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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring

Definitions

• This invention relates to X-ray contrast agents and, more particularly, to novel nonionic X-ray contrast agents, radiological compositions containing such agents and methods for X-ray visualization utilizing such compositions .
• Nonionic contrast agents for intravascular and central nervous system visualization are complex molecules.
• the iodine in the molecule provides opacification to the x-rays.
• the remainder of the molecule provides the framework for transport of the iodine atoms.
• the structural arrangement of the molecule is important in providing stability, solubility and biological safety in various organs.
• a stable carbon-iodine bond is achieved in most compounds by attaching it to an aromatic nucleus.
• An enhanced degree of solubiity as well as safety is conferred on the molecule by the addition of suitable solubilizing and detoxifying groups.
• intravascular and central nervous system nonionic contrast agents are often incompatible so that all such agents represent compromises.
• the controlling factors are pharmacological inertness; i.e., in vivo safety and high water solubility.
• the ideal intravascular or central nervous system nonionic agent represents a compromise in an attempt to obtain the following criteria: (1) maximum opacif ication to x-rays; (2) pharmacological inertness; (3) high water solubility; (4) stability; (5) selective excretion; (6) low viscosity; and (7) minimal osmotic effects.
• non-ionic contrast agents which meet all or substantially all the foregoing criteria.
• X is selected from the group consisting of hydroxymethyl and methoxymethyl and Y is selected from the group consisting of hydroxy and methoxy.
• the invention is specifically directed to the compounds N,N'-bis(2,3-dihydroxypropyl)-5-(N-(2-methoxyethyl)glycolamido]-2,4,6-triiodoisophthalamide and N,N'-bis-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-methoxyacetamido]-2,4,6-triiodoisophthalamide.
• the invention is also directed to radiological compositions containing such compounds and methods for utilizing such compounds in x-ray visualization.
• compounds of the formula set out above are suitable for use as nonionic x-ray contrast agents. More specifically in the practice of the invention, the compounds N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-methoxyethyl)glycolamid ⁇ ]-2,4,6-triiodoisophthalamide and N,N'-bis- (2,3-dihydroxypropyl)-5- ⁇ N-(2-hydroxyethyl)-methoxyacetamido]-2,4,6-triiodoisophthalamide may be used as nonionic x-ray contrast agents. These agents may be used in various radiographic procedures including those involving cardiography, coronary ar teriography, aortography, cerebral and peripheral angiography, orthography, intravenous pyelography and urography.
• radiological compositions may be prepared containing one of the aforementioned compounds as an x-ray contrast agent together with a pharmaceutically acceptable radiological vehicle.
• Radiological vehicles include those that are suitable for injection such as aqueous buffer solutions; e.g., tris(hydroxymethyl) amino methane (and its salts), phosphate, citrate, bicarbonate, etc., sterile water for injection, physiological saline, and balanced ionic solutions containing chloride and/or bicarbonate salts of normal blood plasma cations such as Ca, Na, K and Mg.
• aqueous buffer solutions e.g., tris(hydroxymethyl) amino methane (and its salts), phosphate, citrate, bicarbonate, etc.
• sterile water for injection physiological saline
• physiological saline e.g., sterile water for injection
• physiological saline e.g., sterile water for injection
• physiological saline e.g., sterile water for injection
• physiological saline e.g., sterile water for injection
• physiological saline e.g., sterile water for
• the concentration of the x-ray contrast agents of the invention in the pharmaceutically acceptable vehicle varies with the particular field of use. A sufficient amount is present to provide satisfactory x-ray visualization. For example, when using aqueous solutions for angiography, the concentration of iodine is generally 140-400 mg/ml and the dose is 25-300 ml.
• the radiological composition is administered so that the contrast agent remains in the living animal body for about 2 to 3 hours, although both shorter and longer residence periods are normally acceptable.
• N,N'-bis-(2,3-dihydroxypropyl)-5-[N-(2-methoxyethyl)glycolamido]-2,4,6triiodoisophthalamide and N,N'-bis(2,3-dihydroxypropyl) 5-[N-(2-hydroxyethyl)-methoxyacetamido]-2,4,6-triiodoisophthalamide may be formulated for vascular visualization conveniently in vials or ampoules containing 10 to 500 ml. of an aqueous solution.
• the radiological compositions of the invention may be used in the usual way in x-ray procedures. For example, in the case of selective coronary arteriography, a sufficient amount of the radiological composition to provide adequate visualization is injected into the coronary system and then the system is scanned with a suitable device such as a fluoroscope.
• N,N'-bis(2,3-dihydroxypropyl)-5-[N-( 2-methoxyethyl)glycolamido]-2,4,6-triiodoisophthalamide and N,N'-bis(2,3-dihydroxypro ⁇ yl)-5-[N-(2-hydroxyethyl)- methoxyacetamido]-2,4,6-triiodoisophthalamide and the intermediates therefor may be prepared in accordance with the procedures set out below. All temperature designations are in degrees centigrade. The following examples illustrate the practice of the invention.
• the acute intravenous toxicities of the compounds of Examples 1 and 2 were determined as follows.
• a solution of the compounds of Example 1 and 2 was injected into the lateral tail vein of young adult male and female mice (Sasco mice in the case of the compound of Example 1 and Charles River mice in the case of the compound of Example 2) at the rate of 1 ml/min. Following injections, the animals were observed for immediate reactions and then daily throughout a seven day observation period.
• the LD 50 values were calculated by the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Therap. 96:99-113, 1949) with the following results.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1989
  • 1989-02-09 EP EP19890903414 patent/EP0410974A4/en not_active Withdrawn
  • 1989-02-09 AU AU40727/89A patent/AU612510B2/en not_active Ceased
  • 1989-02-09 WO PCT/US1989/000519 patent/WO1989008101A1/en not_active Application Discontinuation
  • 1989-02-09 JP JP1503065A patent/JPH0625094B2/ja not_active Expired - Lifetime

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