfate or 
sulfonate radical (--OSO.sub.2 --OR.sub.1 or --OSO.sub.2 --alkyl or 
--OSO.sub.2 --aryl), 
or reacting a reactive functional derivative of a 
5-(N-alkyl-.alpha.-hydroxyacyl-amino)-2,4,6-triiodo-isophthalic acid of 
the general formula (V) 
##STR4## 
in which 
R and R.sub.1 have the above-defined meaning, 
A represents a low molecular weight acyloxy residue with about 1 to 5 
carbon atoms or a halogen atom and Y--CO-- reactive acid halide or acid 
anhydride radicals whose hydroxy function may be masked by acetalization 
or ketalization, the masking function A and any acetal or ketal functions 
present in the 
5-(N-alkyl-.alpha.-hydroxyacyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-( 
hydroxy-alkylamide) derivative then being split off into hydroxy functions. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The viscosity of the aqueous solutions of these compounds is very dependent 
on their specific structure. It may vary greatly and may therefore be 
matched optimally to the most widely differing requirements of the 
respective uses. 
It is particularly surprising and, at the same time, valuable that, as a 
result of the attachment even of low molecular weight, unsubstituted, that 
is, hydrophobic alkyl residues to the aromatic nitrogen atom in the 
5-position of the basic compound, for example, 
1-5-.alpha.-hydroxypropionylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3- 
dihydroxyisopropylamide)=IOPAMIDOL or 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(2,3-dihydroxyprop 
ylamide), the water solubility is not only maintained but even considerably 
enhanced, particularly in the case of N-methyl compounds. 
In addition, the stability towards hydrolytic effects is also increased. 
The water solubility of IOPAMIDOL at 20.degree. C. corresponds to 440 mg 
of iodine per ml (that is, 89.7% w/v) and that of the hydrate to 307 mg of 
iodine per ml (that is 62.7% w/v). The 5-N-alkyl derivatives on the other 
hand, which fall within the scope of the present invention, have water 
solubilities of 100% (w/v). In addition, their hydrolysis stability is 
greater than that of the corresponding compounds which have not been 
alkylated. 
Because of their outstanding properties, especially their good water 
solubility, their nonionic character, their high stability, their very 
good tolerance and comparatively relatively simple structure, the 
inventive, novel X-ray contrasting materials have a very broad application 
spectrum. They can be synthesized quite economically and can therefore be 
used for purposes for which the permissible costs of the contrasting 
material are limited. 
The focal point of their use is the visualization of vessels, that is, 
angiography, such as, for example, ateriography, the visualization of the 
heart (cardiography) and of the coronary vessels (coronar graphy), the 
abdominal, the selective abdominal and the thoracic aortography, renal and 
cerebral angiography, phlebography as well as urography and the 
enhancement of contrast in computer tomography. In the case of the 
last-mentioned application, very large quantities of contrasting materials 
are required, for example, 250 ml of contrasting material solution with 
300 mg of iodine per ml, containing a total of 75 g of iodine. 
Understandably, in the case of such large dosages for purely diagnostic 
purposes, the requirements in regard to tolerance and safety are 
exceptionally high. Further areas of application are, for example, 
bronchography, the visualization of body cavities and of fluid cavities as 
well as lymphangiography. 
The 
5-(N-methyl-.alpha.-hydroxyacyl-amino)-2,4,6-triiodo-isophthalic-acid-bis- 
(hydroxyalkylamides) of the general formula (II) 
##STR5## 
in which 
(OH).sub.2-3 alkyl represents 1,3-dihydroxyisopropyl, 2,3-dihydroxypropyl 
or 1,3-dihydroxy-2-hydroxymethylisopropyl and 
R represents hydrogen or methyl, 
are radio-opaque components, which are distinguished in general by their 
particularly high water-solubility and their low viscosity. They are 
exceptionally suitable for the aforementioned uses. 
In preparation of the components of the present invention, a suitable 
5-.alpha.-hydroxyacylamino-2,4,6-triiodo-isophthalic-acid-bis-(hydroxyalky 
lamide) is reacted in the presence of bases with an alkyl halide, alkyl 
sulfate or an appropriate alkyl sulfonate, for example, an alkyl ester of 
methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid. 
Typical concrete examples of alkylating agents of formula R.sub.1 -X are: 
methyl bromide, methyl iodide, methyl chloride, dimethyl sulfate, methyl 
methanesulfonate, methyl benzenesulfonate, methyl toluenesulfonate, ethyl 
bromide, ethyl iodide, diethyl sulfate, ethyl methanesulfonate, ethyl 
benzenesulfonate, ethyl toluenesulfonate, propyl bromide, propyl iodide, 
propyl sulfate, propyl methanesulfonate, propyl benzenesulfonate, propyl 
toluenesulfonate, butyl bromide, butyl iodide, dibutyl sulfate, butyl 
methanesulfonate, butyl benzenesulfonate, butyl toluenesulfonate, amyl 
iodide, amyl bromide, amyl methanesulfonate, amyl benzenesulfonate, amyl 
toluenesulfonate. 
The strong acid (HX), which is released during the alkylation, is 
neutralized by the base which is present. The following may be used as 
bases: strong alkalies, such as, for example, alkali alcoholates (NaOMe, 
NaOEt, KOMe, KOEt, LiOMe, LiOEt), alkali hydroxides (NaOH, KOH, LiOH), 
alkali carbonates (Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3), and quaternary 
ammonium hydroxides (tetramethylammonium hydroxide). 
The reaction is usually carried out in a polar solvent, such as, for 
example, water, lower alcohols, (MeOH, EtOH, ethylene glycol, propylene 
glycol, glycerin), lower glycol ethers (methoxyethanol, ethoxyethanol, 
butoxyethanol), ketones, (acetone, methyl ethyl ketone, methyl isopropyl 
ketone, methyl isobutyl ketone) or in a decidedly aprotic solvent, such 
as, for example, hexametanol (MPT), dimethyl formamide (DMF), 
dimethylacetamide (DMAC), and dimethylsulfoxide (DMSO), or in solvent 
mixtures. The reaction is accelerated by heating. 
The simplified reaction sequence is as follows: 
##STR6## 
However, it is also possible to prepare a reactive derivative of a 
5-(N-alkyl-.alpha.-hydroxyacyl-amino)-2,4,6-triiodo-isophthalic-acid of 
the general formula (V) and react this with dihydroxypropylamine or a 
functional derivative thereof and to hydrolytically split off the masking 
groups in the product obtained and liberate all of the hydroxy functions. 
Acid derivatives suitable for use in this reaction are acid halides, and 
particularly acid chlorides, that is a 
5-(N-alkyl-.alpha.-acyloxyacyl-amino)-2,4,6-triiodo-isophthalic acid 
dichloride or an appropriate acid anhydride with an organic or inorganic 
acid. Suitable organic acids include lower fatty acids, such as, for 
example, propionic acid, butyric acid, valeric acid or semi-esters of 
carbonic acid, such as, for example, monomethyl carbonate, monoethyl 
carbonate or monobenzyl carbonate. Suitable inorganic acids include 
hydrazoic acid, the semi-ester of sulfuric acid, phosphoric acid, 
phosphorous acid, dialkyl phosphate, e.g. diethyl phosphate. 
The reaction with a dihydroxypropylamine is usually carried out in a 
solvent which is inert in this reaction, for example, in an aprotic 
solvent, such as, DMF, DMAC, etc., within a temperature range of about 
-10.degree. C. to to about +150.degree. C. 
In the reaction, the following compounds are preferably used as 
hydroxyalkylamines or their derivatives: 1,3-dihydroxyisopropylamine 
(serinol), 2,3-dihydroxypropylamine, tris-(hydroxymethyl)-aminomethane 
(2-amino-2-hydroxymethyl-1,3-propanediol), as well as ketals or acetals 
thereof, for example, 5-amino-2,2-dimethyl-1,3-dioxane, 
4-aminomethyl-2,2-dimethyl-1,3-dioxolane, 5-amino-2-methyl-1,3-dioxane, 
5-amino-2-phenyl-1,3-dioxane or 5-amino-1,3-dioxane. 
For the introduction of the hydroxyacyl residues and for some reactions of 
compounds containing these, it is necessary to mask the hydroxy function. 
For this purpose, it is customary to use an acyloxy function A, consisting 
of a lower acyloxy residue, preferably, the acetyloxy residue, which can 
easily be converted in the final step into the hydroxy function by 
alkaline saponification. 
It is also possible to start from the corresponding, easily accessible 
halogen acetyl compounds of formula (V), in which R=H and A=halogen, 
preferably chlorine, particularly for the synthesis of the hydroxyacetyl 
derivatives. The halogen acetyl group is easily converted by alkaline 
saponification into the terminal, desired, hydroxyacetyl group.

EXAMPLE 1 
L-5-(N-methyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodoisophthalic-acid 
-bis-(1,3-dihydroxyisopropylamide) 
L-5-.alpha.-hydroxypropionyl-amino-2,4,6-triiodo-isophthalic-acid-bis-(1,3- 
dihydroxyisopropylamide) (58.3 g, 0.075 moles) is dissolved in 200 ml water 
and mixed with exactly the stoichiometric amount (0.075 moles) of 2 N 
NaOH. The solution has a pH of 11.9. It is evaporated to dryness under 
vacuum. The residue consists of the 5-N-sodium compound (Na salt) of 
L-5-.alpha.-hydroxypropionyl-amino-2,4,6-triiodo-isophthalic-acid 
bis-(1,3)-dihydroxyisopropylamide) and is dried under vacuum at 
100.degree. C. Equivalent weight of C.sub.17 H.sub.21 I.sub.3 N.sub.3 
NaO.sub.8 calc. 799.27; found 799.08. 
The sodium salt so obtained (60 g=0.0075 moles) is dissolved in 200 ml of 
dimethylacetamide (DMAC) and, at 30.degree. C., mixed dropwise with 12.7 g 
of methyl iodide (0.09 moles). The mixture is stirred for about 1 hour at 
40.degree. C. until the reaction has been completed according to 
chromatographic analysis. The reaction solution is evaporated under 
vacuum. The sirupy residue is stirred into 600 ml of acetone, the product 
(and NaI) precipitating. The precipitate is filtered off, dissolved in 400 
ml of water and desalinated completely by percolating it first, through a 
cationic exchange resin (e.g. Amberlite.RTM. IR 120) and, subsequently, 
through an anionic exchange resin (e.g. Amberlite.RTM. IR 45) column. The 
column eluate is evaporated to complete dryness. 
Yield: 42.2 g of 
L-5-(N-methyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic-ac 
id-bis-(1,3-dihydroxyisopropylamide), that is, 71% of the theoretical 
yield. 
Melting point (after recrystallization from abs. ethanol) ca. 250.degree. 
C. (sinters at 190.degree. C.); 
Thin-layer chromatography (TLC) on silica gel: solvent 
chloroform/methanol/ammonia (25%)=6:3:1. R.sub.f =0.29 and 0.33; 
C.sub.18 H.sub.24 I.sub.3 N.sub.3 O.sub.8 : I calc. 48.12%, found 47.99%. 
Water solubility: .gtoreq.100% (w/v) at 25.degree. C. 
The same compound is also obtained if the methyl iodide in the 
above-described starting material is replaced by 11.4 g of dimethyl 
sulfate (0.09 moles), the procedure being otherwise unchanged. 
The 
d,L-5-(N-methyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic- 
acid-bis-(1,3-dihydroxyisopropylamide is obtained completely analogously by 
methylation of 
d,L-5-.alpha.-hydroxypropionylamino-2,4,6-triiodo-isophthalic-acid-bis-(1, 
3-dihydroxyisopropylamide), which has only limited solubility in water. 
Melting point: 298.degree.-300.degree. C. (with decomposition) 
TLC: R.sub.f =0.34 and 0.39 with CHCl.sub.3 /MeOH/NH.sub.4 OH=6:3:1. 
This product dissolves in water very readily. The solutions, however, are 
supersaturated. 
EXAMPLE 2 
L-5-(N-ethyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic-acid 
-bis-(1,3-dihydroxyisopropylamide 
The 5-N-sodium compound of 
L-5-.alpha.-hydroxypropionyl-amino-2,4,6-triiodo-isophthalic-acid-bis-(1,3 
dihydroxyisopropylamide) (90 g, 0.112 moles), in 240 ml of DMAC, is 
reacted with 26.5 g of ethyl iodide (0.17 moles) and worked up as in 
Example 1. A total of 66 g of the title compound is obtained, that is, 73% 
of the theoretical yield. 
Melting point: 295.degree.-297.degree. C. (with decomposition), 
TLC: R.sub.f =0.27. Solvent CHCl.sub.3 /MeOH/NH.sub.4 OH (25%)=6:3:1. 
C.sub.19 H.sub.26 I.sub.3 N.sub.3 O.sub.8 : I calc.=47.28%, I found=47.21%. 
[.alpha.].sub.D.sup.20 =+18.83.degree. (c=10% in water). 
EXAMPLE 3 
L-5-(N-propyl-.alpha.-hydroxypropionyl-amino)2,4,6-triiodo-isophthalic-acid 
-bis-(1,3-dihydroxyisopropylamide 
The 5-N-sodium compound of 
L-5-.alpha.-hydroxypropionylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3- 
dihydroxyisopropylamide) (38 g, 0.045 moles) in 120 of DMAC, is reacted 
with 7.5 g of propyl bromide (0.06 moles) at 80.degree. C. as in Example 
1. The product can be desalinated by partitioning it between butanol and 
water. 
Yield: 18.43 g of 
L-5-(N-propyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic-ac 
id-bis-(1,3-dihydroxyisopropylamide), that is, 50% of the theoretical 
yield. 
Melting point: 149.degree. C. (sinters at 142.degree. C). 
TLC: R.sub.f =0.35; 0.42 and 0.48. Solvent: CH.sub.2 Cl.sub.2 /CHCl.sub.3 
=10:3. 
C.sub.20 H.sub.28 I.sub.3 N.sub.3 O.sub.8 : for iodine-calc. 46.47%; found 
46.25%. 
Water solubility: .gtoreq.100% (w/v) at 25.degree. C. 
EXAMPLE 4 
L-5-(N-butyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic-acid 
-bis-(1,3-dihydroxyisopropylamide) 
The sodium salt (80 g) of 
L-5-.alpha.-hydroxypropionylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3- 
dihydroxyisopropylamide)=IOPAMIDOL, in 240 ml of DMAC, is reacted at 
40.degree.-80.degree. C. with 17.8 g of butyl bromide (0.13 moles). The 
product can be desalinated by partitioning it between methyl ethyl ketone 
and water (countercurrent extraction). 
Yield: 30 g of 
L-5-(N-butyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic-aci 
d-bis-(1,3-dihydroxy-isopropylamide). 
Melting point (after reprecipitation from isopropanol/diisopropyl ether and 
repeated precipitation from water): 140.degree.-145.degree. C. 
TLC: R.sub.f =0.36; 0.46 and 0.51. Solvent CH.sub.2 Cl.sub.2 /MeOH=10:3. 
C.sub.21 H.sub.30 I.sub.3 N.sub.3 O.sub.8 : for iodine-calc. 45.69%; found 
45.88%. 
Water solubility: .gtoreq.100% (w/v). 
EXAMPLE 5 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(1,3-di 
hydroxyisopropylamide) 
The sodium salt (50 g) of 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3-dihydroxyisop 
ropylamide) (0.064 moles), in 250 ml of DMAC, is reacted with 13.8 g of 
methyl iodide as in Example 1. 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(1,3-di 
hydroxyisopropylamide) is obtained in a yield of 37.9 g, corresponding to 
77% of the theoretical yield. 
Melting point: 215.degree.-220.degree. C., 
TLC: R.sub.f =0.45, Solvent: ethyl acetate/glacial acetic 
acid/water=15:3:5; 
C.sub.17 H.sub.22 I.sub.3 N.sub.3 O.sub.8 : for iodine-calc. 48.99%; found 
48.61%. 
The 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3-dihydroxyisop 
ropylamide), which is used as an intermediate, is obtained as follows 
according to the method described in German Pat. No. 2,547,789: 
(A) 5-amino-2,4,6-triiodo-isophthalic acid dichloride (59.6 g) is reacted 
in DMAC with 34 g of acetoxyacetyl chloride (0.25 moles), 67.5 g of 
5-acetoxyacetylamino-2,4,6-triiodo-isophthalic acid dichloride melting at 
234.degree.-235.degree. C. being obtained. 
(B) 5-acetoxyacetylamino-2,4,6-triiodo-isophthalic acid dichloride (150 g) 
in 810 ml of DMAC is treated with 80 g of tributylamine and then with 49.2 
g of serinol (=1,3-dihydroxyisopropylamine) in 540 ml of DMAC. 
5-acetoxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3-dihydroxyisop 
ropylamide) (172 g) is obtained, which melts at about 
190.degree.-192.degree. C. with decomposition. This compound is suspended 
in water and treated carefully at 45.degree. C. with 1 N NaOH at a pH of 
11, until the acetoxy group is completely hydrolyzed. 
The solution obtained is desalinated by percolating it through a column of 
cationic exchange resin (Amberlite.RTM. IR 120) and then through a column 
of anionic exchange resin (Amberlite.RTM. IR 45). The eluate is evaporated 
to dryness and taken up in 90% ethanol, whereby the desired intermediate 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3-dihydroxyisop 
ropylamide) is obtained as a crystalline product (73 g). 
Melting point: 300.degree. C. with decomposition. 
EXAMPLE 6 
5-(N-ethyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(1,3-dih 
ydroxyisopropylamide) 
Obtained by the reaction of 50 g of the sodium salt of 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3)-dihydroxyiso 
propylamide) with ethyl iodide. 
Melting point: 210.degree. C., 
C.sub.18 H.sub.24 I.sub.3 N.sub.3 O.sub.8 : for iodine: calc. 48.12%, found 
48.10%. 
EXAMPLE 7 
L-5-(N-methyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic-aci 
d-bis-(1,3-dihydroxyisopropylamide) Alternative Synthesis 
A solution of 14.5 g of 
L-5-(N-methyl-.alpha.-acetoxypropionylamino)-2,4,6-triiodo-isophthalic 
acid dichloride (0.02 moles) in 35 ml of DMF is stirred and treated 
dropwise at 0.degree.-2.degree. C. with 9.1 g of serinol 
(=1,3-dihydroxyisopropylamine) (0.1 moles) in 30 ml of DMF. Stirring is 
continued for an additional 3 hours at 20.degree. C. and the reaction 
solution is subsequently evaporated to a syrup. The crude product is taken 
up in 100 ml of water, freed from adhering solvent by evacuation and, at 
40.degree.-50.degree. C., brought to a pH of 11.6 with aqueous 2 N sodium 
hydroxide solution. The pH is kept at a constant value by the continuous 
addition of NaOH. In all, 29 ml of 2 N NaOH are consumed. 
The alkaline solution obtained is diluted with 200 ml of water and 
desalinated by percolating it through a column of cationic exchange resin 
(Amberlite.RTM. IR-120) and a column of anionic exchange resin 
(Amberlite.RTM. IR-45). The column eluate is evaporated to dryness. 
Yield: 11.08 g of 
L-5-(N-methyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic-ac 
id-bis-(1,3-dihydroxyisopropylamide), that is, 70% of the theoretical 
yield. 
Melting point (after repeated recrystallization from abs. 
ethanol)&gt;280.degree. C. (sinters at 210.degree. C.) 
TLC on silica gel: solvent ethyl acetate/glacial acetic acid/water=10:5:3. 
One spot at R.sub.f 0.29. 
The 
L-5-(N-methyl-.alpha.-acetoxy-propionyl-amino)-2,4,6-triiodo-isophthalic a 
cid dichloride, which is used as an intermediate, is obtained as follows: 
(A) 5-amino-2,4,6-triiodo-isophthalic acid is treated in sulfuric acid with 
formaldehyde according to the method described in German 
Offenlegungsschrift 2,050,217, 5-methylamino-2,4,6-isophthalic acid, 
melting at 198.degree.-200.degree. C., being obtained. 
TLC on silica gel with ethyl methyl ketone/ethanol/water/glacial acetic 
acid=20:8:5:1.5. R.sub.f =0.55. 
(B) 5-methylamino-2,4,6-triiodo-isophthalic acid (23 g) in 120 ml of 
thionyl chloride is boiled for 7 hours under reflux in the presence of 0.1 
ml of quinoline. After completely distilling off the thionyl chloride, the 
residue is stirred into 120 g of ice water, which contains sodium chloride 
(125 g) and NaHCO.sub.3 (12 g). 
The product is extracted with ethyl acetate (200 ml). From the extract, 
5-methylamino-2,4,6-triiodo-isophthalic acid dichloride is obtained by 
evaporation. 
Melting point 167.degree. C. TLC on silica gel with benzene/hexane=1:1; 
R.sub.f =0.50. 
C.sub.9 H.sub.4 Cl.sub.2 I.sub.3 NO.sub.2 Cl calc. 11.62%, Cl found 11.74%, 
I calc. 62.44%, I found 62.74%. 
(C) 5-methylamino-2,4,6-triiodo-isophthalic acid dichloride (12 g, 0.02 
moles) in 30 ml of DMAC is reacted with 1-.alpha.-acetoxy-propionic acid 
dichloride (0.03 moles) added dropwise at 0.degree.-2.degree. C. 
Subsequently, stirring is continued for 1 to 2 hours at 20.degree. C. 
The reaction solution is stirred into ice water. The precipitated product 
is filtered off, dried and recrystallized from a little benzene. 
L-5-(N-methyl-.alpha.-acetoxypropionylamino)-2,4,6-triiodo-isophthalic acid 
dichloride (14 g), melting at 187.degree. C. -190.degree. C., is obtained. 
TLC on silica gel with hexane/chloroform/ethyl acetate=3:1:1, 2 spots with 
R.sub.f of 0.22 and 0.5. 
C.sub.14 H.sub.10 Cl.sub.2 I.sub.3 NO.sub.5 : Cl calc. 9.79%; Cl found 
9.80%, I calc. 52.59%; I found 52.46%. 
EXAMPLE 8 
L-5-(N-methyl-.alpha.-hydroxypropionyl-amino)-2,4,6-triiodo-isophthalic-aci 
d-bis-(2,3-dihydroxypropylamide) 
L-5-(N-methyl-.alpha.-acetoxypropionyl-amino)-2,4,6-triiodo-isophthalic 
acid dichloride (14.5 g, 0.02 moles) in 30 ml of DMF is treated by the 
dropwise addition of 9.4 g of 2,4-dihydroxypropylamine 
(=1-amino-2,3-propanediol) dissolved in 50 ml of DMF and reacted and 
worked up according to the method described in Example 7. 
Yield: 10.8 g of 
L-5-(N-methyl-.alpha.-hydroxyproponyl-amino)-2,4,6-triiodo-isophthalic-aci 
d-bis-(2,3-dihydroxypropylamide), corresponding to 68% of the theoretical 
yield. 
Melting point (after recrystallization from ethanol): 195.degree. C. 
(sinters at 187.degree. C.). 
TLC on silica gel: solvent-ethyl acetate/glacial acetic acid/water=10:5:3. 
One spot at R.sub.f 0.45. 
C.sub.18 H.sub.24 I.sub.3 N.sub.3 O.sub.8.H.sub.2 O: I calc. 47.05%, found 
47.00%, H.sub.2 O calc. 2.23%, found 2.8%. 
EXAMPLE 9 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-di 
hydroxypropylamide) 
The 5-N sodium compound of 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(2,3-dihydroxyprop 
ylamide) (49 g, 0.0625 moles), prepared as described in Example 1, is 
dissolved in 250 ml of DMAC and treated at 5.degree. C. by the dropwise 
addition 13.5 g of methyl iodide. It is subsequently stirred for some 
hours. 
The reaction solution is concentrated under vacuum, and the residue of the 
evaporation is treated with 300 ml methylene chloride, whereupon the 
product formed is precipitated in admixture with sodium iodide. The crude 
product is dissolved in water and desalinated with ion-exchange resin. 
Yield: 36 g of 
5-(N-methylhydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-di 
hydroxypropylamide), corresponding of 75% of the theoretical yield. 
Melting point: 190.degree.-191.degree. C. (amorphous product). 
TLC on silica gel: solvent-2 butanone/glacial acetic acid/water=15:3:5. 
Spots at R.sub.f 0.48 and 0.40. 
Solubility: very readily soluble in water and methanol. Solubility in 
ethanol limited. (in 20 parts by volume at the boiling point and in 35 
parts by volume at 25.degree. C.). 
The 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(2,3-dihydroxyprop 
ylamide), used as an intermediate, is obtained according to the method 
described in German Pat. No. 2,457,789 as follows: 
To a solution of 24.4 g of 5-acetoxyacetylamino-2,4,6-triiodo-isophthalic 
acid dichloride (0.035 moles) in 60 ml of DMAC, there is added dropwise 
with stirring a solution of 15.9 g of 2,3-dihydroxypropylamine 
(=1-amino-2,3-dihydroxypropane) (0.175 moles) in 100 ml of DMAC. 
An oily 5-acetoxyacetylamino-2,4,6-triiodo-isophthalic 
acid-bis-(2,3-dihydroxypropylamide) is obtained. This compound is taken up 
in 250 ml of water and treated carefully at 40.degree. C. with 40 ml of 1 
N sodium hydroxide until the acetoxy group is hydrolyzed off completely. 
The solution obtained is desalinated by percolation through a column of 
cationic exchange resin (Amberlite.RTM. IR-120) and a column of anionic 
exchange resin (Amberlite.RTM. IR-45). The eluate is evaporated. After 
some time, crystallization takes place. By recrystallization from a little 
water, the desired intermediate, 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(2,3-dihydroxyprop 
ylamide) is obtained in a pure form. 
Melting point: 290.degree. C. 
TLC: R.sub.f =0.24, solvent: ethyl acetate/ethanol/ammonia (25%)=15:7:6. 
C.sub.16 H.sub.20 I.sub.3 N.sub.3 O.sub.8 : C calc. 25.18%, found 25.01%, I 
calc. 49.89%, found 49.75%. EXAMPLE 10 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-di 
hydroxypropylamide) 
(A) 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(2,3-dihydroxyprop 
ylamide) (90 g, 0.117 moles) is suspended in 700 ml of DMAC and treated at 
40.degree. C. with 95 g of a solution of sodium hydroxide in methanol 
(1.233 moles). The 5-N sodium compound is formed. Methanol, water of 
reaction and a portion of the DMAC are distilled off under vacuum. A 496 g 
solution containing 0.234 moles of the 5-N-Na compound of 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(2,3-dihydroxyprop 
ylamide) is obtained. 
(B) The solution (390 g, 0.091 moles), described in Section A, is added 
dropwise with stirring and within 45 minutes to a solution of 13 g of 
methyl bromide (0.137 moles) in 160 g of DMAC at 0.degree. C. Stirring is 
then continued at 0.degree. to 5.degree. C. for some hours. 
Yield: 60.1 g of 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-d 
ihydroxypropylamide), that is, 85% of the theoretical yield. 
TLC on silica gel with a solvent consisting of acetyl acetate/glacial 
acetic acid/water=10:5:3. Spots at R.sub.f 0.3 and 0.45. The product can 
be recrystallized from 95% ethanol. 
Melting point: 305.degree.-310.degree. C. with decomposition. The melting 
point is not very characteristic. 
(C) A solution (390 g, 0.091 moles) of the sodium compound of 
5-hydroxyacetylamino-2,4,6-triiodo-isophthalic-acid-bis-(2,3-dihydroxyprop 
ylamide), described in Section A, is added dropwise with stirring and 
within 50 minutes to a solution of 13.8 g of dimethyl sulfate (0.109 
moles) in 150 ml of DMAC. The reaction solution is stirred for some hours 
and subsequently worked up according to the method described in Example 1. 
Yield: 62.4 g of 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-d 
ihydroxypropylamide), that is, 88% of the theoretical yield. 
Melting point (after recrystallization from 95% ethanol): 
305.degree.-310.degree. C. with decomposition. 
EXAMPLE 11 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-( 
2,3-dihydroxypropylamide) Alternative Synthesis 
A solution of 28.4 g of 
5-(N-methyl-acetoxyacetylamino)-2,4,6-triiodo-isophthalic acid dichloride 
in 90 ml of DMAC is added dropwise, with stirring and within 45 minutes to 
a solution of 18.2 g of 1-amino-2,3-propanediol in 70 ml of DMAC at 
5.degree. C. The reaction mixture is stirred for some hours and 
subsequently evaporated under vacuum to a syrup. The residue is triturated 
with methylene chloride and acetone and the solvet decanted off. The 
residue is freed under vacuum from adhering solvent, taken up in 200 ml of 
water and carefully kept at a pH of 11 to 11.5 at 45.degree. C. by the 
addition of a total of 50 ml of 2 N sodium hydroxide solution, during 
which process the acetoxy group is hydrolyzed off. 
The solution obtained is desalinated by percolating it first through a 
column of cationic exchange resin (e.g. 200 ml of Amberlite.RTM. IR-120) 
and then through a a column of an anionic exchange resin (e.g. 250 ml of 
Amberlite.RTM. IR-45). The eluate is evaporated, the residue dissolved in 
methanol and the solution treated with methylene chloride, whereby the 
desired product is precipitated. 
Yield: 22 g of the title compound, that is, 71% of the theoretical yield. 
Melting point: ca. 190.degree. C. (sinters at ca. 165.degree. C.). 
TLC on silica gel: solvent consisting of 2-butanol/glacial acetic 
acid/water=15:3:5. Spots at R.sub.f 0.48 and 0.40. 
C.sub.17 H.sub.22 I.sub.3 N.sub.3 O.sub.8 : I calc. 48.99%, found 48.69%. 
The compound is very soluble in water (3 g in 1 ml of water) and in 
methanol (100 w/v). 
The 5-(N-methyl-acetoxy-acetyl-amino)-2,4,6-triiodo-isophthalic acid 
dichloride, which is used as an intermediate, is obtained as follows: 
A solution of 32 g of 5-methylamino-2,4,6-triiodoisophthalic acid 
dichloride (0.0525 moles in 80 ml of DMAC is treated dropwise at 0.degree. 
to 5.degree. C. with stirring with 10.7 g of acetoxyacetylchloride. 
Subsequently, stirring is continued over night and at room temperature. 
The reaction solution is stirred into ice water. A total of 36.7 g of 
5-(N-methylacetoxyacetylamino)-2,4,6-triiodo-isophthalic acid dichloride, 
melting at 198.degree.-200.degree. C., are obtained, corresponding to a 
theoretical yield of 98.8%. 
TLC on silica gel with benzene/methanol=10:3, R.sub.f =0.64. 
C.sub.13 H.sub.8 Cl.sub.2 I.sub.3 NO.sub.5 calc. Cl 9.9%, I 53.3% found Cl 
10.05% I 53.41%. 
EXAMPLE 12 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(R(+)2, 
3-dihydroxypropylamide) 
This compound is obtained similarly as the corresponding racemic compound 
by, as described in Example 11, adding a solution of 20.2 g of 
5-(N-methyl-acetoxyacetyl-amino)-2,4,6-triiodo-isophthalic acid dichloride 
in 40 ml of DMAC dropwise to a solution of 7 g of 
R(+)1-amino-2,3-propanediol (0.077 moles) in 40 ml of DMAC, in which 10.8 
g of potassium carbonate (0.077 moles) are suspended. The reaction mixture 
is stirred for some hours and subsequently worked up as described in 
Example 10. 
A total of 15.2 g of the title compound, corresponding to a theoretical 
yield of 69.5%, are obtained. 
Melting point: 283.degree.-284.degree. C. 
TLC: R.sub.f =0.24. Solvent-isopropanol/isobutanol/ammonia (25%)=7:7:6. 
C.sub.17 H.sub.22 I.sub.3 N.sub.3 O.sub.8 : I calc. 48.99%, found 48.74%. 
[.alpha.].sub.D.sup.20 =+4.85.degree., [.alpha.].sub.436.sup.20 
=+11.1.degree. (c=10% in water). 
EXAMPLE 13 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-di 
hydroxypropylamide) 
(A) 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-i 
sopropylidenedihydroxypropylamide)=5-(N-methylhydroxyacetyl-amino)-2,4,6-tr 
iiodo-isophthalic-acid-bis-(2,3-dimethyl-1,3-dioxolan-(4)-ylmethylamide). 
A solution of 17.8 g of 
5-(N-methyl-acetoxyacetyl-amino-2,4,6-triiodo-isophthalic acid dichloride 
(0.025 moles) in 50 ml of DMAC is treated dropwise with stirring at 
5.degree.-8.degree. C. with a solution of 16 g of 
4-aminomethyl-2,2-dimethyl-1,3-dioxolan (0.122 moles). Stirring is 
continued for 18 hours at room temperature. The precipitated hydrochloride 
is filtered off and the filtrate is evaporated to dryness under vacuum. 
The residue from the evaporation is suspended in water, filtered, 
dissolved in aqueous methanol and treated at 50.degree.-55.degree. C. with 
2 N sodium hydroxide at a pH of 10.5 to 11, whereby the acetoxy group is 
hydrolyzed off completely. The solution obtained is neutralized exactly by 
the careful addition of hydrochloric acid, filtered until clear and 
evaporated to dryness. The residue is taken up in water from which the 
5-(N-methyl-hydroxy-acetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3- 
isopropylidenedihydroxypropylamide) crystallizes out. 
Yield: 15.2 g, corresponding to 71% of the theoretical yield. 
Melting point: (after recrystallization from dilute methanol) 
180.degree.-181.degree. C. 
TLC: R.sub.f =0.295, solvent--chloroform/hexane/methanol=3:3:1. 
C.sub.23 H.sub.30 I.sub.3 N.sub.3 O.sub.8 : I calc. 44.41%, found 44.08%. 
This compound is very soluble in methanol, ethanol and chloroform and, on 
the other hand, only slightly soluble in water. 
B. 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-d 
ihydroxypropylamide). 
A solution of 15 g of 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-i 
sopropylidenedihydroxypropylamide) in 185 ml of 0.1 N aqueous hydrochloric 
acid and 185 ml of methanol is kept for 5 hours at 50.degree. C. with 
stirring. The reaction solution is freed from hydrochloric acid by 
percolation through a column filled with 75 ml of a weakly basic 
ion-exchange resin, e.g., Amberlite.RTM. IR-45, and evaporated to dryness. 
Yield: 12.2 g of 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-d 
ihydroxypropylamide) that is, 90% of the theoretical yield. 
Melting point: 190.degree. C. (amorphous product). 
After crystallization from 95% ethanol Melting point: 300.degree. C. with 
decomposition. 
Use: 
Of the compounds described in the above Examples, the 
5-(N-methyl-.alpha.-hydroxy-acyl-amino)-2,4,6-triiodo-isophthalic-acid-bis 
-(hydroxyalkylamides) of formula (II) are in general preferred because they 
are more water-soluble as well as more readily accessible than the higher 
N-alkyl derivatives thereof. 
Within the preferred amounts of formula (II), the hydroxyacetyl derivatives 
are usually preferred to the .alpha.-hydroxypropionyl derivatives, because 
they are more easily synthesized, have no center of asymmetry and 
nevertheless generally have the required high water-solubility. 
Because they are easily synthesized, the 2,3-dihydroxypropylamides are the 
preferred hydroxyalkylamides. A typical representative of this group is 
the 5-(N-methyl-hydroxyacetylamino)-2,4,6-triiodo-isophthalic-acid-bis-(2, 
3-dihydroxypropylamide) (Compound A). This compound is distinguished by its 
comparatively particularly high water-solubility, by the low viscosity of 
its aqueous solutions and by the high stability. 
In the following table, important properties of Compound A are compared 
with those of two previously known nonionic X-ray contrasting materials, 
namely, with 
B: 
L-5-.alpha.-hydroxypropionylamino-2,4,6-triiodo-isophthalic-acid-bis-(1,3- 
dihydroxyisopropylamide) (international non-proprietary name=IOPAMIDOL); 
C: 3-acetylamino-4-N-methyl-acetylamino-2,4,6-triiodobenzoylglucosamine 
(international non-proprietary name (I.N.N.)=METRIZAMIDE) 
TABLE 1 
______________________________________ 
Viscosity in Centipoise (cP) 
Solubility in 
Aqueous solutions containing 
Water in % 300 mg 
400 mg 
Compound (w/v) at 20.degree. C. 
.degree.C. 
I/ml I/ml 
______________________________________ 
A &gt;100 20.degree. C. 
7.55 22.0 
37.degree. C. 
4.19 9.87 
B 89 20.degree. C. 
8.95 40.6 
37.degree. C. 
4.70 16.1 
C .about.80 20.degree. C. 
11.7 77.8 
37.degree. C. 
5.98 26.9 
______________________________________ 
TABLE 2 
______________________________________ 
Osmolality Osmotic Pressure 
Compound mg I/ml (mOsm/kg) 37.degree. C. 
atm 37.degree. C. 
______________________________________ 
A 250 452 11.52 
300 536 13.64 
350 628 15.98 
B 250 514 13.09 
300 619 15.76 
350 737 18.77 
______________________________________ 
It is clearly evident from Table 1 that the inventively obtained Compound A 
has a higher water solubility and an appreciably lower viscosity than the 
previously known Compounds B and C. Solutions of A can therefore be used 
at a higher concentration and, because of their low viscosity, can 
nevertheless be injected without difficulties. It is evident from Table 2 
that the osmotic pressure of the inventively obtained Compound A is less 
than that of IOPAMIDOL. The stress on the organism is therefore less when 
administering Compound A than when administering Compound B. 
The novel 
5-(N-alkyl-.alpha.-hydroxyacyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-( 
hydroxyalkyl-amide) of the general formula (I) are used primarily in the 
form of their aqueous solutions. 
Depending on the intended purpose, ca. 15 to 85% solutions w/v (100%=100 g 
of contrasting material per 100 ml of solution) with a content of about 60 
to about 420 mgI/ml are used. Concentrated solutions are preferred. The 
nature of their application depends on the organ which is to be made 
visible. 
For vasography, the solutions are injected or infused into the appropriate 
blood vessels. 
For urography, the solutions are injected or infused intravenously. 
For the enhancement of contrast in computer tomography, the solutions are, 
depending on the organ or tissue contrast to be intensified, either 
introduced by intravenous administration into the blood stream or 
concentrated by selective injection in the vascular system of a particular 
organ or of a body cavity. 
For myelography and radiculography, the solutions are installed after 
lumbar or suboccipital puncture. In the case of ventriculography, the 
ventricles are punctured directly. 
______________________________________ 
Dosage: 
______________________________________ 
Myelography ca. 5-15 ml 
Radiculography ca. 3-5 ml 
Ventriculography ca. 1-2 ml 
______________________________________ 
Solutions of X-ray contrasting materials are easily prepared because it is 
unnecessary to prepare salt solutions. 
For example, the pure 2,4,6-triiodo-isophthalic amides, obtained according 
to the preceding examples, are dissolved under sterile conditions in the 
required amount of doubly distilled water, filtered, filled into serum 
bottles or ampoules and subsequently sterilized. The triiodo-isophthalic 
acid amides of the present invention are not decomposed by heat 
sterilization. 
EXAMPLE 14 
Injection Solutions Containing 
5-(N-methyl-hydroxyacetyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-(2,3-d 
ihydroxypropylamide)=Compound A 
______________________________________ 
Iodine Content of Injection Solution 
Composition of 20 ml 
in mg/ml 
Aliquots of Solution 
200 300 420 
______________________________________ 
Compound A g 8.16 12.25 17.15 
Di-sodium-calcium salt 
of ethylenediamine- 
tetra-acetic acid 
hexahydrate mg 5.2 7.8 11 
Tromethamine mg 9.5 14.2 20 
(tris-(hydroxymethyl)- 
aminomethane) 
Doubly distilled 
ml 20 20 20 
water to 
Density at 37.degree. C. 
d 1.207 1.316 1.453 
Viscosity at 37.degree. C. 
cP 1.87 4.19 20.03 
______________________________________ 
(cP = Centipoise) 
Procedure: The sodium-calcium salt of ethylenediaminetetra-acetic acid, the 
tromethamine and the contrasting material are dissolved in doubly 
distilled water. The pH of the solution is adjusted, if necessary, to ca. 
7 by the addition of 1 N hydrochloric acid. The volume is made up to 20 
ml. The solution is filtered using a membrane of 0.45 m.mu.. The filtrate 
is filled into ampoules and sterilized for 30 minutes at 120.degree. C. 
EXAMPLE 15 
______________________________________ 
Injection Solution 
______________________________________ 
5-(N--methyl-hydroxyacetyl-amino)- 
2,4,6-triiodo-isophthalic-acid-bis- 
(1,3-dihydroxyisopropylamide) 
82 g 
5-(N--methyl-hydroxyacetyl-amino)- 
2,4,6-triiodo-isophthalic-acid-bis- 
(2,3-dihydroxypropylamide) 
20.5 g 
Sodium carbonate 0.4 g 
Disodium salt of ethylenediamine- 
tetraacetic acid 0.02 g 
Doubly distilled water to a volume of 
125 ml 
______________________________________ 
Procedure: The combined components are diluted to 125 ml with doubly 
distilled water, filtered, filled under hygienically satisfactory 
conditions into ampoules under nitrogen and subsequently sterilized. 
Iodine content: 400 mg/ml. 
EXAMPLE 16 
______________________________________ 
Infusion Solution 
______________________________________ 
5-(N--methyl-.alpha.-hydroxypropionylamino)- 
2,4,6-triiodo-isophthalic-acid-bis- 
(1,3-dihydroxypropylamide) 
155.9 g 
Disodium salt of ethylenediaminetetra- 
acetic acid 0.02 g 
Doubly distilled water up to a volume of 
250 ml 
______________________________________ 
Procedure: The combined components are diluted to 250 ml, filled under 
nitrogen into a infusion flask and sterilized. 
Iodine content: 300 mg/ml.