US3666800A - Substituted triiodoisophthalamic acids - Google Patents

Substituted triiodoisophthalamic acids Download PDF

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Publication number
US3666800A
US3666800A US47886A US3666800DA US3666800A US 3666800 A US3666800 A US 3666800A US 47886 A US47886 A US 47886A US 3666800D A US3666800D A US 3666800DA US 3666800 A US3666800 A US 3666800A
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Prior art keywords
acid
triiodo
methylisophthalamic
ethyl
amino
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US47886A
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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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    • 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
    • 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

Definitions

  • the present invention relates to new compounds of the formula and to basic salts of these compounds, e.g., alkali metal salts such as, for example, sodium and potassium; alkaline earth salts such as, for example, calcium; ammonium salts such as, for example, N-methylglucamine, as well as lower aliphatic esters of up to 6 carbon atoms such as methyl, ethyl, propyl, ipropyl, n-butyl, i-butyl, n-pentyl, 2-methylbutyl, neopentyl, nhexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2 ,3-dimethylbutyl esters.
  • the R and R. are hydrogen or an alkyl radical of up to six carbon atoms and R is an alkyl radical of up to six carbon atoms.
  • the new compounds of the present invention include the following compounds as well as the above-mentioned basic salts and aliphatic esters thereof:
  • the reaction is carried out in an inert solvent such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformarnide, dimethylacetamide, tetrahydrofuran, dimethylsulfoxide and the like.
  • an inert solvent such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformarnide, dimethylacetamide, tetrahydrofuran, dimethylsulfoxide and the like.
  • a hydrogen chloride acceptor such as pyridine, N-methylmorpholine, triethyl-amine, etc., in which case the hydrogen chloride acceptor may also be used as the solvent, if desired.
  • the starting materials of formula II in which R is hydrogen are readily obtained by the procedure described by Hoey et al. [1. Med. Chem. 6, 24 (1963)].
  • the starting materials of formula II in which R is alkyl are obtained by condensing 5- arnino N-substituted-isophthalamic acids with an aldehyde, followed by reduction of the Schiff base thus obtained to the 5-alkylamino-N-substituted-isophthalamic acid.
  • the acids are reacted with an inorganic or organic base, e.g., alkali metal hydroxide such as sodium hydroxide, or amines, such as nmethylglucamine.
  • an inorganic or organic base e.g., alkali metal hydroxide such as sodium hydroxide, or amines, such as nmethylglucamine.
  • the esters may be formed by treating an alkaline solution of a compound offormula l with a di(lower alkyl) sulfate such as dimethyl sulfate or by treatment with a diazoalkane such as diazomethane.
  • the salts, especially insoluble salts frequently provide a convenient means of isolating and purifying the product.
  • the new products of fonnula l are useful as radiopaque agents for visualization of animal systems or organs, preferably in the fom'l 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.
  • physiologically acceptable salts such as sodium or methylglucamine salts
  • 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.
  • the precipitated solid is filtered, washed with dilute hydrochloric acid and dried under reduced pressure at about 100.
  • The; 5- (3-methylureido)-2,4,6-triiodo-N-methylisophthalamic acid thus obtained is a white solid melting at about l-l85 with decomposition.
  • EXAMPLE 4 S-( 3-Methylureido )-2,4,6-Triiodo-N-Ethylisophthalamic Acid Following the procedure of Example 1 but substituting an equivalent amount of -5 -amino-2,4,6-triiodo-N-ethylisophthalamic acid for the 5-amino-2,4,6-triiodoN-methylisophthalamic acid, there is obtained the desired 5-(3- methylureido)-2,4,6-triiodo-N-ethylisophthalamic acid.
  • EXAMPLE 6 5-( S-Ethylureido )-2,4,6-Triiodo-N-Ethyl-N- Methylisophthalamic Acid a. Methyl N-Ethyl-N-Methyl-S-Nitroisophthalamate A solution of 55.6 grams of 3-carbomethoxy-5-nitrobenzoyl chloride in 200 ml of carbon tetrachloride is added slowly to a well-stirred mixture of 13.5 grams of ethylmethylamine, 200 ml of water, 50 ml of acetone and 9.3 grams of sodium hydroxide. The carbon tetrachloride and acetone are removed by concentration under reduced pressure.
  • the precipitated solid is filtered, washed with water and redissolved in dilute aqueous ammonia.
  • the solution is treated with decolorizing carbon, filtered and acidified with dilute hydrochloric acid.
  • the precipitate is collected by filtration, washed with water and then recrystallized from aqueous alcohol to yield the desired N-ethyl-N-methyl-S- nitroisophthalamic acid.
  • 5-Amino-N-Ethyl-N-Methylisophthalamic Acid A mixture of 12 grams of N-ethyl-N-methyl-S- nitroisophthalamic acid, 1 gram of 5 percent palladium on carbon and l50 ml of methanol is shaken in a Parr hydrogenator under a pressure of 50 lbs/sq.in. of hydrogen. After the theoretical quantity of hydrogen has been absorbed, the mixture is filtered and the catalyst washed thoroughly with methanol. The filtrate and washings are combined and concentrated under reduced pressure to yield the desired 5- amino-N-ethyl-N-methylisophthalamic acid. d.
  • EXAMPLE 7 5-( 3 ,3-Dimethylureido )-2,4,6-Triiodo-N- Methylisophthalamic Acid To 3 grams of 5-amino-2,4,6triiodoN-methylisophthalamic acid in 25 ml of anhydrous pyridine there is added dropwise, with vigorous stirring, a solution of 1 gram of dimethylcarbamoyl chloride in l0 ml of anhydrous benzene. The reaction mixture is warmed gently to complete the reaction and then concentrated under reduced pressure to remove the benzene. The residue is poured onto a mixture of ice and 20 percent hydrochloric acid.
  • the precipitated solid is filtered, washed with dilute acid, and dried at 100 under reduced pressure to yield the desired 5-(3,3-dirnethyl-ureido)-2,4,6-trii0do-N- methylisophthalamic acid.
  • the product may be purified by solution in dilute alkali and reprecipitation with hydrochloric acid.
  • EXAMPLE 8 5-( 3-Methyll -n-Propylureido )2,4,6-Triiodo-N- Methylisophthalamic Acid a) 5-nPropylamino-N-Methylisophthalamic Acid To a solution of 9.7 grams of S-amino-N- methylisophthalamic acid in 150 ml of methanol, there is added 4 ml of propionaldehyde and the mixture hydrogenated at room temperature and atmospheric pressure using 4 grams of Raney nickel as catalyst. The catalyst is filtered off, and the filtrate concentrated under reduced pressure to yield the desired 5-n-propylamino-N-methylisophthalamic acid. b.
  • EXANIPLE 9 5-( 3 ,B-Dimethyll-n-Propylureido )-2,4,6-Triiodo-N-Methyllsophthalarnic Acid Following the procedure of Example 7 but substituting an equivalent amount of 5-n-propylamino-2,4,6-triiodo-N- methylisophthalamic acid for the 5-amino-2,4,6-triiodo-N- methylisophthalamic acid, there is obtained the desired 5- EXAMPLE l 3-Methyll -n-Propylureido )-2,4,6-Triiodo-N-Ethyl-N- Methylisophthalamic Acid a) 5-n-Propylamino-2,4,6Triiodo-N-Ethyl-N- Methylisophthalarnic Acid Following the procedure of Example 8 a,b, but substituting an equivalent amount of S-arnino-N-ethyl
  • EXAMPLE 14 a 5-Ethylamino-2,4,6-Triiodoisophtha1amic Acid Following the procedure of Example 8 a,b, but substituting an equivalent amount of S-aminoisophthalamic acid for the 5- amino-N-methylisophthalamic acid and an equivalent amount EXAMPLE l5 5-( l,3,3-Triethylureido)-2,4,6-Triiodoisophthalamic Acid Following the procedure of Example 7 but substituting an equivalent amount of 5-ethylamino-2,4,6-triiodoisophthalamic acid for the 5-amino-2,4,6-triiodo-N-methyl-isophthalamic acid and an ealuivalent amount of dieth 'l-carbamoyl chloride ere is obtained the for the dime ylcarbamoyl chloride, desired 5-( l,3,3-triethylureido)-2,4,6-triiodoiso
  • EXAMPLE l6 Ethyl 5-( 3-methylureido)-2,4,6-Triiodo-N-Methylisophthalamate To a stirred slurry of 21 grams of 5-( 3-methyl-ureido)-2,4,6 -triiodo-N-methylisophthalamic acid in ml of absolute ethanol, there is added a solution of '2.2 grams of potassium hydroxide in 50 m] of absolute ethanol. To this mixture there is added 4.5 ml of diethyl sulfate. The mixture is allowed to stir overnight and I00 ml of water added. The reaction mixture is concentrated to dryness and suspended in dilute alkali.
  • the solution is filtered and the crude ester thus obtained is the desired ethyl 5-( 3-methylureido)-2,4,6-triiodo-N- methylisophthalamate.
  • the product may be purified by solution in warm dimethylformamide, treating with decolorizing carbon and dilution of the filtrate with water to precipitate the desired ester.
  • R and R are hydrogen or alkyl of up to six carbon atoms and R is alkyl of up to six carbon atoms, as well as lower alkyl esters and physiologically acceptable salts thereof wherein the alkyl ester has up to six 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)
US47886A 1970-06-19 1970-06-19 Substituted triiodoisophthalamic acids Expired - Lifetime US3666800A (en)

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DE (1) DE2129887A1 (OSRAM)
FR (1) FR2100792A1 (OSRAM)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3914294A (en) * 1972-06-01 1975-10-21 Squibb & Sons Inc 3,5-Disubstituted-2,4,6-triiodobenzoic acids
US3953497A (en) * 1974-07-29 1976-04-27 Mallinckrodt, Inc. 2,4,6-Triiodo-5-methoxyacetamido-N-methylisophthalamic acid and salts, acyl halides and esters thereof
US4018783A (en) * 1970-09-09 1977-04-19 Beecham Group Limited Esters of metrizoic acid

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3926797B2 (ja) 2001-12-15 2007-06-06 ヘルムスドルファー インスティテュート フュアー テヒニッシェ ケラーミック エー． ファウ． ハニカム体を有する電気的な抵抗加熱エレメント

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Fieser, L. F., et al. Organic Chemistry, 3rd Edit. (1956), pub. by Reinhold Pub. Corp. page. 608 cited. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018783A (en) * 1970-09-09 1977-04-19 Beecham Group Limited Esters of metrizoic acid
US3914294A (en) * 1972-06-01 1975-10-21 Squibb & Sons Inc 3,5-Disubstituted-2,4,6-triiodobenzoic acids
US3953497A (en) * 1974-07-29 1976-04-27 Mallinckrodt, Inc. 2,4,6-Triiodo-5-methoxyacetamido-N-methylisophthalamic acid and salts, acyl halides and esters thereof

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HU163043B (OSRAM) 1973-05-28
FR2100792A1 (OSRAM) 1972-03-24
DE2129887A1 (de) 1973-07-12

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