NO122430B - - Google Patents

Description

Triiodobenzoic acid derivatives for use

in X-ray contrast agents.

This invention relates to new triiodobenzoic acid derivatives for use as X-ray contrast agents, in particular for making visible the cardiovascular system and the cavities containing the cerebrospinal fluid.

By X-ray exposure of relatively large parts

of the human body, e.g. the cardiovascular system or the cavities containing the cerebrospinal fluid, very large amounts of X-ray contrast agents must be injected to achieve sufficient density in the desired area. The toxicity of the contrast agent at high concentrations is therefore of great importance. For visualization of the cardiovascular system, a large number of compounds have been proposed as contrast agents, and although many are

used successfully, their toxicity, although often very small, will cause some unwanted side effects. When making the cavities containing the cerebrospinal fluid visible, the compounds used for vascular visualization are often far too toxic, as explained below.

The space that contains the cerebrospinal fluid consists of several different cavities that are connected to the central nervous system, and includes the cerebral ventricles, the cisterns and the subarachnoid space around the brain as well as in the spinal column. The radiological examination of these cavities can be divided into three main groups: ventriculography, cisternography and myelography. Myelography, i.e. radiological examination of the spinal subarachnoid space, which can be divided into two zones; the radiological examination of the lower part of the spine is called radiculography, and examination of the remaining part is called lumbar myelography.

These areas' tolerance to e.g. water-soluble X-ray contrast agents, vary considerably, and an approximate order of decreasing tolerance is radiculography, ventriculo-graph i, lumbar myelography and cisternography. However, these different fields cannot be considered separate areas, because there exists a connection throughout the system which enables leakage from one area to adjacent areas. Lumbar myelography is e.g. particularly demanding with regard to the tolerance of the X-ray contrast agent, but the higher cavities are even more demanding in this respect. One reason for this is the risk of leakage to the cisterns, an area that is far more sensitive than, for example, the ventricles.

Agents for use in this field should ideally be safely applicable in all areas, but an ideal agent has not yet been found. Iodized oils used as such or as aqueous emulsions, the water-soluble sodium iodomethanesulfonate and gas (oxygen) are examples of agents that are often used. Among other things, the oils have the disadvantage that they remain in the system without

to be resorbed and excreted, and radiologists today will generally not accept contrast agents that remain in the body for a very long time. Use of these oils in myelography can also cause aseptic meningitis which is considered a very serious complication. Gases such as oxygen, which in many ways represent good contrast agents, give a so-called negative contrast, and this is not sufficient in many cases.

When a positive contrast is desired and the contrast agent cannot be allowed to remain in the system (although mechanical removal of most of the oil is possible), the water-soluble sodium iodomethanesulfonate is the principal conventional agent. However, this substance is far from ideal; it is often used for radiculography, but simultaneous use of an anesthetic is necessary, and it is not advisable to use it for lumbar myelography.

We have now found that triiodobenzoic acids which in the molecule carry at least one group -N-R', where R' means a hydroxyalkyl group, are generally more suitable than the corresponding compounds which do not contain any hydroxyalkyl group, for use for making visible the cardiovascular system and of the cavities containing the cerebrospinal fluid, from a tolerance point of view for the tissues involved, and also from a water solubility and viscosity point of view, properties that are important when it comes to the use of highly concentrated aqueous solutions . The compounds 3-N-(6-hydroxyethyl)-acetamido-5-acetamido-2,4,6-triiodobenzoic acid, 3,5-bis-N-(B-hydroxyethyl)-acetamido-2,4,6-triiodobenzoic acid, 3 -N-(B-hydroxyethyl)-acetamido-2,4,6-triiodobenzoic acid and 3-(N-B-hydroxy-ethylacetamido)-5-(N-B-hydroxyethylacetamido)-methyl-2,4,6-triiodobenzoic acid have previously been proposed as cardiovascular x-ray contrast agents, but no other hydroxyalkyltriiodobenzoic acids have been described.

According to the present invention, new triiodobenzoic acid compounds are provided for use in X-ray contrast agents. The compounds are characterized by having the general formula

where Ac"*" is a lower alkanoyl group with 1-4 carbon atoms,

R"<*>" is a hydrogen atom or an alkyl group with 1-6 carbon atoms which may be unsubstituted or carry one or more hydroxyl groups or groups with the formula

X is a group of the formula -N - Ac <2>where

i<*>

Ac 2 is a lower alkanoyl group with 1-4 carbon atoms which can be the same or different from Ac\ and

2 R is an alkyl group with 1-6 carbon atoms, or X is a group with the formula

where R 3 and R 4 , which may be the same or different, are hydrogen atoms or alkyl groups with 1-6 carbon atoms which may be unsubstituted or carry one or more hydroxyl groups, there being at least one N-hydroxyalkyl group in the molecule.

The most preferred hydroxyalkyl group is the B-hydroxyethyl group.

The salts of the new acids according to the invention are particularly useful, as many of them are generally more water-soluble than the starting acid and have the advantage of being neutral. Salts for radiological purposes must of course be physiologically compatible with the body system in which they are to be used. Other salts may, however, be useful for purification etc. of the acids. Particularly useful salts include the sodium salt, the calcium and magnesium salts and salts with alkanolamines such as ethanolamine or N-methylglucamine.

The following table gives LD^Q values, determined by both intracerebral and intravenous injection in mice and expressed in mg iodine/kg, for a number of related contrast agents, the last three of which are known compounds used in practice as X-ray contrast agents.

The above six compounds according to the invention are the particularly preferred compounds in X-ray contrast agents for intracerebral use.

When investigating the maximum iodine concentration that can be used in cardiovascular X-ray contrast agents for cerebral angiography, without brain lesions occurring in guinea pigs, the following results have been obtained by comparing a compound according to the invention and a known compound (where the compounds are used in the form of N -methylglucamine salts): The latter compound according to the invention is particularly well tolerated in cerebral angiography and is therefore a preferred compound for this purpose.

One or more of the compounds according to the invention or physiologically compatible salts thereof can be used in a radiological preparation together with a radiological carrier.

The concentration of the compounds according to the invention in the aqueous medium for administration varies with the particular area of use. In general, lower concentrations are required for ventriculography than for myelography, while radiculography requires even lower concentrations. The preferred concentrations and dose ranges for the compounds used for these three purposes are as follows:

The preferred concentration range for cardiovascular visualization is 150 - 450 mg iodine/ml. The amount of contrast agent that is administered is preferably such that the agent remains in the system for only approx. 2 to 3 hours, although both shorter and longer stays can normally be accepted. For cerebrospinal visualization, the active material is conveniently made in the form of capsules or ampoules containing 5 to 15 ml of an aqueous solution of the compound, but for cardiovascular visualization, larger quantities are used, e.g. 10 to 500 ml.

In our Belgian patent no. 645634, preparations containing sodium salts of X-ray contrast acids are described, the toxicity of which was modified in a favorable direction when introduced

of relatively small amounts of compounds that release calcium-

and/or magnesium ions. It was assumed that the effect was related to the ion balance in the vascular system. We have now found that although sodium salts of X-ray contrast acids are more toxic when administered intracerebral than when administered intravenously, these toxicities in the cerebrospinal fluid will be modified in a favorable direction by the introduction of calcium and/or

or magnesium ions to sodium ions, similar to what has been observed for the vascular system.

The ratio between calcium and sodium ions is preferably at least 0.00025, preferably at least 0.0005. When magnesium ions are present, these are also present preferably in the above minimum amounts. The ratio between calcium ions and sodium ions is preferably in the range 0.005 to 0.10, while the ratio between magnesium ions and sodium ions is preferably in the range 0.002 to 0.05. It is preferred that both calcium and magnesium ions are present.

The calcium and/or magnesium ions can be supplied by adding a calcium and/or magnesium salt of the X-ray contrast acid or by adding or forming in situ another physiologically and chemically compatible, water-soluble calcium or magnesium salt. The metal ions should of course be in a free state, and ions that are bound by chelating agents, such as ethylenediamine-tetraacetic acid, are not effective and should not be taken into account when calculating the respective ion ratios. Particularly suitable calcium and magnesium salts for addition to X-ray contrast agents containing the compounds according to the invention are the chlorides. Another possibility is to add one or more bases to a solution of the acid which on the one hand provide sodium ions and on the other hand calcium and/or magnesium ions.

The new compounds according to the invention can be prepared in any suitable way, and a number of methods are described in the following:

a) Reaction of a compound with the general formula

with a hydroxyalkylating agent to give a compound of formula I wherein R 1 is a hydroxyalkyl group. The hydroxyalkylating agent can e.g. be a reactive monoester derivative of a glycol or polyol, e.g. a halide such as a chloride or bromide, or a hydrocarbon sulfonate. For the introduction of a hydroxyethyl group, 2-chloroethanol is a suitable agent. The reactive derivative is preferably reacted with the acylamido starting material under basic conditions, e.g. in an aqueous, alkaline medium, e.g. containing an alkali metal hydroxide such as sodium or potassium hydroxide, or in a non-aqueous medium, e.g. in an alkanol such as methanol or ethanol, the base suitably being an alkali metal alkoxide such as sodium methoxide. It is also possible to react the acylamido compound with an epoxide, e.g. ethylene oxide, propylene oxide, glycide, etc., also suitable

under the same conditions as used for reactive esters.

b) Reaction of an amide of formula II with an allylating agent, e.g. a reactive ester of an allyl alcohol, such as allyl chloride

or -bromide, to introduce an N-allyl group which is then subjected to oxidation of the double bond, e.g. using a permanganate oxidizing agent, to form a glycol

group, whereby a compound of formula I is obtained in which R?~ is a dihydroxyalkyl group.

c) For the preparation of mono-hydroxyalkyl-bisacylamido compounds, a compound of the general formula can be used

(where Ac has the above meaning and AlkOH means a mono- or polyhydroxyalkyl group) is reacted with an acylating agent to acylate both the primary amino group and the hydroxyl group

or groups, followed by hydrolysis of the ester group or

- the groups that are formed, e.g. under basic conditions, to give a monohydroxyalkyl compound of the general formula

(where Ac 1 , Ac 2 and AlkOH have the above meanings).

The acylating agent can e.g. be an acid anhydride which can also serve as a solvent) together with catalytic amounts of a mineral acid, e.g. sulfuric acid or perchloric acid, or an acid halide, preferably in a polar solvent such as dimethylformamide or dimethylacetamide, acid halides being preferred because smaller amounts of v by-products are then formed. The basic hydrolysis of the O-acyl group can e.g. is carried out using aqueous alkali metal hydroxide, e.g. sodium hydroxide, the reaction preferably being carried out at room temperature. Depending on the acylating agent used, other products may also be formed and require separation. When an acyl anhydride such as acetic anhydride is used with concentrated sulfuric acid as a catalyst, the primary amino group is often partially bis-acylated, although the bis-acylamino group is readily hydrolyzed to the acylamido under mild basic conditions, but if a substituted amide or imide solvent agent such as dimethylacetamide or dimethylformamide is present, the hydroxyl group is acylated, while the primary amino group remains unreacted. When using an acyl halide in a substituted amide or imide solvent, however, the reaction leading to the formation of the N,0-bisacyl compound will be completely dominant, and this method is preferred.

The starting material with formula III can of course be prepared by the methods a) and b) described above, using compounds where X is an amino group.

d) A further method for the preparation of N-alkylated, monohydroxy-alkyl-bisacylamido compounds comprises reaction

of a compound with the general formula

with an alkylating agent, e.g. a reactive ester of an alkanol, e.g. an alkyl chloride, -bromide, -iodide, -tosylate or -mesylate or a dialkyl sulfate, whereby a corresponding compound of formula is formed in where X is an N-alkylacylamino group.

The compounds of formula II which are used as starting materials can be prepared by usual methods which depend on the nature of the group X.

The compounds of formula II where X is NI^, a particularly important group of intermediates, can be prepared by acylation of 3-amino-4-nitro-benzoic acid, followed by reduction of the nitro group to amino, e.g. by catalytic hydrogenation, e.g. using palladium or platinum, followed by iodination, e.g. with sodium iodide chloride. Compounds of formula II in which X is N-alkylacylamido can be prepared by alkylation of 3-nitro-5-sulfaminobenzoic acid as described in our South African Patent No. 68/6797, e.g. using a reactive ester of an alkanol, preferably in the presence of an acid-binding agent, followed by acid hydrolysis of the sulfamino group to form an alkylamino group which can then be acylated as described previously, to form a 3-N-alkylacylamido-5- nitrobenzoic acid as by reduction, e.g. hydrogenation, gives the 5-amino compound. This can then be iodinated, e.g. with NaICl2 and acylated by the above method to introduce an acyl group, which may be the same or different from that already present, to form the desired 5-acylamido compound.

e) For the preparation of compounds of formula I where X is a 3 4 13 4

group CONR R and where at least one of the groups R , R and R is hydroxyalkyl, a 5-nitro-isophthalic acid ester halide can react

3 4

with ammonia or a primary or secondary amm NHR R (where R 1 and R 2 have the above meanings) to form the desired 3-carbamoyl group, followed by hydrolysis of the ester group, e.g. under basic conditions, e.g. under application of

e.g. by catalytic hydrogenation using e.g. palladium or platinum. Iodination, e.g. the use of an iodide ring agent such as NaCl 2 gives the corresponding 2,4,6-triiodobenzoic acid which can then be subjected to acylation, e.g. using an acylating agent such as an anhydride or acid halide. The product is thus a compound of formula

11 3 4

In where Ac is acyl, R is hydrogen and X is CONR R , and it is possible for a hydroxyalkyl group or even two hydroxyalkyl groups to be present in the molecule in the carbamoyl group instead of in the acetamido group by using an amine in which at least one of the groups R 3 and R 4 is hydroxyalkyl. Optionally, the product may be subjected to further hydroxyalkylation with a 3 4 hydroxylating agent, and if neither R nor R is hydroxyalkyl, such further reaction is necessary to give a compound of formula I. When one or both of the groups R 3 and 4 1

R is hydroxyalkyl, the first product where R is hydrogen can be reacted to introduce an alkyl group that does not carry any hydroxy groups.

The nitro compound which is catalytically reduced in the synthesis described above can also be prepared by reacting a half-ester of 5-nitro-isophthalic acid with the compound NHR 3 R 4 .

f) By another method for producing compounds with

3 4 3 4

formula I where X is CONR R , where R and R have the meanings given above, a half-ester of 5-nitro-isophthalic acid can be reduced to the corresponding 5-amino compound, e.g. by catalytic hydrogenation, followed by iodination as described above, to form the corresponding 2,4,6-triiodophthalic acid ester which can then be acylated to form the corresponding 5-acylamino compound. This is then converted to the ester halide, e.g. by reaction with an agent which serves to convert a carboxyl group into an acid halide group, e.g. a sulfonyl halide or phosphorus halide. The ester halide can then be reacted with the compound NHR^R<4>, followed finally by conversion of the esterified carboxyl group to carboxyl, e.g. by aminolysis. When neither of the groups r\ R<3> and R<4> is hydroxyalkyl, the product must then be reacted with a hydroxyalkylating agent to

introduce a hydroxyalkyl group in the 5-acylamino group and/or

3 4 the carbamoyl group (where one or both of the groups R and R

is hydrogen). When one or both of the groups R <3> and R <4> is hydroxyalkyl, the product can be alkylated as described above

to form the corresponding 5-N-alkyl-acylamido compound.

g) When you want R"<*>" to be an alkyl group bearing a substituent with the formula

the compound of formula II can be reacted with a bifunctional alkane derivative such as an α,tu -dihaloalkane or a bis-epoxy-alkane, e.g. 1,3-butadiene diepoxide.

The isolation of the hydroxyalkylated product from

other water-soluble products such as inorganic salts may cause difficulties. In cases where the desired product is particularly soluble, the residue from the reaction mixture can be dissolved in water and extracted, preferably several times, with phenol, e.g. 3-4 extractions with 1/10 to 1/5 volume of 90% aqueous phenol. The pooled phenolic extracts can then be re-extracted with water to remove inorganic salts, and diluted with a water-immiscible liquid such as diethyl ether. Further extraction with water extracts the desired product into the aqueous phase, which after removal of the remaining phenol can be evaporated to dryness.

The following examples shall serve to further illustrate the invention.

Descending paper chromatography was performed on Whatman

No. 1 paper in a solvent system of butanol-(1)-ethanol-concentrated ammonia-water = 4:1:2:1 (A). Thin layer chromatography was performed on silica gel "GF254" according to Stahl in a solvent system of chloroform-diethyl ether-methanol-formic acid = 55 : 25 : 10 : 10 (B). The spots were observed in ultraviolet light (Hanovia chromatolite). Infrared spectra were taken on a Perkin Eimer Model 237 in KBr Pellets. Melting points are not corrected. All temperatures are in °c.

EXAMPLE 1

3-(N-B-hydroxyethyl-propionamido)-5-(N-methyl-acetamido)-2,4,6-triiodobenzoic acid

3-(N-methyl-acetamido)-5-propionamido-2,4,6-triiodo-

benzoic acid (420 g) was dissolved in a mixture of water (800 ml)

and ION sodium hydroxide (260 mL) and heated at 70° (in the reaction flask) with stirring. Then 2-chloroethanol (88 ml) was added through a dropping funnel over one hour. When the addition was complete, the solution was heated for half an hour. After cooling, the solution was acidified with glacial acetic acid and treated with charcoal overnight. The acid was precipitated using 6N hydrochloric acid. Yield: 401 g (89%). The raw product (390 g)

was dissolved in methanol (780 ml) by addition of concentrated ammonia (50 ml). The acid was then released using 6N hydrochloric acid. This process was repeated once. This acid, which contained ammonium chloride, was dissolved in water as the sodium salt by the addition of ION sodium hydroxide, treated with charcoal overnight and precipitated using 6N hydrochloric acid. Yield: 210 g, m.p. 235 - 242°, mp.

(Found: C 25.72; H 2.69; I 54.0; N 4.08; E 679. Calculated for C^H^I^N^: C 26.26; H 2.50; I 55, 5; N 4.08; E 686).

EXAMPLE 2

a) 3-(N-methyl-propionamido)-5-nitrobenzoic acid

3-(N-methylamino)-5-nitrobenzoic acid (560 g) was dissolved

in propionic anhydride (740 ml) by heating on a steam bath. After half an hour, the solution had cooled to room temperature. After stirring overnight, the mixture was diluted with ether and filtered. Yield: 627 g (87%). After recrystallization from ethyl acetate, the product melted at 163 - 169°.

(Found: C 52.41; H 4.52; N 11.29; E 258.

Calculated for <C>11<H>12<N>2°5<:> C 52'28' H 4'8°; N H.H; E 252).

b) 3-amino-5-(N-methyl-propionamido)-benzoic acid

3-(N-methyl-propionamido)-5-nitrobenzoic acid (25.2 g) was

dissolved in hot methanol (200 ml), 5% palladium charcoal (2 g) was added, and the hot solution was hydrogenated in a low pressure hydrogenator (Parr). When the calculated amount of hydrogen was absorbed, the solution was concentrated in vacuo to 75 mL, then diluted with water (150 mL) and acidified with glacial acetic acid. Yield: 17.4 g (78%). After recrystallization from water, the product melted at 160 - 166°.

(Found: C 59.59; H 6.34; N 12.53; E 224.

Calculated for C^H^N^: C 59.43; H 6.35; N 12.60; E 222).

c) 3-amino-5-(N-methyl-propionamido)-2,4,6-triiodobenzoic acid 3-amino-5-(N-methyl-propionamido)-benzoic acid (177.6 g)

was dissolved in water (460 ml) by addition of ION sodium hydroxide (82 ml), acidified with glacial acetic acid (540 ml) and heated at 70° (in the reaction flask) with stirring. 3.44M Naicl2 (935

ml) was added through a dropping funnel over the course of one hour.

After stirring for 3 1/2 hours after the addition, the mixture was cooled and filtered. The product was suspended twice in acidified water. Yield: 238 g (50%).

d) 3-(N-8-hydroxyethyl-acetamido)-5-(N-methyl-propionamido)-2, 4, 6-triiodobenzoic acid

3-acetamido-5-(N-methyl-propionamido)-2,4,6-triiodobenzoic acid was prepared by acetylation of 3-amino-5-(N-methyl-propionamido)-2,4,6-triiodobenzoic acid with acetic anhydride with concentrated sulfuric acid as a catalyst. 3-acetamido-5-(N-B-hydroxyethyl-propionamido)-2,4,6-triiodobenzoic acid (987 g) was suspended in water (2.6 L) and dissolved by addition of ION sodium hydroxide (630 mL) and heated at 70 ° while stirring. Then 2-chloroethanol (213 ml) was added through a dropping funnel over the course of one hour. Half an hour after the addition, the solution was cooled to room temperature, acidified with glacial acetic acid and treated with charcoal overnight. After the charcoal had been filtered off, the product was precipitated by the addition of 6N hydrochloric acid. Yield: 950 g (90%). The product was dissolved in water (1.5 1)

by adding ION sodium hydroxide and charcoal-treated at approx. pH 6 overnight. Then the acid was released with the help of 6N sodium hydroxide. This process was repeated once. Yield: 890 g, m.p. 227 - 231°.

(Found: C 26.67; H 2.82; I 55.0; N 4.08;,E 697 Calculated for ci5<Hi>7<I>3<N>2°5<:> c 26<26 ; H 2.50; I 55.5; N 4.08; E 686).

EXAMPLE 3

N-(B-hydroxyethyl)-N'-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid Method 1: N-(B-hydroxyethyl)-3,5-diacetamido-2,4,6-triiodobenzoic acid (6.6 g) was dissolved in a mixture of water (20 mL) and ION sodium hydroxide (4 mL). Then the solution was cooled in ice water and dimethyl sulfate (1.9 ml) was added portionwise. One

half an hour after the addition, the reaction solution became neutral

lysed and heated on a steam bath for 15 minutes. After cooling, the mixture was acidified with 6N hydrochloric acid. Yield: 4.4 g (65%).

The paper chromatogram of the reaction solution before heating showed three spots with Rf values of 0.35, 0.48 and 0.58 in a ratio of 5:5:1 after increasing Rf values. The paper chromatogram of the heated reaction solution showed the same three spots in a ratio of approx. 3 : 7 : 1 for increasing R^ values. The paper chromatogram of the precipitated product showed

two spots with Rf values of 0.48 and 0.58 in a ratio of approx.

9 : 1 after increasing Rf values. When the precipitate was dissolved in water as an ammonium salt and the solution heated in a steam bath for 20 minutes, the spot with an Rf value of 0.35 appeared again in an amount of approx. 15%. It should be mentioned that the starting material has an R^-value of 0.35.

Method 2: N-methyl-3,5-diacetamino-2,4,6-triiodobenzoic acid (6.3 g) was dissolved in a mixture of water (10 mL) and ION sodium hydroxide (6 mL). Then 2-bromoethanol (2.1 ml) was added at room temperature. The solution was kept for five hours and then acidified with 6N hydrochloric acid. Yield: 5.6 g (82%). The paper chromatogram of the product showed a spot with an R^ value of 0.48.

The infrared spectra of the product prepared by methods 1 and 2 were identical and their spectra were identical to the infrared spectrum of N-(6-hydroxyethyl)-N'-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid, which was produced by a different method.

Method 3: 3-acetamido-5-N-methylacetamido-2,4,6-triiodobenzoic acid (1000 g, 1.59 mol) was suspended in water (2000 mL) and dissolved by adding 6.4 mol of sodium hydroxide in water ( 1300 ml).

The resulting solution was heated to 70° and 2-chloroethanol (213 mL, 3.18 mol) was added dropwise with stirring for one hour. Stirring was continued for a further 30 minutes at this temperature. The pH was then adjusted to 5.9 with 6N hydrochloric acid (240 ml) and acetic acid (20 ml), treated with charcoal (10 g) and stirred overnight. After filtration, the filtrate was brought to pH<0.5 by adding hydrochloric acid

(200ml). A white, crystalline material was precipitated. The resulting suspension was stirred for 4 hours at room temperature, filtered after standing overnight, and the solid was washed with water acidified with a few drops of hydrochloric acid.

The compound obtained weighed 1065 g (99%) after drying in vacuum at 70°, m.p. 238 - 241 (split.).

The material (1060 g) was suspended in ethanol (2000 ml) and 0.88 ammonia (130 ml) was added until pH<7. Some undissolved material was filtered off, the filtrate was stirred with charcoal (5 g) for 30 minutes, filtered and acidified to pH<0.5 by addition of hydrochloric acid (250 ml). The suspension of the white crystalline material was stirred for one hour, stood overnight and filtered. To remove any co-precipitated ammonium chloride, the material was suspended in water (1000 ml ) containing a few drops of hydrochloric acid and filtered again This material weighed 843 g (79%) after drying in vacuo at 70°, mp 241-243° (dec.).

For analysis, this material was recrystallized once from dimethylformamide/methanol/water, redissolved as the ammonium salt in methanol, precipitated by acidification and washed well with water, m.p. 241 - 243° (dec.).

(Found: C 25.14; H 2.34; I 56.44; N 4.09. Calculated for C14<H>15<I>3<N>2<0>5<:C> 25.00; H 2.25, I 56.70, N 4.17.

EXAMPLE 4

N-(2,3-dihydroxypropyl)-N'-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid

N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid (100 was suspended in methanol (160 mL) and dissolved by addition of N methanolic sodium methoxide solution (160 mL, 1 equiv). Glycide (20 mL , 2 equiv.) was added and the homogeneous solution was allowed to stand at room temperature for 2 days. The solution was concentrated in vacuo to approximately half the volume, diluted with water to the original volume and acidified with concentrated hydrochloric acid to a pH of about 0.5. After stirring overnight, the precipitated product was filtered, suspended in hydrochloric acid-acidified water (80 ml), stirred for about one hour, filtered and dried in vacuo at about 50°C. Yield: 79.8 g (72%).

The product was purified by a double precipitation using hydrochloric acid from a solution of the ammonium salt in a 1:1 mixture of ethanol/water and final crystallization from dimethylformamide/water. Melting point: 244 - 246°C.

(Found: I 52.7; N 4.10; Equiv. weight 710. Calculated for c15Hi7I3N2°6: 1 54'3; N 3' 99' Equiv. weight 702).

A semi-quantitative equivalent weight determination by periodate oxidation: 642 (shows the position of the hydroxyl groups). Paper chromatography in n-butanol:ethanol:NH 4 OH (25%) : H 2 O (4:1: 2:1). Rf value: 0.37.

3-N-(2,3-dihydroxypropyl)acetamido-2,4,6-triiodobenzoic acid and N,N<1->bis(2,3-dihydroxypropyl)-3,5-diacetamido-2,4,6-triiodobenzoic acid was produced as before. The R^ values in the above system were 0.52 and 0.20 respectively.

EXAMPLE 5

N-(2,3-dihydroxypropyl)-N'-methyl-3,5-diacetaraido-2,4,6-triiodobenzoic acid via the corresponding N-allyl derivative.

1. Allylation. N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid (6.3 g) was suspended in water (15 mL), dissolved by addition of ION sodium hydroxide solution (6 mL) and the solution was heated to 50 °C before allyl bromide (4 mL) was added with stirring. Stirring was continued at 50°C until the solution became clear (about 30 minutes). The solution was cooled to room temperature and acidified with hydrochloric acid (1:1) to a pH value of approx. 0.5. The precipitated product was filtered, resuspended in water (about 50 ml) and sodium bicarbonate was added to pH

about. 7. Undissolved by-product (0.4 g) (probably ester) was filtered off, and the desired N-allyl compound was precipitated with concentrated hydrochloric acid, filtered, washed with water and dried in vacuo at approx. 60°C. Yield: 4.8 g (72%, m.p. 220 - 224°C; % I calculated 57.0; found: 55.7%. Paper chromatography in the solvent system n-butanol : ethanol : NH^OH (25 %) : 1^0 = 4:1:2:1. Rf value 0.66. 2. Oxidation. The N-allyl compound from 1. above (200 g) was suspended in water, and sodium carbonate was added to give a clear alkaline solution to which potassium permanganate solution (2.6 ml, 0.3 mmol/ml) was then added. Manganese dioxide was filtered off and the filtrate was acidified with concentrated hydrochloric acid to pH about 0.5. The precipitated product was filtered, washed with water and dried.A paper chromatogram showed about 50% of the desired dihydroxypropyl compound.

EXAMPLE 6

5-( N- B- hydroxyethyl- acetamido)- 2, 4, 6- triiodo- N- methyl- isophthalamic acid

5-acetamido-2,4,6-triiodo-N-methyl-isophthalamic acid

(122.8 g 0.2 mol) was dissolved in methanol (1200 mL) by addition of 5M sodium methoxide (160 mL; 0.8 mol). Then 2-chloroethanol (28 ml; 0.4 mol) was added with stirring. After 24 hours, 5M sodium methoxide (40 mL, 0.2 mol) and 2-chloroethanol (14 mL, 0.2 mol) were added with stirring. After 24 hours, the reaction solution was diluted with water (700 ml), neutralized with glacial acetic acid and evaporated in vacuo to approx. a third of its volume. The product was precipitated by the addition of 6N hydrochloric acid. After filtration, the product was re-dissolved in water (1.2 1) as sodium salt by adding ION sodium hydroxide and treated with charcoal overnight. The product was then precipitated using 6N hydrochloric acid. Yield: 11.5 g (87%). Sm.p. 258 - 280°

(column.).

(Found: I 57.4; E 666.

Calculated for C13<H>13I3N2O5: I 57.9; E 658). Rf value: 0.26.

EXAMPLE 7

3-acetamido-2,4,6-triiodo-(N-B-hydroxyethyl)-isophthalamic acid (a) Methoxycarbonyl-5-nitrobenzoyl chloride was prepared according to the method of Hoey et al., J.Med.Chem. 6, 24 (1963).

(b) Methyl 5-nitro-(N-B-hydroxyethyl)-isophthalate.

At 0-5°, the product from (a) above (100 g; 0.41 mol) i

over 45 minutes was added to a well-stirred solution of ethanolamine (27.5 g, 0.45 mol) and sodium bicarbonate (69.0 g,

6.82 mol) in water (580 ml). After stirring for two hours at 0 - 5°, the reaction mixture was allowed to reach room temperature. Stirring was continued for one hour. After standing overnight, the reaction mixture was filtered, the undissolved material was washed with sodium bicarbonate solution and then with water and finally dried. Yield: 88 g (80%), m.p. 124 - 129°C.

(c) 5-nitro-(N-B-hydroxyethyl)-isophthalamic acid.

Sodium carbonate (29.6 g) was added portionwise to a heated mixture of the product from (b) above (75 g) in methanol (180 ml)

and water (900 ml). After filtration and acidification with hydrochloric acid, the crude product was precipitated. The product was collected, washed and dried. Yield: 51.8 g (73%), m.p. 135 - 138°.

A sample of the crude product was crystallized from

ethanol, m.p. 169 - 170°C.

Neutralization equivalent was 256.5 (calculated 254.2).

(d) 5-amino-(N-G-hydroxyethyl)-isophthalamic acid.

The crude product from (c) above (20 g) was hydrogenated

at atmospheric pressure in methanolic solution (500 ml) with PdO/C (2 g, 10%) as catalyst. When the reaction was complete, the solid material was filtered, extracted with methanol, the extraction solution was mixed with the filtrate, and the solvent was removed under reduced pressure to give a white residue. The crude product had a melting point of 188 - 190°. The neutralization equivalent was 222 (calculated 224.2). (e) 5-amino-2,4,6-triiodo-(N-B-hydroxyethyl)-isophthalamic acid.

The product from (d) above (8 g, 0.0356 mol) was dissolved in 6N hydrochloric acid (ca. 140 mL) and diluted with water (575 mL). The solution was heated to 50° and 3.56M NaCl 2 solution (32.2 mL, 0.114 mol) was added with stirring over 20 minutes. Hydrochloric acid (20 ml) was added and the temperature raised to 85-90°. After several hours at this temperature, the reaction mixture was allowed to stand at room temperature overnight. The product was filtered, washed and dried in vacuo. Yield: 9.73 g. Found: I 62.5% (calcd. 63.2%), neutralization equivalent 600 (calcd. 601.9).

The filtrate was stirred at 90° for a total of 9 hours.

3.56M NaICl 2 solution (16.1 mL) was added during this period. A further 4.86 g of dried product could be isolated. Total yield: 14.59 g (69%). (f) 5-acetamido-2,4,6-triiodo-(N-B-hydroxyethyl)-isophthalamic acid.

To the stirred mixture of the product from (e) above (715 g, 0.0125 mol) and dimethylformamide (15 ml) was slowly added acetyl chloride (2.5 ml, 0.06 mol) at room temperature. The reaction mixture was stirred for 4 hours and allowed to stand for 60 hours. Water (5 mL) was added and the solution was evaporated in vacuo to a thick oil. The acid was dissolved as its sodium salt using water and sodium bicarbonate, and the product was precipitated by adding hydrochloric acid to a pH of approx. 1, filtered, washed and dried in vacuo. Yield: 5.8 g (72%). Found: I 58.7; N 4.29;

(calculated I 59.1; N 4.35). Neutralization equivalent 646 (calculated 644). Found: C 22.90; H 2.11; N 4.62; I 60.31 Calculated: C 22.38; H 1.72* N 4.35; In 59.12.

IN

Decomposition point: 278°C.

R^ values: Thin-layer chromatography was performed with pre-coated plates (silica gel ?254 from Merck AG).

Solvent Systems:

A: CHCl 3 : Et 2 O : MeOH : HCO 2 H =

55 : 25 : 10 : 10

R^: 0.17 (Metrizoic acid (N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid): Rf 0.50)

B: n-BuOH : HOAc : H 2 O = 100 : 22 : 50

Rf: 0.21 (Metrizoic acid: Rf 0.48)

Whatman Paper No. 1

n-BuOH : EtOH - NH 2 : H 2 O = 4:1:2:1

Rf: 0.22 (Metrizoic acid: Rf 0.46)

IR spectrum (KBr):

X -H at 3360 (sharp) and 3140 cm<-1> (broad),

X = N and 0.

-C=0 in -COOH at 1710 cm 1 , amide carbonyl at 1655 cm-"*" and amide II band at 1550 cm-"*". EXAMPLE 8 3-acetamido-5-(N-methyl-N-(B-hydroxyethyl)-carbamyl)-2,4,6-triiodobenzoic acid (a) 3-amino-5-methoxycarbonylbenzoic acid. 3-Methoxy-carboxylic-5-nitrobenzoic acid (25 g) was hydrogenated in methanol (500 mL) using palladium oxide on charcoal (2.5 g, 10%) at atmospheric pressure. When the exothermic reaction was finished, the catalyst was filtered off. After cooling the solution at -20°C for 2 1/2 hours, 12.7 g of product was isolated. A further 6.5 g was isolated by concentration of the mother liquor. The product (lOOjs g) showed only one spot (R^ 0.4) by thin-layer chromatography (silica gel, CHCl 3 : Et 2 O : MeOH : HCOOH = 55 : 25 : 10 : 10).

(b) 3-amino-5-methoxycarbonyl-2,4,6-triiodobenzoic acid. The amino compound from (a) (12.0 g) was suspended in water (280 ml), dissolved by the addition of concentrated hydrochloric acid (7.1 ml)

and glacial acetic acid (28.5 mL). At 60 - 70°C, NalCl 2 solution (73 ml, 58.7 g ICl/100 ml) was added dropwise with stirring over approx. 3 hours. The reaction mixture was heated at 80-90°C for a further 3 hours with stirring. After cooling to room temperature, the mother liquor was decanted, and the residue was

dissolved as ammonium salt in water (80 ml). The ammonium salt was precipitated by adding NH 4 Cl (2.4 g) and cooling to 0°C. The ammonium salt was filtered off and dissolved in water (140 ml) charcoal-treated twice at 80°C, and the acid was precipitated at room temperature by the addition of hydrochloric acid and was filtered off. The crude product was dissolved in ethyl acetate (100 ml) and the solution was washed 3 times with hydrochloric acid (2N). By evaporation of the solvent, 19 g of iodinated product was isolated. Thin layer chromatography on silica gel using BuOH : EtOH : H 2 O : NH 3 = 30 : 5 : 5 : 10 showed only one spot with Rf 0.35 (starting material Rf 0.27). Melting point 170 - 176°.

(c) 3-amino-5-methoxycarbonyl-2,4,6-triiodobenzoyl chloride.

A mixture of 3-amino-5-methoxycarbonyl-2,4,6-triiodobenzoic acid (198 g) and thionyl chloride (400 ml) was heated with stirring at 70°C for 16 hours. The solid material dissolved slowly. Thionyl chloride was evaporated in vacuo, the residue dissolved in chloroform (1000 ml), the solution washed with water, twice with saturated sodium bicarbonate (80 ml each time), then 5 times with 2N sodium hydroxide solution and finally with water to neutrality. The solution was dried with CaCl 2 / filtered and evaporated to dryness. The product was dried at 50° in vacuum. Yield: 203 g. Sm.p. 55 - 60°.

(d) 3-acetamido-5-methoxycarbonyl-2,4,6-triiodobenzoyl chloride.

To the acid chloride from (c) (53 g) was added acetic anhydride

(106ml). After stirring at room temperature for 20 minutes, the insoluble material was filtered off (3-4 g). To the filtrate was added concentrated sulfuric acid (0.3 ml), whereupon a yellowish product began to precipitate. The temperature reached approx. 50°. The product was isolated after overnight storage in a refrigerator. Yield: 39 g, m.p. 210 - 215°. Found: Cl: 5.48%, calculated for C1;LH7C1I3N04<:> Cl: 6.62%. (e) Methyl 5-acetamido-2,4,6-triiodo-(N-methyl-N-(6-hydroxyethyl))-isophthalate.

The acetylated product (36 g) was dissolved in a mixture of dioxane (400 ml) and dimethylformamide (20 ml). Over two hours, this solution was added dropwise to a solution of N-methylethanolamine (5.0 ml, 10% excess) and triethylamine (8.7 ml) in dioxane. Stirring was continued for 48 hours. A sticky precipitate was filtered off. The filtrate was evaporated to dryness in vacuo. The residue was triturated with aqueous sodium bicarbonate, filtered off and mixed with the first fraction. The combined solids were then suspended in aqueous sodium bicarbonate, filtered off, washed with water and dried in vacuo. Yield: 23 g, m.p. 201 - 212°. (Found: I 54.4%, calculated for ci4H15I3N2°5<: >I 56.65%). (f) 5-acetamido-2,4,6-triiodo-(N-methyl,N-(B-hydroxyethyl))-1-sophthalamic acid.

The isophthalate from (e) (21.8 g) was mixed with freshly distilled ethanolamine (4 ml) and stirred at 70° for 9 h. Excess ethanolamine was removed in vacuo at 50-60°C. The residue was dissolved in water and treated with charcoal at pH 5 - 5.5. The crude product was precipitated with hydrochloric acid (pH 0.5) and filtered after stirring for 2 hours at 0°C. 7.6 g of this acid was suspended in ethanol (13.3 ml) and dissolved by the addition of concentrated ammonia (1.54 ml). The ammonium salt began to precipitate within 30 minutes and was isolated after stirring for 2 hours. The salt was dissolved in water (30 mL), filtered, and the acid was precipitated with hydrochloric acid (pH 0.5). After stirring at 0°C for 2 hours, the product was filtered off and dried in vacuo. Yield: 5.7 g.

Found: I 55.8%, calculated for ci3Hi3N2°5<:><1> 57.86%. Neutralization equivalent 664 (theoretical 658).

5-acetamido-2,4,6-triiodo-(N,N-di-(B-hydroxyethyl))-isophthalamic acid was prepared from 3-acetamido-5-carboxymethyl-2,4,6-triiodo-benzoyl chloride by reaction with diethanolamine according to the process described above. (g) 5-(N-B-hydroxyethyl)-acetamido-2,4,6-triiodo-(N-B-hydroxyethyl)-isophthalamic acid.

5-acetamido-2,4,6-triiodo-(N-B-hydroxyethyl)-isophthalamic acid (34.0 g) was suspended in methanol (295 mL) and dissolved by addition of 3N sodium methoxide (70.5 mL). To this solution was added 2-chloroethanol (7.05 ml) and the mixture was allowed to stand at room temperature for 4 days. After neutralization, the solution was concentrated to 150 ml and acidified to a pH of approx. 0.5. After stirring at 0°C, the precipitated product was isolated by filtration (28.18 g). 10 g of this product was suspended in water (50 ml), dissolved by the addition of sodium bicarbonate (2 g), charcoal treated, filtered and acidified (pH 0.8). After stirring at 0°C, 3 g were isolated. Found: I: 54.24% (calculated 55.34%)

NE: 681 (theoretically 688). Found: C 27.34; H 2.86; N 3.67; I 54.32 Calculated for C14H15I3N206: c 24'44? H 2.20; N 4.07; In 55.34.

EXAMPLE 9

N-(3-acetamido-5-carboxy-2,4,6-triiodobenzoyl)-N-methyl-glucamine

(a) N-(3-methoxycarbonyl-5-nitrobenzoyl)-N-methylglucamine. N-methylglucamine (13.9 g) was dissolved in dimethylformamide (400 ml), and then triethylamine (7.14 g) was added. 2-Methoxycarbonyl-5-nitrobenzoyl chloride (14.4 g) dissolved in dioxane (50 ml) was added dropwise over 45 minutes with stirring. After 3 hours, the solution was evaporated to dryness in vacuo.

The residue, a yellow oil, was extracted twice with ether and then dissolved in methanol (80 mL) and water (2 mL). After storage at -20°C for 16 hours, 22.6 g (86%) was isolated. Melting point 144 - 146°C. After recrystallization from methanol/H,,0

a melting point of 158 - 164°C was obtained.

Found: C 47.91; H 5.38; N 7,12.

Calculated for c16H22<N>2°lO<:> C 47.77; H 5>51> ' N 6.97%.

(b) N-(3-amino-5-carboxybenzoyl)-N-methylglucamine.

The nitro ester (4.02 g) was suspended in water (50 mL), heated

to 60°C and, with stirring, added sodium carbonate (1.06 g) in portions during 30 minutes. Stirring was continued 10 minutes after everything had dissolved. The solution was hydrogenated at room temperature at pH 4 using Pd/C as catalyst (1-4 atmospheres are suitable). After removal of the catalyst, the solution was extracted 5 times with phenol (10 ml each time). The combined phenolic extracts were washed 3

times with water (10 ml each), then diluted with ether (150 ml) and extracted 5 times with water (10 ml each). The combined aqueous solutions were washed 3 times with ether (15

ml each) and evaporated to dryness in vacuo. The residue (0.5 g) melted at 94-97°C.

(c) N-(3-amino-5-carboxy-2,4,6-triiodobenzoyl)-N-methyl-glucamine. Nitroester (20.1 g) was hydrolyzed and hydrogenated as

described above. However, the product was not isolated.

After removal of the catalyst, the solution was charcoal treated, acidified with HCl (2N, 25 mL) and heated to 50°C. NaCl 2 solution (41 ml, 4N, 3.3 equiv) was added with stirring over a period of one hour. Stirring was continued for 3 1/2 hours, and for the last two hours the temperature was 80°C. The solution was treated with Na 2 S 2 O 4 at 50°C until maximum decolorization and extracted with phenol (1 x 100 ml + 3 x 50 ml). The phenol phase was diluted with ether (750 mL) and extracted with water (4 x 70 mL). The aqueous solution was washed with ether and evaporated to dryness. Residue: 22.6 g (61%),

sm.p. 138 - 147°c. After recrystallization from ethanol (charcoal), the white product melted at 94 - 140° (crystal ethanol). Found: 1 48.1%, calculated for c15<Hi>9<I>3<N>2<0>8-CH3CH2OH I 48.7%. (d) N-(3-carboxy-5-diacetylamino-2,4,6-triiodobenzoyl)-N-methylglucamine pentaacetate.

The amino compound (21 g) was peracetylated by suspension in acetic anhydride (63 mL) at 60°C using concentrated H 2 SO 4 (0.2 mL) as catalyst. The solution was stirred for one hour at 80° before evaporation to dryness. The residue was dissolved in ethyl acetate (200 ml), washed with water (3 x 15 ml), dried with CaCl 2 and evaporated to dryness in vacuo. Yield: 27.2 g (91%), m.p. 126 - 142°C. (e) N-(3-acetamido-5-carboxy-2,4,6-triiodobenzoyl)-N-methylglucamine.

The peracetylated compound (26.2 g) was suspended in water and dissolved by adding 2N sodium hydroxide solution dropwise until a constant pH value of 10 (60°C). At room temperature and pH 1, the solution was extracted with phenol as described above. From the final aqueous solution, 13.3 g (67%) of a light brown product was isolated by evaporation to dryness, m.p. 174 - 180°C. After recrystallization from ethanol, the melting point was 195 - 205°C.

Found: I 46.0%, calculated for C17H21I3N209.CH3CH2OH: I 46.3%.

This product was dissolved in water and treated with charcoal at 100°C. The solution was evaporated to dryness, m.p. 189 - 194°C.

Found: C 26.77; H 2.80; N 3.63; In 48.5. Calculated for C17<H>21<I>3<N>2<0g:> C 26.23; H 2.72; N 3.59; In 48.93.

According to method a-e, the corresponding glucamine derivative was also prepared.

Step a: Yield 95%, sm.p. 159 - 170°C (H2O)

Found: C 48.84; H 5.15; N 7.09.

Calculated for c15H2oN2°10<:>C 46'38; H 5'19? N 7.21.

Step (b), sm.p. 82 - 92°C.

Step (c), yield: 78%, m.p. 140 - 145°C.

Step (d), yield: 65%, m.p. 125 - 135°C.

Step(s), yield: 91% (crude); sm.p. 184 - 192°C. Found: C 24.92; H 2.57; N 3.49; In 49.4%. Calculated for c16Hi9<I>3<N>2°9<:> C 25'15; H 2.51; N 3.67; In 49.8%.

EXAMPLE 10

N-(3-Carboxy-5-N-methylacetamido-2,4,6-triiodobenzoyl)-N-methylglucamine (a) 3-Methoxycarbonyl-5-N-methylacetamido-2,4,6-triiodobenzoic acid. 3-Amino-5-methoxycarbonyl-2,4,6-triiodobenzoic acid (200 g) was acetylated with acetic anhydride (400 ml) at 70° using concentrated sulfuric acid as catalyst. Excess anhydride was distilled off, the residue suspended in water (500 ml),

and 10N sodium hydroxide solution was added until the pH became stable at 10(60°). The solution was charcoal treated at pH 7.5 at 80°, cooled to room temperature, and the product was precipitated with concentrated hydrochloric acid. Yield: 212.6 g (98%).

Sm.p. 160-168°. Found: In 61.7%; calculated for C^Hgl^NO,.:

In 62.3%. This compound (61.5 g) was N-methylated in aqueous alkaline solution with dimethyl sulfate to give 59.5 g of the desired product. Sm.p. 160 - 165°.

Found: C 23.00; H 1.97; N 2.33; In 59.6%. Calculated for C12H10I3N05: C 22.90; H 1.61; N 2.23; In 60.6%. (b) 3-Methoxycarbonyl-5-N-methylacetamido-2,4,6-triiodobenzoyl chloride.

The N-methyl derivative (48.0 g) was suspended in thionyl chloride (96 ml)

and heated at 60°C with stirring for 30 minutes after the acid had dissolved (2 1/2 hours total). Excess thionyl chloride was distilled off and the residue was crystallized from toluene. Yield: 38.9 g (78%). Sm.p. 205 - 230°. Recrystallization from toluene gave m.p. 208 - 233°. Found: Cl 5.39%; calculated for C12HgClI3N04:Cl 5.48%. (c) N-(3-methoxycarbonyl-N-methylacetamido-2,4,6-triiodo-benzoyl)-N-methyl-glucamine.

The acid chloride (22.7 g, 0.035 mol) was dissolved in dioxane (220 mL) and water (45 mL), and potassium bicarbonate (3.86 g, 0.039 mol) was added. N-methylglucamine (8.2 g, 0.042 mol) was added portionwise

show within 30 minutes. The mixture was stirred at room

temperature for 40 hours, and water (45 ml) was added after re-

stirring for 16 hours. The solution was evaporated to dryness in vacuo, the residue was dissolved in hot water (50 ml), and 14.9 g of product, m.p. 120-160°, was isolated after storage at 3°.

The mother liquor was extracted with phenol, the phenol solution was

washed with water, diluted with ether, extracted with water, the aqueous solution was washed with ether and finally evaporated to dryness in vacuo. Yield: 10.4 g, m.p. 111-140°.

Total yield: 25.3 g (89%). The product was crystallized

from water, m.p. 170-180°.

(d) N-(3-carboxy-5-N-methylacetamido-2,4,6-triiodobenzoyl)-N-

methyl-glucamine.

The ester prepared according to (c) (30 g) was aminolyzed

by addition of ethanolamine (60 ml) and heated with stirring at 70° under nitrogen for 4 hours. The ethanolamine was distilled off

dried in high vacuum, the residue was dissolved in water (200 ml) acidified to pH 1, charcoal-treated at room temperature for 1 hour and extracted with phenol (5 x 50 ml). The phenol layer was washed with water (6 x 50 ml), diluted with ether (600 ml) and extracted with water (4 x 70 ml). The resulting aqueous solution was washed with ether (2 x 30 ml), treated with charcoal at room temperature for 16 hours and evaporated to dryness. The residue (24.4 g, 83%,

sm.p. 145 - 155°) was crystallized from isopropanol/ethyl acetate,

then dissolved in water, treated with charcoal for 20 minutes at 100° and evaporated to dryness in vacuo. Sm.p. 150-170°.

Found: C 27.77; H 3.13; N 3.54; In 47.6%.

Calculated for <C>18<H>23I3<N>2°9<:> c 21>30> H 2>92' N 3.54; In 48.0%.

Claims (8)

1. Triiodobenzoic acid compounds for use in X-ray contrast agents, characterized in that they have the general formula where Ac^ is a lower alkanoyl group with 1-4 carbon atoms, R"*" is a hydrogen atom or an alkyl group with 1-6 carbon atoms which may be unsubstituted or carry one or more hydroxyl groups or groups with the formula X is a group with the formula where Ac <2> is a lower alkanoyl group with 1-4 carbon atoms which can be the same or different from Ac\ and R 2 is an alkyl group with 1-6 carbon atoms, or X is a group of the formula 3 4 where R and R , which may be the same or different, are hydrogen atoms or alkyl groups with 1-6 carbon atoms which may be unsubstituted or bear one or several hydroxyl groups, there being at least one N-hydroxyalkyl group in the molecule; and salts thereof. 2. Compound as stated in claim 1, characterized in that it is 3-(N-B-hydroxyethyl-acetamido)-5-N'-methylacetamido-2,4,6-triiodobenzoic acid. 3. Compound as stated in claim 1, characterized in that it is 3-(N-BjV-dihydroxy-propyl-acetamido)-5-N'-methylacetamido-2,4,6-triiodobenzoic acid. 4. Compound as stated in claim 1, characterized in that it is 5-(N-B-hydroxyethyl-acetamido)-2,4,6-triiodo-N-methyl-isophthalamic acid. 5. Connection as stated in claim 1, characterized in that it is 3-(N-B-hydroxyethyl-propionamido)-5-N<1->methylacetamido-2,4,6-triiodobenzoic acid. 6. Compound as stated in claim 1, characterized in that it is 3-(N-G-hydroxyethyl-acetamido)-5-N'-methyl-propionamido-2,4,6-triiodobenzoic acid. 7. Compound as stated in claim 1, characterized in that it is 3-N<1->6-hydroxyethyl-acetamido-2,4,6-triiodo-N-G-hydroxyethyl-isophthalamic acid. 8. Compound as stated in claim 1, characterized in that it is 3-acetamido-2,4,6-triiodo-N-B-hydroxyethyl-isophthalamic acid.