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Publication numberUS3702866 A
Publication typeGrant
Publication dateNov 14, 1972
Filing dateJun 9, 1969
Priority dateJun 10, 1968
Also published asDE1928838A1
Publication numberUS 3702866 A, US 3702866A, US-A-3702866, US3702866 A, US3702866A
InventorsHaavaldsen Johan, Haugen Leif Gunnar, Nordal Vegard, Salvesen Sigbjorn
Original AssigneeNyegaard & Co As
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Novel 3,5 - bis-acylamido - 2,4,6-triiodobenzoic acids and 5-acylamido-2,4,6-triiodoisophthalamic acids
US 3702866 A
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United States Patent US. Cl. 260-501.11 6 Claims ABSTRACT OF THE DISCLOSURE Novel 3,S-bis-acylamido-2,4,6-triiodohenzoic acids and -acylamido-2,4,6-triiodo-isophthalarnic acids. The compounds of the present invention are useful as X-ray contrast agents.

This invention relates to novel triiodobenzoic acid derivatives of use as X-ray contrast agents, particularly in the visualisation of the cardiovascular system and the cavities containing the cerebrospinal fluid.

In the X-ray visualisation of relatively extensive regions of the human body, for example the cardio-vascular system or the cavities containing the cerebrospinal fluid, very large quantities of X-ray contrast agents have to be injected in order to provide suflicient opacity in the region concerned. Consequently, the toxicity of the contrast agent at high concentrations is of great importance. In the visualisation of the cardiovascular system a large number of compounds have been proposed as contrast agents and while many have been used successfully, their toxicity, although often very slight, does give rise to some undesirable side effects. In the visualisation of the cavities containing the cerebrospinal fluid, the compounds used in vascular visualisation are frequently far too toxic as is explained below.

The space which contains the cerebrospinal fluid consists of several different cavities associated with the central nervous system and comprises the ventricles of the brain, the cisterns and the subarachnoidal space around the brain as well as in the spinal column. The radiological examination of these cavities may be divided into three main groups; ventriculography, cisternography and myelography. Myelography, is the radiological examination of the spinal subarachnoidal space, which may be divided into two zones; the radiological examination of the lowest part of the spine is termed radiculography and examination of the remaining part is termed lumbar myelography.

The tolerance of these areas towards, for example, water soluble X-ray contrast agents, ditfers considerably and an approximate order of decreasing tolerance is radiculography, ventriculography, lumbar myelography and cisternography. These diflerent fields cannot, however, be regarded as separate areas because there exists a communication throughout the entire system making leakage from one area into adjacent areas possible. Lumbar myelography, for example, is especially demanding with regard to tolerance of the contrast medium 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 which is far more sensitive than, for example, the ventricles.

Agents for use in this field should ideally be safely usable in all areas but an ideal medium has not yet been found. Iodinated oils used as such or as aqueous emulsions, the water soluble sodium iodomethanesulphonate and gas (oxygen) are examples of media which are 3,702,866 Patented Nov. 14, 1972 commonly used. The oils have the disadvantage among others that they remain in the system without being resorbed and excreted whereas radiologists today will generally not accept contrast agents which remain in the organism for an extremely long time. Furthermore, use of these oils in myelography may give rise to aseptic meningitis which is regarded as 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 in many cases not sufiicient.

When a p;ositive contrast is required and the contrast agent cannot be allowed to remain in the system (even though mechanical removal of most of the oil is possible), the water soluble sodium iodomethanesulphonate is the principal conventional medium. This substance, however, is far from ideal; it is commonly used for radiculography but simultaneous application of an anaesthetic is necessary and its use for lumbar myelography is contraindicated.

We have now found that triiodobenzoic acids carrying in the molecule at least one grouping where R represents a hydroxyalkyl group, are generally more suitable than the corresponding compounds carrying no hydroxy-alkyl grouping for use in the visualisation of the cardio-vascular system and of the cavities containing the cerebrospinal fluid, from the point of view of tolerance by the tissues concerned and also from the point of view of water-solubility and viscosity, properties which are important in allowing very concentrated aqueous solutions to be used. The compounds 3-N-(B-hydroxyethyl)acetamido-5 acetamido-2,4,6-

triidobenzoic acid,

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

3-N- ({i-hydroxyethyl) acetamido-3,4,6-triiodobenzoic acid, and

3- (N-fl-hydroxyethylacetamido -5- N-B-hydroxyethylacetamido)-methyl-2,4,6-triiodobenzoic acid have previously been proposed as cardiovascular X-ray contrast agents but no other hydroxyalkyl triiodobenzoic acids have been described.

According to the present invention We provide 2,4,6- triiodobenzoic acids, carrying at least one group of the formula where R is a hydroxyalkyl group, there being no N-(B- hydroxyethyl)-acetamido group in the 3-position when there is a hydrogen atom or an amino, acetamido or N- (fi-hydroxyethyl)-acetamido group in the 5-position; and salts thereof.

The new compounds may largely be summarised by the following formula:

( icon x NAc where Ac is an acyl group, R is a hydrogen atom or an alkyl group which may be 3 unsubstituted or carry one or more substituents, for example, hydroxyl groups or groups of the formula C O O H N-Ae X is a hydrogen atom, an amino group, an acylaminomethyl group, a group of the formula in which Ac is an acyl group which may be the same as or different from Ac and R is a hydrogen atom or an alkyl group which may be unsubstituted or carry one or more substituents, for example, hydroxyl groups, or X is a group of the formula CON wherein R and R which may be the same or different, are hydrogen atoms or alkyl groups which may be unsubstituted or carry one or more substituents, or together with the adjacent nitrogen atom form a heterocyclic ring, there being at least one N-hydroxyalkyl group in the molecule, R having at least 3 carbon atoms when AC is an acetyl group and X is a hydrogen atom, an amino group, an acetamido group or an N-(fi-hydroxyethybacetamido group.

The salts of the new acids according to the invention are particularly useful since many of them are generally more water-soluble than the parent 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 in the purification etc. of the acids. Especially useful salts include the sodium salt, the calcium and magnesium salts and salts with alkanolamines such as ethanolamine or N-methylglucamine.

Those compounds of Formula I are particularly preferred in which R is a hydroxyalkyl group and X is an acylamino group or an N-substituted acylamino group. Another particularly useful class are those compounds of Formula I in which X is a group CONR R and at least one of R R and R is a hydroxyalkyl group.

The acyl groups Ac and AC2 are preferably lower alkanoyl groups having 1-4 carbon atoms, especially acetyl and propionyl groups.

The most preferred hydroxyalkyl group is the p-hydroxyethyl group. Other hydroxyalkyl groups of especial interest include the 2,3-dihydroxypropyl group and the 2- and 3-hydroxypropyl groups. The groups R R R and R preferably contain 1-6 carbon atoms. In general it is preferred that the total number of carbon atoms in the group Nac R is greater than 4 especially when X is an amino group or acetamido group or a hydrogen atom. Where R and R form part of a heterocyclic ring, this is preferably a 5 or 6 membered saturated ring (which may contain other hetero atoms such as oxygen) e.g. a piperidino, rnethylpiperidino, or morpholino ring.

Particularly useful compounds according to the invention include:

3-(N-fl-hydroxyethyl-acetamido)-5-N'-methylacetamido- 2,4,6-triiodobenzoic acid;

3-(N-B-y-dihydroxypropyl-acetamido)-5-N- methylacetamido-2,4,6-triiodobenzoic acid;

5-(N'-B-hydroxyethyl-acetamido)-2,4,6-triiodo-N- methylisophthalamic acid;

3-(N-;8-hydroxyethyl-propionamido)-5-N'- methylacetamido-2,4,G-triiodobenzoic acid;

3- (N-B-hydroxyethyl-acetamido -5-N'-methy1- propionamido-2,4,6-triiodobenzoic acid,

and their salts.

The following table gives LD values, determined by both intracerebral and intravenous injection into mice and expressed in mg. I/kg., for a number of related contrast agents.

ACUTE TOXICITIES IN MICE LDso intra- LDso cereintrabral, venous mg. mg Compound I/kg. I/kg.

3-(N-B-hydroxyethyl-acetamldo) -5-N -methylacetamide-2 4,6-triiodobenzoic acid 425 9, 500 3-(N-fi Y- ihydroxypropyl-acetamldo)-5-N-methylacetamido-2,4,6-triiodobenzoic acid 425 8, 300 5-(N-B-hydroxyethyl-acetamido)-2,4,6-triiodo-N- methyl-isophthalamic acid- 400 3-(N 8-11ydroxyethyl-propionamido)-5-N- methylacetamido-2,4,5-triiodob enzoic acid 345 9, 500 3-(N-B-hydroxeythyl-acetarnido) -5-N-methylropionamido-2,4-6-triiodobenzoic acid 340 3- N -fl-hydroxyethyl-aeetamido)-5-(N-B-hydroxyethyl-propionamido)-2,4,6-triio dobenzoic acid- 290 3-(N-fl-hydroxyethyl-acetamido)-5-acetamldomethyl-2,4,fi-triiodobenzoic acid- 210 Io domethanesulphonic acid 195 N-rnethyl-3,5-diacetamide-2,4,6-triiodobenzolc acid. 8, 700 5acetarnido-2,4,6-triio do-N-methylisophthalamic old 210 According to a further feature of the present invention we provide a radiological composition containing at least one acid according to the invention or a physiologically compatible salt thereof together with a radiological carrier.

The concentration of the X-ray contrast agent according to the invention in the aqueous medium for administration varies with the particular field of use. In general lower concentrations are required for ventriculography than for myelography while radiculography requires still lower concentrations. The preferred concentration and dosage ranges of the compounds for these three applications are as follows:

Concentration, mg. I/ml. Dose, ml.

Radlculography. -250 6-12 Ventriculography- 250-850 3-7 Myelography 350-450 4-9 The preferred concentration range for cardiovascular visualisation is 150-450 mg. I/ml. The quantity of contrast agent to be administered is preferably such as to stay in the system only for about 2 to 3 hours, although both shorter and longer residence periods are normally acceptable. The active material may thus be formulated for cerebrospinal visualisation conveniently in vials or ampoules containing 5 to 15 ml. of an aqueous solution thereof, but for cardiovascular visualisation larger quantities e.g. 10 to 500 ml. will be given.

In our Belgian Pat. No. 645,634 we described compositions containing sodium salts of X-ray contrast acids the toxicity of which was favourably modified by the inclusion of relatively small quantities of substances liberating calcium and/or magnesium ions. The effect was thought to be connected with the ion balance in the vascular system. We have now found that in the cerebrospinal fluid, although sodium salts of X-ray contrast acids are much more toxic by the intracerebral route than the intravenous route, these toxicities are favorably modified by inclusion of calcium and/or magnesium ions to sodium ions being similar to those observed for the vascular system.

The ratio of calcium to sodium ions is preferably at least 0.00025, advantageously at least 0.0005. Where magnesium ions are present, these are also preferably at least at the above minimum ratios. The ratio of calcium ions to sodium ions is, in fact, preferably in the range 0.005 to 0.10, while the ratio of magnesium ions to sodium ions is preferably in the range 0.002 to 0.05. It is preferred that both calcium and magnesium ions be present.

The calcium and/or magnesium ions may 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 the free state and ions bound by chelating agents, such as ethylene diamine tetracetic acid, are not effective and should not be considered in calculating the respective ion ratios. Particularly useful calcium and magnesium salts for addition to the compositions are the chlorides. Another possibility is to add to a solution of the acid, one or more bases supplying the sodium ions on the one hand and the calcium and/or magnesium ions on the other hand.

The new compounds according to the invention may be prepared in any convenient way, a number of methods being set out hereinafter:

(a) Reaction of a compound of the general formula with a hydroxyalkylating agent to produce a compound of Formula I in which R is a hydroxyalkyl group. The bydroxyalkylatin agent may, for example, be a reactive mono-ester derivative of a glycol or polyol, for example a halide, e.g. a chloride or bromide, or a hydrocarbonsulphonate. For the introduction of a hydroxyethyl group, 2-chloroethanol is one suitable reagent. The reactive derivative is preferably reacted with the acylamido starting material under basic conditions, e.g. in an aqueous alkaline medium, for example containing an alkali metal hydroxide such as sodium or potassium hydroxide or in a nonaqueous medium, e.g. in an alkanol such as methanol or ethanol, the base conveniently being an alkali metal alkoxide such as sodium methoxide. It is also possible to react the acylamido compound with an epoxide, for example ethylene oxide, propylene oxide, glycide etc., also advantageously under the same conditions as those which are used for reactive esters.

(b) Reaction of an amide of Formula II with an allylating agent, e.g. a reactive ester of an allylic alcohol, for example allyl chloride or bromide, to introduce an N- allylic grouping which is then subjected to oxidation of the double bond thereof, e.g. using a permanganate oxidising agent, to form a glycol grouping, whereby a compound of Formula I is formed in which R is a dihydroxy alkyl group.

For the production of mono-hydroxyalkyl-bisacylamido-compounds, a compound of the general formula AlkO H I III (where Ac has the above meaning and AlkOH represents a monoor polyhydroxyalkyl group) may be reacted with an acylating agent to acylate both the primary amino group and the hydroxyl group or groups, followed by hydrolysis of the ester grouping or groupings so formed, e.g. under basic conditions, to yield a mono-hydroxyalkyl compound of the general formula (where Ac AC2 and AlkOH have the above meanings).

The acylating agent may, for example, be an acid anhydride (which can also serve as solvent) together with catalytic amounts of a mineral acid, e.g. sulphuric or perchloric acid, or an acid halidepreferably in a polar solvent such as dimethylformamide or dimethylacetamide, acid halides being preferred due to smaller amounts of by-products formed. The basic hydrolysis of the O- acyl grouping may for example, be effected using aqueous alkali metal hydroxide e.g. sodium hydroxide, the reaction preferably being carried out at room temperature. In addition, depending on the acylating agent used, other products may be formed and require separation. When an acyl anhydride such as acetic anhydride is used with concentrated sulphuric acid as catalyst, the primary amino group is often, in part, bis-acylated, although the bis-acylamino group is very readily hydrolysed to acylamido under mild basic conditions, while if a substituted amide or imide solvent such as dirnethylacetamide or dimethylformamide is present the hydroxyl group is acylated while the primary amino group is left unreacted. Using an acyl halide in a substituted amide or imide solvent, however, the reaction to form the N,O-bisacyl compound is greatly predominant and this method is prefcrred.

The starting material of Formula III can be prepared, of course, by the processes (a) and (b) above, using compounds wherein X is an amino group.

(d) A further method for producing N-alkylated monohydroxyalltyl bisacylam-ido compounds comprises reaction of a compound of the general formula with an alkylating agent, e.g. a reactive ester of an alkanol, for example an alkyl chloride, bromide, iodide, tosylate or mesylate or a dialkyl sulphate, whereby a corresponding compound of Formula I is formed in which X is an N-alkylacylamino group.

The compounds of Formula 11' used as starting materials may be prepared by conventional methods which depend on the nature of the group X.

The compounds of Formula II in which X is NH a particularly important group of intermediates, may 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, for example using palladium or platinum, followed by iodination e.g. with sodium iodochloride. Compounds of Formula II in which X is N-alkyl acylamido may be prepared by alkylation of 3-nitro-5- sulphaminobenzoic acid as described in our South African Pat. No. 68/ 6,797 e.g. using a reactive ester of an alkanol, preferably in the presence of an acid binding agent, followed by acid hydrclysis of the sulphamino group to pro duce an alkylamino group which may then be acylated as described previously to form a 3-N-alkyl acylamino-- nitrobenzoic acid which on reduction, for example hydrogenation yields the S-amino compound; this can then be iodinated, e.g. with NaICl 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 S-acylamino compound.

(e) For the preparation of compounds of Formula I in which X is a group CON R R and wherein at least one of the group R R and R is hydroxyalkyl, a S-nitro-isophthalic acid ester halide may be reacted with ammonia or a primary or secondary amine NHR R (where R and R have the above meanings) to form the desired 3- carbamoyl grouping, followed by hydrolysis of the ester grouping e.g. under basic conditions, for example using aqueous alkali, and reduction of the nitro group to an amino group, e.g. by catalytic hydrogenation using, for example palladium or platinum; iodination, e.g. using an iodinating agent such as Na'ICI yields the corresponding 2,4,6-triiodobenzoic acid which may 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 I in which 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 grouping rather than in the acetamido grouping by using an amine in which at least one of R and R is hydroxyalkyl. If desired the product can be subjected to further hydroxyalkylation by reaction with a hydroxylating agent and if neither of R and R is hydroxyalkyl, such further reaction is indeed necessary to produce a compound of Formula -I. Where one or both of R and R are hydroxyalkyl, the initial product in which R is hydrogen may be reacted to introduce an alkyl group carrying no hydroxy groups.

The nitro compound which is catalytically reduced in the above synthesis may also be prepared by reaction of a half ester of S-nitro-isophthalic acid with the compound NHR R (f) In a further method for the preparation of compounds of Formula I in which X is CONR R where R and R have the above meanings, a half-ester of S-nitroisophthalic acid may 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 may then be acylated to form the corresponding S-acylamino compound; this is then converted into the ester halide, e.g. by reaction with a reagent serving to convert a carboxyl group into an acid halide group, for example a sulphonyl halide or phosphorus halide. The ester halide may then be reacted with the compound NHR R followed finally by conversion of the esterified carboxyl group into carboxyl, for example by aminolysis. Where none of R, R and R is hydroxyalkyl the product must then be reacted with a hydroxyalkylating agent to introduce a hydroxyalkyl group at the S-acylamino grouping and/or the carbamoyl group (where one or both of R and R is hydrogen). Where one or both of R and R is hydroxyalkyl, the product may be alkylated as described above to form the corresponding S-N-alkyl-acylamido-compound.

(g) Where it is intended that R should be an alkyl group carrying a substituent of formula the compound of Formula II may be reacted with a bifunctional alkane derivative such as an a,w-dihalogeno alkane or a bisepoXy-alkane, e.g. 1,3-butadiene diepoxide.

The isolation of the hydroxyalkylated product from other water-soluble products such as inorganic salts may give rise to difficulty. In cases where the desired product is especially soluble, the residue from the reaction mixture may be dissolved in water and extracted, preferably several times, with phenol, for example 3-4 extractions with A vol. of aqueous phenol. The combined phenol extracts may then be re-extracted with water to remove inorganic salts and diluted with a water-immiscible liquid such as diethylether. Further extraction with water then extracts the desired product into the aqueous phase which, after removal of residual phenol, can be evaporated to dryness.

The following examples are given by way of illustration only:

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 GF according to Stahl in a solvent system of chloroformdiethyl ether-methanol-formic acid=55 :25 :l0:l0 (B). The spots were observed in UV. light (Hannovia Chromatolite). IR spectra were recorded on a Perkin Elmer Model 237 in KBr pellets. Melting points are not corrected. All temperatures are in degrees C.

EXAMPLE 1 3-amino-5- (N-p-hydroxyethyl-acetamido -2,4,6- triiodobenzoic acid Procedure 1: 3-acetamido-5-amino-2,4,6-triiodobenzoic acid (5.72 g.) was dissolved in water (16 ml.) by adding 5 N sodium hydroxide (8 ml.). Then 2-chloroethanol (1.35 ml.) was added under vigorous stirring at room temperature. After six hours, the solution was neutralized and treated with charcoal at room temperature overnight. The charcoal was filtered ofi and the acid liberated by adding 6 N hydrochloric acid. Yield: 5.7 g. (93% Procedure 2: 3-acetamido-5-amino-2,4,6-triiodobenzoic acid (1036 g.) was suspended in water (3.1 l.) and dissolved by adding 10 N sodium hydroxide (740 ml.). The solution was heated at 70 (in the reaction flask) and 2- chloroethanol (250 ml.) added during an hour. The mixture was heated at 70 for an additional half an hour. After cooling, the solution was neutralized and stirred with charcoal overnight. The charcoal was filtered off and the acid precipitated by adding 6 N hydrochloric acid after dilution of the reaction solution with water (9 1.). Yield: 1048 g. (94%).

Procedure 3: 3-acetamido-5-amino-2,4,o-triiodobenzoic acid (57.2 g.) was dissolved in the solvent ml.) as sodium salt by adding sodium hydroxide or sodium methoxide. Then the ethylene oxide was led into the bottom of the cylindrical reaction flask through a delivery tube. Table 1 describes a number of preparations using this procedure under various conditions.

EXAMPLE 2 N-(p-hydroxyethyl)-3,5-diacetamido-2,4,6-triiodobenzoic acid Procedure 1: 3 amino 5 (N fl hydroxyethylacetamido) 2,4,6 triiodobenzoic acid (462 g.) was dissolved in a mixture of acetic anhydride (1400 ml. (and concentrated sulphuric acid (14 ml.) and heated on a steam bath for forty-five minutes. Then water (185 ml.) was added through a dropping funnel. When the anhydride was hydrolyzed, the solution was concentrated in vacuo to about half of the volume. The mixture was diluted with water (4 l.) and acidified with 6 N hydrochloric acid. The next day, the mixture was decanted and the precipitate dissolved in water (900 ml.) by adding 10 N sodium hydroxide to pH about 7. More 10 N sodium hydroxide (265 ml.) was added and the solution heated on a steam bath for forty-five minutes. After cooling, the acid was liberated by means of 6 N hydrochloric acid. Yield: 326 g. The product was dissolved in methanol (650 ml.) by heating on a steam bath. After cooling, the ammonium salt was precipitated by adding concentrated ammonia (81 ml.). The mixture was cooled down to and filtered. Yield: 138 g. The salt was suspended in water (280 ml.) and acidified with 6 N hydrochloric acid. Yield: 127 g. This procedure was repeated three times. Yield: 76 g. Then, the product was recrystallized from dioxane (charcoal). Yield: 66 g. The procedure with precipitation of the ammonium salt from methanol and liberating of the acid in aqueous solution was repeated three times. Yield: 52 g. The acid was dissolved in water as sodium salt by adding 10 N sodium hydroxide, treated with charcoal, filtered and the acid precipitated by adding 6 N hydrochloric acid. Yield: 37 g. (7%); M.P. 247-263 dec. (Found: C, 24.18; H, 2.30; I, 56.3; N, 4.36; E, 665. Calcd. for C H I N O C, 23.73; H, 1.99; I, 57.9; N, 4.26; E, 658.)

Procedure 2: 3 amino 5 (N 8 hydroxyethylacetamido) 2,4,6 triiodobenzoic acid (62 g.) was dissolved in N,N-dimethylacetamide (150 ml.) and acetyl chloride (34 ml.) added. After one hour at room temperature, the solution was diluted with water (20 ml.). Then the solution was evaporated in vacuo and the residue dissolved in water (50 ml.) by adding 10 N sodium hydroxide (10 ml. excess). The solution was heated on a steam bath for half an hour, then cooled and neutralized with glacial acetic acid. Ammonium chloride (22 g.) was added and the mixture stirred overnight. The precipitate was suspended in water (500 ml.) and the acid liberated by adding 6 N hydrochloric acid. Yield: 45 g. This acid was dissolved in methanol (90 ml) and precipitated by adding concentrated ammonia (11 ml.). The precipitate was suspended in water and the acid liberated by means of hydrochloric acid. Yield: 34 g. This procedure was repeated once. Yield: 30 g. After recrystallisation from dioxane, the acid melted at 232-263 dec. Yield: 24 g. (36%). A mixed melting point of the substances from the two procedures gave no depression. The IR spectra were identical.

TABLE 1.-N-ALKYLATION OF 3-ACETAMIDO-E-AggglgCfi-flAfl-TRIIODOBENZOIG ACID WITH ETHYLENE Solvents 01- MeOH MeOH MeOH MeOH-Hf? H20 H20 H20 Base NaOMe NaOMe NaOMe NaOH NaOH NaOH NaOH Equivalent of base 1 1 1 l 1 1 pH-12-13 Equivalent of ethylene oxide 1. 0 1. 5 2.0 2. 0 1.0 2.0 2. 5 Reaction temperature, C 20 20 20 20 20 20 2.0 Reaction time in days 2-3 3 2 1 3-4 3-4 2-3 Percent unchanged starting material 25 5 6 5 3H0 Traces The chromatograms showed small amounts of ester. EXAMPLE 3 N,N'-di (B-hydroxyethyl)-3,5-dibutyramido-2,4,6-

triiodobenzoic acid 3,5 dibutyramido 2,4,6 triiodobenzoic acid (13.4 g., 0.02 mole) was dissolved in methanol ml.) by adding 5 N sodium methoxide (16 ml., 0.08 mole). Then 2-chloroethanol (2.8 ml., 0.04 mole) was added at room temperature in one portion with vigorous stirring. After twenty-four hours 5 N sodium methoxide (8 ml., 0.04 mole) and 2-chloroethanol (2.8 ml., 0.04 mole) were added. The mixtures was stored for twenty-four hours before the latter addition was repeated. The next day the reaction mixture was diluted with water (120 ml.) and neutralized witth acetic acid and concentrated in vacuo to half the original volume. The reaction product was precipitated by adding 6 N hydrochloric acid. After filtration, the acid was redissolved in water (120 ml.) by adding 10 N sodium hydroxide and treated with charcoal at room temperature overnight. The product was liberated by means of 6 N hydrochloric acid. Yield: 12.2 g. (81% The product was redissolved in water (50 m1.) as sodium salt, treated with charcoal overnight and the acid precipitated by adding 6 N hydrochloric acid. Yield: 11 g. Melting point: 203-270 C. dec.. (Found: C, 29.63%; H, 3.38%; I, 49.2%; N, 3.86%; N.E., 771. Calcd. for C H I N O C, 30.10; H, 3.25; I, 50.21; N, 3.70; N.E., 758.)

EXAMLE 4 3-(N-fi-hydroxyethyl-acetamido)-5-propionamido-2,4,6- triiodobenzoic acid 3 amino 5 (N )8 hydroxyethyl acetamido)- 2,4,6-triiodobenzoic acid (138 g.) was dissolved in a mixture of propionic anhydride (415 ml.) and concentrated sulphuric acid (4.1 ml.) and heated on a steam bath for one hour. Then water (56 ml.) was added through a dropping funnel. The solution was concentrated in vacuo to about the half of the volume and water added to the residue until further addition gave no more precipitate and the mixture acidified with 6 N hydrochloric acid. The residue was dissolved in water (550 ml.) by adding 10 N sodium hydroxide to pH about 7, then more 10 N sodium hydroxide (138 ml.) was added and the solution heated on a steam bath for forty-five minutes. After cooling, the solution was neutralized with glacial acetic acid and treated with charcoal overnight. The charcoal was filtered oif and the acid liberated by means of 6 N hydrochloric acid. After decantation, the precipitate was dissolved in water as sodium salt and reprecipitated by means of 6 N hydrochloric acid. Yield: 87 g. This substance was recrystallized from dioxan (700 ml.). Yield: 64 g. The substance was dissolved in ethanol ml.) by adding concentrated ammonia (16 ml.) by heating on a steam bath. After cooling, the ammonium salt precipitated and was filtered. The salt was dissolved in water (340 ml.) by adding 10 N sodium hydroxide and precipitated by adding 6 N hydrochloric acid. This procedure was repeated twice. Yield: 40 g. (27%), M.P. 246-259 dec. (Found: C, 24.76; H, 2.29; I, 56.9; N, 4.22; E, 665.

11 Calcd. fol C14H15I3N205: C, 25.02, H, I, N, 4.17; E, 672.)

EXAMPLE 3-acetamidomethyl-5-(N-B-hydroxyethyl-acetamido)- 2,4,6-triiodobenzoic acid 3 acetamido 5-acetamidomethyl-2,4,6-triiodobenzoic acid (62.8 g.; 0.1 mole) was dissolved in methanol (500 ml.) by adding 5 M sodium methoxide (80 ml.; 0.4 mole). Then 2-chloro-ethanol (14 ml.; 0.2 mole) was added at room temperature under stirring. After twenty-four hours 5 H sodium methoxide (20 ml.; 0.1 mole) and 2chloro-ethanol (7 ml.; 0.1 mole) were added. After twenty-four hours the reaction mixture was diluted with water (600 ml.), neutralized with glacial acetic acid and evaporated in vacuo to about one half of its volume. The acid was liberated by adding 6 N hydrochloric acid. After stirring overnight, the product was filtered off and redissolved in water (600 ml.) as sodium salt by adding N sodium hydroxide. The solution was treated with charcoal for one day at room temperature. After filtering, the product was precipitated by adding 6 N hydrochloric acid. Yield: 59.5 g. (80% Melting point: 232-245 dec. (Found: I, 56.2; N.E., 668. Calcd. for C H I N O I, 56.7; NE, 672.)

EXAMPLE 6 3- N-fi-hydroxyethyl-propionamido -5- (N-methylacetamido) 2,4,6-triiodobenzoic acid 3 (N methyl-acetamido)-5-propionamido-2,4,6-triiodobenzoic acid (420 g.) was dissolved in a mixture of water (800 ml.) and 10 N sodium hydroxide (260 ml.) and heated at 70 (in the reaction flask) with stirring. Then 2-chloroethano1 (88 ml.) was added through a dropping funnel during one hour. When the addition was finished 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 by means of 6 N hydrochloric acid. Yield: 401 g. (89% The crude product (390 g.) was dissolved in ethanol (780 ml.) by adding concentrated ammonia (50 ml.).

Then the acid was liberated by means of 6 N hydrochloric acid. This procedure was repeated once. This acid, containing ammonium chloride, was dissolved in water as sodium salt by adding 10 N sodium hydroxide, charcoaled overnight and precipitated by adding 6 N hydrochloric acid. Yield: 210 g. M.P. 235242 dec. (Found: C, 25.72; H, 2.69; I, 54.0; N, 4.08; E, 679. Calcd. for C 'H I N O C, 26.26; H, 2.50; I, 55.5; N, 4.08; E, 686.)

EXAMPLE 7 3-(N-methyl-propionamido)-5-nitrobenzoic acid 3-(N-methylamino)-5nitrobenzoic acid (560 g.) was dissolved in propionic anhydride (740 ml.) by heating on a steam bath. After half an hour, the solution was 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. Calcd. for C H N O C, 52.28; H, 4.80; N, 11.11; E, 252.)

EXAMPLE 8 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.) added and the hot solution hydrogenated in low pressure hydrogenating apparatus (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. Calcd. for 'C H N O C, 59.43; H, 6.35; N, 12.60; E, 222.)

12. EXAMPLE 9 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 adding 10 N sodium hydroxide (82 ml.), acidified with glacial acetic acid (540 ml.) and heated at (in the reaction flask) with stirring. 3.44 M NaICI (935 ml.) was added through a dropping funnel during one hour. After heating for three and a half hours after the addition, the mixture was cooled and filtered. The product was suspended twice in acidified water. Yield: 238 g. (50%).

EXAMPLE 10 3- (N-p-hydroxyethyl-acetamido -5- (N-methyl-propionamido -2,4,6-triiodobenzoic acid 3 acetamido-S-(N-methyl-propionamido)-2,4,6-triidobenzoic acid was prepared by acetylation of 3-amino-5- (N-methyl-propionamido)-2,4,6-triiodobenzoic acid with acetic anhydride with concentrated sulphuric acid as catalyst.

3 acetamido-S-(N-p-hydroxyethyl-propionamido)-2,4, 6-triiodobenzoic acid (987 g.) was suspended in water (2.6 l.) and dissolved by adding 10 N sodium hydroxide (630 ml.) and heated at 70 with stirring. Then 2-chloroethanol (213 ml.) was added through a dropping funnel during one hour. Half an hour after the addition the solution was cooled to room temperature, acidified with glacial acetic acid and charcoaled overnight. After the charcoal was filtered ofi, the product was precipitated by adding 6 N hydrochloric acid. Yield: 950 g. The product was dissolved in water (1.5 l.) by adding 10 N sodium hydroxide, and charcoaled at about pH 6 overnight. Then the acid was liberated by means of 6 N sodium hydroxide. This procedure 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. Calcd. for C15H17I3N2O5: C, H, I, N, 4.08; E, 686.)

EXAMPLE 11 N- (fi-hydroxyethyl)-N'-methyl3,S-diacetamido- 2,4,6-triiodobenzoic acid Procedure 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 10 N sodium hydroxide (4 ml.). Then the solution was cooled in ice-water and dimethyl sulphate (1.9 ml.) added in portions. Half an hour after the addition, the reaction solution was neutralized and heated on a steam bath for fifteen minutes. After cooling, the mixture was acidified with 6 N hydrochloric acid. Yield: 4.4 g. (65%).

The paper chromatogram of the reaction solution before heating showed three spots with R values 0.35, 0.48 and 0.58 in a ratio of about 5:5 :1 in order of increasing R; values. The paper chromatogram of the heated reaction solution showed the same three spots in a ratio of about 3:7:1 in order of increasing Rf values. The paper chromatogram of the precipitated product showed two spots with R, values 0.48 and 0.58 in a ratio of about 9:1 in order of increasing R; values. When the precipitate was dissolved in water as ammonium salt and the solution heated on a steam bath for twenty minutes, the spot with R, value 0.35 re-appeared in an amount of about 15%. It may be mentioned that the starting material has R, value 0.35.

Procedure 2: N-methyl 3,5-diacetamido-2,4,6-triiodobenzoic acid (6.3 g.) was dissolved in a mixture of water (10 ml.) and 10 N 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 6 N hydrochloric acid. Yield: 5.6 g. (82%). The paper chromatogram of the product showed one spot with R, value 0.48.

The IR spectra of the product prepared by procedures 1 and 2 were identical and their spectra were identical with the IR spectrum 01: N-(B-hydroxyethyl)-N'-methyl- 3,S-diacetamido-2,4,G-triiodobenzoic acid, which was prepared by a diflerent method.

Procedue 3: 3 acetamido-5-N-methylacetarnido-2,4,6- triiodobenzoic acid (1000 g., 1.59 mole) was suspended in water (2000 ml.) and dissolved by addition of 6.4 mole of sodium hydroxide in water (1300 ml.). The resultant solution was warmed to 70 and 2-chloroethanol (213 ml., 3.18 mole) added dropwise with stirring over 1 hour. The stirring was continued for another 30 minutes at this temperature. The pH was then adjusted to 5.9 with 6 N 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 addition of hydrochloric acid (200 ml.). A white crystalline material precipitated. The resultant suspension was stirred for 4 hours at room temperature, filtered after standing overnight and the solid material washed with water which had been acidified with a few drops of hydrochloric acid. The substance weighed 1065 g. (99%) after drying in vacuo at 70. M.P. 238241 (dec.).

The material (1060 g.) was suspended in ethanol (2000 ml.) and 0.88 ammonia (130 ml.) was added until pH 7. A little undissolved material was filtered off, the filtrate 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 1 hour, stood overnight and filtered. To remove any coprecipitated ammonium chloride the material was suspended in water (1000 ml.) containing a few drops of hydrochloric acid and refiltered. This material weighed 843 g. (79%) after drying in vacuo at 70, M.P. 241243 (dec.).

For analysis this material was recrystallised once from DMF/methanol/water, redissolved as ammonium salt in methanol, precipitated by acidification and washed well with water, M.P. 241-43 (dec.). (Found: C, 25.14; H, 2,34; I, 56.44; N, 4.09. Calcd. for C H I N O c, 25.00; H, 2.25; I, 56.70; N, 4.17.)

EXAMPLE 12 N-(2,3-dihydroxypropyl)-N'-methyl-3,5-diacetamido- 2,4,6-triiodobenzoic acid N-methyl 3,5 diacetarnido-2,4,6-triiodobenzoic acid (100 g.) was suspended in methanol 160 ml.) and and dissolved by addition of N methanolic sodium methoxide solution (160 ml., 1 equiv.). Glycide ml., 2 equiv.) was added and the homogeneous solution left at room temperature for 2 days. The solution Was concentrated in vacuo to about half the volume, diluted with water to original volume and acidified with concentrated hydrochloric acid to pH about 0.5. After stirring overnight the precipitated product was filtered and suspended in hydrochloric acid acidified water (80 m1.) 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 twofold precipitation by means of hydrochloric acid from a solution of the ammonium salt in a 1:1 mixture of ethanol/water and final crystallisation from dimethylformamide/water. M.P. 244- 246" C. I, 52.7%; N, 4.10; Equiv. wt.: 710. Calcd. for C H I N O I, 54.3; N, 3.99. Equiv. wt.: 702.

A semiquantitative equivalent weight determination based on periodate oxidation: 642 (proving the positions of the hydroxyl groups). Paper chromatography in n-BuOH:NH OH (-%):H O (4:1:2:1)1. Rf value: 0.37.

3 N (23 dihydroxypropyl)acetamido-2,4,6-triiodobenzoic acid and N,N-bis(2,3 dihydroxypropyl)-3,5-diacetamido 2,4,6 triiodobenzoic acid were prepared as previously. The Rf values in the above system were 0.52 and 0.20 respectively.

14 EXAMPLE 13 N (2,3-dihydroxypropyl) -N-methyl3,5-diacetamido-2,4,

6-triiodobenzoic acid via the corresponding N-allyl derivative (1) Allylation rivative:

(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 10 N sodium hydroxide solution (6 ml.) and the solution was heated to 50 C. before allyl bromide (4 ml.) was added by stirring. The stirring was continued at 50 until the solution became clear (abt. 30 minutes). The solution was cooled to room temperature and acidified with hydrochloric acid 1:1) to a pH of about 0.5. The precipitated product was filtered, resuspended in water (about 50 ml.) and sodium bicarbonate was added to pH about 7. Undissolved byproduct (0.4 g.) (probably ester) Was filtered off and the desired N-allyl compound precipitated with concentrated hydrochloric acid, filtered, washed with Water and dried in vacuo at about 60 C. Yield: 4.8 g., 72%; M.P. 220-224 C.; percent I, calc. 57.0; found: 55.7%. Paper chromatography in the solvent system n-BuOHzEtOHzNHfiI-I (25%): H O=4:l:2:l. R; value: 0.66.

(2) Oxidation: The N-allyl compound from (1) above 200 gm.) Was suspended in water and sodium carbonate was added to give a clear alkaline soltuion to which potassium permanganate solution was then added (2.6 ml., 0.3 mmol/rnl.). 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 revealed about 50% of the desired dihydroxypropyl compound.

EXAMPLE 14 3-amino-5-N-(fl-hydroxyethyl-propionamido)-2,4,6- triiodobenzoic acid 3-amino-5-propionamido-2,4,6-triiodobenzoic acid (117 g.) was suspended in water (300 ml.) and dissolved by addition of 10 N sodium hydroxide solution ml.). 2-chloroethanol (27 ml.) was added dropwise with stirring at 70 C. in the course of 30 minutes. After stirring for altogether 1% hours, the solution was cooled to room temperature and the pH was adjusted to about 6 by the addition of concentrated hydrochloric acid. The solution was treated with charcoal (3 g. charcoal), filtered and acidified with concentrated hydrochloric acid to pH about 0.5. The precipitated product was filtered, washed With water and dried in vacuo at about 50. Yield: 117 g. (93%). M.P.: -155".

EXAMPLE 15 5- (N-B-hydroxyethyl-acetamido)-2,4,6-triiodo-N- methylisophthalamic acid 5-acetamido-2,4,6-triiodo-N-methyl-isophthalamic acid (122.8 g. 0.2 mole) was dissolved in methanol (1200 ml.) by adding 5 M sodium methoxide ml. 0.8 mole). Then 2-chloroethanol (28 ml. 0.4 mole) was added under stirring. After twenty-four hours, 5 M sodium methoxide (40 ml., 0.2 mole) and 2-cl1loroethanol (14 ml., 0.2 mole) were added under stirring.

After twenty-four hours, the reaction solution was diluted with water (700 ml.), neutralized with glacial acetic acid and evaporated in vacuo to about one third of its volume. The product was precipitated by adding 6 N hydrochloric acid. After filtration, the product was redissolved in water (1.2 l.) as sodium salt by adding 10 N sodium hydroxide and treated with charcoal overnight. Then the product was precipitated by means of 6 N hydrochloric acid. Yield: 11.5 g. (87%). Melting point: 258-280 dec. (Found: I, 57.4; E. 666. Calcd. for C H I N O I, 57.9; E. 658.) R value: 0.26.

15 EXAMPLE 16 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)-isophthalamate: At -5 the product from (a) above (100 g. 0.41 mole) was during 45 min. added to a well stirred solution of ethanolamine (27.5 g., 0.45 mole) and sodium bicarbonate (69.0 g., 0.82 mole) in water (580 ml.). After stirring for 2 hours at 05, the reaction mixture was allowed to reach room temperature. The stirring was continued for 1 hour. After standing overnight the reaction mixture was filtered, the undissolved material washed with sodium bicarbonate solution and then with water, and finally dried. Yield: 88 g. (80%), M.P. 12 4-129.

(c) 5 nitro (N-[i-hydroxyethyl)-isophthalamic acid: Sodium carbonate (29.6 g.) was added in portions 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, crude III 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. Neutralisation equivalent 256.5 (calcd. 254.2).

(d) S-amino-(N-fl-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 combined with the filtrate and the solvent removed under reduced pressure to give a white residue of 'IV. M.P. crude 188- 190. Neutralisation equivalent 222 (calcd. 224.2).

(e) 5 amino 2,4,6 triiodo-(N-fl-hydroxyethyD-isophthalamic acid: The product from (d) above (8 g., 0.0356 mole) was dissolved in 6 N hydrochloric acid (abt. 140 ml.) and diluted with water (575 ml). The solution was heated to 50 and 3.56 M NaICI -solution (32.2 ml., 0.114 mole) was added under stirring in the course of 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 left at room temperature overnight. The product was filtered,

washed and dried in vacuo. Yield: 9.73 g. Found: I 62.5% (calcd. 63.2%), Neutralisation Equivalent 600 (calcd. 601.9).

The filtrate was stirred at 90 for a total of 9 hours. 3.56 M NaICI -solution (16.1 ml.) was added during this period. Another 4.86 g. of dried product could be isolated. Total yield: 14.59 g. (69%).

(f) 5 acetamido 2,4,6 triiodo-(N-fl-hydroxyethyl)- isophthalamic acid: To the stirred mixture of the product from (e) above (715 g., 0.0125 mole) and dimethylformamide ml.) was slowly added acetylchloride (2.5 ml.) (0.06 mole) 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 by water and sodium bicarbonate and the product precipitated by the addition of hydrochloric acid to pH about 1, filtered, washed and dried in vacuo. Yield: 5.8 g. (72%). Found: I 58.7; N 4.29; (calcd. I, 59.1; N, 4.35). Neutralisation Equivalent 646 (calcd. 644). Found: C, 22.90; H, 2.11; N, 4.62; I, 60.31. Calcd. C, 22.38; H, 1.72; N, 4.35; I, 59.12.

EXAMPLE 17 N,N'-di( B-hydroxyethyl) -3-acetamido-5-propionamide-2,4,d-triiodobenzoic acid 3 acetamido-S-propionamide-2,4,6-triiodobenzoic acid (62.8 g. 0.1 mole) was dissolved in methanol (600 ml.)

16 by adding 5 N sodium methylate ml. 0.4 mole). Then 2-chloroethanol (14 ml. 0.2 mole) was added at room temperature in one portion under stirring. After twentyfour hours, 5 N sodium methylate (40 ml., 0.2 mole) and 2-chloroethanol (14 ml., 0.2 mole) were added under stirring. After twenty-four hours, the latter addition was repeated. The next day, the reaction mixture was diluted with water (600 ml.), neutralized with glacial acetic acid and concentrated in vacuo to half the original volume. The reaction product was precipitated by adding 6 N hydrochloric acid. The product was redissolved in water (600 ml.) by adding sodium hydroxide, treated with charcoal overnight, and precipitated by means of 6 N hydrochloric acid. After filtration, the latter procedure was repeated. Yield: 48 g. (67%). Melting point: 234-276 (dec). (Found: C, 26.37; H, 2.87; I, 51.4; N, 3.89; M.W. 727. Calcd. for C H I N O C, 26.83; H, 2. 67; I, 53.2; N, 3.91; M.W. 716.)

N,N-di(,B-hydroxyethyl) -3,5-dipropionamido- 2,4,6-triiodobenzoic acid 3,5-dipropionamido-2,4,6-triiodobenzoic acid (64.2 g., 0.1 mole) was hydroxyethylated and purified as described above. Yield: 52 g. (71%). M.P. 193275 dec. (Found: C, 27.17; H, 3.07; I, 50.5; N, 3.98; NE. 752. Calcd. for C H I N O :C, 27.97; H, 2.90; I, 52.1; N, 3.84 NE. 730.)

EXAMPLE 18 3-acetamido-5- N-methyl-N- fl-hydroxyethyl carbamyl)-2,4,6-triiodobenzoic acid (a) 3-amino-5-methoxycarbonylbenzoic acid: 3-methoxycarboxyl-S-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 completed the catalyst was filtered off. After cooling the solution at -20 C. for 2 /2 hours, 12.7 g. product was isolated. An additional 6.5 g. was isolated by concentrating the mother liquor.

The product ,ug.) showed one spot only (R 0.4) when chromatographed on thin layer (Silicagel,

(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 addition of concentrated hydrochloric acid (7.1 ml.) and glacial acetic acid (28.5 ml.). At 60-70 C. NaICI solution (73 ml., 58.7 g. 101/ 100 ml.) was added dropwise while stirring in the course of about 3 hours. The reaction mixture was heated at 80-90 C. for additional 3 hours while stirring. After cooling to room temperature the mother liquor was decanted and the residue dissolved as ammonium salt in water (80 ml.). The ammonium salt was precipitated by adding NHCl (2.4 g.) and cooling to 0 C. The ammonium salt was filtered off and dissolved in water ml.), charcoaled twice at 80 C. and the acid was precipitated at room temperature by addition of hydrochloric acid and was filtered ofif. The crude product was dissolved in ethyl acetate (100 ml.) and the solution was washed 3 times with hydrochloric acid (2 N). By evaporating the solvent, 19' g. iodinated product was isolated. TLC on Silica gel using showed one spot only with R; 0.35 (starting material R; 0.27). M.P. -176" (c) 3 amino-S-methoxycarbonyl-Z,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 while 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 (80 ml. each), twice with saturated sodium bicarbonate, then 5 17 times with 2 N sodium hydroxide solution and finally with water to neutral. The solution was dried with CaCl filtered and evaporated to dryness. The product was dried at 50 in vacuo. Yield: 203 g. M.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 (106 ml.). After stirring at room temperature for 20 min. then insoluble material Was filtered off (34 g.). To the filtrate was added concentrated sulphuric acid (0.3 ml.) whereby a yellowish product started to precipitate. The temperature reached about 50: The product was isolated after storing in refrigerator overnight. Yield: 39 g. M.P. 210-215. Found: Cl, 5.48%. Calcd. for C H ClI NO Cl, 6.62%.

(e) Methyl 5 acetamido 2,4,6-triiodo-(N-methyl-N- (fl-hydroxyethyl))-isophthalamate: The acetylated product (36 g.) was dissolved in a mixture of dioxan (400 ml.) and dimethylformamide (20 rnl.). In the course of 2 hours this solution was added dropwise to a solution of N-methyl-ethanolamine (5.0 ml., 10% excess) and triethylamine (8.7 ml.) in dioxan. The 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 oil and mixed with 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%. Calcd. for C14H15I3N2O'5: I,

(f) 5 acetamido 2,4,6 triiodo-(N-methyl, N-(/8- hydroxyethyl))-isophthalamic acid: The isophthalamate from (e) (21.8 g.) was mixed with fresh distilled ethanolamine (4 ml.) and stirred at 70 for 9 hours. The excess ethanolarniue was removed in vacuo at 5060 C. The residue was dissolved in water, and charcoaled at pH 5- 5.5. The crude product was precipitated with hydrochloric acid (pH 0.5) and filtered after stirring for 2 hours. at C. 7.6 g. of this acid were suspended in ethanol (13.3 ml.) and dissolved by addition of concentrated ammonia (1.54 rnl.). The ammonium salt started to precipitate in the course of about 30 min. 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 (pl-l 0.5 After stirring at 0 C. for 2 hours, the product was filtered 01f and dried in vacuo Yield: 5.7 g. Found: 1, 55.8%. Calcd. for C H N O I, 57.86%; NE. 664 (theoret. 658).

5 acetamido 2,4,6 triiodo (N,N-di-(B-hydroxyethyl))-isophthalamic acid was prepared from 3-acetamido 5 carboxymethyl 2,4,6 triiodobenzoyl chlo: ride by reaction with diethanolamine according to the procedure described above.

(g) 5 (N B hydroxyethyl) acetamido-2,4,6-triiodo (N [i hydroxyethyl)-isophthalamic acid: 5- acetamido 2,4,6 triiodo (N ,6 hydroxyethyD-isophthalamic acid (34.0 g.) was suspended in methanol (295 ml.) and dissolved by addition of 3 N sodium methoxide (70.5 rnl.). To this solution was added 2-chloroethanol (7.05 ml.) and the mixture left at room temperature for 4 days. After being neutralized the solution was concentrated to 150 ml. and acidified to pH about 0.5. After stirring at 0 C. the precipitated product was isolated by filtration (28.18 g.). g. of this product was suspended in water (50 ml.), dissolved by addition of sodium bicarbonate (2 g.), charcoaled, filtered and acidified (pH 0.8). After stirring at 0 C., 3 g. was isolated. Found I: 54.24% (Calcd. 55.34%) (NIE: 681 (theoret. 688). Found: C, 27.34; H, 2.86; N, 3.67; I, 54.32. Calcd. for C H I N 0 C, 24.44; H, 2.20; N, 4.07; I, 55.34.

EXAMPLE 19 N-(3-acetamido-5-carboxy-2,4,6-triiodobenzoyl)- N-methylglucamine (a) N-(S-methoxycarbonyl 5 nitrobenzoyl)-N-methylglucamine: N-methylglucamine (13.9 g.) was dissolved in DMF (400 ml.), then triethylamine (7.14 g.) was added. Z-methoxycarbony1-5-nitro'benzoyl chloride (14.4 g.) dissolved in dioxan (50 ml.) was added dropwise in the course of 45 min. while stirring. After 3 hours the solution was evaporated to dryness in vacuo. The residue, 8. yellow oil, was extracted twice with ether and then dissolved in methanol ml.) and water (2 rnl.). After storing at -20 C. for 16 hours, 22.6 g. (86%) were isolated. M.P. 144-146 C. Recryst. MeOH/H O: M.P. 158-164 C. Found: C, 47.91; H, 5.38; N, 7.12. Calcd. for C15H22N2O10 C, 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 by stirring added sodium carbonate (1.06 g.) in portions in the course of 30 min. The stirring was continued 10 min. after all substance was dissolved. The solution was hydrogenated at room temperature at pH 4 using Pd/C as catalyst 1-4 atm. is convenient. After removal of the catalyst the solution was extracted 5 times with phenol (10 ml. each). The combined phenol 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 solution was 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- methylglucamine: Nitro-ester (20.1 g.) was hydrolyzed and hydrogenated as described above. The product was, however, not isolated. After removal of the catalyst the solution was charcoaled, acidified with HCl (2 N, 25 ml.) and heated to 50 C. NaICI solution (41 ml., 4 N, 3.3 eqv.) was added by stirring during a period of 1 hour. The stirring was continued for 3 /2 hours, the last 2 hours the temperature was 80 C. The solution was treated with Na S O at 50 until maximum decolorization and extracted with phenol (1X m1. +3 50 rnl.). The phenol phase was diluted with ether (750 ml.) and extracted with Water (4X 70 rnl.). The aqueous solution was washed with ether and evaporated to dryness. Residue: 22.6 g. (61%), M.P. 138-147" C. After recrystallization from ethanol (charcoal) the white product melted at 94- 140 (cryst. EtOH).

Found: I, 48.1. Calcd. for C H I N O .CH CH OH:

(d) N-(3-carboxy 5 diacetylamino2,4,6-triiodobenzoyl)-N-methylglucamine pentaacetate: The amino compound (21 g.) was peracetylated by suspending it in acetic anhydride (63 ml.) at 60 using H SO eonc. (0.2) as a catalyst. The solution was stirred for 1 hour at 80 before evaporation to dryness. The residue was dissolved in ethyl acetate (200 ml.), washed with water (3X 15 ml.), dried with CaCl 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 addition of 2 N sodium hydroxide solution dropwise until pH 10 became constant (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 evaporating to dryness M.P. 174-180 C. Recryst. (EtOH) -205 Found: I, 46.0. Calcd. for C H I N O .CH CH OH: I, 46.3.

This product was dissolved in water and charcoaled at 100 C. The solution was evaporated to dryness. M.P. 189-194 C. Found: C, 26.77; H, 2.80; N, 3.63; I, 48.5; Calcd. for C H I N O C, 26.23; H, 2.72; N, 3.59; I, 48.93.

Step (a)Yie1d: 95%; M.P. 159-170" C. (H O). Found: C, 48.84; H, 5.15; N, 7.09. Calcd. for C H N O C, 46.38; H, 5.19; N, 7.21.

Step (b)-M.P. 82-92 C.

Step (c)-Yield: 78%; M.P. l40-145 C.

Step (d)Yield: 65%; M.P. 125-135 C.

Step (c)-Yield: 91% (crude); M.P. 184-192 C.

Found: C, 24.92; H, 2.57; N, 3.49; I, 49.4%; Calcd. for C H I N O C, 25.15; H, 2.51; N, 3.67; I, 49.8%.

EXAMPLE 20 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 rnethoxycarbonyl-2,4,6- triiodobenzoic acid (200 g.) was acetylated with acetic anhydride (400 ml.) at 70 using concentrated sulphuric acid as catalyst. The excess anhydride was distilled oif, the residue suspended in water (500 ml.), N sodium hydroxide solution added until the pH became stable at 10 (60). The solution was charcoaled at pH 7.5 at 80, cooled to room temperature and the product precipitated with cone. hydrochloric acid. Yield: 212.6 g. (98%). M.P. 160-168. Found: I, 61.7%. Calcd. for C H I NO I, 62.3%. This compound (61.5 g.) was N-methylated in aqueous alkaline solution with dimethyl sulphate to yield 59.5 g. of the desired product. M.P. 160-165 Found: C, 23.00; H, 1.97; N, 2.33; I, 59.6%. Calcd. for C H I NO C, 22.90; H, 1.61; N, 2.23; I, 60.6%.

(b) 3-methoxycarbonyl 5 N-methylacetamido-2,4,6- triiodobenzoyl chloride: The N-methyl derivative (48.0) was suspended in thionyl chloride (96 ml.) and heated at 60 While stirring for 30 minutes after acid was dissolved (total 2 /2 hours). Excess thionyl chloride was distilled off and the residue crystallised from toluene. Yield: 38.9 (78%). M.P. 205-230. Recryst. from toluene, M.P. 208- 233. Found: Cl, 5.39%. Calcd. for C H ClI NO Cl, 5.48%.

(c) N-(3-methoxycanbonyl-N-methylacetamido 2,4,6- triiodobenzoyl)-N-methyl-glucamine: The acid chloride (22.7 g., 0.035 mol) was dissolved in dioxan (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 in portions in the course of 30 minutes. The mixture was left while stirring at room temperature for 40 hours, (water (45 ml.) was added after stirring for 16 hours). The solution was evaporated to dryness in vacuo, the residue 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 washed with water, diluted with ether, extracted with water, the aqueous solution 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- triiodo-benzoyl)-N-methyl-glucamine: The ester prepared according to (c) (30 g.) was aminolysed by adding ethanolamine (60 ml.) and heating while stirring at 70" under nitrogen for 4 hours. The ethanolamine was distilled off under high vacuum, the residue dissolved in water (200 ml.) acidified to pH 1, charcoaled at room temperature for 1 hour and extracted with phenol (5X 50 ml.). The phenol layer was washed with water (6X 59 ml.), diluted with ether (600 ml.) and extracted with water (4X 70 ml.). The aqueous solution obtained was washed with ether (2X 30 ml.), :charcoaled at room temperature for 16 hours and evaporated to dryness. The residue (24.4 g., 83%, M.P. 145-155") was crystallised from isopropanoI/ethyl acetate, then dissolved in water, charcoaled for 20 minutes at 100 and evaporated to 20 dryness in vacuo. M.P. 150-170". Found: C, 27.77; H, 3.13; N, 3.54; I, 47.6%. Calcd. for C H I N O C, 27.30; H, 2.92; N, 3.54; I, 48.0%.

EXAMPLE 21 5-(N-B-hydroxyethyl-acetamido) 2,4,6 triiodo-N- acetamido-2,4,6-triiodobenzoic acid (36.85 g.) was suspended in water for injection (about 70 ml.) and titrated in solution by adding strong sodium hydroxide solution. Calcium disodium ethylenediamine tetraacetate (15 mg.), calcium chloride dihydrate (68 mg.) and magnesium chloride 'hexahydrate (62 mg.) were dissolved in the solution, the volume adjusted to ml., the pH adjusted to 7.4; and the solution filtered, ampouled and autoclaved at C. for 20 minutes resulting in a composition containing 200 mg. I/ml. and the ratios of calcium ions and magnesium ions to sodium ions being 0.015 and 0.006 respectively.

The intracerebral LD in mice of this solution was 625 mg. I/kg. body weight as compared to 425 I/kg. when no calcium and magnesium were added.

EXAMPLE 22 5-(N-'fl-hydroxyethyl-acetamido) 2,4,6 triiodo-N- methylisophthalamic acid (346 g.), calcium oxide (25 mg), magnesium oxide (12 mg.) and calcium disodium ethylenediamine tetracetate (15 mg.) was suspended in water for injection (about 70 ml.). The remaining acid which was not neutralized by the alkaline earth metal oxides was neutralized by addition of strong sodium hydroxide solution. The resulting solution was treated as above resulting in a composition equivalent to that described above with regard to iodine concentration and ionic ratios.

The intracerbral LD in mice was 580 mg. I/kg. as compared to 400 mg. I/kg. when no calcium and magnesium were added.

We claim:

1. A compound of the formula C O OH X N-Ac wherein:

Ac is a lower alkanoyl group having 1 to 4 carbon atoms;

R is selected from the group consisting of hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms substituted with at least one hydroxyl group;

X is selected from the group consisting of a group of the formula wherein Ac is a IOlWCI alkanoyl group having 1 to 4 carbon atoms, and

R is selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, hydroxypropyl, and dihydroxypropyl,

and a group of the formula wherein R and R are each a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, or an alkyl group having from 1 to 6 carbon atoms substituted by at least one hydroxyl group,

provided that there is at least one =N-hydroxyalkyl group in the molecule; and their sodium, calcium, and mag nesium salts or their salts with ethanolamine or N- methylglucamine.

2. The compound of claim 1 wherein R is a hydroxyalkyl group and X is the group.

3. The compound of claim 1 wherein X is the group CONR R and at least one of R R and R is a hydroxyallcyl group.

4. The compound of claim 1 in which the hydroxyalkyl group is B-hydroxyethyl.

5. A compound as claimed in claim 1 selected from the group consisting of 3-(N-fl-hydroxyethyl-acetamido)-5-N'-methylacetamido- 2,4,6-triiodobenzoic acid,

3- (N-Bgy-dihydroXypropyl-acetamido -5-N-methy1- acetamido-2,4,6-triiodobenzoic acid,

5-(N-fi-hydroxyethy1-acetamido)2,4,6-triiodo-N-methylisophthalamic acid,

3-(N-B-hydroxyethyl-propionamido)-S-N'-methylacetamide-2,4,6-triiodobenzoic acid,

22 3-(N-B-hydroxyethyl-acetamido)-5-N'-methyl-priopionamide-2,4,6-triiodobenzoic acid, and 3-acetamido-2,4,6-triiodo-N-hydroxyethyl isophthalamic acid and their sodium, calcium and magnesium salts 5 or their salts with ethanolamine or N-methylglucamine. 6. A compound as claimed in claim 1 which is selected from the group consisting of 3-acetamido-2,4,'6-triiodo-N-hydroxyethyl-isophthalamic acid and its calcium, sodium and magnesium salts or its salts with ethanolamine 10 or N-methylglucamine.

References Cited UNITED STATES PATENTS 3,076,024 1/1963 Larsen 260 618 A 3,178,473 4/1965 Holtermann et a1. 260-518 A 3,476,802 11/1969 Holtermann et a1. 260-518 A LORRAINE A. WEINBERGER, Primary Examiner 20 L. A. THAXT ON, Assistant Examiner US. Cl. X.R.

Disclaimer 3,702,866.Sigbj0m Sal'vesen, Leif Gunmen" H augen, J 07mm H acwaldsen, and

Vegomi Nm'dal, Oslo, Norway. NOVEL 3,5-BIS-ACYLAMIDO- 2,4,6-TRIIODOBENZOIC ACIDS AND 5-ACYLAMIDO-2,4,6- TRIIODOISOPHTHALAMIG ACIDS. Patent dated Nov. 14, 1972. Disclaimer filed July 9, 1974, by the assignee, Nyegaoml d2- Uo. A/S.

Hereby enters this disclaimer toall claims of said patent.

[Oficial Gazette May 27,1975]

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US3867431 *Jul 25, 1972Feb 18, 1975Bracco Ind Chimica SpaContrast agent for angiography and urography
US4069250 *Apr 12, 1976Jan 17, 1978Mallinckrodt, Inc.Substituted 2,4,6-triiodoisophthalamic acids
US4125599 *Aug 19, 1976Nov 14, 1978Mallinckrodt, Inc.2,4,6-triiodo-amido-benzoic acids
US4138589 *Jul 21, 1977Feb 6, 1979Mallinckrodt, Inc.Chemical intermediates for compounds used as x-ray contrast agents
US4160015 *Aug 28, 1978Jul 3, 1979Mallinckrodt, Inc.2,4,6-Triiodobenzoic acid derivatives and their use as x-ray contrast agents
US4584401 *Oct 20, 1983Apr 22, 1986Biophysica FoundationMethods and compositions involving polyhydroxylated polyiodo non-ionic contrast media
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US5886169 *Feb 12, 1988Mar 23, 1999Guerbet S.A.Iodinated polymers, processes for preparing them and their applications as contrast media
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WO1985001727A1 *Oct 12, 1984Apr 25, 1985Biophysica FoundationNovel synthetic methods for non-ionic radiographic contrast media
Classifications
U.S. Classification562/448, 424/9.455, 546/189, 544/165, 544/130, 546/226, 562/455, 544/86, 562/456
International ClassificationC07C67/00, C07C233/54, A61K49/04, C07C231/02, C07C231/00, C07C233/00
Cooperative ClassificationA61K49/0433
European ClassificationA61K49/04H
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