Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
• • 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

Definitions

• This invention relates to iodine-bearing X-ray contrast agents, and particularly to compounds and compositions which preferentially make the gall bladder and bile ducts radiopaque after oral ingestion.
• the cholecystographic properties of the compounds were determined by the method of J. O. Hoppe (J. Amer. Pharm. Assoc., Sci. Ed. 48, 368-379, 1959) and were evaluated in the Hoppe Index scale on which 0 indicates no X-ray image, 1 a weak, 2 an adequate, 3 a good, and and 4 an excellent opacity and contrast quality of the image.
• the visibility of the bile ducts is indicated in the Table on an arbitrary, but reproducible scale on which indicates no image or only an occasion image, indicates visibility in all instances, and indicates an image of superior detail.
• the cholecystographic tests were performed on dogs (1) or on cats (2) at a dosage rate (a) of mg./kg. body weight or (b) of 200 mg./kg. body weight, all test compounds being administered orally. Hoppe Index values were determined 2, 4, 6, 8, and 24 hours after ingestion.
• the compounds of the invention are significantly better tolerated than Compounds I and K which are now in Wide clinical use. Their Hoppe Index values are better than or at least as good as those of all other tested compounds, and they are unique in their ability of precisely and reliably visualizing the bile ducts in a manner not possible heretofore except after intravenous injection of the contrast agents.
• the compounds of the invention may be employed at higher dosage rates than conventional X-ray contrast agents which are administered orally. Because of the rapid excreation of the contrast agents of this invention and because of the absence of residues in the intestine, frequently observed with known orally applied radiopaque materials, such higher dosage rates are permissible with the compounds of the invention without causing disturbing side effects.
• the compounds of the invention may be employed in the form of the free carboxylic acids or as salts with metals and amines which are physiologically tolerated when orally administered in amounts suificient for cholecystography.
• the alkali metal salts such as the sodium and lithium salts, the alkaline earth metal salts, particularly the magnesium and calcium salts, and salts of alkanolamines are preferred.
• Suitable alkanolamines include N- methylglucamine, N-methylxylamine (l-methylamino-ldesoxy- [D] -xylite) 1-methylamino-2, 3-propanediol, ethanolamine, and diethanolamine.
• Other suitable alkanolamines will readily suggest themselves to the pharmaceutical chemist.
• the free acids and their salts may be compounded individually or as mixtures in radiopaque compositions.
• the compounds of the invention may be prepared by reacting a 3-carbamoyl-2,4,6-triiodophenol of the formula with a reactive derivative of 3-alkoxy-Z-alkylpropionic acid of the formula nol may be employed in the form of the corresponding alkali metal phenolate.
• the preferred reactive derivatives are the 3-haloethoxy-Z-alkylpropionic acid esters and the 3-alkylsulfonyloxy-or 3-arylsulfonyloxyethoxy-2-alkylpropionic acid esters, and the condensation products are saponified after ether formation to obtain the free acid or the salt to be employed as an X-ray contrast agent.
• EXAMPLE 1 27.5 g. Sodium 3-N-methylcarbamoyl-2,4,6 triiodophenolate (0.05 mole) was dissolved in 50 ml. dimethylformamide, and 16.5 g. 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester (0.055 mole) was added with stirring at 70 C. over a period of to 20 minutes. The reaction mixture was heated to NW C., and stirring was continued for 16 hours at that temperature. The mixture was then cooled to ambient temperature and poured into 500 ml. water. An oily product precipitated and gradually solidified. It was separated from the supernatant liquid and dissolved in ethyl acetate.
• EXAMPLE 2 11.3 g. Sodium 3-N ethylcar-bamoyl 2,4,6 triiodophenolate (the sodium salt of 3-hydroxy-2,4,6-triiodo- N-ethylbenzamide, 0.02 mole) was dissolved in 200 ml. dimethylformamide, and the solution was heated at 90 C. for 15 hours with 6.6 g. 3--(2-iodoethoxy)-2-ethylpropionic acid ethyl ester (0.022 mole). The ethyl ester of Compound A was obtained in an amount of "10.5 g. (73.5% yield) and melted at -8 2 C. when recrystallized from aqueous ethanol. The same result was achieved by using 4.6 g. of the less costly 3-(2-chloroethoxy)-2- ethylpropionic acid ethyl ester with 3-4 g. sodium iodide.
• EXAMPLE 3 22 g. 3-N-Methylcarbamoyl-2,4,6-triiodophenol sodium salt was dissolved in 40 ml. dimethylformamide. 7.9 g. 3-(2-Chloroethoxy)-2-methy1propionic acid methyl ester was added, and the mixture was stirred at C. for 20 hours to form the methyl ester of Compound C. When recrystallized from a small amount of ethyl acetate, the ester melted at 7475 C. and had an R value of 0.56 in a thin layer chromatogram on silica gel (chloroform/ glacial acetic acid 19:?1).
• the 3-(2-chloroethoxy)-2-methylpropionic acid methyl ester employed as a starting material is prepared in a manner analogous to the preparation of the homologus ethyl ester described in Example 1.
• Methylmalonic acid diethyl ester was reacted with 20 g. sodium hydride and 103.2 g. 2-chloroethoxymethyl chloride to 118.7 g. 2-(2-chloroethoxymethyl)-2- methylmalonic acid diethyl ester boiling at 132139 C./ 4 mm. Hg.
• the ester was saponified with 42 g. sodium hydroxide to 2-(2-chloroethoxymethyl) 2 methylmalonic acid which was partly decarboxylated to form 3-(2- chloroethoxy)-2-methylpropionic acid.
• the free acid was converted by means of diazomethane to the desired methyl ester which boiled at 103 105 C./ 16 mm. Hg.
• EXAMPLE 4 13.4 g. Sodium 3-N-ethylcarbamoyl-2,4,6-triiodophenolate was dissolved in 30 ml. dimethylformamide and reacted with 7.65 g. 3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester or with 5.16 g. 3-(2-chloroethoxy)-2-methylpropionic acid ethyl ester in the presence of 4.5 g. so-
• the acid is practically insoluble in water, but dissolves readily in aqueous solutions of the afore-mentioned bases to form the corresponding salts which were readily obtained in solid form by evaporating the solutions in a vacuum.
• the 3-(2-alkylor -arylsulfonyloxyethoxy)-2-methylor -ethylpropionic acid esters generally give better yields than the analogous 3-(2-haloethoxy)-2-methylor -ethylpropionic acid alkyl esters, the highest yields being generally produced by means of the 3-(2-benzenesulfonyloxyethoxy)-2-ethylpropionic acid ethyl ester.
• the condensation reactions may also be performed in ethanol, methoxyethanol, methylethylketone and other alochols and ketones in which the alkali metal phenolates are not readily soluble.
• the phenols are reacted in the alcohls in the presence of an alkali metal alcoholate corresponding to the alcohol employed as a solvent medium (for example, NaO-C H and NaOC H OCH with the afore-mentioned alcohols).
• An alkali metal carbonate such as potassium carbonate, is preferably employed as a basic condensation agent when the solvent is a ketone.
• the compounds of the invention are compounded with excipient in the manner conventional in galenic pharmacy for convenient oral administration.
• the free acids and the metal or amine salts may be combined with suitable carriers, diluents, coatings, or ingestible containers to produce dosage units which are capsules, granulates, tablets, drages, globuli, suspensions or solutions.
• the liquid compositions may also be administered rectally, but oral administration is preferred.
• the compounds of the invention are perferably micronized before being combined with other solid ingredients transparent to X-rays. Quicker absorption and denser shadows are normally obtained by the micronized compounds than by other forms, while no intestinal residues interfering with observation of the gall bladder or the bile ducts are formed.
• EXAMPLE 6 Compound A was micronized to a particle size of less than 4 2, and the fine powder was mixed intimately with 20.4 g. Pluronic F68, a surface active material obtained by subjecting polypropyleneglycol to condensation with ethylene oxide, which is a solid at normal ambient temperature and prevents aggregation of the fine particles. The mixture was driven through a stainless steel screen having 324 openings per square centimeter, and 20.4 g. microcrystalline starch were admixed.
• Pluronic F68 a surface active material obtained by subjecting polypropyleneglycol to condensation with ethylene oxide, which is a solid at normal ambient temperature and prevents aggregation of the fine particles.
• the mixture was driven through a stainless steel screen having 324 openings per square centimeter, and 20.4 g. microcrystalline starch were admixed.
• the resulting mixture was moistened with enough distilled water to permit the mass to be granulated by passage through a screen having 56 openings per square centimeter.
• the granulate was dried in an air stream at 40 C., mixed with 7.2 g. magnesium stearate as a lubricant, and distributed uniformly in 600 soft gelatin capsules containing each 500 mg. of the active compound.
• EXAMPLE 7 3 kg. Compound B was kneaded mechanically into a dough-like mass with 2 liters starch paste containing g. corn starch. When the moist mass was tacky, a little dry starch was added. The mixture was then granulated on a granulating dish, and the granulate was dried in a vacuum. The dry granules were further mixed with 0.5 kg. corn starch and 25 g. magnesium stearate, and compressed to tablets containing each 500 mg. of the active ingredient.
• EXAMPLE 8 The sodium salt of Compound D in an amount of 5 kg. was mixed intimately with 0.75 kg. granulated sugar, and 0.75 kg. corn starch. The mixture was moistened with one liter 50% aqueous ethanol and then granulated. The granulate was dried, screened, mixed with 0.65 kg. corn starch, 0.05 kg. talcum, and 0.05 kg. magnesium stearate and pressed to make 10,000 tablets.
• EXAMPLE 9 Granules containing Compound A as the active ingredient were prepared as described in Example 1. They were coated in a kettle with sugar syrup in a weight ratio of 3:1, and the pills so formed were waxed whan dry.

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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)

Applications Claiming Priority (1)

Publications (1)

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Family Applications (1)

Country Status (26)

Cited By (11)

• 1971
  • 1971-06-23 CH CH914771A patent/CH545628A/xx not_active IP Right Cessation
• 1972
  • 1972-03-16 DE DE2212741A patent/DE2212741C3/de not_active Expired
  • 1972-03-29 AT AT270872A patent/AT315150B/de not_active IP Right Cessation
  • 1972-03-29 AT AT270972A patent/AT313469B/de not_active IP Right Cessation
  • 1972-04-17 RO RO7270578A patent/RO68261A/ro unknown
  • 1972-04-19 DD DD162404A patent/DD95912A5/xx unknown
  • 1972-04-26 ES ES402140A patent/ES402140A1/es not_active Expired
  • 1972-04-27 NL NL7205712.A patent/NL157798B/xx unknown
  • 1972-05-01 IL IL39329A patent/IL39329A/xx unknown
  • 1972-05-05 ZA ZA723058A patent/ZA723058B/xx unknown
  • 1972-05-12 CA CA141,950A patent/CA957371A/en not_active Expired
  • 1972-05-17 CS CS7200003361A patent/CS182769B2/cs unknown
  • 1972-05-25 SE SE7206802A patent/SE391178B/xx unknown
  • 1972-05-29 JP JP47052580A patent/JPS529666B1/ja active Pending
  • 1972-05-31 BG BG20617A patent/BG20336A3/xx unknown
  • 1972-06-01 US US00258777A patent/US3825591A/en not_active Expired - Lifetime
  • 1972-06-07 FI FI1618/72A patent/FI53660C/fi active
  • 1972-06-12 FR FR7221086A patent/FR2142986B1/fr not_active Expired
  • 1972-06-19 BE BE785109A patent/BE785109R/xx active
  • 1972-06-20 BR BR4002/72A patent/BR7204002D0/pt unknown
  • 1972-06-20 PL PL1972156140A patent/PL90341B1/pl unknown
  • 1972-06-21 PH PH13646A patent/PH10571A/en unknown
  • 1972-06-21 AU AU43716/72A patent/AU461847B2/en not_active Expired
  • 1972-06-21 SU SU1801083A patent/SU451237A3/ru active
  • 1972-06-21 DK DK309472AA patent/DK128108B/da unknown
  • 1972-06-22 HU HUBA2764A patent/HU163382B/hu unknown
• 1979
  • 1979-03-28 IT IT7921397A patent/IT7921397A0/it unknown

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