US3842124A - Orally administered contrast agents for cholecystography - Google Patents

Orally administered contrast agents for cholecystography Download PDF

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US3842124A
US3842124A US00202381A US20238171A US3842124A US 3842124 A US3842124 A US 3842124A US 00202381 A US00202381 A US 00202381A US 20238171 A US20238171 A US 20238171A US 3842124 A US3842124 A US 3842124A
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D Pitre
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  • FIGJ E FELDER ET AL ORALLY ADMINISTERED CONTRAST AGENTS FOR CHOLECYSTOGRAPHY 2 Sheets-Sheet I 24 HOURS MlCROMOLE/WLQ INVENTORS.
  • This invention relates to contrast agents for use in cholecystography, and particularly to new radiopaque compounds, their synthesis, and their use in cholecystography by oral administration.
  • contrast agents to be employed in cholecystography by oral administration are complex. They include (1) preferential secretion from the liver into the gall bladder as compared to secretion from the kidney into the urinary tract;
  • the Table includes data on biliary transport maxima which are indicative of contrast in the representation of the gall bladder and associated organs.
  • the data were determined in dogs by the technique of Rosati et al. (Investigative Radiology, 5, No. 4, 232, 1970).
  • the toxicity of the tested compounds was determined in rats (R) and mice (M) in oral and intravenous application and is expressed as L-D in the usual manner.
  • Hoppes Index was determined by actual cholecystography in dogs (1) and in cats (2) after oral administration of the tested compounds in a dosage of ing/kg. (a) and/or 200 rug/kg. (b). On Hoppes scale (J. Amer. Pharm. Assoc. Sci. Ed. 48, 368-379, 1959), the density of the X-ray shadow and the contrast quality are expressed as 0 (negative), 1 (weak), 2 (adequate), 3 (good), or 4 (excellent).
  • the visualization of the bile ducts in the animals employed for determining Hoppes index is recorded in the Table for some of the tested compounds on a scale in which indicates no visibility or only occasional visibility, (-l) indicates visibility in all tests, and indicates optimum visibility with good details.
  • the compounds of the invention compare favorably in their toxicity with all tested known compounds, and are inferior in this respect only to Compound I which is not absorbed from the intestine in significant amounts and is not suitable for cholecystography, as is indicated by the minimal values of Hoppes Index.
  • the ratio of LD (oral) to LD (intravenous) is a measure of the rate at which a compound is absorbed from the intestinal tract into the blood stream. A low ratio is indicative of rapid absorption.
  • the respective ratios for Compounds A, F, G, H, and I, as calculated from toxicity values for mice in the Table, are 2.4, 3.9, 5.4, 3.6, and 6.6, and show the exceptionally rapid absorption of Compound A from the intestinal tract in good agreement with the observed absence of intestinal residues and the lack of absorption of Compound I which is still found in the intestine after 24 hours.
  • the toxicity values determined in rats and listed in the Table show a corresponding superiority of Compound A.
  • Compound A is superior to each of Compounds F, G, and H in the ratio of the amounts secreted with the bile to the amounts secreted with the urine, and the nephrotoxicity of Compound A is significantly lower than that of iopanoic acid.
  • FIG. 1 illustrates concentrations of radiopaque compounds in the blood of dogs as a function of time after oral administration
  • FIG. 2 shows the percentage of radiopaque compounds secreted with the bile three hours after intravenous administration to rats as a function of injected dosage.
  • the concentrations in FIG. 1 are expressed in micromole per milliliter after oral administration of 148.5 micromole per kg. (56.57 mg. I per kg. body weight). The values were calculated by the method of the Latin square (5x5). A high initial value combined with rapid decrease is indicative of rapid absorption from the intestine and rapid secretion by the liver.
  • the dosage values of FIG. 2 are expressed in mg. per kg. body weight.
  • Compound A is the first known, orally administered contrast agent which consistently shows the bile ducts in radiographs.
  • the bile ducts could be shown with certainty heretofore only by intravenous injection of radiopaque compounds, a relatively hazardous procedure.
  • Compound A Because of its very low toxicity, the rapid absorption, and the resulting absence of intestinal residues, Compound A can be employed safely and effectively at higher dosage rates than the known contrast agents, and X-ray images of high contrast are readily and safely produced.
  • the compounds of the invention are equally effective in the form of the free acids and in the form of non-toxic and otherwise physiologically tolerated ionizable salts.
  • the sodium, lithium, calcium, and magnesium salts are typical of the metal salts of the invention, and alkanolamines are the preferred, salt-forming amines.
  • N-methylglucamine, N-rnethylxylamine (l-methylamino-l-desoxy- D-xylitol), l-methylaminopropanediol, and diethanolamine are representative alkanolarnines, but others will readily suggest themselves to those skilled in the art.
  • the several metal and amine salts may be used individually or mixed as may be convenient and desired.
  • the compounds of the invention are prepared by methods which involve reactions of a 3-acylamino-2,4,6-triiodophenol with a reactive derivative of a 3-alkoxy-2- alkylpropionic acid having the formula R (III) wherein X is the reactive radical of a strong acid, that is, halogen, more specifically chlorine, bromine, or iodine, or a sulfate or sulfonate radical, R is hydrogen or alkyl, and n and R' are as defined above.
  • R is hydrogen or alkyl
  • n and R' are as defined above.
  • an ether is formed by elimination of X from the compound of formula (III), the remainder of the compound being bound to the oxygen of the phenol in the 3-acylamino- 2,4,6-triiodophenol.
  • the acyl group of the latter is identical with R in formula (I).
  • the desired 3-[(3-acylamino- 2,4,6-triiodophenoxy)-alkoxy]-2-alkylpropionic acid is recovered from the reaction mixture in one or more steps.
  • a basic condensation agent such as an alkali metal alcoholate or an alkali metal carbonate, may be employed in the formation of the ether, or the 3-acylamino-2,4,6- triiodophenol is employed in the form of its sodium salt.
  • R in formula (III) is alkyl
  • the ether obtained is an alkyl ester which is saponified prior to recovery of the desired acid or salt.
  • 3-(Alkylsulfonyloxyor arylsulfonyloxy-alkoxy)-2-alkylpropionic acid alkyl esters or 3- haloalkoxy-Z-alkylpropionic acid alkyl esters are the most conveniently employed starting materials.
  • EXAMPLE 1 3- 2- (3-Acetylamino-2,4,6-triiodophenoxy) -ethoxy] -2- ethylpropionic acid (Compound A)
  • the ester (70 g., 0.1 mole) was saponified in a boiling mixture of 250 ml. methanol and 250 ml. water to which 100 ml. N sodium hydroxide solution was added in small batches with stirring.
  • the methanol was distilled from the saponification mixture, the residue was mixed with water and extracted with ethyl acetate.
  • the aqueous phase was acidified with hydrochloric acid in the presence of sodium bisulfite.
  • the acid is insoluble in water, soluble in chloroform, and readily soluble in methanol and ethanol. Its sodium salt dissolves in water at 20 C. at a rate of 50 g. per 100 ml., and the N-methylglucamine salt is soluble at 20 in an equal weight of water.
  • the salts were prepared by mixing solutions of equimolecular amounts of acid and base in a common solvent, such as methanol, and evaporating the solvent.
  • the salts with ethanolamine and other alkanolamines were prepared in an analogous manner, Whereas the calcium and magnesium salts and nontoxic salts of other metals were prepared from aqueous dispersions of the acids and bases by stirring at temperatures of about 4050 C., and evaporation of the water in a vacuum.
  • EXAMPLE 2 22 g. 3-acetylamino-2,4,6-triiodophenol sodium dissolved in 40 ml. dimethylformamide was mixed gradually over a period of 10 minutes with 9.2 g. 3-(2-chloroethoxy)-2-ethylpropionic acid ethyl ester, and the mixture was stirred 20 hours at 110 C. to produce the ethyl ester of Compound A. The ester was recovered as described in Example 1 and saponified to produce the free acid which was obtained in an amount of 15.2 g. (56.5% yield).
  • the etherification reaction in the first step of this procedure can be accelerated somewhat by adding 5-7 g. sodium iodide.
  • the other lower alkyl esters of 3-(2-iodoethoxy)-2- ethylpropionic acid and 3-(2-chloroethoxy)-2-ethylpro pionic acid may be substituted for the afore-described ethyl esters in equimolecular amounts, the nature of the alcohol moiety being without significant effect on the reaction with the phenolate.
  • the methyl, propyl, isopro pyl, and butyl esters are most readily available and equivalent to the ethyl ester, but other lower alkyl esters having up to five carbon atoms may be used instead.
  • EXAMPLE 3 14.7 g. 3-acetylamino-2,4,6-triiodophenol, 8.6 g. 3 (2- iodoethoxy)-2-ethylpropionic acid ethyl ester, and 0.037 mole sodium ethylate were heated 40 hours in 35 ml. ethanol to refluxing temperature to produce the ethyl ester of Compound A which was recovered and saponified in the manner described in Example 1 to produce 10.2 g. Compound A (54.5% yield).
  • EXAMPLE 4 A solution of 275.5 g. 3-acetylamino-2,4,6-triiodophenol sodium (0.5 mole) in 600 ml. absolute ethanol was mixed by stirring with gradually added 181.7 g. 3-(2-benzenesulfonyloxyethoxy)-2-ethylpropionic acid ethyl ester (0.55 mole), and the mixture was kept at boiling temperature for about five hours. One half of the solvent present was distilled off at ambient pressure, and the residue was stirred into four liters water, adjusted to pH 6 by means of added acetic acid, and extracted with methylene chloride. The extract was Washed at 5 C. with dilute sodium carbonate solution and Water, and dried, and the anhydrous extract was evaporated to dryness.
  • the ethyl ester of Compound A was obtained as a residue weighing 334 g. (95% yield). When recrystallized from isopropanol or aqueous ethanol, it melted at 85 86 C., and was saponified to the free Compound A as described in Example 1.
  • the 3-(2-benzenesulfonyloxyethoxy) 2-ethylpropionic acid employed as a starting material was prepared by reacting 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester with the silver salt of benzenesulfonic acid in acetonitrile.
  • the intermediate so obtained is a viscous liquid not capable of being distilled without decomposition.
  • Ethyl ester (0.2 mole) was saponified in boiling 35% aqueous methanol with 52 ml. 4 N sodium hydroxide, and the free acid (Compound B) was recovered from the saponification mixture as in Example 1 in an amount of 119 g. (90% yield). When recrystallized from ethyl acetate, it melted out 151 C. and had an R value of 0.34 on silica gel with chloroform/glacial acetic acid 19/ 1.
  • the free acid is insoluble in water, soluble in chloroform, and readily soluble in methanol and ethanol. Its sodium and N-methylglucamine salts were prepared as described in Example 1 and dissolve in 100 ml. water at 20 C. in respective amounts of 30 and 60 g.
  • Methylmalonic acid diethyl ester was reacted with 20 g. sodium hydride and with 103.2 g. 2-chloroethoxymethyl chloride to produce 118.7 g. 2-(2-chloroethoxymethyl)-2-methylmalonic acid diethyl ester which had a boiling point of l32139 C. at 4 mm. Hg.
  • EXAMPLE 6 3- 3-Acetylamino-2,4,6-triiodophenoxy) propoxy] 2-ethylpropionic acid (Compound C) 38.5 g. 3-Acetylamino-2,4,6-triiodophenol sodium in 80 ml. dimethylformamide was reacted with 34.1 g. 5-(3- iodopropoxy)-2-ethylpropionic acid ethyl ester at 70 C. in 16 hours with agitation. The crude material was recovered by the method of Example 1 and dissolved in ethyl acetate.
  • the solution was washed in sequence with sodium carbonate solution, Water, sodium bisulfite solution, and water, dehydrated with sodium sulfate, and evaporated.
  • the amorpous residue was crystallized from 70% ethanol for a yield of 37.5 g. (75%).
  • the ethyl ester of Compound C thus obtained melted at 81-82 C., and had an R value of-( ).5 3 in a thin layer chromatogram on silica gel with benzene/chloroform/acetic acid 7/3/2.
  • Ethyl ester was saponified by boiling for about 5 hours in 150 ml. ethanol and 60 ml. water in the presence of 41 ml. N sodium hydroxide solution.
  • the crude acid was recovered as in Example 1. It melted at 77-- 80 C. and was taken up in about 75 ml. boiling ethyl acetate in which it dissolved completely, but from which the higher melting stable modification soon crystallized.
  • the free acid is sparingly soluble in water, but is soluble in 2.5 weights ethanol, 7 weights ethanol, or about 10 weights boiling chloroform per one weight of the acid.
  • the sodium salt dissolves in water at 20 C. at a rate of 50 g. per ml., and the N-methylglucamine salt at 100 g. per 100 ml.
  • the 3-(3-iodopropoxy)-2-ethylpropionic acid ethyl ester was prepared from ethylmalonic acid in the manner described above with reference to the 3-(2-iodoethoxy)- 2-ethylpropionic acid ethyl ester from ethylmalonic acid diethyl ester by way of intermediates as follows:
  • EXAMPLE 7 3- [4- 3-Acetylamino-2,4,6-triiodophenoxy) butoxy]-2-ethylpropionic acid (Compound D)
  • the method of Example 6 was employed for reacting 27.5 g. 3-acetylamino-2,4,6-triiodophenol sodium with 17.3 g. 3-(4-iodobutoxy)-2-ethylpropionic acid ethyl ester in 60 ml. dimethylformamide.
  • the resulting amorphous ethyl ester of Compound D was saponified as in Example 6 and converted to the crystalline Compound D which melts at approximately 120 C. and has an R value of 0.43 on silica gel with benzene/chloroform/ glacial acetic acid 7/3/2. It was identified by elementary analysis:
  • the free acid is practically insoluble in water even at a boil, but is soluble in about 40 times its weight of cold chloroform, 10 times its weight of hot chloroform, and approximately 7 weights of cold ethanol, and is very soluble in methanol and in boiling ethanol.
  • 100 Ml. water at 20 C. dissolves 30 g. of the sodium salt or 25 g. of the N-methylglucamine salt.
  • the free acid (Compound E) was obtained by saponification of the ethyl ester as in Example 1 and melted at 114 C. when recrystallized from ethyl acetate. It had an R; value of 0.70 in a thin layer chromatogram on silica gel with benzene/chloroform/glacial acetic acid 7/3/2.
  • the acid was identified by elementary analysis:
  • Compound E is insoluble in water, but dissolves freely in chloroform, methanol, and ethanol.
  • the sodium salt dissolves in water of 20 C. at a rate of 10 g./100 ml., and the analogous solubility of the N-methylglucamine salt is 50 g./100 ml.
  • EXAMPLE 9 3- [2- 3-Propyionylamino-2,4,6-triiodophenoxy ethoxy] -2-methylpropionic acid
  • the ethyl ester was prepared in a manner obvious from Example 8 and had a melting point of 79 C. when recrystallized from a 2:1 (vol.) mixture of ethanol and water, and had an R; value of 0.56 in a thin layer chromatogram on silica gel with benzene/ chloroform/ glacial acetic acid 7/3/2. It was identified by its elementary analysis:
  • the free acid obtained by saponification of the ester melted at 145 C. when recrystallized from ethyl acetate and had an R value of 0.68 in a thin layer chromatogram on silica gel with benzene/chloroform/glacial acetic acid 7/3/2.
  • the afore-described compounds of the invention may be combined with suitable excipients conventional in ga lenic pharmacy for administration prior to cholecysteography.
  • suitable excipients conventional in ga lenic pharmacy for administration prior to cholecysteography.
  • Those skilled in the art will readily formulate X- ray contrast compositions containing the compounds of the invention as radiopaque ingredients, and produce capsules, granulates, tablets, dragees, pellets, liquids for rectal application, and suspensions or solutions for oral administration. It has been found advantageous orally to administer the radiopaque compounds of the invention in the micronized condition in which they are absorbed most readily and produce denser images of the gall bladder and associated organs without leaving radiopaque residues in the intestinal tract.
  • Radiopaque compositions of the invention may contain the novel compounds either in the form of the free acids or as salts with metals and amines which are physiologically tolerated and non-toxic in the relatively large doses required.
  • the following Examples illustrate methods of preparing compositions for oral administration which contain the compounds of the invention as the sole active agents.
  • EXAMPLE 10 300 g. Compound A was micronized to a particle size smaller than 4 microns and intimately mixed with 20.4 g. of Pluronic F68, a normally solid surfactant which is a condensation product of ethylene oxide and polypropylene glycol and prevents agglomeration of the micronized particles.
  • Pluronic F68 a normally solid surfactant which is a condensation product of ethylene oxide and polypropylene glycol and prevents agglomeration of the micronized particles.
  • the dual mixture was sieved through a stainless steel Wire screen having 324 openings per square centimeter and further mixed with 20.4 g. microcrystalline starch.
  • the ternary mixture was moistened with distilled water and granulated by passage through a screen having 56 openings per square centimeter into an air stream at 40 C.
  • the granules were coated with 7.2 g. of magnesium stearate and distributed uniformly in 600 soft gelatin capsules which each received 500 mg. of the active agent.
  • Granules prepared in the same manner were converted to drages by coating in a kettle with syrup at a ratio of 4:1, as is conventional. The drages so obtained were mixed.
  • EXAMPLE 11 5 kg. Compound A and 2 liters starch paste containing g. corn starch were worked into a homogeneous dough on a kneading machine, and a little dry starch was added to the moist mixture to reduce its tackiness. It was then granulated and dried in a vacuum. The granulate was further mixed with 0.5 kg. corn starch and 25 g. magnesium stearate and tabletted, each tablet containing 500 mg. of Compound A.
  • EXAMPLE 12 0.75 kg. Granulated sugar (sucrose) and 5 kg. of the sodium salt of Compound A were mixed with 0.75 kg. corn starch. The mixture was moistened with 1000 ml. 50% aqueous ethanol and thereafter granulated. The granulate was dried, screened, further mixed with 0.65 kg. corn starch, 0.05 kg. talcum, and 0.05 kg. magnesium stearate, and converted to 10,000 tablets.
  • a compound as set forth in claim 1 which is a salt UNITED STATES PATENTS of said acid with an alkali metal, calcium, magnesium, 3,553,259 1/1971 Felder et a1 260-419 or an alkanolamine.
  • a compound as set forth in claim 4 is a salt 10 P R R P of said acid with sodium or N-methylglucamine.

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Abstract

1. A COMPOUND WHICH IS A 3-(3-ACYAMINO-2,4,6-TRIIODOPHENOXY)-ALKOXY)-2-ALKYLPROPIONIC ACID OF THE FORMULA

1-(HOOC-CH(-R'')-CH2-O-(CH2)N-O-),2,4,6-TRI(I-),3-(R-NH-)-

CYCLOHEXANE

OR A WATER-SOLUBLE SALT OF SAID ACID WITH A PHYSIOLOGICALLY TOLERATED METAL OR AMINE, IN SAID FORMULA R BEING ACETYL OR PROPIONYL, R'' BEING METHYL OR ETHYL, AND N BEING AN INTEGER BETWEEN 2 AND 4.

Description

Filed Nov. 26. 1971 FIGJ E. FELDER ET AL ORALLY ADMINISTERED CONTRAST AGENTS FOR CHOLECYSTOGRAPHY 2 Sheets-Sheet I 24 HOURS MlCROMOLE/WLQ INVENTORS.
ERNST FELDER'E DAVIDE PITRE Wm M y W M AGENTS Oct. 15, 1974 FELDER ET AL 3,842,124
ORALLY ADHINISTERED CONTRAST AGENTS FUR CHOLECYSTOGRAPHY Filed Nov. 26, 1971 2 Sheets-Sheet 2 O O (O Y 2 ll.
I I l I I O O O O O INVENTORS. o 9 co 0 v N ERNST FELDER 8 DAVIDE'PITRE AGENTS United States Patent 3,842,124 ORALLY ADMINISTERED CONTRAST AGENTS FOR CHOLECYSTOGRAPHY Ernst Felder and Davide Pitre, Milan, Italy, assignors to Bracco Industria Chimica, Societa per Azioni, Milan,
Italy Filed Nov. 26, 1971, Ser. No. 202,381 Claims priority, application Switzerland, Dec. 15, 1970, 18,621/ 70 Int. Cl. C07c 101/72 US. Cl. 260501.11 6 Claims ABSTRACT OF THE DISCLOSURE 3- [2- 3-Acetylamino-2,4,'6-triiodophenoxy) -ethoxy] 2- ethylpropionic acid and its physiologically tolerated salts are safe and effective contrast agents for oral administration prior to cholecystography. Homologs in which acetyl is replaced by propionyl, and ethoxy is replaced by propoxy or butoxy, are moderately inferior, but are also useful for cholecystography.
This invention relates to contrast agents for use in cholecystography, and particularly to new radiopaque compounds, their synthesis, and their use in cholecystography by oral administration.
The requirements for contrast agents to be employed in cholecystography by oral administration are complex. They include (1) preferential secretion from the liver into the gall bladder as compared to secretion from the kidney into the urinary tract;
(2) high biliary transport maxima (see G. Miller et al.,
Schweiz. med. Wochenschrift 99, 577-581, 1968);
(3) consistent visualization of the bile ducts;
(4) low toxicity, particularly when measured by intravenous injection in test animals, the toxicity of the intravenously administered compounds being a more reliable and reproducible measure of physiological tolerance than the toxicity determined after administration through the gastrointestinal system;
(5) rapid excretion without residuals in the intestine;
(6) low nephrotoxicity;
(7) convenient synthesis in high yield and high purity,
more specifically, avoidance of the formation of isomers which require to be separated.
It has been found that the requirements enumerated above are met to a degree not available heretofore by compounds which are acids of the formula or physiologically tolerated and non-toxic salts of such acids with metals or amines, in the formula R being acetyl or propionyl, R being methyl or ethyl, and n being an integer between 2 and 4. 3-[2-(3-Acetylamino-2,4,6-triiodophenoxy)-ethoxy]-2-ethylpropionic acid and its salts are distinctly superior to the homologs of the above formula. The compounds of the invention differ from all pre- ICC.
viously known radiopaque compounds of similar chemical structure by the ionizable terminal group and it appears that this terminal group is of significant importance for ensuring the favorable properties of the compounds.
The superiority of 3-[2-(3-acetylamino-2,4,6-triiodophenoxy)-ethoxy]-2 ethylpropionic acid, its homologs within the limits of Formula (I), and of the corresponding salts will be apparent from the following Table of results obtained in comparison tests with the two orally administered radiopaque compounds most widely used heretofore, iopanoic acid and ipodate, and with radiopaque compounds closely related to the compounds of the instant invention by their chemical structure, yet lacking the terminal group of Formula (II).
The Table includes data on biliary transport maxima which are indicative of contrast in the representation of the gall bladder and associated organs. The data were determined in dogs by the technique of Rosati et al. (Investigative Radiology, 5, No. 4, 232, 1970).
The toxicity of the tested compounds was determined in rats (R) and mice (M) in oral and intravenous application and is expressed as L-D in the usual manner.
Hoppes Index was determined by actual cholecystography in dogs (1) and in cats (2) after oral administration of the tested compounds in a dosage of ing/kg. (a) and/or 200 rug/kg. (b). On Hoppes scale (J. Amer. Pharm. Assoc. Sci. Ed. 48, 368-379, 1959), the density of the X-ray shadow and the contrast quality are expressed as 0 (negative), 1 (weak), 2 (adequate), 3 (good), or 4 (excellent).
The visualization of the bile ducts in the animals employed for determining Hoppes index is recorded in the Table for some of the tested compounds on a scale in which indicates no visibility or only occasional visibility, (-l) indicates visibility in all tests, and indicates optimum visibility with good details.
Additional explanations of the Table are found in footnotes.
The tested compounds are identified in the Table and elsewhere in this specification by capital letters as follows:
All tests were performed under uniform conditions and are directly comparable. 20% suspensions of the acids were prepared with gum arabic and were administered to the test animals by means of a stomach tube in the determination of Hoppes Index and of oral toxicity. Salts with sodium or N-methylglucamine, which are physiologically equivalent, were employed in determining toxicity by intravenous injection.
TABLE [Part 1] Bil. transp. Toxicity LDs mgJkg. max., Bile micromole} Compound Oral Intraven. ducts kgJmin.
R: 3,800.-- 13-.-- M: 5,200... O M: 3,700.-- D M: 2,200--- E M:2,800 F {M; 1,600..- seat-- G "ihI tlz 558570... E "{R: 2,500- I M: 9,800--- [Part 2] Animal and Compound dosage 19 As determined by the technique of W. Segerer (dissertation, Munich,
Maximum not entirely reached, because some animals died from higher dosage.
As is evident from the Table, the compounds of the invention compare favorably in their toxicity with all tested known compounds, and are inferior in this respect only to Compound I which is not absorbed from the intestine in significant amounts and is not suitable for cholecystography, as is indicated by the minimal values of Hoppes Index.
The ratio of LD (oral) to LD (intravenous) is a measure of the rate at which a compound is absorbed from the intestinal tract into the blood stream. A low ratio is indicative of rapid absorption. The respective ratios for Compounds A, F, G, H, and I, as calculated from toxicity values for mice in the Table, are 2.4, 3.9, 5.4, 3.6, and 6.6, and show the exceptionally rapid absorption of Compound A from the intestinal tract in good agreement with the observed absence of intestinal residues and the lack of absorption of Compound I which is still found in the intestine after 24 hours. The toxicity values determined in rats and listed in the Table show a corresponding superiority of Compound A.
All compounds of the invention (A-E) are consistently superior in their Hoppe Index values to the known compounds G and H which have been in clinical use for a long time, and compound A is significantly superior to all other compounds tested, as would be expected from the very high values of biliary transport maxima. Compound I is not useful for cholecystography.
As not specifically stated in the Table, Compound A is superior to each of Compounds F, G, and H in the ratio of the amounts secreted with the bile to the amounts secreted with the urine, and the nephrotoxicity of Compound A is significantly lower than that of iopanoic acid.
In the attached drawing, the results of additional comparison tests of Compound A with other radiopaque compounds are graphically illustrated.
The several curves are labeled with the capital letters assigned to the compounds in the Table, and with A-Na etc. where the sodium salts were empolyed.
FIG. 1 illustrates concentrations of radiopaque compounds in the blood of dogs as a function of time after oral administration; and
FIG. 2 shows the percentage of radiopaque compounds secreted with the bile three hours after intravenous administration to rats as a function of injected dosage.
The concentrations in FIG. 1 are expressed in micromole per milliliter after oral administration of 148.5 micromole per kg. (56.57 mg. I per kg. body weight). The values were calculated by the method of the Latin square (5x5). A high initial value combined with rapid decrease is indicative of rapid absorption from the intestine and rapid secretion by the liver.
The dosage values of FIG. 2 are expressed in mg. per kg. body weight.
The outstanding ability of Compound A to be excreted rapidly even at high dosage rates is evident.
Because of the absence of an alkyl group attached to nitrogen in position 3 of the triiodophenol radical of Compound A, geometric isomers cannot be formed during synthesis, and the pure compound is readily obtained in high yields without the need for removal of unwanted isomers.
Compound A is the first known, orally administered contrast agent which consistently shows the bile ducts in radiographs. The bile ducts could be shown with certainty heretofore only by intravenous injection of radiopaque compounds, a relatively hazardous procedure.
Because of its very low toxicity, the rapid absorption, and the resulting absence of intestinal residues, Compound A can be employed safely and effectively at higher dosage rates than the known contrast agents, and X-ray images of high contrast are readily and safely produced.
The compounds of the invention are equally effective in the form of the free acids and in the form of non-toxic and otherwise physiologically tolerated ionizable salts. The sodium, lithium, calcium, and magnesium salts are typical of the metal salts of the invention, and alkanolamines are the preferred, salt-forming amines. N-methylglucamine, N-rnethylxylamine (l-methylamino-l-desoxy- D-xylitol), l-methylaminopropanediol, and diethanolamine are representative alkanolarnines, but others will readily suggest themselves to those skilled in the art. The several metal and amine salts may be used individually or mixed as may be convenient and desired.
The compounds of the invention are prepared by methods which involve reactions of a 3-acylamino-2,4,6-triiodophenol with a reactive derivative of a 3-alkoxy-2- alkylpropionic acid having the formula R (III) wherein X is the reactive radical of a strong acid, that is, halogen, more specifically chlorine, bromine, or iodine, or a sulfate or sulfonate radical, R is hydrogen or alkyl, and n and R' are as defined above. In this reaction, an ether is formed by elimination of X from the compound of formula (III), the remainder of the compound being bound to the oxygen of the phenol in the 3-acylamino- 2,4,6-triiodophenol. The acyl group of the latter is identical with R in formula (I). The desired 3-[(3-acylamino- 2,4,6-triiodophenoxy)-alkoxy]-2-alkylpropionic acid is recovered from the reaction mixture in one or more steps.
A basic condensation agent, such as an alkali metal alcoholate or an alkali metal carbonate, may be employed in the formation of the ether, or the 3-acylamino-2,4,6- triiodophenol is employed in the form of its sodium salt.
When R in formula (III) is alkyl, the ether obtained is an alkyl ester which is saponified prior to recovery of the desired acid or salt. 3-(Alkylsulfonyloxyor arylsulfonyloxy-alkoxy)-2-alkylpropionic acid alkyl esters or 3- haloalkoxy-Z-alkylpropionic acid alkyl esters are the most conveniently employed starting materials.
The following Examples are further illustrative of this invention.
EXAMPLE 1 3- 2- (3-Acetylamino-2,4,6-triiodophenoxy) -ethoxy] -2- ethylpropionic acid (Compound A) A solution of 192 g. (3-acetylamino-2,4,6-triiodophenol sodium (0.35 mole) in 350 ml. dimethylacetamide, was mixed with 107.5 g. 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester (0.35 mole) at 90 C. with stirring over a period of about 30 minutes. Stirring was continued while the mixture was held at 95 l00 C. for 16 hours. The solvent was then removed by distillation in a vacuum, and the residue was poured into 4000 ml. water. The solid precipitate formed was recovered and washed with water, dilute sodium carbonate solution, dilute sodium bisulfite solution, and again with much water. The ethyl ester of Compound A was obtained in a yield of 220 g. (90%). When recrystallized from 75% aqueous ethanol, it melted at 8086 C., and its thin layer chromatogram on silica gel with chloroform/glacial acetic acid 19/1 gave an R value of 0.57. The ester was identified by elementary analysis:
Calculated for C1'1H22I3NO'5: C, 29.12%; I, 54.31% Found: C, 29.15%; I, 54.53%
The ester (70 g., 0.1 mole) was saponified in a boiling mixture of 250 ml. methanol and 250 ml. water to which 100 ml. N sodium hydroxide solution was added in small batches with stirring. The methanol was distilled from the saponification mixture, the residue was mixed with water and extracted with ethyl acetate. The aqueous phase was acidified with hydrochloric acid in the presence of sodium bisulfite.
The free acid (Compound A) gradually crystallized from the acidified solution in the amount of 42.4 g. (63% yield). When recrystallized from 50% ethanol and from ethyl acetate, it melted at 130 C. The R value of a thin layer chromatogram prepared on silica gel with chloro form/acetic acid 19/1 was 0.32
The acid is insoluble in water, soluble in chloroform, and readily soluble in methanol and ethanol. Its sodium salt dissolves in water at 20 C. at a rate of 50 g. per 100 ml., and the N-methylglucamine salt is soluble at 20 in an equal weight of water. The salts were prepared by mixing solutions of equimolecular amounts of acid and base in a common solvent, such as methanol, and evaporating the solvent. The salts with ethanolamine and other alkanolamines were prepared in an analogous manner, Whereas the calcium and magnesium salts and nontoxic salts of other metals were prepared from aqueous dispersions of the acids and bases by stirring at temperatures of about 4050 C., and evaporation of the water in a vacuum.
The 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester was prepared in the following sequence of steps:
0.8 Mole ethylmalonic acid diethyl ester was reacted in ether solution with 0.84 mole sodium hydride, and thereafter with 0.8 mole 2-chloroethoxy-methyl chloride. 2-(2- Chloroethoxymethyl)-2-ethylmalonic acid diethyl ester was recovered as a liquid boiling at 136-144 C./4 mm. Hg.
0.47 Mole 2 (2-chloroethoxymethyl)-2-ethylmalonic acid diethyl ester was partly saponified in 500 ml. 60% aqueous methanol with 0.5 mole sodium hydroxide within two hours at 60 to 65 C. The methanol was evaporated, and the residue was acidified and extracted with ethyl to produce 2-(2-chloroethoxymethyl)-2-ethylmalonic acid monoethyl ester which was decarboxylated by heating at 140150 C. The 3-(2-chloroethoxy)-2-ethylpropionic acid ethyl ester formed thereby was isolated, and it boiled at 119-124 C./4 mm. Hg.
0.325 Mole 3-(Z-chloroethoxy)-2-ethylpropionic acid ethyl ester was refluxed for 16 hours with 0.65 mole sodium iodide in 300 ml. ethanol, and the 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester was recovered 6 as a liquid boiling at 128 C./3-4 mm. Hg. It had an index of refraction n of 1.482.
The following additional methods also produced the ethyl ester of Compound A and the free acid.
EXAMPLE 2 22 g. 3-acetylamino-2,4,6-triiodophenol sodium dissolved in 40 ml. dimethylformamide was mixed gradually over a period of 10 minutes with 9.2 g. 3-(2-chloroethoxy)-2-ethylpropionic acid ethyl ester, and the mixture was stirred 20 hours at 110 C. to produce the ethyl ester of Compound A. The ester was recovered as described in Example 1 and saponified to produce the free acid which was obtained in an amount of 15.2 g. (56.5% yield).
The etherification reaction in the first step of this procedure can be accelerated somewhat by adding 5-7 g. sodium iodide.
The other lower alkyl esters of 3-(2-iodoethoxy)-2- ethylpropionic acid and 3-(2-chloroethoxy)-2-ethylpro pionic acid may be substituted for the afore-described ethyl esters in equimolecular amounts, the nature of the alcohol moiety being without significant effect on the reaction with the phenolate. The methyl, propyl, isopro pyl, and butyl esters are most readily available and equivalent to the ethyl ester, but other lower alkyl esters having up to five carbon atoms may be used instead.
EXAMPLE 3 14.7 g. 3-acetylamino-2,4,6-triiodophenol, 8.6 g. 3 (2- iodoethoxy)-2-ethylpropionic acid ethyl ester, and 0.037 mole sodium ethylate were heated 40 hours in 35 ml. ethanol to refluxing temperature to produce the ethyl ester of Compound A which was recovered and saponified in the manner described in Example 1 to produce 10.2 g. Compound A (54.5% yield).
Similarly, a mixture of 14.7 g. 3-acetylamino2,4,6-triiodophenol, 8.6 g. 3-(2-iodoethoxy)-2-ethylpropionic acid, ml. methylethylketone, and 9 g. anhydrous potassium carbonate was refluxed for about 30 40 hours with agitation to produce the ethyl ester of Compound A which was converted to 9.6 g. of the free acid in the afore-described manner (51.3% yield).
EXAMPLE 4 A solution of 275.5 g. 3-acetylamino-2,4,6-triiodophenol sodium (0.5 mole) in 600 ml. absolute ethanol was mixed by stirring with gradually added 181.7 g. 3-(2-benzenesulfonyloxyethoxy)-2-ethylpropionic acid ethyl ester (0.55 mole), and the mixture was kept at boiling temperature for about five hours. One half of the solvent present was distilled off at ambient pressure, and the residue was stirred into four liters water, adjusted to pH 6 by means of added acetic acid, and extracted with methylene chloride. The extract was Washed at 5 C. with dilute sodium carbonate solution and Water, and dried, and the anhydrous extract was evaporated to dryness.
The ethyl ester of Compound A was obtained as a residue weighing 334 g. (95% yield). When recrystallized from isopropanol or aqueous ethanol, it melted at 85 86 C., and was saponified to the free Compound A as described in Example 1.
The 3-(2-benzenesulfonyloxyethoxy) 2-ethylpropionic acid employed as a starting material Was prepared by reacting 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester with the silver salt of benzenesulfonic acid in acetonitrile. The intermediate so obtained is a viscous liquid not capable of being distilled without decomposition.
Procedures analogous to those described above were employed in producing additional homologs of Compound A, however, none of the several homologs were superior nor even equal to Compound A in the properties essential to a contrast agent for cholecystography.
7 EXAMPLE 3- [2-( 3-Acetylamino-2,4,6-triiodophenoxy) -etl1oxy] Z-methylpropionic acid (Compound B) A solution of 165 g. 3-acetylamino-2,4,6-triiodophenol sodium (0.3 mole) in 350 ml. dimethylacetamide was reacted with 83.5 g. 3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester (0.3 mole) according to the procedure of Example 1. The ethyl ester of Compound B was obtained in an amount of 192 g. (93% yield). When recrystallized from ethyl acetate, it had a melting point of 125 C. and an R value of 0.54 on silica gel with chloroform/ glacial acetic acid 19/1. It was identified by elementary analysis:
Calculated for C H I NO C, 27.97%; I, 55.42% Found: C, 27.77%; I, 55.85%
134.4 g. Ethyl ester (0.2 mole) was saponified in boiling 35% aqueous methanol with 52 ml. 4 N sodium hydroxide, and the free acid (Compound B) was recovered from the saponification mixture as in Example 1 in an amount of 119 g. (90% yield). When recrystallized from ethyl acetate, it melted out 151 C. and had an R value of 0.34 on silica gel with chloroform/glacial acetic acid 19/ 1.
The free acid is insoluble in water, soluble in chloroform, and readily soluble in methanol and ethanol. Its sodium and N-methylglucamine salts were prepared as described in Example 1 and dissolve in 100 ml. water at 20 C. in respective amounts of 30 and 60 g.
The 3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester was prepared in the same manner in which the higher homolog had been prepared in Example 1.
140 g. Methylmalonic acid diethyl ester was reacted with 20 g. sodium hydride and with 103.2 g. 2-chloroethoxymethyl chloride to produce 118.7 g. 2-(2-chloroethoxymethyl)-2-methylmalonic acid diethyl ester which had a boiling point of l32139 C. at 4 mm. Hg.
When 267 g. of the diethyl ester so obtained was partly saponified with 42 g. sodium hydroxide, and the resulting monoethyl ester was decarboxylated, 103 g. 3-(2- chloroethoxy)-2-methylpropionic acid ethyl ester of hp. 102105 C./14 mm. Hg was recovered. From 93 g. of the last-mentioned compound, 98 g. 3-(2-iodoethoxy)2- methylpropionic acid ethyl ester boiling at 119 C./35 mm. Hg was formed by reaction with 144 g. sodium iodide.
EXAMPLE 6 3- 3- 3-Acetylamino-2,4,6-triiodophenoxy) propoxy] 2-ethylpropionic acid (Compound C) 38.5 g. 3-Acetylamino-2,4,6-triiodophenol sodium in 80 ml. dimethylformamide was reacted with 34.1 g. 5-(3- iodopropoxy)-2-ethylpropionic acid ethyl ester at 70 C. in 16 hours with agitation. The crude material was recovered by the method of Example 1 and dissolved in ethyl acetate. The solution was washed in sequence with sodium carbonate solution, Water, sodium bisulfite solution, and water, dehydrated with sodium sulfate, and evaporated. The amorpous residue was crystallized from 70% ethanol for a yield of 37.5 g. (75%). The ethyl ester of Compound C thus obtained melted at 81-82 C., and had an R value of-( ).5 3 in a thin layer chromatogram on silica gel with benzene/chloroform/acetic acid 7/3/2.
26.9 g. Ethyl ester was saponified by boiling for about 5 hours in 150 ml. ethanol and 60 ml. water in the presence of 41 ml. N sodium hydroxide solution. The crude acid was recovered as in Example 1. It melted at 77-- 80 C. and was taken up in about 75 ml. boiling ethyl acetate in which it dissolved completely, but from which the higher melting stable modification soon crystallized.
til
8 It melted at 135-137 C. in an amount of 17 g. (64% yield).
Compound C was identified by its elementary analysis:
Calculated for C H I NO C, 27.97%; I, 55.42% Found: C, 2809%; I, 55.64%
The thin layer chromatogram on silica gel with benzene/ chloroform/ glacial acetic acid 7/ 3/ 2 gave an R; value of 0.46.
The free acid is sparingly soluble in water, but is soluble in 2.5 weights ethanol, 7 weights ethanol, or about 10 weights boiling chloroform per one weight of the acid. The sodium salt dissolves in water at 20 C. at a rate of 50 g. per ml., and the N-methylglucamine salt at 100 g. per 100 ml.
The 3-(3-iodopropoxy)-2-ethylpropionic acid ethyl ester was prepared from ethylmalonic acid in the manner described above with reference to the 3-(2-iodoethoxy)- 2-ethylpropionic acid ethyl ester from ethylmalonic acid diethyl ester by way of intermediates as follows:
'2-(3-chloropropoxymethyl)-2-ethylma1onic acid diethyl ester (b.p. 142-148 C./2 mm. Hg, n =1.443)
3-(3-chloropropoxy)-2-ethylpropionic acid ethyl ester (b.p. 103 -107 C./2 mm. Hg, n =1.438)
3-(3-iodopropoxy)-2-ethylproponic acid ethyl ester (b.p.
-127 C./2 mm. Hg, 21 1.478)
EXAMPLE 7 3- [4- 3-Acetylamino-2,4,6-triiodophenoxy) butoxy]-2-ethylpropionic acid (Compound D) The method of Example 6 was employed for reacting 27.5 g. 3-acetylamino-2,4,6-triiodophenol sodium with 17.3 g. 3-(4-iodobutoxy)-2-ethylpropionic acid ethyl ester in 60 ml. dimethylformamide. The resulting amorphous ethyl ester of Compound D was saponified as in Example 6 and converted to the crystalline Compound D which melts at approximately 120 C. and has an R value of 0.43 on silica gel with benzene/chloroform/ glacial acetic acid 7/3/2. It was identified by elementary analysis:
Calculated for C1'7H22I3NO5I C, 29.12%; I, 54.31% Found: C, 29.16%; I, 53.99%
The free acid is practically insoluble in water even at a boil, but is soluble in about 40 times its weight of cold chloroform, 10 times its weight of hot chloroform, and approximately 7 weights of cold ethanol, and is very soluble in methanol and in boiling ethanol. 100 Ml. water at 20 C. dissolves 30 g. of the sodium salt or 25 g. of the N-methylglucamine salt.
The 3-(4-iodobutoxy)-2-ethylpropionic acid ethyl ester was prepared from ethylmalonic acid diethyl ester in a manner analogous to the afore-described synthesis of its homologs. The following compounds were obtained in the several steps:
2-(4-chlorobutoxymethyl)-2-ethylmalonic acid diethyl ester (b.p. 155 C./2 mm. Hg; n =1.446
3-(4-chlorobutoxy)-2-ethylpropionic acid ethyl ester (b.p.
117l24 C./2 mm. Hg, n =1.438)
3-(4-iodobutoxy)-2-ethylpropionic acid ethyl ester (b.p.
137-142 C./2 mm. Hg; n =1.475)
EXAMPLE 8 3- [2- 3-Propionylamino-2,4,6-triiodophenoxy ethoxy] -2-ethylpropionic acid (Compound E) The ethyl ester of Compound E was prepared from 16.95 3-propionylamino-2,4,6-triodophenol sodium (0.3
mole) and 10 g. 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester (0.032 mole) by reaction in 30 ml. dimethylformamide at 90 C. as in Example 1 in an amount of 15.2 g. (71% yield). When recrystallized from ethyl acetate, the ester melted at 86 C. and had an R, value of 0.65 in a thin layer chromatogram on silica gel with benzene/ chloroform/ glacial acetic acid 7/ 3/ 2.
Calculated for C H I NO C, 30.23%; I, 53.24% Found: C, 30.38%; I, 52.94%
The free acid (Compound E) was obtained by saponification of the ethyl ester as in Example 1 and melted at 114 C. when recrystallized from ethyl acetate. It had an R; value of 0.70 in a thin layer chromatogram on silica gel with benzene/chloroform/glacial acetic acid 7/3/2. The acid was identified by elementary analysis:
Calculated fOr C H I NO C, 27.97%; I, 55.42% Found: C, 28.12%; I, 55.39%
Compound E is insoluble in water, but dissolves freely in chloroform, methanol, and ethanol. The sodium salt dissolves in water of 20 C. at a rate of 10 g./100 ml., and the analogous solubility of the N-methylglucamine salt is 50 g./100 ml.
EXAMPLE 9 3- [2- 3-Propyionylamino-2,4,6-triiodophenoxy ethoxy] -2-methylpropionic acid The ethyl ester was prepared in a manner obvious from Example 8 and had a melting point of 79 C. when recrystallized from a 2:1 (vol.) mixture of ethanol and water, and had an R; value of 0.56 in a thin layer chromatogram on silica gel with benzene/ chloroform/ glacial acetic acid 7/3/2. It was identified by its elementary analysis:
Calculated for C H I NO C, 29.12%; I, 54.31% Found: C, 29.40%; I, 54.19%
The free acid obtained by saponification of the ester melted at 145 C. when recrystallized from ethyl acetate and had an R value of 0.68 in a thin layer chromatogram on silica gel with benzene/chloroform/glacial acetic acid 7/3/2.
Calculated for C H I NO C, 26.77%; I, 56.57% Found: C, 27.00%; I, 56.19%
The following additional compounds were prepared by interchanging reactants and substituents in the procedures described above:
The afore-described compounds of the invention may be combined with suitable excipients conventional in ga lenic pharmacy for administration prior to cholecysteography. Those skilled in the art will readily formulate X- ray contrast compositions containing the compounds of the invention as radiopaque ingredients, and produce capsules, granulates, tablets, dragees, pellets, liquids for rectal application, and suspensions or solutions for oral administration. It has been found advantageous orally to administer the radiopaque compounds of the invention in the micronized condition in which they are absorbed most readily and produce denser images of the gall bladder and associated organs without leaving radiopaque residues in the intestinal tract.
Radiopaque compositions of the invention may contain the novel compounds either in the form of the free acids or as salts with metals and amines which are physiologically tolerated and non-toxic in the relatively large doses required. The following Examples illustrate methods of preparing compositions for oral administration which contain the compounds of the invention as the sole active agents.
EXAMPLE 10 300 g. Compound A was micronized to a particle size smaller than 4 microns and intimately mixed with 20.4 g. of Pluronic F68, a normally solid surfactant which is a condensation product of ethylene oxide and polypropylene glycol and prevents agglomeration of the micronized particles. The dual mixture was sieved through a stainless steel Wire screen having 324 openings per square centimeter and further mixed with 20.4 g. microcrystalline starch.
The ternary mixture was moistened with distilled water and granulated by passage through a screen having 56 openings per square centimeter into an air stream at 40 C. The granules were coated with 7.2 g. of magnesium stearate and distributed uniformly in 600 soft gelatin capsules which each received 500 mg. of the active agent.
Granules prepared in the same manner were converted to drages by coating in a kettle with syrup at a ratio of 4:1, as is conventional. The drages so obtained were mixed.
EXAMPLE 11 5 kg. Compound A and 2 liters starch paste containing g. corn starch were worked into a homogeneous dough on a kneading machine, and a little dry starch was added to the moist mixture to reduce its tackiness. It was then granulated and dried in a vacuum. The granulate was further mixed with 0.5 kg. corn starch and 25 g. magnesium stearate and tabletted, each tablet containing 500 mg. of Compound A.
EXAMPLE 12 0.75 kg. Granulated sugar (sucrose) and 5 kg. of the sodium salt of Compound A were mixed with 0.75 kg. corn starch. The mixture was moistened with 1000 ml. 50% aqueous ethanol and thereafter granulated. The granulate was dried, screened, further mixed with 0.65 kg. corn starch, 0.05 kg. talcum, and 0.05 kg. magnesium stearate, and converted to 10,000 tablets.
What is claimed is:
1. A compound which is a 3-[(3-acylamino-2,4,6triiodophenoxy)-alkoxy]-2-alkylpropionic acid of the formula or a water-soluble salt of said acid with a physiologically tolerated metal or amine, in said formula R being acetyl or propionyl, R being methyl or ethyl, and n being an integer between 2 and 4.
1 1 1 2 2. A compound as set forth in claim 1 which is said References Cited acid.
3. A compound as set forth in claim 1 which is a salt UNITED STATES PATENTS of said acid with an alkali metal, calcium, magnesium, 3,553,259 1/1971 Felder et a1 260-419 or an alkanolamine.
4. A compound as set forth in claim 1, wherein R is 5 BERNARD HELEN Primary Examiner acetyl, R is ethyl and n is 2. M. W. GLYNN, Assistant Examiner 5. A compound as set forth in claim 4, which is said acid. US. Cl. X.R.
6. A compound as set forth in claim 4, is a salt 10 P R R P of said acid with sodium or N-methylglucamine.

Claims (1)

1. A COMPOUND WHICH IS A 3-(3-ACYAMINO-2,4,6-TRIIODOPHENOXY)-ALKOXY)-2-ALKYLPROPIONIC ACID OF THE FORMULA
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US5250283A (en) * 1990-03-28 1993-10-05 Molecular Biosystems, Inc. Organic contrast agent analog and method of making same
US5434267A (en) * 1991-12-20 1995-07-18 Bayer Aktiengesellschaft Process for the preparation of substituted 3-alkoxyacrylates
US20070255203A1 (en) * 2004-10-13 2007-11-01 Hyprotek, Inc. Syringe Devices and Methods for Mixing and Administering Medication

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US5250283A (en) * 1990-03-28 1993-10-05 Molecular Biosystems, Inc. Organic contrast agent analog and method of making same
WO1994005335A1 (en) * 1990-03-28 1994-03-17 Molecular Biosystems, Inc. New organic contrast agent analog and method of making same
US5434267A (en) * 1991-12-20 1995-07-18 Bayer Aktiengesellschaft Process for the preparation of substituted 3-alkoxyacrylates
US20070255203A1 (en) * 2004-10-13 2007-11-01 Hyprotek, Inc. Syringe Devices and Methods for Mixing and Administering Medication

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