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
• • 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
  • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
• • 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
  • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
  • A61K49/0452—Solutions, e.g. for injection
• • 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
  • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
  • A61K49/0461—Dispersions, colloids, emulsions or suspensions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides

Definitions

• the primary object of the invention is the provision of contrast media which are better tolerated than known iodine bearing contrast media.
• the invention aims at providing radioopaque substances which do not tend to be bound to protein in the body, and which are well tolerated for this reason.
• Another object is the provision of radioopaque substances which are rapidly excreted by the urinary tract.
• the compounds of the invention which achieve the afore-mentioned objects have the formula (IJOOX R-NH(
• R and R may be identical, or they may be different lower alkanoyl radicals.
• the alkali metal salts of the triiodobenzoic acid derivatives of the invention have very high solubility in water, and salts of certain organic bases are even more soluble.
• the readily water soluble salts of the invention are therefore suitable for urography or angiography, including the preparation of cerebral angiograms.
• Other body cavities which are more accessible from the outside than the kidneys or the blood vessels may be instilled with suspensions of the water insoluble esters of the invention.
• Formulations based on water insoluble radioopaque compounds of the invention may thus be employed forsalpingography, and particularly for bronchography:
• the radioopaque compounds of the invention are distinguished by their chemical inertness which makes them stable, and causes them to be well tolerated by-living organisms. Even when employed intravenously in high dos- 3,360,436 Patented Dec. 26, 1967 ages, the radioopaque compounds of the invention do not lower the blood pressure, but produce a slight rise in blood pressure. The danger of circulatory collapse, always present in intravenous application of contrast media, is thus significantly reduced. The compounds of the invention have not been found to have the unfavorable effects on breathing observed with some clinically useful contrast media.
• the intracerebral toxicity of the compounds of the invention is particularly low, and this property makes them eminently suitable for cerebral angiography.
• the compound-s, when applied by intravenous injection as is customary in urography and angiography, are practically completely excreted in a very short period.
• the following table shows a comparison of test results obtained with 3acetylaminomethyl-5-acetylamino-2,4,6- triiodobenzoic acid, a typical compound of this invention, and with 3,5-diacetylamino-2,4,6-triiodobenzoic acid which is a well known and clinically proved radioopaque material.
• the two compounds differ by a CH radical which in the compound of the invention is interposed between the benzene nucleus and a nitrogen atom. The compounds, therefore, are not members of the same homologous series.
• the invention 1s also concerned with methods of preparing the novel triiodobenzoic acid derivatives of the invention. There is no known sequence of steps for synthesizing the compounds. We have developed methods 3 which permit the radioopaque compounds of the invention to be produced in relatively few steps, and with good overall yields.
• the starting material for the method of the invention is a compound of the formula C O OH (II) wherein Y and Y are hydrogen or a substituent which is readily exchanged against hydrogen, such as halogen, and more specifically chlorine.
• the compound of Formula II is reacted in the presence of a strong acid with an N-hydroxymethyl-acylamide to form the compound Monoand dichloroacetyl radicals are preferred acyl radicals, but it will be appreciated that the chemical nature of the acyl radical introduced with the N-hydroxymethylacylamide and subsequently removed by hydrolysis is not critical.
• Nitration of the compound (IV) yields NH2-CHz N02 which is then acylated by means of a compound R-Z wherein R represents a lower alkanoyl radical as in Formula I, and Z is a radical capable of reacting with a hydrogen atom of the amino radical in Formula V. Oxygen or halogen are typical representatives of Z.
• the acylation product has the formula and is hydrogenated, for example, by molecular hydrogen in the presence of a catalyst, to produce the compound R-NII-CH N H:
• Y or Y are halogen, they may be simultaneously exchanged for hydrogen in the hydrogenation step, and chlorine should be so exchanged. If Y or Y is iodine, the hydrogenation may readily be controlled to avoid removal of iodine.
• sequence of the steps outlined above may be altered to some extent.
• sequence of steps leading from compound (V) to compound (IX) may be rearranged in many ways.
• the two acylating steps may be combined as a terminal operation, whereby R and R become identical. If the acyl radical of the N-hydroxymethyl-acylamide is R, the hydrolysis reaction leading to compound (IV) and the subsequent acylation leading from compound (V) to compound (VI) are unnecessary. If RZ is employed in excess in the last step of the sequence of reactions outlined above in more detail, R may be replaced by R in the following sequence of reactions:
• the preferred iod-ating agent of the invention is potassium iodochloride, KICL but it will be understood that iodine chlorides such as 1G1 and complex compounds thereof other than KICl may be employed as well.
• Example 1 100 grams 4-chlorobenz0ic acid and 165 grams N hydroxymethyl-dichloroacetamide were st rred consecutively at room temperature into 1,000 milliliters concentrated sulfuric acid. The mixture was left standing for six days at ambient temperature. It was then gradually adm xed with agitation to 2.5 kilograms crushed ice. A precipitate formed in the aqueous mixture. It was filtered off with suction, washed with water, dissolved in sodium 'bicar bonate solution, and precipitated from the latter with hydrochloric acid.
• the purified precipitate weighed 163 grams (80 percent of theoretical yield). It was recrystallized from 50 percent ethanol and identified as 3-dichloroacetyla ninomethyl-4-chlorobenzoic acid having a melting point of 190 C. to 191 C. The equivalent weight was determined experimentally to be 295.2 in close approximation to the theoretical value of 296.45.
• the hydrochloride was suspended in 1,800 milliliters water. The suspension was heated to 55 -60 C., whereby the solid material was dissolved. When a solution of 31.5 grams sodium hydroxide in 180 milliliters water was added, the free 3-aminomethyl-4echlorobenzoic acid was precipitated in the form of white crystals. A small amount of acetic acid was added to the reaction mixture, whereupon the crystals were filtered oil with suction and dried. M.P. 288290 C. Yield 133 grains (90%).
• a nitrating acid was prepared by dropwise addition of 28.6 milliliters nitric (sp. gr. 1.52) to 240 milliliters sulfuric acid monohydrate at to 5 C. 64 grams 3-aminomethyl-4-chlorobenzoic acid were added in small batches to the nitrating acid the temperature of which was kept at 45 to 50 C. The mixture was held at 50 to 55 C. for three hours, and was then carefully poured over 1.5 kilograms ice. The precipitate formed in the aqueous system was filtered off with suction, and dissolved in a mixture of 70 milliliters concentrated sodium hydroxide solution and 500 milliliters water.
• the catalyst was removed by filtration.
• the filtrate was diluted to about 18 liters, and was acidified with 15 milliliters concentrated hydrochloric acid. With vigorous stirring, 1152 milliliters N KICl solution were run into the diluted filtrate over a period of about 20 to 30 minutes.
• a solid precipitate was formed, and Was filtered off after about six hours.
• the solid material was washed with water, with sodium bisulfite solution, and again with water. It was dissolved in aqueous ammonium hydroxide solution, the solution was filtered, and the filtrate was acidified with concentrated hydrochloric acid containing a small amount .of sodium bisulfite. After a short time, the precipitate formed was filtered with suction, washed with water, and dried.
• the reaction mixture was then evaporated to dryness in a vacuum at a temperature not exceeding 50 C.
• the residue was treated with a mixture of 30 milliliters concentrated aqueous ammonium hydroxide and 40 milliliters water, whereby the solid material dissolved with spontaneous heating.
• the ammonium salt of the acetylated product started precipitating.
• the precipitate and residual liquid were cooled externally with ice after about 15 minutes.
• the salt was separated from the liquid by filtration with suction, and was washed with ice cold saturated ainmonium chloride solution.
• the salt was dissolved in 300 milliliters water, and insoluble matter was removed from the solution by filtration.
• the free acid was precipitated from the filtrate at 50 to 60 C. by the addition of 40 milliliters 1:1 hydrochloric acid.
• the precipitate was filtered oif after a few hours, washed with water, and dried.
• the equivalent weight of this practically pure acid was found to be 631 as compared to the calculated value of 627.96.
• 3-acetylaminomethyl 5 acetylamino 2,4,6 triiodobenzoic acid is only sparingly soluble in water.
• the solubility at 22 C. is 0.3 gram per milliliters water.
• Example 2 Salts and esters of 3-acetylaminomethyl 5 acetylamino-2,4,6-triiodobenzoic acid are readily prepared by conventional methods.
• the sodium salt is obtained by dissolving the free acid in an equivalent amount of aqueous sodium hydroxide solution.
• the solubility of the salt at ambient temperature is approximately 80 grams per 100 milliliters water.
• Sterile solutions ofthe sodium salt in concentrations of 20 to 70 percent may be injected as contrast media for urography and arteriography in the conventional manner.
• the N-methylglucamine salt of 3-acetylaminomethyl- S-acetylamino 2,4,6 triiodobenzoic acid is obtained by dissolving equivalent amounts of acid and base in water.
• the N-glucosamine salt is miscible with water in almost all proportions.
• Aqueous solutions containing 90% of the salt can be prepared in the manner indicated. Injectable solutions containing about 20 to 90 percent of the salt are well suited for urography and arteriography.
• the lithium salt is prepared by reacting the free acid with the equivalent amount of lithium hydroxide.
• a lithium hydroxide solution was prepared from 4.2 grams lithium hydroxide and approximately 100 milliliters water. 62.8 grams 3-acetylaminomethyl acetylamino- 2,4,6-triiodobenzoic acid were dissolved in the aqueous lithium hydroxide solution.
• the lithium salt is freely soluble in water. It may be employed either singly or in mixture with the other salts as a contrast medium for urography, arteriography, or for visualizing other body cavities under X-rays.
• esters of lower alkanols with 3-acetylaminomethyl 5 acetylamino 2,4,6 triiodobenzoic acid The methyl ester which melts at approximately 230 C. is conveniently obtained by reacting the acid with diazomethane.
• esters of homologous alkanols may be prepared in a manner analogous to the aforedescribed preparation of the methyl ester, or by a method patterned on the following method of preparing the ethyl ester:
• Example 3 The method of Example 1 may be modified in many details as to sequence of steps, reaction conditions, and reagents without affecting the results obtained.
• the homologs of 3-acetylamidomethyl 5 acetamido 2,4,6 triiodobenzoic acid are obtained in an analogous manner by substituting equivalent amount of homologs for certain reagents as will be apparent from the following description of the preparation of 3-propionylaminomethyl-5- propionylamino-2,4,6-triiodobenzoic acid.
• the precipitate formed was filtered off, washed with dilute sodium bisulfite solution, dissolved in dilute aqueous ammonium hydroxide solution, and reprecipitated with hydrochloric acid.
• the 3 propionylaminomethyl-S-amino 2,4,6 triiodobenzoic acid was filtered from the mother liquor with suction, washed with water and dried. It weighed 91 grams (76% yield), melted at 230 C. with decomposition, and had an equivalent weight of 599 (calculated 599.97).
• the acid was dissolved in a mixture of 84 milliliters N sodium hydroxide solution and milliliters water, and the alkaline solution was kept at 60 C. for six hours with stirring. It was then acidified to precipitate 3-propionylaminomethyl 5-propionylamino-2,4,6-triiodoberlz0ic acid. The latter acid was isolated by filtration, washed, and dried. As recovered, it weighed 24 grams and had a melting point of 183-185 C. After recrystallization from 95% ethanol, the pure acid was obtained and had a melting point of 234-235 C. The equivalent weight found by titration was 658 (calculated 656.04).
• the acid is only sparingly soluble in water, but it is soluble in warm methanol and ethanol. Its sodium and N-methylglucamine salts are readily soluble in water and are useful contrast media for urography, angiography, and the X-ray examination of other body cavities.
• Example 4 When 69 grams 3-aminomethyl-4-chloro-5-nitrobenzoic acid obtained as described in Example 3 were reacted with 52.5 grams butyric anhydride in the manner apparent from Examples 1 and 2, there were obtained 60 grams (0.2 mole) 3butyrylaminomethyl-4-chloro-5-nitrobenzoic acid having a melting point of 197 C. The equivalent weight was found to be 301 (calculated 300.7).
• Example 5 The same compound as in Example 4 was prepared from 3 acetylaminomethyl-5-amino-2,4,6-triiodobenzoic acid.
• the acetyl radical was replaced by a butyryl radical by treatment with butyric anhydride, and other homologs of 3-acetylaminomethyl-S-acetyl-amino-Z,4,6-triiodic acid may be prepared in an analogous manner.
• the crude product was identified as 3-butyrylaminomethyl-5-butyrylamino 2,4,6 triiodobenzoic acid having a melting point of 189 to 190 C. (decomposition).
• the equivalent weight was found as 690 (calculated 684.1).
• the acid is only sparingly soluble in water, but is soluble in lower alkanols, chloroform, and acetic acid, particularly at elevated temperature. Its sodium and N- methylglucamine salts are readily Water soluble.
• Example 6 3-acetylaminomethyl-S-acetylamino 2,4,6 triiodobenzoic acid and its homologs may also be prepared from 10 4,6-dihalobenzoic acid in the following sequence of reactions:
• a nitration mixture was prepared from 70 milliliters sulfuric acid monohydrate by dropwise addition of 8.4 milliliters fuming nitric acid (sp.gr.1.52) at 0 to 6 C. 22 grams 3-amino-methyl-4,6-dichloro-benzoic acid were added to the nitration mixture in small portions while the temperature was kept at about 40 C. After addition was completed, stirring was continued for about three hours at 50 C. The reaction mixture was cooled and then poured over 500 grams ice. A precipitate of fine particles formed in the aqueous medium. It was filtered off with suction, and was dissolved without drying in a mixture of 45 milliliters concentrated sodium hydroxide solution and milliliters water.
• the alkaline solution was heated to 40 C., and 11 milliliters acetic anhydride were added.
• the mixture obtained spontaneously heated to 50 C. It was stirred for three hours. It was then acidified with hydrochloric acid, whereby 3-acetylaminomethyl-4,6-dichloro-5-nitrobenzoic acid was precipitated.
• the acid was recovered by filtration, and purified by dissolutron in aqueous sodium hydroxide solution and precipitation by hydrochloric acid.
• the purified acid had a meltmg point of 239 C. which was raised to 240 C. by recrystallization from 50% aqueous ethanol. The yield was 27.1 grams (88.5%).
• benzoic acid may also be prepared by a sequence of reactrons starting with unsubstituted benzoic acid.
• the solids retained on the filter weighed 34 grams after drying, and consisted of 3-acetylaminomethyl-5-nitrobenzoic acid having a melting point of 266-268" C.
• the mother liquor mainly contained 3-acetylaminomethylnitrobenzoic acid.
• Example 8 4-iodobenzoic acid is a suitable starting material for the synthesis of 3-acetylaminomethyl-5-acetylamino-2,4,6- triiodobenzoic acid and of its homologs.
• HCl addition compound of 3-aininomethyl-4-iodobenzoic acid was obtained in a yield of 30 grams from 38.3 grams 3'dichloroacetylaminomethyl-4-iodobenzoic acid by refluxing in a mixture of water, hydrochloric and acetic acid in a manner analogous to Example 1 yield).
• the free acid was obtained in a yield of practically by reaction of the addition compound with sodium hydroxide in water, and precipitation by acetic acid. It had a melting point of 282283 C.
• Example 9 81.7 grams of the monomethyl ester of S-nitroisophthalic acid (3-methylcarboxy-5-nitrobenzoic acid) were heated :barely to boiling temperature in a large excess of thionyl chloride for one hour. The excess of thionyl chloride was then removed by distillation, and the residue was recrystallized from hexane. 84.5 grams 3-methylcarboxy-S-nitrobenzyl chloride were obtained (93.5% yield).
• One gram-atom magnesium chips was refluxed for six hours with agitation in a mixture of 230 milliliters absolute ethanol and 6.2 milliliters carbon tetrachloride.
• the resulting magnesium ethylate was mixed with milliliters (one mole) diethyl malonate and 228 milliliters chloroform.
• the mixture was heated to 80 C. for 2% hours.
• the solutions were then distilled off in a vacuum.
• the residue consisting essentially of was dissolved in milliliters chloroform.
• the solution was mixed under agitation with a solution of 140 grams (0.575 mole) 3-methylcarboxy-S-nitrobenzoyl chloride in 180 milliliters chloroform.
• the benzoyl chloride derivative had been prepared as described in the preceding paragraph.
• the reaction mixture was heated to 40 C. for one hour, and was then cooled to 35' C. 323 milliliters 21% sulfuric acid were admixed at this stage.
• the mixture separated into an aqueous and an organic solvent layer.
• the latter was separated from the aqueous layer, was washed with water and sodium bicarbonate solution, dried, and then evaporated to remove the organic solvents.
• An oily residue of (3-methylcarboxy-5- nitro-benzoyl) -bis (ethylcarboxy -methane was obtained. It was heated to 120-130 C. for eight hours in a mixture of 200 milliliters glacial acetic acid, 140 milliliters water, and 24 milliliters concentrated sulfuric acid. Ethyl acetate formed during the reaction and was continuously distilled off. After completion of the reaction, the residue was stirred into 100 grams ice water.
• the sodium and lithium salts of the acid are readily soluble.
• the N-methylglucamine salt and the diethanolamine salt have even greater solubility.
• the N-methylglucamine salt is miscible with water in practically all proportions.
• Example 10 35.1 grams (0.06 mole) 3-acetylaminomethyl-S-amino- 2,4,6-triiodobenzoic acid were mixed with 180 milliliters formic acid, and the mixture was heated to 50 C. 0.25 milliliter concentrated sulfuric acid were then added, and the mixture was agitated for 90 minutes while its temperature was maintained at 50 C. The reaction mixture was cooled, and a precipitate was filtered off. The precipitate was dissolved in 300 milliliters 3% aqueous sodium bicarbonate solution and the solution was filtered to remove innsolub-le material.
• the acid was further purified by conversion to the cyclohexylamine salt. 16.8 grams crude 3-acetylaminomethyl-5- formylamino-2,4,6-triiodobenz0ic acid and 3 milliliter cyclohexylamine were dissolved in 15 milliliters methanol, and the salt formed thereby was precipitated from the methanol solution with ether. It was then dissolved in water, and the aqueous solution was filtered to remove insoluble impurities. The filtrate was acidifiied to precipitate the purified acid which was filtered off nad dried.
• the purified 3-acetylaminomethyl-S-formylamino-2,4,6- triiodobenzoic acid has a melting point of 245-246 C. (decomp) and was found to have an equivalent weight of 612 (calculated 613.9).
• One gram 3-acetylaminomethyl-S-formylamino-2,4,6- triiodobenzoic acid is soluble at the boiling point in about 3 milliliters methanol, 50 milliliters ethanol, or in 15-16 milliliters dioxane.
• the acid is practically insoluable in ethyl ether.
• the sodium and N-methylglucamine salts are soluble in water to approximately grams per milliliter of solution.
• the water soluble salts of the 3-lower-alkanoylamidolower alkyl-5-lower-alkanoylamido-2,4,6-triiodenbenzoic acids of the invention are suitable for intravenous injection in aqueous solution for urography, angiography, and angiocardiography.
• the water insoluble esters may be employed in salpingography and in the X-ray investigation of other body cavities which are directly accessible from the outside for the instillation of a contrast medium.
• contrast medium formulations containing the compounds of the invention as radioopaque constituents, and adjuvants not necessarily novel in themselves, and performing known functions.
• Example 11 The following formulation of an injectable aqueous solution has been found suitable for urography:
• Example 12 The following aqueous contrast medium was found suitable for angiography and angiocardiography:
• Example 13 The solution was made up in a manner analogous to the procedure described in Example 1.
• Example 14 A colloidal suspension of a radioopaque material of the invention was made for use in bronchography and hysterosalpingography to the following formulation:
• the p-hydroxybenzoates were dissolved in the alcohol.
• the CMC was moistened with this alcoholic solution whereupon it was mixed with about 500 milliliters water.
• the mixture was heated to 6070 C. while mixing continued until a homogeneous gel free from solid particles was obtained.
• the iodobenzoic acid derivative was dissolved in 240 milliliters water at 6070 C. by means of the N-methylglucamine. The aqueous solution was filtered. The filtrate had a pH of 7.2-7.7.
• the N -bromoacetylnicotinamide was separately dissolved in about 5.5 milliliters hot water.
• the gel, the aforementioned filtrate, and the last mentioned solution were combined, and the total volume was adjusted to 1000 milliliters with the remainder of the water.
• the resulting mixture was homogenized on a colloid mill and bottled.
• the bottles and their contents were sterilized in live steam at 105 C. for 30 minutes.
• Example 15 Another colloidal suspension for use in bronchiography and hysterosalipingography was made up to the following formula:
• triiodobenzoic acid 381.4 2. N-methylglucamine 118.6 3. Cinchonine hydrochloride 1.0 4. CMC, medium viscosity 15.0 5. Methyl p-hydroxybenzoate 0.7 6. Propyl p-hydroxybenzoate 0.3 7. Ethanol, 96% 50 8. Double distilled water to make 1000 grams.
• the p-hydroxybenzoates were dissolved in the alcohol, and the CMC was moistened with the alcoholic solution. The moistened CMC was then homogenized with 300 milliliters of boiling water to produce a smooth gel.
• the triiodobenzoic acid derivative and the cinchonine hydrochloride were dissolved in 350 milliliters boiling water in the presence of the N-methylglucamate, and the solution so produced was combined with the previously mentioned gel. A uniform mixture was produced by stirring, and the volume was adjusted to 1000 milliliters wtih the balance of the water. The diluted solution was filtered and sterilized.
• Example 16 A suspension of an ester of the invention was formulated for bronchography, and for visualizing the mucous membranes of the stomach in relief:
• 6-triiodobenzoate grams 50.00 2. Pure glucose do 34.16 3. CMC, medium viscosity do 7.00 4. Tween 20 (a commercial emulsifying agent and detergent which is a sorbitan monolaurate polyoxyalkylene derivative) do 5.00 5. Methyl p-hydroxy-benzoate do 0.52 6. Propyl p-hydroxybenzoate do 0.22 7. Benzyl alcohol -do 0.25 8. 96% ethanol milliliters 4 9. Double distilled water to make 100 milliliters.
• a gel was first prepared from the CMC, the alcohol, the p-hydroxybenzoates, the glucose, and a little water.
• the Tween 20 and ultimately the triiodobenzoate derivative Were then admixed to the gel in small batches.
• the mixture obtained was diluted with water to 100 milliliters, and homogenized mechanically.
• the viscosity was adjusted to a desired value by addition of the benzyl alcohol.
• the finished suspension had a specific gravity of 1.28, and was bottled under sterile conditions.
• Examples 11 to 16 are merely illustrative of the manner in which the salts and esters of the several acids of the invention may be employed.
• the salts and lower alkyl esters of the other 3-(oc-lOW6l' alkanoylamino)-lower alkyl-S-lower alkanoylamino-2,4,6-triiodobenzoic acids with the bases mentioned in Examples 11 to 16, and the salts of other physiologically tolerated bases with the triiodobenzoic acid derivatives of the invention are employed in an analogous manner, and produce similar results.
• Suitable organic bases other than those specifically referred to hereinabove include morpholine, lysidine, and such additional alkanolamines as aminopropanediol, N-methylaminopropanediol, dipropanolamine, and aminobutanol.
• the organic base components of the radioopaque salts of the invention have merely the function of making the salt water soluble. They do not contribute to the effect produced, and are therefore not critical beyond their ability to promote solubility. They must not be toxic.
• the potassium salts are readily prepared, but they are toxic in the concentrations necessary to produce sufficient contrast for X-ray examination.
• the lithium and sodium salts thus constitute the physiologically tolerated common alkali metal salts.
• a compound of the formula CODE R-NH-OH NH-R' which comprises reacting a benzoic acid compound of the formula with an N-hydroxymethylacylamide to form the compound COOH 18 hydrolyzing the last mentioned compound until the acyl radical is replaced by hydrogen; nitrating the hydrolyzed compound to form the nitro compound acylating said nitro compound, to replace one of the hydrogen atoms in the amino radical with the radical R; hydrogenating the acylated nitro compound to reduce the nitro radical to another amino radical; iodating the hydrogenated acylated nitro compound by reacting the same with an iodating agent selected from the group consisting of iodine chloride and alkali metal iodochloride until the positions 2, 4, and 6 of the benzene ring in the benzoic acid compound are occupied by iodine; and acylating said other amino radical to replace one of the hydrogenatoms of said other amino radical with the radical R; in said formulas R and R being lower alkano
• acyl radical of said N-hydroxymethylacylamide is selected from the radicals of a group of acids consisting of monochloroacetic acid and dichloroacetic acid.
• acyl radical of said N-hydroxymethylacylamide is selected from the radicals of a group of acids consisting of monochloroacetic acid and dichloroacetic acid, and at least one of said Y and Y is chlorine and the remainder of said Y and Y is hydrogen, said chlorine being replaced by hydrogen during the hydrogenating of said acylated nitro compound.
• Alk is lower alkyl
• A is hydrogen or lower alkanoyl

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• 1962
  • 1962-11-23 CH CH1378862A patent/CH414063A/de unknown
• 1963
  • 1963-09-24 DE DE1493627A patent/DE1493627C3/de not_active Expired
  • 1963-11-06 FR FR952835A patent/FR1382277A/fr not_active Expired
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