WO1993015093A1 - Agents de contraste pour imagerie par resonance magnetique de l'intestin grele et dus systeme hepatobiliaire - Google Patents

Agents de contraste pour imagerie par resonance magnetique de l'intestin grele et dus systeme hepatobiliaire Download PDF

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Publication number
WO1993015093A1
WO1993015093A1 PCT/US1992/000678 US9200678W WO9315093A1 WO 1993015093 A1 WO1993015093 A1 WO 1993015093A1 US 9200678 W US9200678 W US 9200678W WO 9315093 A1 WO9315093 A1 WO 9315093A1
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Prior art keywords
phenyl
complex according
carbon atoms
substituted
amino
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PCT/US1992/000678
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English (en)
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David L. White
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The Regents Of The University Of California
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Priority to PCT/US1992/000678 priority Critical patent/WO1993015093A1/fr
Publication of WO1993015093A1 publication Critical patent/WO1993015093A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds

Definitions

  • the present invention is directed to a novel class of carboxylic acid derivatives of the iron (III) chelate of desferrioxamine B which are useful as magnetic resonance imaging contrast agents for renal, hepatobiliary and, in particular, small intestine image enhancement.
  • the iron (III) chelate of desferrioxamine B is a known magnetic resonance imaging contrast agent that gives both renal and hepatobiliary enhancement. It is one of the soluble paramagnetic compounds used for this purpose.
  • Other soluble paramagnetic compounds, such as Gd-DTPA suffer from various disadvantages, such as, rapid diffusion from the vascular system into the extracellular space, lack of specificity for liver and essentially no concentration in the bile.
  • Manganese dichloride concentrates in the liver after IV injection. is transported to the bile and excreted in the feces. However, it is toxic and is not practically useful in a clinical situation.
  • Iron (III) complexes Fe-EHPG and Fe-HBED are useful contrast agents in the liver and are secreted into the bile. However, their appearance in the bile does not take place until approximately 20 minutes post injection and furthermore, enhancement of the lumen of the small intestine is seldom observed using these agents.
  • the magnetic resonance imaging of the gastrointestinal tract is limited by inherently low image contrast, motion and variable anatomic appearance. Agents for this purpose are normally administered orally and reside within lumen of the GI tract to provide either positive (increased signal strength) or negative (decreased signal strength) contrast.
  • positive contrast is provided by ingestion of paramagnetic agents .
  • paramagnetic agents such as Gd-DTPA or iron citrate
  • negative contrast is provided by displacement of the luminal proton-containing contents by gas (such as carbon dioxide from gas tablets) or perfluorocarbons.
  • Negative contrast can also be obtained by ingestion of ferromagnetic or superparamagnetic particles, such as ferrite.
  • MRI contrast agents which are useful both for hepatobiliary studies and for gastrointestinal studies, particularly when introduced by intravenous administration, rather than by oral administration. It is thus an object of the present invention to provide improved desferrioxamine B contrast agents for magnetic resonance imaging. It is yet another object of the present invention to provide magnetic resonance imaging contrast agents having high stability, low toxicity, physiological tolerability and which provide for positive imaging of the small intestine rapidly after intravenous administration.
  • the present invention provides a method for performing magnetic resonance imaging diagnostic procedures in a subject comprising the step of administering intravenously to the subject a magnetic resonance imaging enhancement effective amount of a diagnostic medium comprising the compound of the following formula in a physiologically acceptable carrier:
  • R is -desferrioxamine B
  • j is an integer from 1 to n
  • k is an integer from O to m
  • s is an integer from 0 to p
  • p+n+m is less than or equal to 18
  • each R 1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R 2 j , R 3 k , R 4 k , R 7 s and R 8 s is independently hydrogen, aryl or substituted ary
  • FIGS. 1A through IE are graphs showing the distribution of 59 Fe in labelled contrast agents, DF, GDF, PSDF, SDF and PGDF, respectively.
  • Media according to the present invention are useful for magnetic resonance imaging diagnosis.
  • Production of the diagnostic media according to the present invention may be performed according to ways known in the art, i.e., by forming a complex salt as described hereinbelow, optionally with the addition of customary additives such as galenicals, which may be suspended or dissolved in an aqueous medium followed by sterilization.
  • Suitable additives include, for example, physiologically biocompatible buffers such as tromethamine hydrochloride, complexing agents such as diethylenediiaminepentaacetic acid, or if necessary electrolytes such as sodium chloride.
  • the compounds according to the present invention which are utilized in the present method are those of the following formula I: wherein X is carbon or nitrogen; R is -desferrioxamine B; j is an integer from 1 to n; k is an integer from O to m; s is an integer from 0 to p; p+n+m is less than or equal to 18; each R 1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R 2 j , R 3 k , R 4 k
  • aryl groups are phenyl, substituted phenyl, biphenyl, substituted biphenyl, phenanthryl, anthracyl, substituted phenanthryl.
  • a more preferred aryl group or aryloxy group are phenyl and phenoxy and preferably para substituted phenyl or phenoxy.
  • a second class of complexes are those comprising a metal ion selected from the group consisting of Fe (III), Dy (III), Gd (III), Cr (III) and Mn (II) and a ligand of the formula (III)
  • R is -desferrioxamine-B; t and u are integers from 0 to 3 ; R ⁇ is hydroxy or an alkoxy of 1 to 18 carbon atoms or an aryloxy of 6 to 14 carbon atoms, or substituted aryloxy having at least one substituent selected from the group consisting of aryl, nitro, sulfonyl, hydroxl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxy carbonyl of 2 to 6 carbon atoms and sulfhydryl.
  • Components of the above formula may be made by treating a salt of desferrioxamine B, such as the mesylate, with an appropriate anhydride of an aromatic dicarboxylic acid, such as phthalic anhydride.
  • anhydride of an aromatic dicarboxylic acid such as phthalic anhydride.
  • the primary amino group of the desferrioxamine B will react with the anhydride and form an N-carboxylate desferrioxamine B derivative.
  • Any -O- esters that may have formed during the amidation reaction may. then be removed under conventional conditions to result in the N-carboxylated desferrioxamine B contrast agents according to the present invention.
  • Treatment of the anhydride with desferrioxamine B will normally be conducted at around 100 to 110°C in a suitable solvent, such as pyridine. Treatment of the ligand with an appropriate metal salt of the desired metal counterion will form the metal complex. Alternatively, the NOH groups may be protected by esterification or by complexation with a metal ion.
  • the preferred iron (III) complex of the N-carboxylated desferrioxamine B compound may be prepared by treatment thereof with ferric chloride in an acidic aqueous medium, followed by basification to a pH of about 7.5 to 8.
  • radical desferrioxamine B is of the following formula II
  • the active ingredient of the contrast agents according to the present invention are generally prepared by treating a salt of desferrioxamine B, such as the mesylate, with an appropriate anhydride of a dicarboxylic acid.
  • a salt of desferrioxamine B such as the mesylate
  • an appropriate anhydride of a dicarboxylic acid By using two or more equivalents of the anhydride to one equivalent of the protected desferrioxamine B, in a basic medium, the primary amino group of the desferrioxamine B will react with the anhydride and form an N-carboxylate desferrioxamine B derivative. Any -O- esters that may have formed during the amidation reaction may then be removed under conventional conditions to result in the N-carboxylated; desferrioxamine B contrast agents according to the present invention.
  • Treatment of the anhydride with desferrioxamine B will normally be conducted at around 100 to 110°C, in a suitable solvent, such as pyridine. Treatment of the ligand with an appropriate metal salt of the desired metal counterion will form the metal complex. Alternatively, the N-OH groups may be protected by esterification or by complexation with a metal ion.
  • the preferred iron (III) complex of the N-carboxylated desferrioxamine B compound may be prepared by treatment thereof with ferric chloride in an acidic aqueous medium, followed by basification to a pH of about 7.5 to 8.
  • Preferred ligands are shown in Table 1.
  • the N-(3-phenylglutaramido) desferrioxamine B iron (III) complex is advantageously used for MRI imaging of the small intestine.
  • N-carboxylated desferrioxamine B ligands and complexes thereof with metals according to the present invention having the following formula are novel.
  • R is -desferrioxamine B
  • j is an integer from 1 to n
  • k is an integer from 0 to m
  • s is an integer from 0 to p
  • p+n+m is less than or equal to 18
  • each R 1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R 2 j , R 3 k , R 4 k , R 7 s and R 8 s is independently hydrogen, aryl or substituted
  • the contrast agents according to the present invention are particularly advantageous in that upon intravenous injection, they concentrate in bile, and in some cases, appear in the small intestine very rapidly, usually within about two minutes post injection. They are useful in that they may be administered by the intravenous route, thus the entry into the small intestine is by the hepatobiliary system. Therefore, in addition to contrast enhancement of alimentary tract lumen, with its resulting increased anatomical information, the contrast agents also provide functional information. For example, hepatobiliary dysfunctions, such as bile duct occlusion will retard, lessen or prevent the transport of the contrast agent and thus be revealed by MRI.
  • the contrast agents according to the present invention not only show specificity for the biliary system and small intestines, but they also are relatively non-toxic and substantially completely excreted.
  • Conventional hepatobiliary contrast agents, such as Gd-DTPA distribute in the extracellular volume and are not useful therefore for imaging the small intestine.
  • the reagents according to the present invention therefore can reveal additional details regarding the anatomy of the small intestines, and because of their very rapid localization in the bile and gut lumen, the MRI of these organ systems are simplified and thereby expedited.
  • metal ions besides iron (III) may be utilized to complex with the ligands according to the present invention for use in magnetic resonance imaging.
  • Useful metal ions include Dy (III), Gd (III), Cr (III), and Mn (II).
  • the agents according to the present invention are utilized preferably in solutions made by addition of a solvent such as water, serum, albumin solutions, or saline to the complex.
  • a typical injectable composition will contain about 10 mg/ml human serum albumin with a metal complex concentration of about 20 to 200 mg/ml.
  • a 0.1 m phosphate buffer (7.5 pH) may be employed containing, for example, about 0.9% sodium chloride.
  • the pH of the aqueous solutions may range between about 5 to 9 over a volume range of about 5 to 150 ml.
  • This viscous diagnostic reagent may then be injected into a subject usually in an amount of .001 to 5 mmole of contrast agent, and the subject may then be imaged by a conventional magnetic resonance imaging system. Typical imaging systems are disclosed, for example; in Scientific American. May 1982, pp.
  • N- (glutaramido) desferrioxamine B was prepared similarly using 1.41 g (12.37 mmoles) of glutaric anhydride and 4.91 g (7.47 mmoles) of desferrioxamine B mesylate. Recrystallization from dilute HCl (pH 2.5) gave 3.08 g (4.6 mmoles, 62% of theory) of white solid, mp. 154-158oC.
  • Anal. Calc'd for C 30 H 58 N 6 O 11 C, 53.41; H, 8.01; N, 12.46. Found: C, 53.29; H, 7.88; N, 12.37.
  • a normal, male Sprague-Dawley rat was anesthetized with 50 mg/kg i.p. sodium pentobarbital and fitted with a tail-vein catheter. The animal was then placed in an imaging coil, and the coil plus animal was inserted into the magnet bore of a General Electric Model CSI-II Iagnetic Resonance Imager/Spectrometer. Non-gated spinecho images were acquired using TR and TE equal to 320 and 15 msec, respectively. Following these pre-contrast images, 0.52 mL of a 0.10 M Fe-PGDF solution was injected, and images were acquired at various time intervals post injection. Within one minute of injection the liver, stomach and small intestine showed enhanced contrast, particularly the small intestine. One hour post injection contrast enhancement of the urinary bladder began with the contrast enhancement of the small intestine being diminished. Several hours post injection showed only enhancement of contrast in the urinary bladder.
  • Fe-PGDF 0.25 g (0.31 mmol) was dissolved in 10 mL of anhydrous methanol, and the resulting red solution was treated with 5 mL of a 40% w/w solution of BF 3 in methanol (24 mmol). The solution became purple in color as the BF 3 was added. The reaction mixture was warmed to 60°C for 15 minutes. The methanol then was removed using a rotary evaporator. The residual purple liquid then was treated with aqueous pH 7 buffer, and polystyrene-divinyl benzene beads (e.g., "BioBeads," BioRad, Inc., Hercules, CA). The Fe-PGDF methyl ester was adsorbed onto the beads. Salts and by-products were removed by washing the beads with water. The Fe-PGDF methyl ester was recovered by extraction with methanol. EXAMPLE 9
  • DF desferrioxamine
  • GDF N-(glutaramido) desferrioxamine
  • PSDF N-(phenylsuccinamido)-desferrioxamine
  • SDF N-(succinamido)desferrioxamine.

Abstract

On décrit un procédé mettant en ÷uvre des agents de contraste qui produisent de plus amples informations de diagnostic dans l'image par résonance magnétique du système hépatobiliaire et du tube digestif, notamment de l'intestin grêle. On décrit également de nouveaux agents de contraste qui sont des complexes N-carboxylé de desferrioxamine B avec des ions métalliques.
PCT/US1992/000678 1992-01-29 1992-01-29 Agents de contraste pour imagerie par resonance magnetique de l'intestin grele et dus systeme hepatobiliaire WO1993015093A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/US1992/000678 WO1993015093A1 (fr) 1992-01-29 1992-01-29 Agents de contraste pour imagerie par resonance magnetique de l'intestin grele et dus systeme hepatobiliaire

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001049326A1 (fr) * 1999-12-29 2001-07-12 Bracco Imaging S.P.A Utilisation d'agents de contraste dans la fabrication d'agents diagnostiques pour la visualisation de la lumiere intestinale
WO2009055863A1 (fr) * 2007-11-01 2009-05-07 The University Of Sydney Conjugués de la desferrioxamine, dérivés et analogues

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4758422A (en) * 1985-01-04 1988-07-19 Salutar Inc. Ferrioxamine paramagnetic contrast agents for MR imaging
US4999445A (en) * 1988-06-10 1991-03-12 The Regents Of The University Of California Contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4758422A (en) * 1985-01-04 1988-07-19 Salutar Inc. Ferrioxamine paramagnetic contrast agents for MR imaging
US4999445A (en) * 1988-06-10 1991-03-12 The Regents Of The University Of California Contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001049326A1 (fr) * 1999-12-29 2001-07-12 Bracco Imaging S.P.A Utilisation d'agents de contraste dans la fabrication d'agents diagnostiques pour la visualisation de la lumiere intestinale
JP2003519200A (ja) * 1999-12-29 2003-06-17 ブラッコ イメージング エッセ ピ ア 腸管腔の視覚化のための診断剤の製造における造影剤の使用
CN1302814C (zh) * 1999-12-29 2007-03-07 布雷克成像有限公司 造影剂在制备用于对肠腔造影的诊断试剂中的用途
JP4798919B2 (ja) * 1999-12-29 2011-10-19 ブラッコ イメージング エッセ ピ ア 腸管腔の視覚化のための診断剤の製造における造影剤の使用
WO2009055863A1 (fr) * 2007-11-01 2009-05-07 The University Of Sydney Conjugués de la desferrioxamine, dérivés et analogues
US8309583B2 (en) 2007-11-01 2012-11-13 Rachel Codd Desferrioxamine conjugates, derivatives and analogues
AU2008318287B2 (en) * 2007-11-01 2013-01-17 The University Of Sydney Desferrioxamine conjugates, derivatives and analogues

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