Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
  • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent

Definitions

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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
• 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.
• 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.
• 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:
• LD values determined by both intracerebral and intravenous injection into mice and expressed in mg. I/kg., for a number of related contrast agents.
• radiological composition containing at least one acid according to the invention or a physiologically compatible salt thereof together with a radiological carrier.
• 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.
• concentration and dosage ranges of the compounds for these three applications are as follows:
• 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.
• 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.
• 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:
• 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.
• a halide e.g. a chloride or bromide
• a hydrocarbonsulphonate e.g. 2-chloroethanol
• the reactive derivative is preferably reacted with the acylamido starting material under basic conditions, e.g.
• 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.
• an epoxide for example ethylene oxide, propylene oxide, glycide etc.
• 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.
• other products may be formed and require separation.
• 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.
• a substituted amide or imide solvent such as dirnethylacetamide or dimethylformamide
• 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.
• 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.
• 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
• 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.
• 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.
• 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.
• 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.
• 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)
• 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.
• 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.
• a bifunctional alkane derivative such as an a,w-dihalogeno alkane or a bisepoXy-alkane, e.g. 1,3-butadiene diepoxide.
• 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.
• 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.
• 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.
• 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..
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 2-chloroethanol 213 ml., 3.18 mole
• 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.).
• N-(2,3-dihydroxypropyl)-N'-methyl-3,5-diacetamido- 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%).
• 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.
• EXAMPLE 18 3-acetamido-5- N-methyl-N- fl-hydroxyethyl carbamyl)-2,4,6-triiodobenzoic acid
• 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 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.
• 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).
• N-(3-acetamido-5-carboxy-2,4,6-triiodobenzoyl)- N-methylglucamine 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.
• 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.
• 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.
• 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.
• mice The intracerbral LD in mice was 580 mg. I/kg. as compared to 400 mg. I/kg. when no calcium and magnesium were added.
• 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,
• 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,
• N-hydroxyalkyl group in the molecule; and their sodium, calcium, and mag nesium salts or their salts with ethanolamine or N- methylglucamine.
• 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,

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• 1968
  • 1968-06-10 GB GB27497/68A patent/GB1275745A/en not_active Expired
• 1969
  • 1969-06-06 DE DE19691928838 patent/DE1928838A1/de active Pending
  • 1969-06-09 CH CH579972A patent/CH545770A/xx not_active IP Right Cessation
  • 1969-06-09 SE SE6908185A patent/SE373571B/xx unknown
  • 1969-06-09 NL NL696908767A patent/NL150776B/nl not_active IP Right Cessation
  • 1969-06-09 JP JP44044699A patent/JPS4828895B1/ja active Pending
  • 1969-06-09 DK DK309869AA patent/DK127105B/da not_active IP Right Cessation
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