WO1989000988A1 - Iodinated esters - Google Patents

Iodinated esters Download PDF

Info

Publication number
WO1989000988A1
WO1989000988A1 PCT/GB1988/000604 GB8800604W WO8900988A1 WO 1989000988 A1 WO1989000988 A1 WO 1989000988A1 GB 8800604 W GB8800604 W GB 8800604W WO 8900988 A1 WO8900988 A1 WO 8900988A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
group
mmol
water
compound
Prior art date
Application number
PCT/GB1988/000604
Other languages
English (en)
French (fr)
Inventor
Jo Klaveness
Per Strande
Original Assignee
Nycomed As
Holmes, Michael, John
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 Nycomed As, Holmes, Michael, John filed Critical Nycomed As
Publication of WO1989000988A1 publication Critical patent/WO1989000988A1/en
Priority to DK014490A priority Critical patent/DK14490D0/da
Priority to NO900269A priority patent/NO180747C/no
Priority to FI900347A priority patent/FI94095C/fi
Priority to SU904742976A priority patent/RU1829940C/ru

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to contrast agents for medical X-ray and ultrasound imaging and to their preparation and use.
  • reti ⁇ uloendothelial system of the liver and spleen is well known to trap particles by phagocytosis
  • contrast agents in particulate form are particularly well adapted for visualisation of these organs.
  • Emulsions of iodinated oils have been proposed in this context, particularly iodinated ethyl esters of poppy seed oil. (Vermess, M. , et al. Radiology, 137 (1980) 217). However, these substances have proved unduly toxic.
  • liposomes containing water soluble iodinated contrast agents Another possibility is to use liposomes containing water soluble iodinated contrast agents. (Havron A. et al. Radiology, 140 (1981) 507). However, since only a limited amount of iodine can be incorporated in each liposome, it is necessary to administer relatively large amounts of lipids in order to attain adequate contrast enhancement. This tends to cause emboli in the lung capillaries. Furthermore, liposomes have been found to be relatively unstable on storing (Shulkin, P.M., et al, J. Microencapsul. , 1 (1984) 73) .
  • Submi ⁇ ron thorium dioxide particles have been used for liver visualisation and have shown effective enhancement of contrast in clinical testing but their use has been discontinued because of the extremely lengthy retention of the particles in the liver. This, in combination with the inherent radioactivity of thorium, has led to serious adverse side effects, including neoplasm and fibrosis. (Thomas, S.F., Radiology, 78 (1962) 435).
  • particles comprising the ethyl ester of the water soluble X-ray contrast agent, iodipamide (Violante, M.R., et al. Invest. Radiol. , 2, (1984) 133).
  • ethyl esters are not sufficiently metabolically labile and thus would be expected to be retained in the liver for a considerable period.
  • this ester and an iodinated ethyl ester of poppy seed oil gave an increase in lipid vacuoles in the hepatocytes after intravenous administration.
  • Violante M.R., Invest. Radiol., 2 (1984) 133 Such morphological changes indicate an adverse effect on the hepatocytes.
  • contrast agents for the visualisation of the liver and spleen comprises particulate lipophilic iodine- containing esters which are metabolically labile to form water-soluble substances which are substan ⁇ tially non-toxic and are not retained in the target organs.
  • R is a substituted or unsubstituted C-.___ aliphatic, C 7 _ 20 -araliphatic or g_ 20 aryl group or a C,_2 Q heterocyclic group having one or more hetero atoms selected from O, S and N;
  • R is hydrogen or a substituted or unsubstituted aliphatic, aryl or araliphatic group
  • R 3 is a group as defined above for R1, which may be the same as or different from R ,
  • R 2 and R3 together represent a substituted or unsubstituted C, * alkylene group
  • the molecule containing at least one iodine atom and being metabolisable to products which are soluble in body fluids.
  • the metabolic products will be R X COOH, R 3 COOH and R 2 CHO.
  • R 3 and R2 together form an alkylene group, the products will be R ⁇ OOH and HOOC(R 3 .R 2 )CHO.
  • R conveniently is hydrogen or an optionally substituted C- L _ 6 aliphatic group, Cg_ 10 aryl group or _2 Q araliphatic group.
  • Aliphatic groups may be straight or branched, saturated or unsaturated and include, for example, alkyl and alkenyl groups e.g. methyl, ethyl, isopropyl, butyl or allyl groups.
  • Araliphatic groups include monocarbocycli ⁇ aryl-alkyl groups; for example benzyl groups.
  • Aryl groups include mono- or bi- cyclic aryl groups, for example phenyl, tolyl or naphthyl groups.
  • Heterocyclic groups include 5 or 6- membered heterocyclic groups preferably having one heteroatom, for example furyl, thienyl or pyridyl groups.
  • R 1, R2 and R3 Possible substituents in the above hydrocarbon groups R 1, R2 and R3 include hydroxyl, etherified hydroxyl, esterified hydroxyl, etherified thiol, N-alkylamino, N-C, g-acylamino, N-C,_g-acyl-N-C 1 _g alkylamino, carbamoyl and N-C, g alk lcarbamoyl groups and halogen atoms. It should be noted that aromatic rings such as phenyl may carry C, g alkyl groups, as in the tolyl group. Substituents may be present in combination and thus, for example, N-acyl and N-alkyl groups may carry hydroxy or etherified or esterified hydroxyl groups.
  • Etherified hydroxyl groups include C-, 5 alkoxy groups such as methoxy groups.
  • Esterified hydroxyl groups include ⁇ _g acyloxy groups such as acetoxy groups.
  • Halogen atoms include fluorine, chlorine, bromine and iodine. More than one halogen atom may be present in any particular group, as in the trifluoromethyl group. It is particularly prefered that the molecule as a whole carries several iodine atoms, for example at least three.
  • At least one of the groups R 1 and R3 is an iodinated phenyl group, preferably a triiodophenyl group.
  • a group may be selected from the very wide range of such groups present in commercial carboxylic acid or amide X-ray contrast- agents.
  • Such groups include 2,4,6-triiodophenyl groups having at the 3- and/or 5-positions groups selected from carbamoyl, N-alkylcarbamoyl or N-hydroxyalkylcarbamoyl, acylamino, N-alkyl-acylamino and acylaminomethyl groups.
  • acyl groups will commonly be acetyl groups and N-alkyla ⁇ ylamino groups will commonly be N-methylacetamino groups.
  • N-hydroxyalkyl ⁇ carbamoyl groups will commonly comprise 1,3- or 2,3-dihydroxypropyl groups as the hydroxyalkyl moiety.
  • the contrast agent according to the invention is substantially water-insoluble and thus, when administered in particulate form, will be entrapped by the liver or spleen. It is possible for relatively hydrophilic groups, such as hydroxyl, to be present provided the remainder of the molecule is sufficiently lipophilic to ensure minimal overall water-solubility. However, after metabolic enzymolysis, it is important that the metabolic products have sufficient water-solubility at physiological pH to be excreted from the target organs. They should also themselves be physiologically acceptable.
  • particulate compounds according to the invention on intravenous administra ⁇ tion appear to be captured by the reticuloendothelial system of the liver and spleen, the resulting accumula ⁇ tion of particles greatly assisting the imaging of these organs.
  • the phagocytosing cells of the liver contain lysosomes which possess a broad spectrum of hydrolytic enzymes including a number of esterases.
  • the particles Once the particles are phagocytised, they enter the lysosomes and are converted into water-soluble products which are subsequently excreted.
  • the relative rapidity of the conversion of the compounds into water-soluble products significantly decreases the risk of toxic reactions.
  • the particles of solid contrast agent according to the invention have a very much higher iodine content.
  • a far smaller amount of material has to be used and the risk of producing lung emboli is greatly reduced.
  • the particulate material according to the invention which is commonly crystalline, is generally much more stable to storage than the previously proposed liposomes.
  • the compounds of the invention due to their iodine content, provide excellent X-ray image enhance- ment. Due to the presence of the relatively heavy iodine atoms, the particles reflect ultrasound and can also be used in enhancement of ultrasound images.
  • the invention also provides injectable contrast media comprising a compound according to the invention in particulate form in suspension in a liquid for injection.
  • the mean particle size of the contrast agent will, in general, be within the range 0.002 to 7 microns, preferably 0.01 to 3 microns.
  • the injectable liquid may be any sterile physiologically acceptable liquid such as physiological saline which may usefully contain a physiologically acceptable stabilising agent such as polyvinylpyrroli- done. for example having a molecular weight about 30,000 daltons or a polysorbate, for example Polysor- bate 80.
  • physiologically acceptable stabilising agent such as polyvinylpyrroli- done. for example having a molecular weight about 30,000 daltons or a polysorbate, for example Polysor- bate 80.
  • the contrast media may be used in the enhancement of X-ray and ultrasound images of the liver and/or spleen of a human or non-human animal subject, in which method they will be administered intravas- cularly, normally intravenously, prior to imaging.
  • the compounds according to the invention may be prepared in any convenient way.
  • the compounds will be formed by esterification of an acid of the formula R COOH or a functional derivative thereof with a compound of the formula X-CHR 2.O.COR3, where X is a hydroxyl group or a leaving group such as a halogen atom or a mesyloxy or tosyloxy group.
  • X represents a leaving group
  • the functional derivative of the acid of formula R COOH will normally be a salt such as the potassium salt.
  • Such a reaction will normally be carried out in solution, for example in a polar solvent such as dimethylformamide.
  • Esterification may also be achieved by reacting the compound XCHR 2.O.COR' ' ⁇ in which X is OH with the acid R COOH, in the presence of a coupling agent such as a diimide e.g. dicyclohexyl- carboiimide, or with an acid halide R COHal where
  • a coupling agent such as a diimide e.g. dicyclohexyl- carboiimide, or with an acid halide R COHal
  • Hal is a halogen atom such as chlorine.
  • esterification may be achieved by reacting
  • R COOH such as a salt
  • the particulate form of the contrast agent according to the invention may advantageously be prepared by precipitation from solution in a water- mis ⁇ ible solvent such as ethanol by admixture with water, which may conveniently contain a stabilising agent such as polyvinylpyrrolidone, with vigorous agitation, e.g. using ultrasound.
  • a stabilising agent such as polyvinylpyrrolidone
  • Cesium carbonate (12.9 g, 39.6 mmol) is added to a solution of phenylacetic acid (5.40 g, 39.6 mmol) in dry DMF (60 ml) .
  • the mixture is stirred at 60°C for 15 minutes and cooled to 0°C, before chloro- methyl phenylsulfide (5.76 g, 36 mmol) is added dropwise. Stirring is continued at 0°C for 30 minutes, then at ambient temperature for 3.5 hours and finally at 70°C for 30 minutes, before water is added and the product extracted into diethyl ether.
  • the ether solution is washed with 1 M sodium hydroxide and 4 times with brine, dried (MgSO.) and evaporated.
  • Example 1 Made in accordance with the procedure given in Neuenschwander, Markus et. al., Helv. Chim. Acta, J51 (1978) 2047. The crude product is used in Example 12 without further purification. Yield: 81%.
  • Diiodomethane (300 microl, 3.8mmol) is added dropwise during 5 minutes at 60°C to a solution of potassium 5-(N-a ⁇ etylaraino)-3-(N-acetyl-N-methylamino)-2,4,6- triiodobenzenecarboxylate (5.0g, 7.5mmol) in dry DMF (75ml) .
  • the precipitate is removed by filtration after stirring for 4 days and the solvent removed at reduced pressure. The residue is triturated with warm dioxane and filtered to give the title compound: yield 3.35g (67%). 1H-N.M.R.
  • Chloromethylpivalate (7.62 g, 50.6 mmol) in dry DMF (84 ml) is added dropwise at 50°C to a solution of potassium 5-(N-acetylamino)-3-(methylaminocarbonyl)- 2,4,6-triiodobenzenecarboxylate (30.00 g, 46.0 mmol) and sodium iodide (0.37 g, 2.5 mmol) in dry DMF (450 ml) .
  • the precipitate is removed by filtration after stirring for 4 hours and the solvent is removed at reduced pressure.
  • the residue is triturated and washed repeatedly in water and finally recrystal- lised from isopropanol. Yield:.32.30 g (96%).
  • Chloromethylacetate (Neuenschwander, Markus et. al., Helv. Chi . Acta, .61 (1978) 2047) (2.30 g, 21.2 mmol) in dry DMF (100 ml) is added dropwise at 50°C to a solution of cesium 5-(N-acetylamino)- 3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzene- carboxylate (13.4 g, 17.7 mmol) and sodium iodide (133 mg, 0.89 mmol) in dry DMF (210 ml). The precipi ⁇ tate is removed by filtration after stirring for 21 hours and the solvent is removed at reduced pressure.
  • Chloromethyl phenylacetate (Neuenschwander, Markus et. al., Helv. Chim. Acta, .61 (1978) 2047) (1.59 g. 8.6 mmol) in dry DMF (20 ml) is added dropwise at 50°C to a solution of cesium 5-(N-acetylamino)- 3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzene ⁇ carboxylate (7.28 g, 9.6 mmol) and sodium iodide (64 mg, 0.42 mmol) in dry DMF (100 ml). The precipitate is removed by filtration after stirring for 20 hours and the solvent is removed at reduced pressure.
  • Polyvinylpyrrolidone (l.OOg, MW 30,000 daltons) is dissolved in distilled water (25.0ml) and filtered through a membrane filter with pore size 0.22 micro ⁇ meter. A filtered, solution of the product of Example 1 (O.lg) in 96% ethanol (5.0ml) is slowly added to the polyvinylpyrrolidone solution under vigorous ultrasonic stirring. The microparticles formed are centrifuged and washed repeatedly. The size and size distribution of the particles may be analyzed by light- and electron microscopy. The mean diameter is 1.0 micrometers which is also the diameter of the main fraction. Particle Preparation 2
  • Polyvinylpyrrolidone (1.00 g, MW 40,000 daltons) is dissolved in distilled water (25.0 ml) and filtered through a membrane filter with pore size 0.22 micro ⁇ meter. A filtered solution (0.22 micrometer) of the product of Example 2 (0.2 g) in methanol (5.0 ml) is slowly added to the polyvinylpyrrolidone solution under vigorous ultrasonic stirring. The microparticles formed are centrifuged and washed repeatedly. The size and size- distribution of the particles may be analysed by light- and electron microscopy. . The mean diameter is 0.2 micrometer which is also the diameter of the main fraction.
  • Polyvinylpyrrolidone (1.00 g, MW 40,000 daltons is dissolved in distilled water (25.0 ml) and filtered through a membrane filter with pore size 0.22 micro ⁇ meter. A filtered solution (0.22 micrometer) of the product of Example 3 (0.1 g) in 96% ethanol (5.0 ml) is slowly added to the polyvinylpyrrolidone solution under vigorous ultrasonic stirring. The. microparticles formed are centrifuged and washed repeatedly. The size and size-distribution of the particles may be analysed by light- and electron microscopy. The mean diameter is 2.0 micrometers which is also the diameter of the main fraction. Pharmaceutical Formulation 1
  • the particles of Particle Preparation 1 (1.0 g) are dispersed in a sterile filtered isotonic 0.9% sodium chloride/water for injection solution (100 ml) under vigorous stirring until a homogenous suspension is achieved.
  • the particles of Particle Preparation 1 (1.0 g) are suspended in a sterile filtered 0.9% sodium chloride/water for injection solution (100 ml) containing polyvinylpyrrolidone (4.0g, MW 40,000), under vigorous stirring until a homogenous suspension is achieved.
  • the particles of Particle Preparation 1 (1.0 g) are suspended in a sterile filtered 0.9% sodium chloride/water for injection solution (100 ml) containing polyvinylpyrrolidone (4.0 g, MW 40,000 daltons) adjusted to pH 7.4 by addition of 0.1 N sodium hydroxide, under vigorous stirring until a homogeneous supension is achieved.
  • the particles of Particle Preparation 3 (1.0 g) are dispersed in a sterile filtered isotonic 0.9% sodium chloride/water for injection solution, (100 ml) under vigorous stirring until a homogeneous suspension is achieved.
  • Pharmaceutical Formulation 5
  • the particles of Particle Preparation 3 (1.0 g) are suspended in a sterile filtered 0.9% sodium chloride/water for injection solution (100 ml) containing polyvinylpyrrolidone (4.0 g, MTV 40,000 daltons) under vigorous stirring until a homogeneous suspension is achieved.
  • the particles of Particle Preparation 3 (1.0 g) are suspended in a sterile filtered 0.9% sodium chloride/water for injection solution (100 ml) containing polyvinylpyrrolidone (4.0 g, MW 40,000 daltons), adjusted to pH 7.4 by the addition of 0.1N sodium hydroxide, under vigorous stirring until a homogeneous suspension is achieved.
  • the particles of Particle Preparation 4 (1.0 g) are dispersed in a sterile filtered isotonic 0.9% sodium chloride/water for injection solution (100 ml) under vigorous stirring until a homogeneous suspension is achieved.
  • the particles of Particle Preparation 4 (1.0 g) are suspended in a sterile filtered 0.9% sodium chloride/water for injection solution (100 ml) containing polyvinylpyrrolidone (4.0 g, MW 40,000 daltons), adjusted to pH 7.4 by addition of 0.1 N sodium hydroxide, under vigorous stirring until a homogeneous suspension is achieved.
  • Example 1 The powdered product of Example 1 is suspended in Seronor (5 mg/ml) (Seronorm is a trade mark of Nycomed AS) at pH 7.4 and agitated at 37°C. As a control the experiment is also performed in phosphate buffered saline (PBS) at pH 7.4. At different time points samples are taken from the supernatant after centrifugation of the vial (4,000 rpm, 10 minutes). The release of Isopaque (5-(N-acetylamino)- 3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylic acid) is analysed by HPLC. More than 50% of the substance is hydrolysed during 6 hours and after 24 hours 90% is hydrolysed. In PBS no hydrolysis could be detected.
  • Seronor 5 mg/ml
  • PBS phosphate buffered saline
  • Example 3 The powdered product of Example 3 is suspended in Seronorm (0.5 mg/ml) at pH 7.4 and agitated at 37°C. As a control the experiment is also performed in phosphate buffered saline (PBS) at pH 7.4 At different time points samples are taken from the supernatant after centrifugation of the vial (4,000 rpm, 10 minutes). The release of Isopaque (5-(N-acetylamino)- 3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylic acid) is analysed by HPLC. 4.1% of the substance is hydrolysed during 24 hours. In PBS 0.12% is hydrolysed during 72 hours.
  • Seronorm 0.5 mg/ml
  • PBS phosphate buffered saline
  • Example 10 The powdered product of Example 10 is suspended in Seronorm (0.5 mg/ml) at pH 7.4 and agitated at 37°C. As a control the experiment is also performed in phosphate buffered saline (PBS) at pH 7.4. At different time points samples are taken from the supernatant after centrifugation of the vial (4,000 rpm, 10 minutes). The release of Isopaque
  • Example 4 The powdered product of Example 4 is suspended in Seronorm at (0.5 mg/ml) pH 7.4 and agitated at 37°C. As a control the experiment is also performed in phosphate buffered saline (PBS) at pH 7.4. At different time points samples are taken from the supernatant after centrifugation of the vial (4,000 rpm, 10 minutes). The release of Isopaque (5-(N-acetylamino)-3-(N-acetyl-N-methylamino)- 2,4,6-triiodobenzenecarboxylic acid) is analysed by HPLC. 29% of the substance is hydrolysied during a 2 hour incubation and hydrolysis is complete after 24 hours in Seronorm. In PBS 34% was hydrolysed during 24 hours.
  • PBS phosphate buffered saline
  • the particles of Pharmaceutical Formulation 2 are injected intravenously into the tail vein of rats.
  • the dose is 200 mg/kg, injection rate 1 ml/min and concentration 10 mg/ml. 30 minutes after injection about 35% of the dose is found in the liver. This uptake gives 0.9 mg I/g liver.
  • the iodine content then gradually decreases to 7% after 6 hours. 24 hours p.i. no iodine can be detected in the liver.
  • Bile and urine are sampled during the first 3 hours after injection. Excretion through these routes is 49 and 16% of injected dose respectively.
  • Isopaque 5-(N-acetylamino)- 3-(N ⁇ acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylic acid
  • All the iodine is excreted through urine or faeces in equal amounts (about 50% each) .
  • the particles of Pharmaceutical Formulation 8 are injected intravenously into the tail vein of rats.
  • the dose is 200 mg/kg, injection rate 1 ml/min and concentration 10 mg/ml. 30 minutes after injection more than 80% of the dose is found in the liver. This uptake gives 1.8 mg I/g liver.
  • the iodine content then gradually decreases to 1-2% after 72 hours.
  • Bile and urine are sampled during the first 3 hours after injection. Excretion through these routes is 9.5 and 42% of injected dose respectively.
  • Isopaque 5-(N-acetylamino)- 3-(N-acetyl-N-methylamino)-2,4,6-t iiodobenzenecarboxylic acid
  • All the iodine is excreted through urine or faeces in equal amounts (about 50% each) .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Hydrogenated Pyridines (AREA)
  • Indole Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Pyrrole Compounds (AREA)
PCT/GB1988/000604 1987-07-24 1988-07-22 Iodinated esters WO1989000988A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
DK014490A DK14490D0 (da) 1987-07-24 1990-01-18 Joderede estere
NO900269A NO180747C (no) 1987-07-24 1990-01-19 Injiserbart kontrastmiddel
FI900347A FI94095C (fi) 1987-07-24 1990-01-23 Ruiskutettu varjoaine
SU904742976A RU1829940C (ru) 1987-07-24 1990-01-23 Способ получени инъектируемой контрастной среды

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8717625 1987-07-24
GB878717625A GB8717625D0 (en) 1987-07-24 1987-07-24 Chemical compounds

Publications (1)

Publication Number Publication Date
WO1989000988A1 true WO1989000988A1 (en) 1989-02-09

Family

ID=10621281

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1988/000604 WO1989000988A1 (en) 1987-07-24 1988-07-22 Iodinated esters

Country Status (17)

Country Link
EP (1) EP0300828B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
JP (1) JP2563555B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AT (1) ATE73763T1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AU (1) AU609858B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
DE (1) DE3869256D1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
DK (1) DK14490D0 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
ES (1) ES2030170T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
FI (1) FI94095C (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
GB (1) GB8717625D0 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
GR (1) GR3004614T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
HU (1) HU210550B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
IE (1) IE61263B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
NO (1) NO180747C (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
NZ (1) NZ225551A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
RU (1) RU1829940C (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1989000988A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
ZA (1) ZA885411B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580600A (en) * 1991-06-14 1996-12-03 Associated Food Technology Pty, Ltd. Monounsaturated dairy products
US8003079B2 (en) 2005-04-05 2011-08-23 Bar-Ilan University Core and core-shell nanoparticles containing iodine for X-ray imaging
DE102018212966A1 (de) * 2018-08-02 2020-02-06 Siemens Mobility GmbH Verkleidungselement

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US4863714A (en) * 1987-02-05 1989-09-05 Cook Imaging Corporation Sterilization of compositions of limited stability
US5354549A (en) * 1987-07-24 1994-10-11 Nycomed Imaging As Iodinated esters
US5330739A (en) * 1992-12-04 1994-07-19 Sterling Winthrop Inc. Iodinated benzoyl acetals and ketals for x-ray imaging
CN119564969B (zh) * 2025-01-24 2025-04-04 四川大学华西医院 一种荧光显影剂合成注射控制系统、注射泵及存储介质

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2428140A1 (de) * 1973-06-28 1975-01-23 Beecham Group Ltd Derivate der 3-acetamido-2,4,6-trijodbenzoesaeure, verfahren zu ihrer herstellung und ihre verwendung
GB2157283A (en) * 1984-03-30 1985-10-23 Squibb & Sons Inc Esters of 3,5-diacetylamino-2,4,6-triiodobenzoic acid as X-ray contrast agents

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU473168B2 (en) * 1971-04-15 1973-10-18 Nippon Steel Corporation Magnetic conveyor
AT325762B (de) * 1972-04-12 1975-11-10 Beecham Group Ltd Rontgenkontrastmittel
ATE79368T1 (de) * 1987-05-22 1992-08-15 Bracco Spa Herstellung von 5-acylamino-2,4,6-trijodo- oder tribromo-benzoesaeure-derivate.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2428140A1 (de) * 1973-06-28 1975-01-23 Beecham Group Ltd Derivate der 3-acetamido-2,4,6-trijodbenzoesaeure, verfahren zu ihrer herstellung und ihre verwendung
GB2157283A (en) * 1984-03-30 1985-10-23 Squibb & Sons Inc Esters of 3,5-diacetylamino-2,4,6-triiodobenzoic acid as X-ray contrast agents

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580600A (en) * 1991-06-14 1996-12-03 Associated Food Technology Pty, Ltd. Monounsaturated dairy products
US8003079B2 (en) 2005-04-05 2011-08-23 Bar-Ilan University Core and core-shell nanoparticles containing iodine for X-ray imaging
DE102018212966A1 (de) * 2018-08-02 2020-02-06 Siemens Mobility GmbH Verkleidungselement

Also Published As

Publication number Publication date
DK14490A (da) 1990-01-18
DK14490D0 (da) 1990-01-18
NO180747B (no) 1997-03-03
ZA885411B (en) 1989-04-26
HU884573D0 (en) 1990-09-28
GB8717625D0 (en) 1987-09-03
JPH02504270A (ja) 1990-12-06
IE882247L (en) 1989-01-24
IE61263B1 (en) 1994-10-19
EP0300828B1 (en) 1992-03-18
DE3869256D1 (de) 1992-04-23
NO180747C (no) 1997-06-11
FI900347A0 (fi) 1990-01-23
ATE73763T1 (de) 1992-04-15
JP2563555B2 (ja) 1996-12-11
GR3004614T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1993-04-28
NO900269D0 (no) 1990-01-19
AU609858B2 (en) 1991-05-09
RU1829940C (ru) 1993-07-23
ES2030170T3 (es) 1992-10-16
FI94095B (fi) 1995-04-13
EP0300828A1 (en) 1989-01-25
HU210550B (en) 1995-05-29
NZ225551A (en) 1991-06-25
NO900269L (no) 1990-01-19
FI94095C (fi) 1995-07-25
HUT53585A (en) 1990-11-28
AU2087088A (en) 1989-03-01

Similar Documents

Publication Publication Date Title
US5354549A (en) Iodinated esters
AU631837B2 (en) Iodinated esters
US4845090A (en) Nitroxyl compound and diagnostic media based thereon useful for enhancing NMR imaging
JPH0196160A (ja) 新規ジカルボン酸‐ビス（３，５‐ジカルバモイル‐２，４，６‐トリヨード‐アニリド）、その製法及びこれを含有するレントゲン造影剤
EP0300828B1 (en) Iodinated esters
CZ235593A3 (en) Iodinated aroyloxycarboxamides
WO1991016337A1 (en) S-(lower fatty acid)-substituted glutathione derivative
WO1996022994A1 (en) Bismuth compounds
KR970011452B1 (ko) 치환된 디카복실산-비스(3,5-디카바모일-2,4,6-트리요오도아닐리드) 및 이를 함유하는 x-선 조영제
FR2505834A1 (fr) Derives de la thiazolidine
WO1994019025A2 (en) Contrast agents
US4395391A (en) Unsymmetrically substituted dicarboxylic-acid-bis-(2,4,6-triiodo-anilides), their preparation, and x-ray contrast media containing same
US3910989A (en) N-triiodobenzyl-carbamic acid derivatives
US4044048A (en) Radiopaque esters of tetra-iodoterephthalic acid
JPH1025292A (ja) 新規なピロロキノリンキノン化合物
CS223899B2 (cs) Způsob výroby monoamidových sloučenin kyseliny 2,4,6-trijodisoftalové C-substituované v poloze 5

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU DK FI GB HU JP NO SU US

WWE Wipo information: entry into national phase

Ref document number: 900347

Country of ref document: FI

WWG Wipo information: grant in national office

Ref document number: 900347

Country of ref document: FI