US3553259A - Contrast media for cholecystography - Google Patents

Contrast media for cholecystography Download PDF

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Publication number
US3553259A
US3553259A US728894A US3553259DA US3553259A US 3553259 A US3553259 A US 3553259A US 728894 A US728894 A US 728894A US 3553259D A US3553259D A US 3553259DA US 3553259 A US3553259 A US 3553259A
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Prior art keywords
acid
ethyl
triiodophenoxy
acetylamino
water
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US728894A
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Ernst Felder
David Pitre
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Bracco SpA
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Bracco SpA
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    • 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
    • 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
    • A61K49/0495—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 intended for oral administration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/17—Unsaturated ethers containing halogen
    • C07C43/174—Unsaturated ethers containing halogen containing six-membered aromatic rings

Definitions

  • 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.
  • 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.
  • 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:
  • compound A 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.
  • 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.
  • 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
  • R is metal or lower alkyl.
  • 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.
  • 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.
  • 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 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.
  • 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:
  • EXAMPLE 4 8.5 g. rat-2-chloroethoxybutyronitrile (Lingo, J.A.C.S. 61 [1939] 1574) wrerere 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.
  • 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.
  • 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:
  • Saturated solutions of the sodium and N-glutamine salts contain more than 100 g. salt per 100 ml. solution at 20 C.
  • 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).
  • 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.
  • 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.
  • 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.).
  • the compound was identified as C H I NO by its equivalent weight.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US728894A 1967-05-29 1968-05-14 Contrast media for cholecystography Expired - Lifetime US3553259A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH748267A CH483262A (de) 1967-05-29 1967-05-29 Neue Röntgenkontrastmittel und Verfahren zu ihrer Herstellung

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US (1) US3553259A (enrdf_load_stackoverflow)
AT (2) AT284825B (enrdf_load_stackoverflow)
BE (1) BE715799A (enrdf_load_stackoverflow)
CH (2) CH494576A (enrdf_load_stackoverflow)
DE (1) DE1768553B1 (enrdf_load_stackoverflow)
DK (1) DK123762B (enrdf_load_stackoverflow)
ES (1) ES354410A1 (enrdf_load_stackoverflow)
FR (2) FR1596453A (enrdf_load_stackoverflow)
GB (1) GB1228851A (enrdf_load_stackoverflow)
NL (1) NL6807381A (enrdf_load_stackoverflow)
NO (1) NO121611B (enrdf_load_stackoverflow)
SE (1) SE352340B (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4314055A (en) * 1975-09-29 1982-02-02 Mallinckrodt, Inc. 3,5-Disubstituted-2,4,6-triiodoanilides of polyhydroxy-monobasic acids
US5310538A (en) * 1993-03-11 1994-05-10 Sterling Winthrop Inc. Compositions of iodophenoxy alkylene ethers in film-forming materials for visualization of the gastrointestinal tract
US5348727A (en) * 1993-03-11 1994-09-20 Sterling Winthrop Inc. Compositions of iodophenoxy alkylene ethers for visualization of the gastrointestinal tract

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4314055A (en) * 1975-09-29 1982-02-02 Mallinckrodt, Inc. 3,5-Disubstituted-2,4,6-triiodoanilides of polyhydroxy-monobasic acids
US5310538A (en) * 1993-03-11 1994-05-10 Sterling Winthrop Inc. Compositions of iodophenoxy alkylene ethers in film-forming materials for visualization of the gastrointestinal tract
US5348727A (en) * 1993-03-11 1994-09-20 Sterling Winthrop Inc. Compositions of iodophenoxy alkylene ethers for visualization of the gastrointestinal tract

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DK123762B (da) 1972-07-31
FR7769M (enrdf_load_stackoverflow) 1970-03-23
FR1596453A (enrdf_load_stackoverflow) 1970-06-22
AT277452B (de) 1969-12-29
NL6807381A (enrdf_load_stackoverflow) 1968-12-02
DE1768553B1 (de) 1970-09-16
ES354410A1 (es) 1969-11-01
SE352340B (enrdf_load_stackoverflow) 1972-12-27
GB1228851A (enrdf_load_stackoverflow) 1971-04-21
BE715799A (enrdf_load_stackoverflow) 1968-11-28
CH483262A (de) 1969-12-31
CH494576A (de) 1970-08-15
NO121611B (enrdf_load_stackoverflow) 1971-03-22
AT284825B (de) 1970-09-25

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