US3553259A - Contrast media for cholecystography - Google Patents

Abstract

COMPOUNDS OF THE FORMULA

1,3,5-TRI(I-),2-(HOOC-CH(-R4)-O-R3-O-),4-(R2-CO-N(-R1)-)-

BENZENE

WHEREIN R1 AND R2 ARE LOWER ALKYL, R3 IS LOWER, DIVALENT ALKYLENE, AND R4 IS LOWER ALKYL OR PHENYL, AND THEIR SALTS WITH PHYSIOLOGICALLY TOLERATED METALS AND AMINES ARE RADIOPAQUE, TEND TO ACCUMULATE IN THE GALL BLADDER OF LIVING CREATURES, AND ARE NON-TOXIC IN EFFECTIVE AMOUNTS.

Description

United States Patent 3,553,259 CONTRAST MEDIA FOR CHOLECYSTOGRAPHY Ernst Felder and David Pitre, Milan, Italy, assignors to gracco Industria Chimica, Societa per Azioni, Milan,

ta y No Drawing. Filed May 14, 1968, Ser. No. 728,894 Claims priority, application Switzerland, May 29, 1967, 7,482/67 Int. Cl. C07c 103/32 U.S. Cl. 260-519 7 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula R4 I I wherein R and R are lower alkyl, R, is lower, divalent alkylene, and R is lower alkyl or phenyl, and their salts with physiologically tolerated metals and amines are radiopaque, tend to accumulate in the gall bladder of living creatures, and are non-toxic in effective amounts.

This invention relates to iodine-bearing, radiopaque organic compounds and to the use of the compounds in contrast media for cholecystography.

Iodine-bearing organic compounds are commonly employed in radiography, particularly for visualizing the gall bladder. When the known contrast media are applied orally prior to cholecystography, they are not very readily resorbed from the intestinal tract so that the density of the contrast achieved may leave something to be desired. Known contrast media which are applied intravenously are often superior in this respect, but may lead to dangerous and even lethal accidents.

It has now been found that carboxylic acids of the formula wherein R is lower alkyl, R is lower alkyl, R is divalent, lower alkylene, and R is lower alkyl or phenyl, and their water soluble salts have a greater tendency to accumulate in the gall bladder than compounds which are closely related to them in chemical structure and compounds which were most commonly employed heretofore in clinical practice.

The preferred compound of this invention (A), a chemically very closely related, novel compound (B), three compounds (C-E) proposed heretofore for use in contrast media, but not yet in widespread clinical use, and the most widely'used contrast agent (F) for cholecystography are listed in the table below together with their toxicities in oral application (p.0s) and intravenous application (i.v.) to white mice (DL mg./kg.), the percentage of each compound which was secreted by the liver into the gall bladder with the bile, and by the kidney with urine three hours after intravenous application of 100 mg./kg. to rabbits, and the ratio of these percentage figures. The six compounds listed are identified in the table by capital letters as follows:

TABLE DLso, mgJkg. Excretion, percent Excretion ratio, Compound p.0s i.v. Bile Urine bile/urine As is evident from the table, the compound A of the invention is as well tolerated as iodopanoic acid (compound F) which is now in widespread clinical use, but compound A accumulates in the gall bladder at a much higher rate than iodopanoic acid and is similarly superior to the chemically related compounds B to E. It is therefore more effective in smaller dosages as a contrast me dium for cholecystography than the known compounds heretofore proposed for the same purpose.

When applied to dogs by mouth in amounts of 200 mg. per kg., compound A produced useful X-ray shadows of the gall bladder in four hours. The contrast reached optimal values in eight hours, and the gall bladder could still be visualized 24 hours after oral application. Compound A has also been found to be very effective in humans. Five female and three male patients were each given oral contrast media consisting of 3 g. of compound A and inert carriers. Excellent radiographs of the gall bladder were Obtained approximately 8 hours after ingestion in two of the patients and radiographs of very good contrast in five others. Only in one case was the contrast of the cholecystographs less than very good.

The homologs and analogs of compound A encompassed by the above formula are also effective and nontoxic in effective amounts. The compounds of the invention may be employed in the form of the free acids which are generally insoluble in neutral and moderately acid aqueous media, but are soluble in alkaline aqueous solutions, or in the form of the water soluble salts of physiologically tolerated metals and amines. The alkali metal salts, such as the sodium and lithium salts, the alkaline earth metal salts, such as the magnesium and calcium salts are the preferred metal salts. The amines commonly combined in pharmacy in salts with active acids are also applicable to this invention. The compounds of the invention may thus be salts of diethanolamine, N-methylglucamine or morpholine.

The contrast agents of the invention may be prepared by reacting the novel compounds of the formula HI T-CORa 7 wherein R R and R are the same as above with alkylating agents such as alkyl halides, sulfonates, or sulfates. Alternatively, 3-N-alkyl-N-acylamino-2,4,6-triiodophenols may be reacted in the presence of alkaline condensation agents with reactive derivatives of alkoxyalkanoic acids of the formula wherein X is the radical of a strong acid, such as halogen, particularly chlorine, bromine, or iodine, a sulfate radical or a sulfonate radical, such as that of an alkyl or aryl sulfonate, and R is metal or lower alkyl.

The following examples are further illustrative of the methods of preparing the compounds of the invention, and of their use.

EXAMPLE 1 30 g. ot-2-chloroethoxypropionitrile were dissolved in 30 ml. ethanol, and hydrogen chloride gas was introduced into the solution for two hours. The iminoether hydrochloride so produced was stirred into 200 g. crushed ice, and the ethyl a-2-chloroethoxypropionate formed thereby was extracted with ethyl ether and recovered by fractional distillation. B.P. 96-100 C. at 12-l4 mm. Hg. Yield 23.8 g. (57.5%)

5.6 g. a-2-chloroethoxypropionate and 14.7 g. 3-acetylamino-2,4,6-triiodophenol were refluxed in approximately 20 ml. ethanol in the presence of 0.037 mole sodium eth ylate for 40 hours. 11 g. ethyl a-2-(3'-acetylamino-2,4, 6-triiodophenoxy)-ethoxypropionate were obtained thereby, and melted at 148 l5 1 C. when recrystallized from ethanol. The sodium salt of the free acid was formed by saponifying 6.1 g. of the ethyl ester with 0.5 g. sodium hydroxide in 30 m1. methanol and 120 ml. water, and 4.95 g. a-2-(3' acetylamino 2,4,6 triiodophenoxy)- ethoxypropionic acid were precipitated from the solution of the sodium salt upon acidifying. M.P. 173 175 C.

17.85 g. a-2-(3'-acetylamino 2',4,6'-triidophenoxy)- ethoxypropionic acid (0.028 mole) were dissolved in 30 ml. 4 N aqueous potassium hydroxide solution (0.12 mole), and a mixture of 6.5 g. ethyl iodide (0.042 mole) and 3 m1. acetone was added drop by drop at 30.35 C. over a period of 20 minutes with stirring. Stirring was continued for four hours at 40 C., whereupon the reaction solution was diluted with 200 ml. water, decolorized by adding a little NaHSO and acidified with concentrated hydrochloric acid. The tacky precipitate was separated from the aqueous phase by extraction with ethyl acetate. The extract was washed with water, treated with active carbon, and evaporated to dryness.

The residue readily crystallized, and 15.8 g. Ot-2-(3 -N- ethyl-N-acetylamino 2,46 triiodophenoxy) ethoxypropionic acid were obtained. When recrystallized twice from 50% ethanol, the compound melted at 150151 C. In thin layer chromatography on silica gel GF 254 (Merck) with a 19:1 chloroform-glacial acetic acid solvent mixture, it give an R value of 0.32.

The compound was identified as C H I NO by its equivalent weight and by elementary analysis:

Calculated: Eq. wt. 673; C, 26.76%; I, 56.57%. Found: Eq. wt. 676; C, 26.85%; I, 56.65%.

The free acid is insoluble in water, only sparingly soluble in cold methanol and ethanol, moderately soluble in cold chloroform, but readily soluble in methanol, ethanol, or chloroform at the boiling temperature of the solvent.

The salts are readily prepared from stoichiometrically equivalent amounts of the acid and of the desired base in a common solvent. The sodium and N-glucamine salts form solutions which contain more than 100 g. of salt per 100 ml. of solution at 20 C.

EXAMPLE 2 18.5 g. 3-methylaminophenol, 25 ml. water, 25 ml. glacial acetic acid, and 25 ml. acetic anhydride were heated at 70 C. for two hours and the reaction mixture was then evaporated to dryness in a vacuum. The residue was taken up in ethyl ether, and the solution was permitted to crystallize. 10.7 g. 3-N-Methyl-N-acetylaminophenol of M.P. 115 C. were obtained.

5 g. 3-N-methyl-N-acetylaminophenol were dissolved in 250 ml. glacial acetic acid at 60 C., and 30 g. of a 45% solution of iodine chloride were gradually added with vigorous agitation. Stirring was then continued at the same temperature for three hours, whereupon a saturated aqueous solution of 35 g. sodium acetate was added dropwise to the reaction mixture over a period of an hour. An hour later, 600 ml. water were added.

The precipitate formed was filtered olf and washed with water containing a little sodium bisulfite. The 3-N-methyl- N-acetylamino-2,4,6-triiodophenol was purified by dissolving the phenol in aqueous sodium hydroxide solution and precipitating it with hydrochloric acid. It was ultimately recrystallized from acetic acid. Its melting point was 170-171 C. The equivalent weight agreed with the calculated value of 543.

27.1 g. 3-N-methyl-N-acetylamino-2,4,6-triiodophenol prepared as described above were reacted with 8.5 g. ethyl a-Z-chloroethoxypropionate in the presence of 0.05 mole sodium ethylate in 60 ml. ethanol for 40 hours at a boil. The ethyl ester of a-2-(3'-N-methyl-N-acetylamino-2,4, 6'-triiodophenoxy) ethoxypropionic acid was obtained in an amount of 28 g. It was saponified with sodium hydroxide in a boiling mixture of methanol and water from which the methanol was distilled off, and the free acid was precipitated by acidifying the resulting aqueous solution of the sodium salt.

The acid melted at 152154 C.

EXAMPLE 3 86.6 g. 3 propionylamino 2,4,6 triiodophenol were mixed with 32.8 g. ethyl a-2-chloroethoxypropionate and 0.176 mole sodium ethylate in 140 ml. ethanol. The mixture was refluxed for 40 hours to form 45.9 g. ethyl -a-2-(3'-propionylamino-2',4,6'-triiod0phenoxy) ethoxypropionate having a melting point of 129-130 C. and an R value of 0.60 in thin layer chromatography on silica gel with a 7 :3:2 mixture of benzene-chloroform-glacial acetic acid.

The ester was saponified by refluxing for our hour with 3.2 g. sodium hydroxide in 200 ml. ethanol and 50 ml. water. The solution of the sodium salt was diluted with 500 ml. water and acidified. The precipitated free acid was recrystallized from ethanol. It weighed 37.5 g. yield) and had a melting point of 149l5 1 C. R =0.33 (on silica gel with a 55:35:20 mixture of ethyl acetate, isopropanol, and concentrated ammonium hydroxide solution).

6.6 g. u-2-(3-propionylamino-2',4',6'-triiodophenoxy)- ethoxypropionic acid (0.01 mole) were dissolved in 12 ml. aqueous 3.33 N potassium hydroxide (0.04 mole), and a mixture of 2.35 g. ethyl iodide and 1.5 ml. acetone was added with stirring. Stirring was continued at 40 C. for three hours.

The reaction solution was diluted with 50 ml. water, extracted with ethyl ether to remove impurities, and acidified with 18% hydrochloric acid. The tacky precipitate was extracted from the reaction mixture with ethyl acetate, and the extract was washed with water and evaporated to remove the solvent. The residue was taken up in 5 ml. boiling ethyl acetate and kept in the boiling solvent for 30 minutes, whereby ct-2-(3"N-6thYl-N-PI'OPIO- nylamino-2',4',6'-triiodophenoxy) ethoxypropionic acid gradually crystallized. M.P. 1'05106 C. R =0.65 on silica gel GF 254 with a benzene-chloroform-glacial acetic acid mixture 7:3 :2. The acid is insoluble in water, but readily dissolved in lower alkanols and in chloroform.

It was identified as C H I NO by its equivalent weight and by elementary analysis:

Calculated: Eq. wt. 687; C, 27.97%; I, 55.42%. Found: Eq. wt. 686; C, 27.88%; I, 55.26%.

a-2-(3'-N-methyl-N propionylamino 2',4,6' triiodophenoxy)-ethoxypropionic acid was prepared in an analogous manner from 41-2-(3'-propionylamino-2,4,6'- triiodophenoxy) -eth0xypropionic acid and methyl iodide.

The crystalline acid obtained in a yield of 61.6% melted at l13-115 C., and gave an R value of 0.53 on silica gel GF 254 with a 7:3:2 mixture of benzene, chloroform and glacial acetic acid. It is practically insoluble in water, but very readily soluble in methanol, ethanol and chloroform. The sodium and N-glucamine salts dissolve in water at 20 C. at a rate of more than 100 g. per 100 ml. of solution.

The free acid was identified as C H I NO by its equivalent weight and by elementary analysis:

Calculated: Eq. wt. 673; C, 26.77%; I, 56.57%. Found: Eq. wt. 669; C, 26.84%; I, 56.40%.

EXAMPLE 4 8.5 g. rat-2-chloroethoxybutyronitrile (Lingo, J.A.C.S. 61 [1939] 1574) wrere dissolved in 15 ml. ethanol, and the solution was saturated with HCl gas for two hours and thereafter refluxed for four hours. The iminoether hydrochloride formed was saponified with ice water, whereby ethyl a-2-chloroethoxybutyrate was formed which was recovered by fractional distillation in a yield of 5.25 g. (45%). B.P. 104108 C. at 12 mm. Hg n =1.4400.

5 g. ethyl a-2-chloroethoxybutyrate, 12.6 g. 3-acetylamino-2,4,6-triiodophenol, and 0.026 mole sodium ethylate in about 20 ml. ethanol were kept at the boiling point of the mixture to produce 7.5 g. ethyl ot-2-(3'-acety1 amino-2,4',6' triiodophenoxy) ethoxybutyrate which, when recrystallized from ethanol, melted at 120 C. and gave an R value of 0.41 on silica gel with a 19:1 mixture of chloroform and glacial acetic acid.

The ester (1.5 g.) was saponified with 3.5 ml. 1 N NaOH in 8 ml. methanol and 24 ml. water by boiling for an hour. When the resulting solution of the sodium salt was acidified, 1.1 g. a-2-(3'-acetylamino-2',4',6-triiodophenoxy)-ethoxybuty-ric acid (89%) was recovered as a precipitate. It melted at 163165 C. when recrystallized from 50% ethanol. R =0.195 (on silica gel with 19:1 chloroform-glacial acetic acid eluent). It was identified as C H I NO by elementary analysis:

Calculated (percent): C, 25.51; I, 57.77. Found (percent): C, 25.53; I, 57.81.

5.5 g. a-2-(3' acetylamino-2,4,6'-triiodophenoxy)- ethoxybutyric acid (0.0084 mole) prepared as described above, were dissolved in 8 ml. 4- N KOH (0.032 mole), and a solution of 2 g. ethyl iodide in 1 ml. acetone was added. The mixture was stirred for four hours at 40 C.

4.5 g. a-2-(3-N-ethyl-N- acetylamino 2,4',6-triiodophenoxy)-ethoxybutyric acid were recovered from the reaction mixture in the manner described in Example 1. The free acid, when recrystallized from a little ethyl acetate, melts at 131 C. and has an R value of 0.41 on silica gel 254 with a 19:1 chloroform-glacial acetic acid eluent. It is insoluble in water, but dissolves readily in lower alkanols and chloroform. It was identified by its equivalent weight and by elementary analysis:

Calculated: Eq. Wt. 687; C, 27.97%; I, 55.42%. Found: Eq. Wt. 690; C, 28.08%; I, 55.60%.

Saturated solutions of the sodium and N-glutamine salts contain more than 100 g. salt per 100 ml. solution at 20 C.

When u-2(3' acetylamino 2',4,6 triiodophenoxy)- ethoxybutyric acid was reacted with methyl iodide, oc-Z- (3'-N-methyl-N-acetylamino 2',4',6' triiodophenoxy)- ethoxybutyric acid was produced in a yield of 52.5%. It melted at 118-120 C. and had an R value of 0.41 on silica gel with a 19:1 mixture of chloroform and glacial acetic acid. Its solubility and the solubilities of its sodium and N-methylglucamine salts were closely similar to those of the afore-described N-et-hyl homologs. The free acid was identified as C H I NO by its equivalent weight and by elementary analysis:

Calculated: Eq. wt. 673; C, 26.77%; I, 56.57%. Found: Eq. wt. 678; C, 26.80%; I, 56.40%.

EXAMPLE 5 27.5 g. u-2-chloroethoxyvaleronitrile were dissolved in 40 ml. ethanol, and the solution was saturated with HCl gas for two hours while being cooled with ice. The reaction mixture was left to stand overnight, and was thereafter refluxed for four hours, whereby the iminoether hydrochloride was precipitated. The reaction mixture was then stirred into ice water, and the ethyl ester of a-2- chloroethoxyvaleric acid was extracted with ethyl ether and distilled in a vacuum after evaporation of the solvent fro-m the extract. B.P. 119-124 C. at 12 mm. Hg. Yield 11.2 g. (31.6%).

The compound was identical with the reaction product of the ethyl ester of a-2-chloroethoxyvaleric acid with ethylene oxide prepared according to D. Klarnann et al., Liebigs Ann. Chem. 710, 59-70 (1967).

19 g. 3-acetylamino-2,4,6-triiodophenol and 8.3 a-2- chloroethoxyvaleric acid ethyl ester were refluxed for 40 hours with 0.04 mole sodium ethylate in about 30 ml. ethanol. The solvent was then evaporated, the residue was washed with a little ethyl ether, dissolved in ethyl acetate, purified by extraction of the ethyl acetate solution with water and sodium bicarbonate solution, and the ethyl ester of a-2-(3'-acetylamino 2',4',6 triiodophenoxy) ethoxyvaleric acid was recovered by evaporation of the ethyl acetate. When recrystallized from ethanol, it melted at -111 C. and had an R value of 0.61 (on silica gel with chloroform-glacial acetic acid 19:1).

1.8 g. ethyl ester were saponified by boiling for one hour with 3.5 ml. N NaOH in 10 ml. methanol and 30 ml. water. The free acid was obtained by evaporation of the methanol, removal of impurities from the aqueous solution with ethyl ether and acidification with hydrochloric acid. a-2-(3-acetylamino-2,4',6-triiodophenoxy)- ethoxyvaleric acid melts at 151 C. when recrystallized from 50% ethanol and has an R value of 0.31 on silica gel with a 19:1 mixture of chloroform and glacial acetic acid.

6.65 g. batches of u-Z (3acetylamino 2',4',6'-triiodophenoxy)-ethoxyvaleric acid were alkylated with ethyl iodide and methyl iodide respectively as described above. The a-2-(3-N-ethyl-N-acetylamino 2,4,6 triiodophenoxy)-ethoxyvaleric acid was obtained as an amorphous solid in an amount of 5.15 g. (74% yield) and was identified by its equivalent weight (calculated 701, found 715). The N-methyl homolog was obtained by means of methyl iodide as an amorphous solid melting at approximately 100 C. The yield was 3.1 g. It was identified as C I-I I NO by its equivalent weight and by elementary analysis:

Calculated: Eq. wt. 687; C. 27.97%; I, 55.42%. Found: Eq. wt. 692; C, 28.25%; I, 55.18%.

Both alkylation products are insoluble in water, but readily dissolve in methanol.

EXAMPLE 6 49.2 g. benzaldehyde-bis-2-chloroethyl acetal (Arbuzowa et al., Chem. Abstracts 55, 19318 cd, 1961) were dissolved in 39 ml. acetyl chloride, and 0.5 ml. thionyl chloride were added to the solution. Hydrogen chloride gas was introduced for 30 seconds into the reaction solution which was then heated at 55 -60 C. for one hour with agitation and was left to stand overnight, whereafter it was fractionated. a-2-chloroethoxybenzylchloride was obtained in an amount of 37 g. (90%) as a fraction boiling at 128130 C. at 2 mm. Hg.

17 g. o2-chloroethoxybenzyl chloride were stirred with 9 g. cuprous cyanide in 15 ml. toluene at -150 C. for three hours. 11.5 g. a-2-chloroethoxybenzyl cyanide (70% yield) were recovered from the reaction mixture as a fraction boiling at 147 C. at 2 mm. Hg. 9.8 grams of the nitrile were converted to ethyl oc-Z-ChlOlO- ethoxyphenyl acetate by dissolving the starting compound in 15 ml. ethanol, saturating the solution with HCl gas at 15 -20 C., refluxing the mixture for 4 hours to form the iminoether hydrochloride, and saponifying the latter with ice water. The ester boils at 155 -157 C. at 2 mm. Hg, and was obtained in an amount of g. (84%).

The same ester can also be prepared from ethyl Z-chlorophenyl acetate by reaction with ethylene oxide in the presence of tetraethylammonium bromide by the method of Klamann (l.c.).

8 g. ethyl a-Z-chloroethoxyphenyl acetate and 15.8 g. 3-acetylamino-2,4,6-triiodophenol were mixed with 0.03 mole sodium ethylate in about 20 ml. ethanol, and the mixture was refluxed for 40 hours. The solvent was distilled off, and the residue was dissolved in 200 ml. ethyl acetate. The solution was washed with water and sodium bicarbonate, and the solvent was evaporated to yield ethyl a 2 (3'-acetylamino-2',4,6'-triiodophenoxy)-ethoxyphenylacetate having a melting point of 136l37 C. when recrystallized from 95% ethanol. R =0.64 (on silica gel With benzene-chloroform-glacial acetic acid 723:2).

When 3.65 g. of the last-mentioned ester were saponified by 90 minutes boiling in a mixture of 30 ml. 50% ethanol and 6 ml. N NaOH, the free acid could be precipitated from the saponification mixture with hydrochloric acid after removal of the ethanol by evaporation. The crude precipitate was taken up in ml. boiling ethyl acetate in which it dissolved at first, but crystallized shortly thereafter. The yield was 2.4 g. (68%). M.P. 181-182 C. R =0.4l (on silica gel with benzenechloroform-glacial acetic acid 7 :3 :2).

3.5 g. a-2-(3'-acetylamino-2',4,6'-triiodophenoxy)-ethoxyphenylacetic acid (0.005 mole) were dissolved in 6 ml. water containing 0.02 mole potassium hydroxide, and a solution of 1.1 g. (0.075 mole) methyl iodide in 0.5 ml. acetone was added drop by drop with stirring at C. Stirring was continued for about 3 to 4 hours at 40 C., whereupon the reaction mixture was diluted with 50 ml. water and purified by extraction with ethyl ether. The aqueous phase was exposed to a vacuum to remove dissolved ether, and was then acidified with hydrochloric acid.

The amorphous precipitate of a-2-(3'-N-methyl-N-ace tylamino-2',4',6'-triiodophenoxy) ethoxy phenylacetic acid weighed 3.5 g. and melted at 100-l03 C. It is insoluble in water, but readily dissolves in lower alkanols. R =0.61 on silica gel GF 254 with a 19:1 mixture of chloroform and acetic acid.

The compound was identified as C H I NO by its equivalent weight.

Calculated: 721. Found: 728.5.

The corresponding N-ethyl homolog was prepared in the same manner, using ethyl iodide as an alkylation agent. It was amorphous, melting at 8590 C., and was obtained in a yield of 89.5%. R =0.63 (silica gel GF 254, chloroform-benzene-glacial acetic acid 3:7:2). It is insoluble in water, but readily soluble in lower alkanols.

It was identified as C H I NO by its equivalent weight.

Calculated: 735. Found: 745.

The following additional compounds of the invention have been prepared by analogy with one or several of the methods described in Examples 1 to 6:

a-2-(3-propyl-N-acetylamino-2,4',6'-triiodophenoxy)-ethoxypropionic acid;

u-2-(3'-N-butyl-N-acetylamino-2,4',6-triiodophenoxy)-ethoxybutyric acid;

11-2-(3-N-methyl-N-butyroylamino-2',4,6'-triiodophenoxy)-ethoxybutyric acid;

a-2- 3 -N-ethyl-N-acetylamino-2,4,6'-triiodophenoxy) ethoxycaproic acid;

04'2-(3'-N-ethyl-N-acetylamino-2',4',6'-triiodophenoxy)-propoxy-propionic acid.

EXAMPLE 7 5 kg. a-2-(3-N-ethyl-N-acetylamino' 2',4,6' triiodophenoxy)-ethoxypropionic acid were kneaded in a mechanical mixer with two liters starch paste containing 200 g. corn starch. When the moist mass became tacky, a little dry starch was added, and the mixture was granulated on a granulating machine. The granules were dried in a vacuum, mixed with 0.5 kg. corn starch and 25 g. magnesium stearate, and compressed into tablets, each tablet containing 500 mg. of the active agent.

Six tablets were given orally to an adult 6-8 hours prior to cholecystography, and very clear and distinct radiographs of the gall bladder were produced in almost all instances. The dosage was reduced to four tablets (2 g. active agent) for children, and increased up to 12 tablets in special cases.

EXAMPLE 8 5 kg. sodium a-2-(3'-N ethyl-N-acetylamino-Z',4,6'-triiodophenoxy) ethoxypropionate and 0.75 g. granular sugar were mixed with 0.75 kg. corn starch. The mixture was moistened with one liter 50% aqueous ethanol and granulated. The granules were dried, screened, mixed with 0.65 kg. corn starch, 0.05 kg. talcum powder, and 0.05 kg. magnesium stearate, and compressed into 10,000 tablets which were used as described in Example 7.

EXAMPLE 9 Granules prepared by the method of Example 7 were coated with 25% sugar syrup in a dragee making kettle, and were waxed after the coating hardened. They were applied orally prior to radiography in amounts sufficient to provide 2 to 6 g. active agent, the usual dosage being 3 g.

EXAMPLE 10 750 g. u-2-(3'-ethyl-N-acetylamino-2,4',6'-triiodophenoxy)-ethoxypropionic acid were mixed into a homogeneous paste with 600 g. sesame oil and g. vegetal lecithin, and the paste was distributed in 1000 soft gelatine capsules of which four were normally applied to patients prior to cholecystography.

Examples 7 to 10 are merely exemplary of the basically conventional methods by which the acids and salts of the invention are compounded with pharmaceutically acceptable carriers which are practically transparent to X-rays. The afore-mentioned other water-soluble metal and amine salts may be substituted for the sodium salt specifically referred to in Example 8, and other variations and permutations will readily suggest themselves to those skilled in the art.

What is claimed is:

1. A radiopaque compound which is a carboxylic acid of the formula wherein R is lower alkyl, R is lower alkyl, R is lower, divalent alkylene, and R is lower alkyl or phenyl; or a water soluble salt of said carboxylic acid with a physiologically tolerated metal or amine.

2. A compound as set forth in claim 1, wherein R is -CH CH 3. A compound as set forth in claim 2, wherein R is lower alkyl and R is methyl.

4. A compound as set forth in claim 3, wherein R is methyl or ethyl.

5. A compound as set forth in claim 4, wherein R is methyl or ethyl.

6. A compound as set forth in claim 3, wherein R is ethyl and R is methyl.

9 10 7. A compound of the formula References Cited I UNITED STATES PATENTS 1 3,452,134 6/1969 Tilly et a1 260519 -O-R3O-CHC O OH 5 LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, Assistant Examiner 1141-00-3, US 01. X.R.

wherein R is lower alkyl, R is lower, divalent alkylene, 10 260247.2, 465, 465.6, 501.11, 562, 471, 473, 484; and R is lower alkyl or phenyl. 4245