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WO1989008101A1 - Agents de contraste de rayons x non-ioniques, compositions et procedes - Google Patents

Agents de contraste de rayons x non-ioniques, compositions et procedes Download PDF

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Publication number
WO1989008101A1
WO1989008101A1 PCT/US1989/000519 US8900519W WO8908101A1 WO 1989008101 A1 WO1989008101 A1 WO 1989008101A1 US 8900519 W US8900519 W US 8900519W WO 8908101 A1 WO8908101 A1 WO 8908101A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
bis
dihydroxypropyl
triiodoisophthalamide
radiological
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1989/000519
Other languages
English (en)
Inventor
David H. White
Youlin Lin
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.)
Mallinckrodt Inc
Original Assignee
Mallinckrodt Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mallinckrodt Inc filed Critical Mallinckrodt Inc
Priority to JP1503065A priority Critical patent/JPH0625094B2/ja
Publication of WO1989008101A1 publication Critical patent/WO1989008101A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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)
  • 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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Des composés tels que N, N'-bis(2,3-dihydroxypropyle)-5-[N-(2-méthoxyéthyle)glycolamido]-2,4,6-triiodoisophthalamide, et N, N'-bis (2,3-dihydroxypropyle)-5-[N-(2-hydroxyéthyle)méthoxyacétamido]-2,4,6-triiodoisophthalamide, sont utiles pour une utilisation comme agents de contraste de rayons X.
PCT/US1989/000519 1988-03-01 1989-02-09 Agents de contraste de rayons x non-ioniques, compositions et procedes Ceased WO1989008101A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP1503065A JPH0625094B2 (ja) 1988-03-01 1989-02-09 非イオン性ｘ線コントラスト剤、組成物及び方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16263288A 1988-03-01 1988-03-01
US162,632 1988-03-01

Publications (1)

Publication Number Publication Date
WO1989008101A1 true WO1989008101A1 (fr) 1989-09-08

Family

ID=22586472

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1989/000519 Ceased WO1989008101A1 (fr) 1988-03-01 1989-02-09 Agents de contraste de rayons x non-ioniques, compositions et procedes

Country Status (4)

Country Link
EP (1) EP0410974A4 (fr)
JP (1) JPH0625094B2 (fr)
AU (1) AU612510B2 (fr)
WO (1) WO1989008101A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011431A1 (fr) * 1990-01-31 1991-08-08 Mallinckrodt, Inc. Procede de production d'ioversol
WO1991013636A1 (fr) * 1990-03-09 1991-09-19 Cockbain, Julian, Roderick, Michaelson Milieux contrastants
WO1992009562A1 (fr) * 1990-11-21 1992-06-11 Mallinckrodt Medical, Inc. Nouveaux agents de contraste aux rayons x, composition et procede de preparation
EP0516050A3 (en) * 1991-05-31 1993-03-03 E.R. Squibb & Sons, Inc. Methods and compositions for using non-ionic contrast agents to reduce the risk of clot formation in diagnostic procedures
US5869024A (en) * 1989-11-29 1999-02-09 Bracco International B.V. Methods and compositions for using non-ionic contrast agents to reduce the risk of clot formation in diagnostic procedures
KR101833334B1 (ko) * 2016-04-29 2018-02-28 (주)유케이케미팜 신규 중간체 화합물 및 이를 이용한 이오메프롤의 제조방법
CN115160174A (zh) * 2022-07-09 2022-10-11 浙江海洲制药有限公司 一种碘佛醇的合成方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5013865A (en) * 1988-04-06 1991-05-07 Mallinckrodt, Inc. Process for the preparation of 2,4,6-triiodo-5-amino-N-alkylisophthalamic acid and 2,4,6-triiodo-5-amino-isophthalamide compounds
DE4109169A1 (de) * 1991-03-20 1992-09-24 Koehler Chemie Dr Franz Wasserloesliche nicht ionische roentgenkontrastmittel sowie mittel und verfahren zu ihrer herstellung
GB9710726D0 (en) * 1997-05-23 1997-07-16 Nycomed Imaging As Compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4364921A (en) * 1979-03-08 1982-12-21 Schering, Aktiengesellschaft Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media
US4396598A (en) * 1982-01-11 1983-08-02 Mallinckrodt, Inc. Triiodoisophthalamide X-ray contrast agent
US4474747A (en) * 1981-08-28 1984-10-02 Guerbet S.A. Process for increasing the tolerance of X-ray contrast media, and contrast media obtained thereby

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3429949A1 (de) * 1984-08-10 1986-02-20 Schering AG, 1000 Berlin und 4709 Bergkamen Neue nicht -ionische 2,4,6-trijod-isophthalsaeure-bis-amide, verfahren zu ihrer herstellung und ihre verwendung als roentgenkontrastmittel
IL86450A (en) * 1987-05-22 1994-05-30 Bracco Int Bv Process for making a history of 5-acylamino-2,4,6-triiodo and tribromo-benzoic acid, and some such new compounds
DE3731542A1 (de) * 1987-09-17 1989-03-30 Schering Ag Neue dicarbonsaeure-bis(3,5-dicarbamoyl-2,4,6-triiod-anilide), verfahren zu deren herstellung sowie diese enthaltende roentgenkontrastmittel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4364921A (en) * 1979-03-08 1982-12-21 Schering, Aktiengesellschaft Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media
US4474747A (en) * 1981-08-28 1984-10-02 Guerbet S.A. Process for increasing the tolerance of X-ray contrast media, and contrast media obtained thereby
US4396598A (en) * 1982-01-11 1983-08-02 Mallinckrodt, Inc. Triiodoisophthalamide X-ray contrast agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0410974A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5869024A (en) * 1989-11-29 1999-02-09 Bracco International B.V. Methods and compositions for using non-ionic contrast agents to reduce the risk of clot formation in diagnostic procedures
WO1991011431A1 (fr) * 1990-01-31 1991-08-08 Mallinckrodt, Inc. Procede de production d'ioversol
WO1991013636A1 (fr) * 1990-03-09 1991-09-19 Cockbain, Julian, Roderick, Michaelson Milieux contrastants
TR25738A (tr) * 1990-03-09 1993-09-01 Nycomed As Katiyonlar iceren kontrast ortami.
US5328680A (en) * 1990-03-09 1994-07-12 Nycomed Imaging As Contrast media comprising a non-ionic contrast agent with low levels of sodium & calcium ions
USRE36418E (en) * 1990-03-09 1999-11-30 Nycomed Imaging As Contrast media comprising a non-ionic contrast agent with low levels of sodium and calcium ions
WO1992009562A1 (fr) * 1990-11-21 1992-06-11 Mallinckrodt Medical, Inc. Nouveaux agents de contraste aux rayons x, composition et procede de preparation
EP0516050A3 (en) * 1991-05-31 1993-03-03 E.R. Squibb & Sons, Inc. Methods and compositions for using non-ionic contrast agents to reduce the risk of clot formation in diagnostic procedures
KR101833334B1 (ko) * 2016-04-29 2018-02-28 (주)유케이케미팜 신규 중간체 화합물 및 이를 이용한 이오메프롤의 제조방법
CN115160174A (zh) * 2022-07-09 2022-10-11 浙江海洲制药有限公司 一种碘佛醇的合成方法

Also Published As

Publication number Publication date
JPH03504124A (ja) 1991-09-12
AU4072789A (en) 1989-09-22
EP0410974A1 (fr) 1991-02-06
AU612510B2 (en) 1991-07-11
EP0410974A4 (en) 1991-09-11
JPH0625094B2 (ja) 1994-04-06

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