US3047466A - X-ray contrast agent - Google Patents

X-ray contrast agent Download PDF

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Publication number
US3047466A
US3047466A US779065A US77906558A US3047466A US 3047466 A US3047466 A US 3047466A US 779065 A US779065 A US 779065A US 77906558 A US77906558 A US 77906558A US 3047466 A US3047466 A US 3047466A
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US
United States
Prior art keywords
compounds
carbon atoms
ray contrast
general formula
compound
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Expired - Lifetime
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US779065A
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English (en)
Inventor
Priewe Hans
Poljak Alexander
Junkmann Kart
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
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Schering AG
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • 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

  • the present invention relates to X-ray contrast agents, and more particularly to X-ray contrast agents suit-able for peroral administration to serve as a contrast agent for the taking of X-ray pictures of the gall bladder and in general for cholecystography.
  • the present invention mainly comprises a compound selected from the group consisting of compounds of the followinggeneral formula:
  • R is a hydrocarbon radical of 1-6 carbon atoms, and non-toxic salts thereof.
  • the advantages of the compounds of the present invention are: considerably lower toxicity, a markedly excellent resorbability upon peroral administration, and a preferred deposition in the gall with a simultaneous increased degree of contrast development. Furthermore, the new compounds of the present invention have the advantage of being able to leave the body, if necessary, through the urinary tract, which in the case of occlusions of the bile duct represents a considerable advantage as compared to the above mentioned monoamino compounds which do not have this property.
  • the compounds of the present invention are primarily useful as radiopaque substances to be given orally for cholecystography, these compounds being given in the form of the free acids or in the form of their non-toxic salts.
  • the compounds may also, however, be given for the purpose of taking X-ray pictures of other organs than the gall bladder, such as body cavities in general.
  • the substituent R is a hydrocarbon radical of preferably 1-6 carbon atoms.
  • the substituent R is an alkyl or cycloalkyl radical of l-6 carbon atoms.
  • the compounds may be used in the form of the tree acids or in the form of non-toxic salts thereof with inorganic or organic bases.
  • suitable salts which may be mentioned are: the methylglucamine, ammonium, sodium, lithium, potassium, calcium, glucamine, ethylglucamine, ethanol-amine, diethanolamine and triethanolamine salts.
  • the compounds may be mixed with suitable pharmaceutical excipients and made up into a form suitable for 3,647,466 Patented July 31, 1962 ice 2 oral administration, for example in the form of capsules, dragees, and the like.
  • the compounds of the present invention are preferably produced by iodinating a compound having the following general formula:
  • the styrene resin may be produced according to the methods generally used in organic synthesis for the production of similar compounds, for example from 3,5-dinitrobenzoyl-acetic ester by introducing into the zit-position in known manner the desired aliphatic or cycloaliphatic radical. This is carried out, for exam le, by reacting the sodium enolate of the 3,S-dinitrobenzoyl-acetic ester in alcoholic solution with an alkyl or cycloalltyl halogenide, e.g. chloromethyl, isopropylbromide, hexyliodide, or the like. Upon hydrogenation the corresponding ,8-3,5-diaminophenyl- 8- hydroxy-a-alkyl. or cycloalkyl-propionic acid ester is obtained. By reaction with thionyl chloride, the ,B-position hydroxyl is replaced by chlorine, which is subsequently replaced by hydrogen by means of hydrogenation.
  • Example 1 18 g. of a-ethyl-B-(3,5-diaminophenyl)-propionic acidethyl ester are heated for saponifioation with a mixture of 150 cc. of 3 N sodium hydroxide and 250 cc. of methanol for 3 hours to boiling under reflux conditions. The reaction mixture is then acidified with dilute hydrochloric acid and the methanol is driven ofi under vacuum.
  • the distillation residue is diluted with ice water to 1200 cc. and 90 cc. of 2 N potassium iodide-dichloride solution is added dropwise under stirring.
  • the precipita ted sand colored precipitate is subjected to suction filtration, washed with water and dissolved in ether.
  • the solution which is dried over sodium sulfate is reacted with alcoholic sodium hydroxide which results in precipitation of the sodium salt of u-ethyl-B-(3,S-diarnino 2,4,6-triiodophenyl)spropionic acid.
  • the salt is filtered by suction, dissolved in water, and the free acid is precipitated from the aqueous solution by means of dilute hydrochloric acid.
  • the yield of the air-dried product is 24 g.
  • the melting point is above C., with decomposition.
  • the substance By treatment with benzene under cold conditions and subsequent recrystallization from a large amount of benzene, the substance is obtained in the form of practically colorless crystals having a melting point of 156.5- 157 C., with decomposition.
  • the salt may be obtained by neutralization of the acid in aqueous solution with the corresponding base, and then freezing-drying.
  • Example 2 10 kg. of the methyl-[H3,S-diamino-2,4,6 triiodophenyl)propionic acid produced according to Example 1 are kneaded in a kneading machine with 4 liters of starch paste containing 200 g. of corn starch. The wet mass is granulated in a normal manner in a granulation machine and then dried under vacuum. The finished granulate is then mixed with 1 kg. of corn starch and 50 g. of magnesium stcarate and pressed into tablets each containing 500 mg. of the active ingredient.
  • Example 3 The easily water soluble sodium salt of methyl-543,5- diamino-2,4,G-triiodophenyl)-propionic acid produced according to Example 1 is introduced into gelatin capsules filling the same. Each capsule contains 750 mg. of the active substance.
  • the sodium salt can be mixed with a 40% mixture of corn oil, soybean lecithin and cocoa fat to a flowing paste.
  • Example 4 The granulate produced according to Example 2 is with 20% of the weight thereof of sugar syrup formed into dragees in a dragee vessel, and subsequently waxed.
  • R is a hydrocarbon radical of 1-6 carbon atoms; and non-toxic salts thereof.
  • R is an alkyl radical of 1-6 carbon atoms.
  • R is a cycloalkyl radical of 1-6 carbon atoms.
  • R is an alkyl radical of l-6 carbon atoms.
  • Hal 1 wherein R is a cycloalkyl radical of 1-6 carbon atoms.
  • R is an alkyl radical of 1-6 carbon atoms.
  • R H N I R iN wherein R is a hydrocarbon radical of 1-6 carbon atoms, and non-toxic salts thereof; and pharmaceutical excipients adapted for pero-ral administration.

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  • 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)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US779065A 1957-12-18 1958-12-09 X-ray contrast agent Expired - Lifetime US3047466A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DESCH23286A DE1125589B (de) 1957-12-18 1957-12-18 Roentgenkontrastmittel

Publications (1)

Publication Number Publication Date
US3047466A true US3047466A (en) 1962-07-31

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ID=7429561

Family Applications (1)

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US779065A Expired - Lifetime US3047466A (en) 1957-12-18 1958-12-09 X-ray contrast agent

Country Status (6)

Country Link
US (1) US3047466A (instruction)
BE (1) BE573412A (instruction)
DE (1) DE1125589B (instruction)
FR (1) FR1280566A (instruction)
GB (1) GB898781A (instruction)
NL (2) NL234265A (instruction)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3419657A (en) * 1964-06-23 1968-12-31 Dagra Nv Iodopanoic acid in a hydrogel
US3542861A (en) * 1967-05-08 1970-11-24 Sterling Drug Inc 3-amino-5-cycloalkylcarbonylamino-2,4,6-triiodobenzoic acids

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2705726A (en) * 1949-07-23 1955-04-05 Sterling Drug Inc Iodinated aminophenyl-carboxylic acids
GB782313A (en) * 1954-07-26 1957-09-04 Mallinckrodt Chemical Works Manufacture of new 2:4:6-triiodobenzoic acid compounds
US2820814A (en) * 1955-03-21 1958-01-21 Schering Corp Polyiodinated 5-aminoisophthalic acids, salts, and esters
US2921884A (en) * 1957-09-30 1960-01-19 Sterling Drug Inc Pharmaceutical compositions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US705726A (en) * 1902-05-05 1902-07-29 James C Wallace Filter-bed.
DE970133C (de) * 1953-02-06 1958-08-21 Schering Ag Verfahren zur Herstellung von N-Acylderivaten der 3, 5-Diamino-2, 4, 6-trijod-benzoesaeure

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2705726A (en) * 1949-07-23 1955-04-05 Sterling Drug Inc Iodinated aminophenyl-carboxylic acids
GB782313A (en) * 1954-07-26 1957-09-04 Mallinckrodt Chemical Works Manufacture of new 2:4:6-triiodobenzoic acid compounds
US2820814A (en) * 1955-03-21 1958-01-21 Schering Corp Polyiodinated 5-aminoisophthalic acids, salts, and esters
US2921884A (en) * 1957-09-30 1960-01-19 Sterling Drug Inc Pharmaceutical compositions

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3419657A (en) * 1964-06-23 1968-12-31 Dagra Nv Iodopanoic acid in a hydrogel
US3542861A (en) * 1967-05-08 1970-11-24 Sterling Drug Inc 3-amino-5-cycloalkylcarbonylamino-2,4,6-triiodobenzoic acids

Also Published As

Publication number Publication date
DE1125589B (de) 1962-03-15
NL105700C (instruction) 1963-08-15
BE573412A (fr) 1959-03-16
GB898781A (en) 1962-06-14
NL234265A (instruction) 1963-03-15
FR1280566A (fr) 1962-01-08

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