US3660464A - Tri-iodinated diaminobenzoic acid derivatives - Google Patents

Tri-iodinated diaminobenzoic acid derivatives Download PDF

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Publication number
US3660464A
US3660464A US47908A US3660464DA US3660464A US 3660464 A US3660464 A US 3660464A US 47908 A US47908 A US 47908A US 3660464D A US3660464D A US 3660464DA US 3660464 A US3660464 A US 3660464A
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bis
tri
carboxy
adipamide
iodophenyl
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Expired - Lifetime
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US47908A
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Jack Bernstein
Kathryn Alice Losee
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • This invention relates to new radiopaque compounds of the formula COOK COOI-I a a a R 1 3 wherein R, R and R are hydrogen or lower alkyl, R is lower alkyl, X is an alkylene chain containing up to 10 carbon atoms, which may be interrupted by heterocyclic atoms such as oxygen, sulfur or and to the basic salts of these compounds, e.g., alkali metal salts such as sodium and potassium, alkaline earth salts such as calcium, ammonium salts and amine salts, such as N-methylglucamine, as well as lower aliphatic esters such as the methyl, ethyl and butyl esters.
  • the new compounds of the present invention include the following types of compounds as well as the abovementioned basic salts and aliphatic esters thereof: N,N- bis[5 (alkylureido) 3 carboxy 2,4,6-tri-iodophenyl] adipamides, such as N,N-bis [5- B-methylureido) -3 -carb oxy-2,4,6-tri-iodophenyl] adipamide,
  • N,N-bis[5- (dialkylureido -3-carboxy-2,4,6-tri-iodophenyl] adipamides such as N,N'-bis [5- (3,3-dimethylureido) -3-carboXy-2,4,6-triiodophenyl] adipamide
  • N,N-bis [5- (trialkylureido -3-carboxy-2,4,6-tri-iodophenyl] adipamides such as N ,N-bis 5 l,3,3-trimethylureido -3-carboXy-2,4,6-triiodophenyl] adipamide;
  • tri-iodophenyl] adipamides such as N,N'-diethyl-N,N'-bis [5- 3-methylureido -3-carb0xy- 2,4,6-tri-iodophenyl] adipamide;
  • N,N'-dialkyl-N,N-bis [5- (dialkylureido) -3-carboxy- 2,4,6-tri-iodophenyl] adipamides such as N,N'-diethyl-N,N'-bis 5-'( 3,3-dimethylureido -3-carboxy-2,4,fi-tri-iodophenyl]adipamide and N ,N'-diethyl-N,N'-bis [5 1,3-dimethylureid0 -3-carboxy-2,4,fi-tri-iodophenyl] adipamide; and
  • N,N-dialkyl-N,N-bis [5- (trialkylureido) -3-carboxy- 2,4,6-tri-iodophenyl] adipamides such as N,N'-diethyl-N,N'-bis [5-( 1,3,3-trimethylu1'eido) -3-carboxy-Z,4,6-tri-iodophenyl] adipamide
  • the compounds of this invention may be prepared by the reaction of a compound of formula coon coon I I I I mix rlr-co-x-co-rii rim R1 I R R R1 with an alkyl isocyanate of the formula III R NCO or a dialkylcarbamoyl halide of the formula N-CO-Y R wherein Y is halogen, preferably chlorine and R, R R R and X are as previously defined.
  • the reaction is carried out in an inert solvent such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or dimethyl formamide.
  • the reaction is preferably carried out in the presence of a hydrogen halide acceptor such as pyridine, N-methylmorpholine, triethylamine and the like.
  • a hydrogen halide acceptor such as pyridine, N-methylmorpholine, triethylamine and the like.
  • the hydrogen halide acceptor may also be used as a solvent for the reaction.
  • the compounds of the Formula II may be prepared by the iodination of a compound of the formula OOl-I coon l p-co-x co-u rim R R R with iodine chloride in aqueous medium or with sodium or potassium iododichloride in aqueous medium.
  • the compounds of Formula V in which R is hydrogen may be prepared by the reduction of a nitro compound of the formula COOH COOl-I
  • the compounds of Formula V in which R is lower alkyl may be prepared by the reduction of the Scange base of a compound of Formula V in which R is hydrogen.
  • the lower alkyl groups R, R and R include straight or branched alkyl chains of up to 6 carbon atoms such as methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, n-pentyl, Z-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • the new products of Formula I are useful as radiopaque agents for visualization of animal systems or organs, preferably in the form of physiologically acceptable salts such as sodium or methylglucamine salts for the preparation of solutions for intravascular injection for urography and for vasographic techniques such as angiocardiography, arteriography, nephrography and venography.
  • the water-insoluble esters are useful in visualizing hollow organs and cavities having external orifices through which the contrast preparation can be introduced in preparation for the examination and removal after the examination is completed. Solutions having about to bound iodine, preferably about 37%, may be used, or on a weight basis from about 20 g. to about g. of a compound of Formula I per ml. of water.
  • the product is then suspended in dilute hydrochloric acid, filtered and washed with water to yield the desired N,N'-bis[5- nitro-3-carboxyphenyl]adipamide.
  • the product may be purified by crystallization of the ammonium salt and conversion to the free acid, which melts at about 300.
  • the solid is washed with water and dried at 50 under reduced pressure to yield the desired N,N'-bis[5-amino 3 carboxy-2,4,6-tri-iodophenyl]adipamide.
  • the product which does not melt below 300, may be purified by crystallization of its ammonium salt.
  • the precipitated solid is filtered, washed with water and dried under reduced pressure at 100 to yield the desired N,N'-bis[5-(3-methylureido) 3 carboxy-2,4,6-tri-iodophenyl] adipamide.
  • the precipitated solid is filtered, dissolved in dilute aqueous sodium hydroxide and treated with decolorizing carbon.
  • the solution is filtered and made strongly acid with hydrochloric acid.
  • the solid is filtered, Washed with water and dried at 60 under reduced pressure to yield the desired N,N-bis[5-(3,3-dimethylureido)-3-carboxy-2,4,6-tri iodophenyl1adipamide.
  • EXAMPLE 6' N,N'-bis [5-( l-ethyl-3-methylureido) -3-carboxy- 2,4,6-tri-iodophenyl] adipamide (a) N,N' bis[5 ethylamino 3 carboxyphenyl] adipamide.A mixture of 10 grams of N,N-bis[5-amino- 3-carboxyphenyl1adipamide and 5 ml. of acetaldehyde in 200 ml. of absolute ethanol is allowed to stand for 12 hours and is then hydrogenated at room temperature and pressure using 5 grams of Raney niekel'as the catalyst. The catalyst is filtered and the filtrate concentrated under reduced pressure to yield the desired N,N'-bis[5-ethylamino-3-carboxyphenyl]adipamide. The product may be purified by crystallization from aqueous alcohol.
  • R, R and R are hydrogen or lower alkyl of up to 6 carbon atoms, R is lower alkyl of up to 6 carbon atoms, X is an alkylene chain of up to 10 carbon atoms which may be interrupted by heterocyclic atoms selected from the group consisting of oxygen, sulfur or as well as lower alkyl esters and physiologically acceptable salts thereof wherein the alkyl ester has up to 6 carbon atoms.

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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)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US47908A 1970-06-19 1970-06-19 Tri-iodinated diaminobenzoic acid derivatives Expired - Lifetime US3660464A (en)

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US (1) US3660464A (OSRAM)
CH (1) CH542822A (OSRAM)
DE (1) DE2130369A1 (OSRAM)
FR (1) FR2100793B1 (OSRAM)
HU (1) HU163045B (OSRAM)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4014986A (en) * 1974-05-31 1977-03-29 Laboratoires Andre Guerbet X-ray contrast media
US4065553A (en) * 1974-05-31 1977-12-27 Laboratoires Andre Guerbet X-Ray contrast media
US4132731A (en) * 1976-06-25 1979-01-02 Schering Aktiengesellschaft Novel iodized isophthalamic acid compounds
US4239747A (en) * 1976-06-23 1980-12-16 Schering Aktiengesellschaft Dicarboxylic acid bis(3,5-dicarbamoyl-2,4,6-triiodoanilides) useful as x-ray contrast agents
US4395391A (en) * 1980-11-25 1983-07-26 Schering Aktiengesellschaft Unsymmetrically substituted dicarboxylic-acid-bis-(2,4,6-triiodo-anilides), their preparation, and x-ray contrast media containing same
US5066823A (en) * 1987-05-22 1991-11-19 Bracco Industria Chemica S.P.A. Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives
WO2019177740A1 (en) * 2018-03-12 2019-09-19 Boston Scientific Scimed, Inc. Scavenging methods, and scavenging system for radiocontrast agents
US11597792B2 (en) * 2017-10-30 2023-03-07 The Texas A&M University System Radiopaque thermoplastic polymer
US12527871B2 (en) 2019-06-05 2026-01-20 Boston Scientific Scimed, Inc. Click chemistry capturable platinum-based antineoplastic agents

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3660469A (en) * 1969-08-04 1972-05-02 Squibb & Sons Inc Bis-triiodoisophthalamic acid compounds

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4014986A (en) * 1974-05-31 1977-03-29 Laboratoires Andre Guerbet X-ray contrast media
US4065553A (en) * 1974-05-31 1977-12-27 Laboratoires Andre Guerbet X-Ray contrast media
US4065554A (en) * 1974-05-31 1977-12-27 Laboratoires Andre Guerbet X-ray contrast media
US4239747A (en) * 1976-06-23 1980-12-16 Schering Aktiengesellschaft Dicarboxylic acid bis(3,5-dicarbamoyl-2,4,6-triiodoanilides) useful as x-ray contrast agents
US4132731A (en) * 1976-06-25 1979-01-02 Schering Aktiengesellschaft Novel iodized isophthalamic acid compounds
US4395391A (en) * 1980-11-25 1983-07-26 Schering Aktiengesellschaft Unsymmetrically substituted dicarboxylic-acid-bis-(2,4,6-triiodo-anilides), their preparation, and x-ray contrast media containing same
US5066823A (en) * 1987-05-22 1991-11-19 Bracco Industria Chemica S.P.A. Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives
US11597792B2 (en) * 2017-10-30 2023-03-07 The Texas A&M University System Radiopaque thermoplastic polymer
WO2019177740A1 (en) * 2018-03-12 2019-09-19 Boston Scientific Scimed, Inc. Scavenging methods, and scavenging system for radiocontrast agents
US11213596B2 (en) 2018-03-12 2022-01-04 Boston Scientific Scimed, Inc. Radiocontrast agents, scavenging methods, and scavenging system
US12527871B2 (en) 2019-06-05 2026-01-20 Boston Scientific Scimed, Inc. Click chemistry capturable platinum-based antineoplastic agents

Also Published As

Publication number Publication date
FR2100793B1 (OSRAM) 1974-08-30
FR2100793A1 (OSRAM) 1972-03-24
DE2130369A1 (de) 1971-12-23
HU163045B (OSRAM) 1973-05-28
CH542822A (fr) 1973-10-15

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