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WO1994005337A1 - Agents de contraste aux rayons x non ioniques, compositions et procedes - Google Patents

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

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Publication number
WO1994005337A1
WO1994005337A1 PCT/US1993/008056 US9308056W WO9405337A1 WO 1994005337 A1 WO1994005337 A1 WO 1994005337A1 US 9308056 W US9308056 W US 9308056W WO 9405337 A1 WO9405337 A1 WO 9405337A1
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Prior art keywords
chloride
group
amino
compound
chohch
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PCT/US1993/008056
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English (en)
Inventor
Mills T. Kneller
Youlin Lin
James Wheatley
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Mallinckrodt Medical, Inc.
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Application filed by Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Priority to AU50939/93A priority Critical patent/AU5093993A/en
Publication of WO1994005337A1 publication Critical patent/WO1994005337A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms

Definitions

  • This invention relates to novel X-ray contrast agents, methods of preparing them, 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, while 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 solubility as well as safety is conferred on the molecule by the addition of suitable solubilizing and detoxifying groups.
  • nonionic contrast agents are particularly desirable compared to contemporary ionic agents due to the minimization of those pharmacological effects associated with colligative properties, e.g., osmolality.
  • 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 opacification to X-rays; (2) pharmacological inertness; (3) high water solubility; (4) stability; (5) selective excretion; (6) low viscosity; and (7) minimal osmotic effects.
  • Illustrative nonionic contrast agents include N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide (Lin, U.S. Patent No. 4,396,598) and 5-N-(2,3-dihydroxypropyl)acetamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (Nordal et al., U.S. Patent No. 4,250,113 and Rakli et al. U.S. Patent No. 4,396,597).
  • nonionic contrast agents which meet all or substantially all of the foregoing criteria. It is an object of the present invention to provide nonionic X-ray contrast agents which substantially meet these criteria. It is a further object of this invention to provide nonionic X-ray contrast agents with improved pharmacological inertness, i.e., low toxicity, by means of the incorporation of highly hydrophilic side chains. It is a still further object of this invention to provide chemically stable nonionic X-ray contrast agents having low osmolality. Other objects and features will be in part apparent and in part pointed out hereinafter. Summary of the Invention
  • R 1 is N(CH 2 CH 2 OH)CH 2 CHOHCH 2 OH
  • R 2 equals R 1 , NHCH 3 , NHCH 2 CH 2 OH, N(CH 3 )CH 2 CH 2 OH or NHCH,CHOHCH 2 OH
  • R 3 equals CH 3 , CH 2 CH 3 , CH 2 OH, CH(CH 3 )OH, CH(CH 3 )OCH 3 , CHOHCH 2 OH, CH 2 OCH 3 , or CH 2 OCH 2 CH 3
  • R 4 equals H, CH 3 , CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CHOHCH 2 OH, or CH 2 CHOHCH 2 OCH 3
  • R 3 , R 4 , and the 5-N together form the group
  • n 0, 1, 2 or 3, preferably 0 or 1 and q equal ' s 0, 1, 2 or 3, but preferably 1, 2 or 3.
  • the present invention is also directed to dimers of the above compound connected at the 5-N position by means of a diamide, thus:
  • R 1 and R 2 have the meanings given above;
  • R 5 is H, CH 3 , CH 2 CH 2 OH, CH 2 CHOHCH 2 OH, and CH 2 OCH 3 ; and m equals 0-4, preferably 0-2.
  • the present invention is further directed to methods for making such compounds by incorporation of an amino-alcohol, 3-(N-2-hydroxyethyl)amino-1,2-propanediol, and methods of making this amino-alcohol.
  • the invention is also directed to radiological compositions containing such compounds and methods for utilizing such compounds in X-ray visualization.
  • an advantage of using 3-(N-2-hydroxyethyl)amino-1,2-propanediol is to provide even higher hydrophilicity for the contrast molecule due to the introduction of an additional hydroxyl group.
  • This highly hydrophilic amino-triol can confer water-solubility and improve the safety of X-ray contrast media.
  • nonionic X-ray contrast agents are suitable for use as nonionic X-ray contrast agents. More specifically in the practice of the invention, the compounds may be used as nonionic X-ray contrast agents. These agents may be used in various radiographic procedures including those involving cardiography, coronary arteriography, aortography, cerebral and peripheral angiography, arthrography, intravenous pyelography and urography.
  • Each of the compounds of the present invention has at least one amide group derived from the amino-alcohol, 3-(N-2-hydroxyethyl)amino-1,2-propanediol.
  • This starting material may be prepared by reacting glycidol with ethanolamine under epoxide-opening conditions or by reacting 3-chloro-1,2-propanediol with ethanolamine under secondary amine-forming conditions and neutralizing the hydrochloride salt thus formed.
  • the Smiles rearrangement can be avoided when the 5-amino group is either a 5-methoxyacetylamino (methoxyacetamido) or a 5-ethoxyacetylamino moiety to give the compounds of the present invention wherein R 3 equals CH 2 OCH 3 or CH 2 OCH 2 CH 3 .
  • the resulting compounds do not undergo the Smiles rearrangement.
  • U.S. Patent No. 4,396,597 teaches that compounds with a 5-[N-( ⁇ -hydroxyalkyl)acetylamino] group are unstable and undergo a base catalyzed cyclization and iodine elimination which renders this class of compounds less useful as X-ray contrast media.
  • An example of such a compound is 5-N-(2,3- dihydroxypropyl)acetamido-2,4,6,-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide.
  • the '597 patent further teaches that this problem may be overcome by utilizing a temperature dependent buffer.
  • the cyclization and deiodination problem may also be averted by replacing the 5-N-( ⁇ -hydroxyalkyl) group with 5-N-( ⁇ -methoxyalkyl) group.
  • This replacement in compounds of the invention that is wherein R 4 equals CH 2 CH 2 OCH 3 , yields a compound that is stable to cyclization and iodine elimination at near neutral to basic pH.
  • the hydroxyl substitution of the lactam structure has the advantage of increasing the water solubility as needed for X-ray contrast compounds.
  • the present invention also includes dimeric compounds.
  • Hyperosmolality is known to cause vascular pain during the injection of an X-ray contrast agent.
  • high osmolality has been shown to be an important factor in perturbation of the normal heart functions at the time of cardioangiography.
  • the main advantage of the dimers of the present invention is the low osmolality with concomitant low toxicity. This is achieved by highly soluble dimeric compounds having six iodine atoms per molecule as provided by the present invention. At a fixed iodine concentration, these compounds exhibit significantly lower osmotic effects than equivalent monomeric agents due to reduced number of solvated particles in the solution.
  • the dimeric compounds of the present invention provide this advantage while maintaining acceptable solubility characteristics due to the high hydrophilicity of the amino-alcohol side chains.
  • radiological compositions may be prepared containing one of the aforementioned compounds of the invention 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 bu f fer solut ions ; e . g . , tris(hydroxymethyl)aminomethane (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. Other buffer solutions are described in Remington's Practice of Pharmacy, Eleventh Edition, for example on page 170.
  • the vehicles may contain a chelating amount, e.g., a small amount, of ethylenediamine tetraacetic acid, the calcium disodium salt, or other pharmaceutically acceptable chelating agent.
  • 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.
  • concentration of iodine is generally 140-440 mg/ml and the dose is 25-300 ml.
  • the radiological compositions of the invention may be used in the usual way in X-ray procedures .
  • 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.
  • R 1 and R 2 are the same are N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-5-acetamido-2,4,6-triiodoisophthalamide; N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl] -5-hydroxyacetamido-2,4,6-triiodoisophthalamide; N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-5-(2-hydroxy)propionamido-2,4,6-triiodoisophthalamide; N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-5-methoxyacetamido-2,4,6-triiodoisophthalamide; N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-5-[N-(2-hydroxyethyl)
  • 5-amino-2,4,6-triiodoisophthaloyl chloride which may be made from 5-amino-2, 4, 6-triiodoisophthalic acid, which is disclosed in U.S. Patent No. 4,396,598, incorporated herein by reference.
  • the 5-amino group may first be substituted under amide-forming conditions to form the desired amide and the resulting compound reacted with 3-(N-2-hydroxyethyl)amino-1,2-propanediol under amide-forming conditions to add the desired amide to the 1 and 3 carbonyl groups.
  • Examples of the compounds that may be used to react with the 5-amine are acetyl chloride, acetoxyacetyl chloride, 2-acetoxypropionyl chloride, and methoxyacetyl chloride.
  • the acetoxy groups may later be hydrolyzed to produce a hydroxy group by various means, including acid hydrolysis or ion-exchange resins.
  • alkyl halides for example, methyl halides, such as methyl iodide; 2-haloethylacetates, such as 2-bromoethylacetate; 2-haloethanols, such as 2-chloroethanol; and 2-haloethyl methyl ethers, such as 2-bromoethyl methyl ether.
  • substitution of the 5-amino group to form the cyclic butyrolactamide is also generally preferred to follow addition of the amino-alcohol.
  • Substitution of the amine may be accomplished by the addition, under amide-producing conditions, of various butyryl acid halides, such as 4-chlorobutyryl chloride, 2-acetoxy-4-(methylthio)butyryl chloride, or 2,4-dibromobutyryl bromide. Use of the latter two will result in a hydroxy- substituted lactamide following hydrolysis. Cyclization of the butyramide chain is caused by exposure to cyclizing conditions appropriate to the starting material.
  • the cyclization may be accomplished by using alkaline alcohol mixtures, such as methanol and aqueous sodium hydroxide mixtures.
  • alkaline alcohol mixtures such as methanol and aqueous sodium hydroxide mixtures.
  • 2-acetoxy-4-(methylthio)butyryl chloride is used, the methyl iodide of the butyramide is preferably formed first, followed by treatment with alkaline alcohol.
  • acetate groups Prior to addition of the butyryl group it is preferred to protect the hydroxyl groups of the amides, preferably by means of acetate groups. This may be simply done by any acetate addition method under suitable protecting conditions, such as by using acetic anhydride under ester-forming conditions, such as in the presence of a base, for example, pyridine. These protecting acetate groups and the one from 2-acetoxy-4-(methylthio)butyryl chloride, if used, can then be removed by hydrolysis utilizing various conditions such as using an aqueous sodium hydroxide and methanol mixture.
  • R 2 does not equal R 1
  • R 2 substitution is preferably made first, followed by a substitution at the 5-amino group.
  • the intermediate compound 5-amino-2,4,6-triiodo-3-N-methylaminocarbonylbenzoic acid chloride may be used to produce compounds wherein R 2 equals NHCH 3 .
  • 5-Amino-2,4,6-triiodo-3-[N-(2-hydroxyethyl)aminocarbonyl]benzoic acid or the acid chloride is used to produce compounds wherein R 2 equals NHCH 2 CH 2 OH.
  • the hydroxyl group is preferably protected during later steps by means of an acetate group as described above.
  • the intermediate compounds may be prepared from 5-nitroisophthalic acid monomethyl ester via well- established synthetic routes. See, for example, U.S. Patent No. 3,290,366, incorporated herein by reference, and European Application 0 308 364.
  • R 2 does not equal R 1
  • examples of such compounds, wherein R 2 does not equal R 1 are [N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-DL-5- ⁇ -hydroxypropionylamino-2, 4, 6-triiodo-3-N-methylaminocarbonylbenzamide, [N-(2,3-dihydroxypropyl)-N- (2-hydroxyethyl)]-5-hydroxyacetyl-amino-2,4,6-triiodo-3-N-methylaminocarbonylbenzamide, [N-(2,3-dihydroxypropyl)-N- (2-hydroxyethyl) ]-DL-5- ⁇ -hydroxypropionylamino-2,4,6-triiodo-3-N-(2-hydroxyethyl)aminocarbonylbenzamide, [N- (2,3-dihydroxypropyl) -N- (2-hydroxyethyl) ] -3-N- (2-hydroxy
  • Examples of the dimeric compounds of the present invention wherein R 2 equals R 1 are N,N'-bis[3,5-bis(N-2,3-dihydroxypropyl-N-2-hydroxyethylaminocarbonyl)-2,4,6-triiodophenyl]malondiamide; N,N'-bis[3,5-bis(N-2,3-dihydroxypropyl-N-2-hydroxyethylaminocarbonyl)-2,4,6-triiodophenyl]oxamide; and N,N'-bis[3,5-bis(N-2,3-dihydroxypropyl-N-2-hydroxyethylaminocarbonyl)-2,4,6-triiodophenyl]succinamide.
  • These compounds may be prepared by first forming a dimer by reacting two moles of 5-amino- 2,4,6-triiodoisophthaloyl chloride under amide-forming conditions with one mole of a diacid chloride such as oxalyl chloride, malonyl chloride, or succinyl chloride.
  • a diacid chloride such as oxalyl chloride, malonyl chloride, or succinyl chloride.
  • These compounds are prepared by first making the desired R 2 substitution and then forming the dimer by reaction with the desired diacid chloride, such as oxalyl chloride, malonyl chloride, or succinyl chloride. The amino-alcohol is then added under amide-forming conditions. If secondary substitution of the diamide nitrogens is desired, i.e., when R 5 is other than hydrogen, this step is performed last.
  • the desired diacid chloride such as oxalyl chloride, malonyl chloride, or succinyl chloride.
  • the amino-alcohol is then added under amide-forming conditions. If secondary substitution of the diamide nitrogens is desired, i.e., when R 5 is other than hydrogen, this step is performed last.
  • alkyl halides for example, methyl halides, such as methyl iodide; 2-haloethylacetates, such as 2-bromoethylacetate; 2-haloethanols, such as 2-chloroethanol; and 2-haloethyl methyl ethers, such as 2-bromoethyl methyl ether.
  • the reactions necessary to produce the compounds of the present invention may be carried out at any convenient temperature and pressure, such as at atmospheric pressure and ambient temperatures. It is preferred that amidation and alkylation reactions be performed at such ambient temperatures. It is preferred that hydrolysis steps be carried out at elevated temperatures to achieve a sufficient rate of hydrolysis, such as at temperatures between 90 and 100 °C.
  • Purification of the compounds of the present invention is desired for their use as X-ray contrast agents. Purification may be by standard isolation methods, such as crystallization, or by preparative HPLC, such as by reverse-phase HPLC, or combinations of these.
  • 5-Amino-2,4,6-triiodoisophthalic acid (234.5 g, 0.42 g-mole) is slurried in 200 ml of ethylacetate at 50°C.
  • Thionyl chloride (399.3 g, 243.8 ml, 3.36 g-mole) is added dropwise over a 1 hour period. The temperature is then increased to 68°C, and the contents are stirred for 7 hours, and then for an additional 16 hours at room temperature (20-25°C).
  • EtOAc and excess thionyl chloride are partially removed by vacuum distillation (vacuum, 35°C pot temperature) to leave a yellow paste.
  • This paste is stirred with 200 ml 1,1,1-trichloroethane (TCE) at 0-5°C for 1 hour, and collected by suction filtration while cold.
  • TCE 1,1,1-trichloroethane
  • the fine yellow powder is washed twice with 100 ml cold 1,1,1-TCE, filtered and dried in a vacuum desiccator to give the desired product (12.5 g, 50% yield).
  • the product develops as one spot by TLC ( EtOAc/MeOH/HOAc ; 10/5/1), and its 13 C nmr spectrum is consistent with the structure.
  • A. 5-Acetamido-2,4,6-triiodoisophthaloyl chloride 5-Amino-2,4,6-triiodoisophthaloyl chloride (190 g,0.32 g-mole) prepared as in Example 1 is dissolved in 475 ml of N,N-dimethylacetamide (DMAc) (dried over molecular sieves), and the solution is stirred and cooled to 0-3°C.
  • Acetyl chloride (75.1 g, 68 ml, 0.96 g-mole) is added dropwise over a period of 100 minutes, keeping the temperature between 0°C and 3°C. The ice bath is removed and the solution is stirred overnight at room temperature (20-25°C).
  • 3-(N-2-hydroxyethyl)amino-1,2-propanediol (48 g, 0.36 g-mole) (96 ml of a 50% w/v DMAc solution) is added dropwise with stirring over a period of 1 hour, keeping the temperature below 5°C.
  • the mixture is stirred for 1 additional hour at 0-5°C, then stirred for 48 hours at room temperature (20-25°C).
  • the mixture is filtered to remove the inorganic salts; the DMAc is removed by rotary evaporation (high vacuum, 80°C) to leave an orange-yellow gum (78.14 g).
  • the gum is dissolved in water to make 250 ml of solution (pH 10.5) and passed through a bed of IRA-118H strong cation exchange resin (62 ml, 1.3 meq./ml). The resin is then washed with two 100 ml portions of water; the washes and the eluent are combined and evaporated to provide an off-white foam (49.8 g) .
  • the product is purified by reverse-phase preparative HPLC to give 37.5 g of a white glassy solid (a 31% yield having a purity of 99.6% by HPLC). The 13 C nmr spectrum is consistent with the structure.
  • A. 5-Acetoxyacetamido-2,4,6-triiodoisophthaloyl chloride 59.6 g (0.1 g-mole) of 5-amino-2, 4, 6-triiodoisophthaloyl chloride prepared as in Example 1, is dissolved in 100 ml of DMAc and 27.3 g (0.2 g-mole) of acetoxyacetyl chloride is added as the solution temperature is maintained at 25-35°C. After the addition, the solution is allowed to stir and heated at 35-40°C for 4 hours to complete the reaction. The solution is cooled to room temperature and poured slowly into 1 L of cold water (0-5°C) with stirring to precipitate the product.
  • the white solid is filtered, washed with cold water and dried, giving 69 g (99% yield) of the desired product.
  • the product shows one spot by TLC analysis (EtOAc/CH 2 Cl 2 ; 30/20).
  • the 13 C nmr data are consistent with the structure.
  • the mixture is heated and stirred at 35-40°C until the reaction is completed as determined by the TLC analysis (EtOAc/CH 2 Cl 2 ; 30/20).
  • the inorganic salts are filtered and the filtrate containing the desired product is evaporated to dryness to give a gum.
  • the gum is triturated with isopropyl alcohol to dissolve the excess amino-triol.
  • the clear supernatant is decanted and the residual solid is dissolved in water (150 ml), treated with Amberlite® IR- 120H resin and evaporated to dryness to give the desired product (77 g, 86% yield).
  • Example 1 (59.6 g, 0.1 g-mole) is dissolved in DMAc (100 ml). The solution is cooled to 5°C and methoxyacetyl chloride (21.7 g 0.2 g-mole) is added slowly keeping the temperature at 5-10°C. When the addition is complete, the reaction mixture is allowed to warm to room temperature and stirred until the reaction is complete. The solution is cooled to room temperature and poured slowly into 1 L of cold water (0-5°C) with stirring to precipitate the product.
  • the white solid is filtered, washed with cold water and dried to provide the desired product.
  • N,N'-Bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-5-methoxyacetamido-2,4,6-triiodoisophthalamide N,N'-Bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-5-methoxyacetamido-2,4,6-triiodoisophthalamide.
  • 5-Methoxyacetamido-2,4,6-triiodoisophthaloyl chloride (56.7 g, 0.085 g-mole) and anhydrous Na 2 CO 3 (18 g, 0.17 g-mole) are mixed in DMAc (70 ml).
  • a solution of DMAc (57 ml) containing 3- (N-2-hydroxyethyl)amino-1,2-propanediol (34.5 g, 0.255 g-mole) is added.
  • the mixture is allowed to stir at 35-40°C until the reaction is complete.
  • the mixture is then filtered to remove the inorganic salts and the filtrate containing the desired product is evaporated to give a gum.
  • the material is triturated with isopropyl alcohol to dissolve the excess amino-alcohol.
  • the clear supernatant is decanted and the residual solid is evaporated to dryness to give the crude product.
  • the crude product is dissolved in water and purified by reverse-phase preparative HPLC to provide the purified product.
  • the solution is stirred at 50°C for 5 hours to complete the reaction.
  • the solution is acidified with H 2 SO 4 and evaporated to dryness under reduced pressure.
  • the residue is triturated with MeOH and the precipitated solid is filtered.
  • the mother liquor is concentrated under vacuum and the crude product is purified by reverse-phase (C 18 ) HPLC to give the purified final product.
  • the yield of this reaction and purification is 80%.
  • N,N'-Bis[ (2,3-dihydroxypropyl) -2-hydroxyethyl] -5- (N-methyl)hydroxyacetamido-2,4, 6-triiodoisophthalamide prepared as in Example 3, Step C, (85.1 g, 0.1 g-mole) is dissolved in 200 ml of water and 110 ml of IN NaOH (0.11 g-mole) is added. The solution is stirred at room temperature for 1 hour and evaporated to dryness under vacuum.
  • 5-Amino-2,4,6-triiodoisophthaloyl chloride prepared as in Example 1 (59.6 g, 0.1 g-mole), and anhydrous Na 2 CO 3 (31.8 g, 0.3 g-mole) are mixed in DMAc (200 ml).
  • a solution of DMAc (100 ml) containing 3-(N-2-hydroxyethyl)amino-1,2-propanediol (40.5 g, 0.3 g-mole) is added slowly and the mixture is allowed to stir at 35-40°C overnight.
  • the mixture is then filtered to remove the inorganic salts.
  • the filtrate is evaporated under vacuum and the gummy residue is triturated with isopropyl alcohol to effect the precipitation of the product.
  • the solid is collected and dried to provide 5-amino-N,N'-bis[(2,3-dihydroxy-propyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide.
  • This compound (79 g, 0.1 g-mole) is slurried in pyridine, and acetic anhydride (71.4 g, 0.7 g-mole) is added dropwise with stirring and cooling so that the reaction temperature is maintained at ⁇ 30°C. After the addition, the mixture is allowed to stir at room temperature overnight to complete the reaction.
  • reaction solution is diluted with EtOAc (350 ml); ice water (350 ml) is added and the mixture is stirred for 30 minutes. A mixture of cold water (350 ml) and cone. HCl
  • the mixture is then poured slowly into 1 L of ice water and the mixture is stirred for 30 minutes as a solid form.
  • the aqueous mixture is extracted 3 times with EtOAc (500 ml each).
  • the combined EtOAc extracts are washed with water (500 ml), saturated NaHCO 3 solution (two times 200 ml), water (400 ml) and saturated NaCl solution (200 ml).
  • the organic layer was dried over anhydrous Na 2 SO 4 and the solvent was evaporated under reduced pressure to provide the crude desired product to be used in the next step.
  • the reaction mixture is then acidified to pH 3 with hydrochloric acid.
  • the solution is concentrated to about 400 ml and ethanol (600 ml) is added to precipitate the inorganic salts.
  • the salts are filtered off and the filtrate is evaporated to dryness under reduced pressure to provide the crude product.
  • the crude product is dissolved in water (45 g in 50 ml) and purified by prep HPLC to give 28 g of purified desired product (40% yield).
  • Step D N,N'-Bis[2,3-dihydroxypropyl)-2-hydroxyethyl]-5-N-(2-hydroxybutyrolactamido)-2,4,6-triiodoisophthalamide.
  • the compound prepared in Step D (28 g, 0.03 g-mole), distilled ethanol (500 ml) and potassium acetate (11.8 g, 0.12 g-mole) are mixed in a 2 L flask equipped with a mechanical stirrer, a reflux condenser and a thermometer. The mixture is refluxed until the reaction is complete. The solvent is removed under vacuum and a solid is obtained.
  • the solid is dissolved in water (200 ml) and the solution is treated with 150 g of pre-washed mixed-bed ion-exchange resins. After stirring for 15 minutes, the resins are filtered off and the solution is evaporated under vacuum to give a foamy solid of crude product.
  • the material is dissolved in water (40 ml) and purified by preparative HPLC to give 8 g of the purified product as an overall 32% yield.
  • the free acid is released from the brucine salt by dissolving 570 g of the solid obtained above in 5.5 L water in a 12 L resin pot. This is treated with concentrated HCl to pH 0.7 (200 ml), and the pale brown solution is extracted twice with 2.5 L ethyl acetate. The extract is washed with water, three times 300 ml, dried over anhydrous sodium sulfate, evaporated to dryness to give brown thick oil, 182.2 g, 97.8% [ ⁇ ] -33.78° (0.1258 g in 10 ml CHCl 3 ).
  • L-2-Hydroxy-4-(methylthio)butyric acid and acetylation In a 1 L, 3-necked flask is dissolved L-2-amino-4-(methylthio)butyric acid (14.9 g, 0.1 g-mole) in aqueous H 2 SO 4 solution (80 ml) and cooled to -5°C. This is treated with a solution of NaN0 2 in 30 ml water. The mixture is stirred overnight at room temperature and extracted with three times 100 ml ether, dried over anhydrous Na 2 SO 4 and evaporated to dryness to give an oil, 1.4 g 9.3%. TLC shows one major spot and IR is in agreement with the structure.
  • Acetylation of the compound is carried out with acetyl chloride (0.07 mol, 6.5 ml); the mixture was refluxed for 1 hour, evaporated to dryness and the residue dissolved in CHCl 3 . This is extracted three times with 30 ml NaHCO 3 solution (5%), washed twice with 30 ml CHCl 3 , filtered and acidified with concentrated HCl (pH 1). The precipitated oil is extracted with chloroform, washed with 30 ml water, dried over anhydrous Na 2 SO 4 and evaporated to dryness to give brown oil, 1.76 g (91.6%).
  • the brucine salt is prepared by dissolving 1.1 g (0.0057 ml) of the above material L-2-acetoxy-4-(methylthio)-butyric acid, in 10 ml EtOH and treatment with a hot filtered solution of brucine (0.0057 mol, 2.26 g in ethanol, 20 ml).
  • the salt obtained is filtered and recrystallized from ethanol (40 ml) three times to obtain pure salt, m.p. 184-186°C [ ⁇ ] -31° (1% H 2 O), identical in m.p., mixed m.p. (undepressed), and optical rotation to compound prepared in Steps A and B.
  • Step B 5-N-Butyrolactamido-N,N'-bis[(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
  • the crude compound prepared in Step A (18.4 g, 0.016 g-mole) is suspended in MeOH (100 ml) in a flask equipped with a mechanical stirrer, an addition funnel and a thermometer.
  • the suspension is cooled to 10°C and NaOH solution (98 ml of 1 N solution) is added slowly so the temperature is maintained at 10-20°C. When 25 ml of NaOH solution is added, the suspension became a clear solution.
  • the cooling ice-bath is removed and the solution is stirred at room temperature overnight.
  • the solution is stirred with Amberlite IR-120H resin (120 ml) for 2 hours and filtered.
  • the filtrate is evaporated to dryness to give the crude desired product at a quantitative yield.
  • the purification of the product is carried out by preparative HPLC using C 18 column and H 2 O/MeOH as the mobile phase. The elutions containing the desired product are combined and evaporated to dryness to provide the purified product (8.2 g, 60% yield).
  • A. DL-5- ⁇ -Acetoxypropionylamino-2,4,6-triiodo-3-N-methylaminocarbonylbenzoyl chloride 5-Amino-2,4,6-triiodo-3-N-methylaminocarbonylbenzoyl chloride (59 g, 0.1 g-mole) is slurried in DMAc (110 ml) at 35-40°C.
  • DL-2-Acetoxypropionyl chloride (30.2 g, 0.2 g-mole) is added dropwise keeping the temperature at 40-48°C. The slurry is stirred at 40°C for 30 minutes, turning into a clear brown solution. After stirring overnight at 40°C, HPLC analysis indicates complete reaction.
  • Step A DL-5- ⁇ -Acetoxypropionylamino-[N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-2,4,6-triiodo-3-N-methylaminocarbonylbenzamide.
  • the compound prepared in Step A (60 g, 0.085 g-mole) is added to a mixture of 3-(N-2-hydroxyethyl)amino-1,2-propanediol dissolved in DMAc (23 g, 0.17 g-mole, in 56.4 ml solution, 40.87% w/v), additional DMAc (70 ml) and sodium carbonate (18 g, 0.17 g- mole) at 40°C.
  • the mixture is stirred at room temperature for 20 hours, then warmed to 40°C for 5 hours, and again stirred overnight at room temperature.
  • the mixture is filtered and the solid collected and washed twice with 50 ml DMAc.
  • the filtrate and washes are combined and evaporated to give a thick oil (105.8 g).
  • the oil is triturated with 200 ml isopropyl alcohol, yielding some solid and again with 700 ml acetone, yielding more solid.
  • the supernatant is decanted and the solid washed with 200 ml acetone.
  • the acetone is decanted and the solid evaporated to dryness, yielding 32 g of crude, desired product.
  • the solution is then treated with ion exchange resins IRA-68, IRA-458, and IR-120 H, 100 ml each, and the resins are washed four times each with 100 ml water. The washings and solution are combined and evaporated to dryness giving a yellow glassy solid (48 g, 80.5% pure).
  • the crude product is then purified by reverse-phase preparative HPLC to yield 34 g. The structure was verified by nmr. The product is 100% water soluble.
  • the i.v. LD 50 in mice is 13.1 g I/kg. Osmolality: 506 mOsm/kg (32% I); viscosity: 4.9 cps (37°), 8.1 cps (25°) (32% I).
  • A. 5-Acetoxyacetylamino-2,4,6-triiodo-3-N-methylaminocarbonylbenzoyl chloride 5-Amino-2,4,6-triiodo-3-N-methylaminocarbonylbenzoyl chloride (61 g, 0.1033 g-mole) is added to DMAc (100 ml) with stirring and heated to 30°C. Acetoxyacetyl chloride is added slowly with stirring. After stirring at 40°C for 4 hours and overnight at room temperature, the product completely solidifies from the solution. Tetrahydrofuran (200 ml) is added and the slurry stirred for 1 hour at room temperature. The white solid is filtered, washed three times with THF (30-40 ml) and dried under vacuum at 50°C to produce the crude, desired product.
  • Step B 5-Acetoxyacetylamino-[N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-2,4,6-triiodo-3-N-methylaminocarbonylbenzamide.
  • the crude product of Step A (theoretically 0.1033 g-mole) is added to a mixture of 3-(N-2-hydroxyethyl)amino-1,2-propanediol (28 g dissolved in 110 ml DMAc) and sodium bicarbonate (17.7 g, 0.21 g-mole) with stirring and heating to 55°C. Carbon dioxide evolution occurs. After stirring at 55-60°C for five hours, the solution is allowed to stir overnight at room temperature and filtered.
  • the solid is washed three times with 50 ml methanol, and the washings are combined with the filtrate.
  • the combined solution is evaporated under vacuum at 70°C yielding a thick oil.
  • the oil is triturated with 500 ml isopropyl alcohol at 65°C for 30 minutes and then allowed to cool.
  • the supernatant is decanted.
  • the residue is again triturated with 350 ml isopropyl alcohol and then allowed to cool.
  • the supernatant is decanted and the residue evaporated to dryness under vacuum at 75°C yielding the desired product (57 g, 70% yield), confirmed by nmr.
  • Step B [N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-5-hydroxyacetylamino-2,4,6-triiodo-3-N-methylaminocarbonylbenzamide.
  • the product of Step B is hydrolyzed and purified as in Example 15, Step C, yielding 10.8 g, 99.8% pure. However, the solubility in water (w/v) was found to be less than 25%.
  • the title compound is prepared by hydrolysis of [N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-5-[(acetoxyacetyl)(2-acetoxyethyl) amino] -2 , 4 , 6-triiodo-3-N-methylaminocarbonylbenzamide by a procedure similar to the hydrolysis of Example 15, Step C.
  • the diacetate is prepared by reacting 5-acetoxyacetylamino- [N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)]-2,4,6-triiodo-3-N-methylaminocarbonylbenzamide (prepared as in Example 16, Steps A and B) with 2-bromoethylacetate in DMSO in the presence of a base such as potassium carbonate.
  • the resulting suspension is filtered, and the collected solids washed with 100 ml water and dried in a vacuum oven (70°C, 140 mm Hg) for 24 hours to yield 98.23 g (86% yield) desired product.
  • the product exhibits one spot by tic employing a solvent system of ethyl acetate/methanol (95:5, v/v). 1 H and 13 C nmr spectra are consistent with the assigned structure.
  • Step B 3-[N-(2-Acetoxyethyl)aminocarbonyl]-5-amino-2,4,6-triiodobenzoyl chloride.
  • thionyl chloride 207.9 g, 1.75 g-mole, 15 equiv.
  • the resulting solution is heated to reflux with stirring for 3 hours.
  • Excess thionyl chloride is removed by distillation under reduced pressure, partly as an azeotrope with THF (200 ml) .
  • Step D [N-(2,3-Dihydroxypropyl)-N-(2-hydroxyethyl]-5-(2-hydroxyacetyl)amino-2,4, 6-triiodo-3-N-(2-hvdroxyethyl)aminocarbonylbenzamide.
  • the crude diacetate product of Step D is dissolved in methanol (90 ml) and water (90 ml) is added.
  • the pH is adjusted to 1 with sulfuric acid, and the mixture is stirred and heated to reflux for 2 hours.
  • the mixture is then concentrated by distillation and purified by passing it through ion-exchange resins and by preparative HPLC, yielding 25.77 g of 98% pure product as confirmed by HPLC, tic, and nmr.
  • the product is 100% w/v water-soluble. Osmolality: 597 mOsm/kg (32% I); viscosity: 5.3 cps (37°), 7.4 cps (25°) (32% I); the i.v. LD50 in mice is 20.6 gl/kg.
  • Example 18 the title compound is prepared stepwise by reacting the product of Example 18, Step B with ( ⁇ ) -2 - acetoxypropionyl chloride, as in Step C and completing the synthesis.
  • N-(2,3-Dihydroxypropyl)-N-(2-hydroxyethyl)-3-N-(2,3-dihydroxypropylaminocarbonyl)-5-(hydroxyacetylamino)-2,4,6-triiodobenzamide To N-(2,3-Dihydroxypropyl)-N-(2-hydroxyethyl)-3-N(2,3dihydroxypropylaminocarbonyl)-5-(acetoxyacetylamino)-2,4,6-triiodobenzamide was added deionized water (200mL) and the mixture was stirred until all the oil dissolved.
  • the pH was adjusted to pH ⁇ l by the addition of concentrated H 2 SO 4 (9.8g, 0.1005 moles) (initial pH 8.54; final pH 0.945).
  • the reaction mixture was steam distilled and the distillate collected while maintaining the original volume of the reaction mixture by periodic addition of additional deionized water.
  • the progress of the reaction was monitored by HPLC [employing a C18 reverse phase 10 ⁇ m silica gel column employing a mobile phase of water-acetonitrile (70:30 v/v) at a flow rate of 2 mL/min, and detection at 254 nm]. After 6 hours of steam distillation, HPLC analysis indicated an 84.5 area % for the desired product.
  • A. 5-Amino-3-(N-2-acetoxyethyl-N-methylaminocarbonyl)-2,4,6-triiodobenzoic Acid To a stirred solution of 5-amino-3-(N-2-acetoxyethyl-N-methylaminocarbonyl)-2,4,6-triiodobenzoic acid (203g, 0.33 g-mole) in DMAc (385 ml) containing 4-dimethylaminopyridine (8.1g, 0.066 g-mole) is added acetic anhydride (135g, 1.32 g-mole) at 25-35°C. Stirring is continued at room temperature for 16 hours to complete the reaction.
  • the solution is then evaporated under vacuum to distill off 350 ml of the solvent to provide a thin oil.
  • the oil is dissolved in 150 ml of DMAc and the solution is added slowly into 2L of water with stirring to precipitate yellow solid.
  • the resulting slurry is acidified with 150 ml of 6N HCl to pH 1.
  • the solid is collected, reslurried in 500 ml of water, treated with NaHSO 3 (20g), collected, washed three times each with 50 ml of water and dried to obtain 180g of the desired product (83% yield).
  • DMAc is evaporated and THF (50 ml) is added to give a thin slurry.
  • the slurry is added into a mixture of methanol (IL) and water (0.4L) with vigorous stirring at 10°C to precipitate the desired product (15g, 28% yield).
  • the structure is confirmed by 13 C NMR.
  • the methanol-water solution still contains the remaining product. However, no attempt is made to isolte the product.
  • Step C The product of Step C (14.9g, 0.02 g-mole) is dissolved in dioxane (40 ml) and a solution of DMAc (14.5 ml) containing 6g (0.044 g-mole) of 3-(N-2-hydroxyethyl)amino-1,2-propanediol is added. The solution is stirred at room temperature overnight to complete the reaction. The solvent is then evaporated to provide the crude desired product. The material is used directly in the following reaction without further purification.
  • N-2,3-Dihydroxypropyl-N-2-hydroxyethyl-5-hydroxyacetylamino-3- (N-2-hydroxyethyl-N-methylaminocarbonyl)-2,4,6-triiodobenzamide The crude product from Step D is dissolved in MeOH (100 ml) and the solution is diluted with water (100 ml). The pH of the solution is adjusted to approximately 1 with 1 ml of concentrated sulfuric acid. The resulting solution is stirred and heated at 90°C overnight to complete the hydrolysis of the acetate groups.
  • Example 12 the title compound is prepared stepwise by first reacting 5-amino-2,4,6-triiodo-3-N-methylaminocarbonylbenzoyl chloride with 3-(N-2-hydroxyethyl)amino-1, 2-propanediol dissolved in DMAc in the presence of sodium carbonate.
  • the title compound is prepared as in Examples 12 and 18 starting from 3-N-(2-acetoxyethyl)aminocarbonyl-5-amino-2,4,6-triiodobenzoyl chloride.
  • N,N'-bis.3,5-bis(chlorocarbonyl)-2,4,6-triiodophenyl]-malondiamide N,N'-bis.3,5-bis(chlorocarbonyl)-2,4,6-triiodophenyl]-malondiamide.
  • 5-Amino-2,4,6-triiodoisophthaloyl chloride 59.58 g, 0.1 g-mole
  • the solution is heated to 90°C and stirred while malonyl chloride (8.5 g, 0.06 g-mole) is added dropwise.
  • the mixture was stirred at 90°C for 3 hours.
  • a pasty precipitate forms.
  • the solid is filtered, washed three times with 25 ml dioxane on the filter, suction-dried and then vacuum dried at 60°C to yield the desired product (51.4 g, 81% yield).
  • the structure of the dimer was confirmed by nmr.
  • Step A N.N'-Bis[3.5-bis(N-2,3-dihydroxypropyl-N-2-hydroxyethylaminocarbonyl)-2,4,6-triiodophenyl]- malondiamide.
  • the product of Step A (50 g, 0.04 g-mole) is added slowly to a mixture of 3-(N-2-hydroxyethyl)amino-1,2-propanediol (32.4 g, 0.24 g-mole) dissolved in DMAc (115 ml) and sodium carbonate (17 g, 0.16 g-mole), with stirring. After 7 hours stirring at room temperature, the reaction is complete as determined by HPLC.
  • the reaction mixture is diluted with 200 ml DMAc and filtered to remove the salts.
  • the clear filtrate is evaporated to dryness yielding a clear yellow gummy solid (86.5 g).
  • the solid is triturated with 50 ml isopropanol at 60°C for 10 minutes. After standing overnight the supernatant is decanted and the solid evaporated to dryness.
  • the solid is dissolved in 150 ml water at 60-65°C yielding a clear solution, pH 10.
  • the solution is stirred with Amberlite IR-120 plus H resin for 30 minutes (pH 1-2) and filtered.
  • the filtrate is evaporated to dryness to give the crude desired product
  • This compound is prepared as in Example 24 using oxalyl chloride in place of malonyl chloride.
  • the title compound is prepared by reacting 3-N-(2-acetoxyethyl)aminocarbonyl-5-amino-2,4,6-triiodobenzoyl chloride, prepared as in Example 18, Step B, with oxalyl chloride in dioxane; reacting the product with 3-(N-2-hydroxyethyl)amino-1,2-propanediol in DMAc; and hydrolyzing the acetate groups with aqueous sulfuric acid (as in Example 18, Step E).
  • Example 29 The title compound is prepared as in Example 27 using malonyl chloride instead of oxalyl chloride.
  • Example 27 The title compound is prepared as in Example 27 using succinyl chloride instead of oxalyl chloride .
  • This compound is prepared by reacting two equivalents of 5-amino-3-(N-2,3-diacetoxypropionaminocarbonyl)-2,4,6-triiodobenzoyl chloride with malonyl chloride, then reacting the dimer with two equivalents of 3-(N-2-hydroxyethyl)amino-1,2-propanediol, and finally removing the acetate groups by hydrolysis.
  • the title compound is prepared as in Example 30 using oxalyl chloride instead of malonyl chloride.
  • Example 36 The title compound is prepared by reacting the product of Example 26 with methyl iodide under basic, alkylating conditions.
  • Example 36 The title compound is prepared by reacting the product of Example 26 with methyl iodide under basic, alkylating conditions.
  • the title compound is prepared by reacting the product of Example 27 with methyl iodide under basic, alkylating conditions.
  • the title compound is prepared by reacting the product of Example 29 with methyl iodide under basic, alkylating conditions.
  • Example 40 The title compound is prepared by reacting the product of Example 30 with methyl iodide under basic, alkylating conditions.
  • Example 40 The title compound is prepared by reacting the product of Example 30 with methyl iodide under basic, alkylating conditions.
  • the title compound is prepared by reacting the product of Example 31 with methyl iodide under basic, alkylating conditions.
  • Example 41 Preparation of N,N'-dimethyl-N,N'-bis[3-(N-2,3-dihydroxypropionamino-carbonyl)-5-(N-2,3-dihydroxypropyl-N-2-hydroxyethyl-aminocarbonyl)-2,4,6-triiodophenyl]-succinamide.
  • the title compound is prepared by reacting the product of Example 32 with methyl iodide under basic, alkylating conditions.

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Abstract

L'invention concerne des dérivés d'isophtalamide tri-ioduré utilisés comme agents de contraste aux rayons X comprenant au moins un groupe amide dérivé d'amino-alcool, du 3-(N-2-hydroxyéthyl)-amino-1,2-propanediol, et qui présentent une solubilité élevée dans l'eau ainsi qu'une faible toxicité mammalienne, ainsi que leurs procédés de préparation. Des procédés de préparation du 3-(N-2-hydroxy-éthyl)amino-1,2-propanediol sont également décrits.
PCT/US1993/008056 1992-09-02 1993-08-25 Agents de contraste aux rayons x non ioniques, compositions et procedes WO1994005337A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19510864A1 (de) * 1995-03-16 1996-09-19 Schering Ag Röntgenkontrastmittel für die Computertomographie und Urographie
US5695742A (en) * 1992-12-24 1997-12-09 Dibra S.P.A. Aqueous injectable formulations useful for radiodiagnosis comprising iodinated aromatic compounds used as X-ray contrast media
CN105636933A (zh) * 2013-10-25 2016-06-01 大熊制药株式会社 制备碘普罗胺的中间体的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4250113A (en) * 1976-06-11 1981-02-10 Nyegaard & Co. A/S Chemical compounds
US4396598A (en) * 1982-01-11 1983-08-02 Mallinckrodt, Inc. Triiodoisophthalamide X-ray contrast agent
US4426371A (en) * 1980-10-10 1984-01-17 Schering, Aktiengesellschaft Novel N-hydroxyalkylated dicarboxylic acid bis(3,5-dicarbamoyl-2,4,6-triiodoanilides), as X-ray contrast media

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4250113A (en) * 1976-06-11 1981-02-10 Nyegaard & Co. A/S Chemical compounds
US4426371A (en) * 1980-10-10 1984-01-17 Schering, Aktiengesellschaft Novel N-hydroxyalkylated dicarboxylic acid bis(3,5-dicarbamoyl-2,4,6-triiodoanilides), as X-ray contrast media
US4396598A (en) * 1982-01-11 1983-08-02 Mallinckrodt, Inc. Triiodoisophthalamide X-ray contrast agent

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5695742A (en) * 1992-12-24 1997-12-09 Dibra S.P.A. Aqueous injectable formulations useful for radiodiagnosis comprising iodinated aromatic compounds used as X-ray contrast media
DE19510864A1 (de) * 1995-03-16 1996-09-19 Schering Ag Röntgenkontrastmittel für die Computertomographie und Urographie
CN105636933A (zh) * 2013-10-25 2016-06-01 大熊制药株式会社 制备碘普罗胺的中间体的方法

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