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WO1996017629A1 - Utilisation d'additifs ajoutes a des agents contrastants pour ameliorer l'imagerie - Google Patents

Utilisation d'additifs ajoutes a des agents contrastants pour ameliorer l'imagerie Download PDF

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Publication number
WO1996017629A1
WO1996017629A1 PCT/EP1995/004826 EP9504826W WO9617629A1 WO 1996017629 A1 WO1996017629 A1 WO 1996017629A1 EP 9504826 W EP9504826 W EP 9504826W WO 9617629 A1 WO9617629 A1 WO 9617629A1
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WO
WIPO (PCT)
Prior art keywords
inn
ray
ultrasound
nuclear
group
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1995/004826
Other languages
German (de)
English (en)
Inventor
Werner Krause
Ulrich Speck
Wolf-Rüdiger Press
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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 Schering AG filed Critical Schering AG
Priority to JP8510449A priority Critical patent/JPH10509691A/ja
Priority to EP95941697A priority patent/EP0789594A1/fr
Publication of WO1996017629A1 publication Critical patent/WO1996017629A1/fr
Priority to NO972613A priority patent/NO972613D0/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/46—Unsaturated compounds containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/62—Unsaturated compounds containing ether groups, groups, groups, or groups containing rings other than six-membered aromatic rings

Definitions

  • the invention relates to the use of prostacyclins and urea as an additive to contrast agents to improve imaging.
  • Contrast agents are indispensable aids in X-ray, magnetic resonance, nuclear or ultrasound diagnostics for general improvement of imaging, for more specific imaging of individual organs or tissues or for the visualization of "dynamic" processes or pathological conditions. Summary representations are described in the literature.
  • X-ray diagnostics imaging is based on the different absorption of the irradiated tissue or on the absorption of the X-ray radiation by the contrast medium.
  • All parenterally administered X-ray contrast media use iodine as a radiation-absorbing element and the substances currently available contain either three or six iodine atoms per molecule in order to achieve the highest possible contrast.
  • All commercially available X-ray contrast media are derivatives of triiodobenzene. It these are either monomeric compounds with three iodine atoms or dimeric derivatives with six iodine atoms, which have two triiodobenzene derivatives connected by a bridge. Additional substituents increase the hydrophilicity and improve the tolerance.
  • contrast media for X-ray diagnostics began immediately after the discovery of X-rays by W.C. Röntgen in 1895. The goals and the hoped-for properties for these contrast agents have not changed significantly since then. We are looking for well-tolerated substances with a high radiation-absorbing potential. With the introduction of three or six iodine atoms per molecule, however, a limit in radiation absorption has apparently been reached which, despite intensive efforts, cannot be exceeded at the moment.
  • Papaverine was the most intensively examined. It could be shown that the addition of papaverine to X-ray contrast media improves the imaging of vessels or that the combination of X-ray contrast media with papaverine can even be used for the differential diagnosis of myocardial poor blood circulation (Cheirif et al. J. Am. Coll. Cardiol. 11: 735-743, [1988]; Hodgson and Williams, Am. Heart J. 114: 704-10 [1987]).
  • prostaglandin derivatives to contrast media is capable of significantly improving imaging in the vessels but also in the kidney and urinary tract and that urea also meets this requirement.
  • Contrast media in this sense are X-ray, MRI or ultrasound contrast media and nuclear diagnostics.
  • the present invention therefore relates to the subject matter characterized in the claims, namely the use of prostaglandin derivatives and urea to improve the imaging of contrast media in X-ray, MRI, ultrasound or nuclear diagnostics.
  • Cyclodextrin clathrates of prostaglandins are also to be understood as prostaglandin derivatives.
  • prostaglandin derivatives which are suitable for this use include Ataprost (INN), Beraprost (INN), Ciprosten (INN), CS 570 (INN), FCE 22509 (INN), Naxaprosten (INN), RS 93427 ( INN), SC 39902 (INN), taprostening (INN), 5 - [(E) - (1S, 5S, 6S, 7R) -7-hydroxy-6 - [(3S, 4S)] - 3-hydroxy-4 -methyl-1, 6-nona-diynyl] bicyclo [3.3.0] oct-3-ylidene] pentanoic acid and 5 - [(E) - (1 S, 5S, 6S, 7R) -7-hydroxy- 6- [3S, 4S) -3-hydroxy-4-methyl-1, 6-nonadiinyl] bicyclo [3.3.0] oct-3-ylidene] -5-fluoro-3
  • R 1 represents hydrogen or a C 8 -C 8 alkyl radical
  • n represents the numbers 0 to 3
  • X, Y independently of one another represent a -CH 2 group or an oxygen atom
  • Z represents hydrogen, fluorine or CN
  • D represents a straight-chain or branched C 1 -C 5 alkylene group
  • E represents a -CsC group
  • R 2 represents a C 1 -C 2 alkyl group
  • R 3 stands for a free or functionally modified hydroxy group, as well as their cyclodextrin clathrates, and - if R 1 is hydrogen - their salts with physiologically compatible bases, to improve imaging when using X-ray, ultrasound, nuclear or NMR Contrast agents.
  • the present invention particularly preferably relates to the use of the prostacyclin derivatives lloprost, iloprost clathrate, cicaprost, cicaprost clathrate, eptaloprost or eptaloprost clathrate.
  • the alkyl groups in R 1 are straight or branched chain alkyl groups with 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. -Butyl.
  • the alkyl groups R 1 can optionally be substituted by fluorine, chlorine, bromine or iodine atoms, methoxy, ethoxy, phenyl or (-C-C 2 ) dialkylamino groups, such as dimethylamine or diethylamine.
  • Preferred alkyl groups R 1 are methyl, ethyl and dimethylaminopropyl.
  • R 2 can represent a methyl or an ethyl radical.
  • the hydroxyl groups in R 3 and W can be present as free hydroxyl groups, the hydroxyl group in W preferably being ⁇ -permanent, or can be functionally modified, for example by etherification or esterification. Free hydroxy groups are preferred.
  • radicals known to the person skilled in the art are suitable as ether or acyl radicals. Easily cleavable ether residues such as tetrahydropyranyl, tetrahydrofuranyl, ⁇ -ethoxyethyl, trimethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert-butylsilyl or tribenzylsilyl are preferred.
  • Acyl radicals which may be mentioned are, for example, acetyl, propionyl, butyryl or benzoyl.
  • Suitable alkylene groups D are straight-chain or branched saturated alkyl groups having 1 to 5 carbon atoms, for example methylene, ethylene, 1-propylene, 2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyldimethylene, 1-methyltrimethylene, 1-methyltetramethylene.
  • examples include: alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine,
  • the clathrates with ⁇ -, ⁇ - or ⁇ -cyclodextrin are obtained analogously to the specification WO 87/05 294. ⁇ -cyclodextrin clathrates are preferred.
  • EP 11 591 B1 describes the following pharmacological properties for prostacyclin derivatives of the formula I:
  • EP 86 404 B1 describes the use of carbacyclins for the prophylaxis and therapy of ischemic attacks of the CNS system, for cytoprotection in the liver and in the pancreas, and the combination with ⁇ -blockers or diuretics.
  • DE 34 27 797 C2 discloses the cytoprotection of the kidney and the suitability of the prostacyclin derivatives of the formula I for the treatment of organs to be transplanted.
  • DE 35 26 362 A1 describes the combination of the prostacyclin derivatives of the formula I with thromboxane antagonists for use in thrombotic or thromboemobolic clinical pictures.
  • DE 35 44 663 A1 discloses the combination of the prostacyclin derivatives of the formula I with fibrinolytics to prevent rethrombosis after thrombosis.
  • DE 3608 088 describes the clathrates of the carbacyclin derivatives of the formula I. From DE 36 31 169 A1, in addition to the administration forms described in EP 11 591 B1, the topical administration form is known.
  • DE 41 35 193 C1 describes the use of the abovementioned compounds as an additive for preventing or treating disorders of the microcirculation - that is to say the terminal current path which cannot be imaged (sub-macroscopic vessels) - after administration of X-ray, ultrasound or MRI contrast media.
  • the concentration range of the prostacyclin derivatives added to the contrast agents is preferably 0.1-100 ng / ml. In this concentration range, imaging improves even without the addition of contrast agents, especially in MRI diagnostics and angiography.
  • the less concentrated contrast agent in the urine should actually cause a poorer image quality.
  • Correspondingly unfavorable results are obtained after adding mannitol to a nonionic contrast medium (I. Lovelt et al., In Recent Developments in Nonionic Contrast Media, V. Taenzer, S. Wende: Schwier. Röntgenstr. Suppl. 128: 105-7 [1989 ]).
  • the concentration range of the urea added to the contrast media is preferably 10-150 mg / ml. In this concentration range, imaging also improves without the addition of contrast agents, especially in MRI diagnostics and angiography.
  • a rabbit with a body weight of approx. 3 kg was injected with the nonionic, low-osmolar X-ray contrast agent Ultravist ® -300 (active ingredient: lopromide (INN)) into the common carotid artery.
  • the dose was 2 ml / kg, the injection rate was 1-1.5 ml / sec.
  • An angiogram was taken immediately afterwards (FIG. 1).
  • the dose was 2 ml / kg, the injection rate was 1-1.5 ml / sec.
  • an initial program was recorded (FIG. 3).
  • the investigation was designed as a block test.
  • 3 animals were treated with Isovis »t • -280 (active ingredient: lotrolan (INN)) and 3 animals with isovist ⁇ -280 + 52 mg urea / ml.
  • Isovis »t • -280 active ingredient: lotrolan (INN)
  • isovist ⁇ -280 + 52 mg urea / ml In the second block - 3 days later, the animals were given the other formulation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne l'utilisation de dérivés de prostacycline, ainsi que celle d'urée pour améliorer l'imagerie dans les diagnostics effectués par radiographie, ultrasons, résonance magnétique ou résonance magnétique nucléaire.
PCT/EP1995/004826 1994-12-09 1995-12-08 Utilisation d'additifs ajoutes a des agents contrastants pour ameliorer l'imagerie Ceased WO1996017629A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP8510449A JPH10509691A (ja) 1994-12-09 1995-12-08 画像表示を改良するために造影剤に加える添加剤の使用
EP95941697A EP0789594A1 (fr) 1994-12-09 1995-12-08 Utilisation d'additifs ajoutes a des agents contrastants pour ameliorer l'imagerie
NO972613A NO972613D0 (no) 1994-12-09 1997-06-06 Anvendelse av additiver i kontrastmidler for å forbedre avbildning

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19944446694 DE4446694A1 (de) 1994-12-09 1994-12-09 Verwendung von Zusätzen zu Kontrastmitteln zur Verbesserung der Bildgebung
DEP4446694.3 1994-12-09

Publications (1)

Publication Number Publication Date
WO1996017629A1 true WO1996017629A1 (fr) 1996-06-13

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ID=6537194

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/004826 Ceased WO1996017629A1 (fr) 1994-12-09 1995-12-08 Utilisation d'additifs ajoutes a des agents contrastants pour ameliorer l'imagerie

Country Status (6)

Country Link
EP (1) EP0789594A1 (fr)
JP (1) JPH10509691A (fr)
CA (1) CA2207025A1 (fr)
DE (1) DE4446694A1 (fr)
NO (1) NO972613D0 (fr)
WO (1) WO1996017629A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076496A1 (fr) * 1999-06-14 2000-12-21 Toray Industries, Inc. Composes facilitant l'accumulation de medicaments dans des tissus tumoraux
US9066990B2 (en) 2001-03-26 2015-06-30 Bayer Intellectual Property Gmbh Preparation for restenosis prevention
US9649476B2 (en) 2002-09-20 2017-05-16 Bayer Intellectual Property Gmbh Medical device for dispersing medicaments

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1209751A (zh) * 1996-01-25 1999-03-03 舍林股份公司 血管内使用的改进的浓缩注射液和输注液
EP2324867B1 (fr) 2002-07-12 2014-06-18 Cook Medical Technologies LLC Ballons d'angioplastie revêtis d'agents pharmaceutiques en forme expansée

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4450149A (en) * 1981-06-15 1984-05-22 Research Corporation Radiohalogenation method
EP0407148A2 (fr) * 1989-07-05 1991-01-09 The Green Cross Corporation Adjuvant angiographique
WO1992022334A1 (fr) * 1991-06-11 1992-12-23 Medical University Of South Carolina Antagonistes de recepteurs plaquettaires utiles pour detecter l'agregation plaquettaire intravasculaire
DE4135193C1 (fr) * 1991-10-22 1993-03-11 Schering Ag Berlin Und Bergkamen, 1000 Berlin, De

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4450149A (en) * 1981-06-15 1984-05-22 Research Corporation Radiohalogenation method
EP0407148A2 (fr) * 1989-07-05 1991-01-09 The Green Cross Corporation Adjuvant angiographique
WO1992022334A1 (fr) * 1991-06-11 1992-12-23 Medical University Of South Carolina Antagonistes de recepteurs plaquettaires utiles pour detecter l'agregation plaquettaire intravasculaire
DE4135193C1 (fr) * 1991-10-22 1993-03-11 Schering Ag Berlin Und Bergkamen, 1000 Berlin, De

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
COLLINS P W ET AL: "SYNTHESIS OF THERAPEUTICALLY USEFUL PROSTAGLANDIN AND PROSTACYCLIN ANALOGS", CHEMICAL REVIEWS, vol. 93, no. 4, 1 June 1993 (1993-06-01), pages 1533 - 1564, XP000370083 *
DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KRAUSE, WERNER ET AL: "Cardiac and hemodynamic tolerability of iopromide with or without sodium or iloprost and of ioversol in the anesthetized rat", XP002001840 *
DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KRAUSE, WERNER ET AL: "Elimination of the diatrizoate-induced effects on the microcirculation by the prostacyclin derivative, iloprost", XP002001851 *
INVEST. RADIOL. (1994), 29(10), 922-7 CODEN: INVRAV;ISSN: 0020-9996, 1994 *
INVEST. RADIOL. (1994), 29(11), 978-84 CODEN: INVRAV;ISSN: 0020-9996, 1994 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076496A1 (fr) * 1999-06-14 2000-12-21 Toray Industries, Inc. Composes facilitant l'accumulation de medicaments dans des tissus tumoraux
US9066990B2 (en) 2001-03-26 2015-06-30 Bayer Intellectual Property Gmbh Preparation for restenosis prevention
US9649476B2 (en) 2002-09-20 2017-05-16 Bayer Intellectual Property Gmbh Medical device for dispersing medicaments

Also Published As

Publication number Publication date
CA2207025A1 (fr) 1996-06-13
DE4446694A1 (de) 1996-06-13
JPH10509691A (ja) 1998-09-22
EP0789594A1 (fr) 1997-08-20
NO972613L (no) 1997-06-06
NO972613D0 (no) 1997-06-06

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