WO1987006138A1 - Dihydrorhodamines et leurs derives halogenes - Google Patents

Dihydrorhodamines et leurs derives halogenes Download PDF

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Publication number
WO1987006138A1
WO1987006138A1 PCT/US1987/000819 US8700819W WO8706138A1 WO 1987006138 A1 WO1987006138 A1 WO 1987006138A1 US 8700819 W US8700819 W US 8700819W WO 8706138 A1 WO8706138 A1 WO 8706138A1
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WO
WIPO (PCT)
Prior art keywords
hydrogen
compound
rhodamine
compounds
dihydrorhodamines
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/US1987/000819
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English (en)
Inventor
Berma Mcdowell Kinsey
Amin I. Kassis
Stanley James Adelstein
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Harvard University
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Harvard University
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Publication date
Application filed by Harvard University filed Critical Harvard University
Publication of WO1987006138A1 publication Critical patent/WO1987006138A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes

Definitions

  • This invention relates to novel dihydrorhodamines and to covalently halogenated labelling, imaging compounds or therapeutic compounds and pertains more specifically to radiohalogenated dihydrorhodamine compounds.
  • the compounds of the invention can be used for detecting, labelling, imaging, or therapeutically treating viable mammalian cells.
  • rhodamine 123 a permeant cationic dye as a mitochondrial stain of viable malian cells and as a probe for the study of mitochondrial function and membrane potential. This compound is retained longer in certain types of tumor cells than in normal cells and exhibits selective toxicity to certain tumor cells in vitro and in vivo .
  • dihydrorhodamines and halogenated dihydrorhodamines are taken up, oxidized to the fluorescent parent rhodamines, and retained by mammalian cells. Furthermore, unlike the rhodamines themselves, the dihydrorhodamines can be covalently halogenated by conventional halogenation procedures, and the halogen of such compounds is internalized by the cells, thus providing the cells with enhanced susceptibility to toxic radiation. Consequently, halogenated and radiohalogenated dihydrorhodamines are useful as detecting, labelling, imaging or therapeutic agents.
  • the present invention comprises a compound having the structure
  • R 1 ,R 2 ,R 3 ,R 4 and R 5 are hydrogen or lower alkyl (preferably having 1-5 carbon atoms), and X 1 ,X 2 ,X 3 and X 4 are hydrogen, lower alkyl (preferably having 1-5 carbon atoms), halogen, or a radiohalogen, Y is -COOR 5 or -SO 3 R 5 , Z is hydrogen, -COOR 5 , or -SO 3 R 5 , and water-soluble salts of such compounds.
  • the salts are those which are physiologically acceptable; they include, for example, the chloride perchlorate, tetrafluoroborate, and internal salts where, for example, both Y and Z are -SO 3 H.
  • the invention also comprises bringing into contact with a mammalian cell an aqueous solution comprising a compound having the structure
  • R 1 -R 5 , X 1 -X 4 , and Y and Z are as defined above, to cause said compound to be taken up by the cell.
  • at least one of X 1 , X 2 , X 3 and X 4 is halogen or radiohalogen, the remainder being hydrogen.
  • the dihydrorhodamine compounds of the present invention can be made by hydrogenation or reduction of the corresponding rhodamine compound by conventional procedures such as by reduction with a borohydride, e.g. sodium borohydride in aqueous medium.
  • a borohydride e.g. sodium borohydride in aqueous medium.
  • corresponding rhodamine compounds are rhodamine B, rhodamine 3B, rhodamine 6-G, rhodamine 19, rhodamine 110, rhodamine 116, rhodamine 123, sulforhodamine B, and including various water-soluble salts.
  • the structure of rhodamine 19 is
  • the dihydrorhodamine products have the structure (1) given above in which X 1 ,X 2 ,X 3 and X 4 are hydrogen.
  • the dihydrorhodamines can be covalently halogenated by any conventional procedure such as the chloramine T, iodogen, or N-chlorosuccinimide procedure, or any other procedure effective to introduce one or more atoms of chlorine, bromine, iodine or astatine into an aromatic amine.
  • the products, containing halogen covalently bonded in any one or more of the four available positions X 1 -X 4 in the amino substituted benzene rings can, if desired, be separated from each other by chromatography. However, separation is not essential and mixtures containing two or more different halogenated compounds are useful in the same way as the individually pure compounds.
  • the dihydrorhodamine compounds after halogenation with a halogen radioisotope such as chlorine, bromine, iodine or astatine may be used as labelling, imaging or therapeutic agents in the same way as rhodamine 123 or any other such agent simply by dissolving the compound in an aqueous medium such as normal saline or any physiologically acceptable medium and bringing it into contact with the viable mammalian cells it is desired to treat, whereupon the compounds are taken up by the cells and located in the cytoplasm.
  • a halogen radioisotope such as chlorine, bromine, iodine or astatine
  • Example 1 Dihydrorhodamine 123: Rhodamine 123 hydrochloride (100 mg, 0.26 mmol; Eastman Kodak) was dissolved in 50 ml of water and 50 ml of Ch 2 Cl 2 was added. Excess solid NaBH 4 was added in portions with vigorous magnetic stirring until almost all the color was discharged. After 1 hr, the pale orange organic layer was separated and the water layer extracted twice with CH 2 Cl 2 . The combined organic layers were passed through anhydrous Na 2 SO 4 and evaporated under reduced pressure.
  • the crude oily reaction mixture was purified by flash chromatography (C) using 10% ethylacetate in CH 2 Cl 2 as eluent, giving 80 mg of a slightly pinkish-orange oil (88% yield).
  • the purified oil was dissolved in a small amount of CH 2 Cl 2 and precipitated with hexane.
  • Iododihydrorhodamine 123 (A) : Dihydrorhodamine 123 (43 mg, 0.12 mmol) was dissolved in 50 mL of CCl 4 and 1 mL of CH 2 Cl 2 , and cooled in ice under red light. A solution of 17 mg Nal in 0.5 mL MeOH and 0.5 mL 0.2 M NH 4 OAc was added with stirring and a cold solution of 17 mg (0.13 mmol) of N-chlorosuccinimide in so mL CCl 4 was added in small portions. The reaction mixture was allowed to warm to room temperature and stirring was continued for 1 hr.
  • dihydrorhodamine 123 is itself a nonfluorescent compound, when an aqueous solution of the compound is applied to viable mammalian cells, its presence in the mitochondria of the cells is observed by fluorescent microscopy, showing that' it is oxidized within the cell to the fluorescent rhodamine 123. Halogenation of the compound does not fnterfere with its being taken up by the cells and oxidized.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pyrane Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On peut produire des dihydrorhodamines par réduction de rhodamines et les halogener de manière covalente par des processus classiques. Ces composés peuvent être utilisés comme agents d'étiquetage, d'imagerie et thérapeutiques pour les cellules de mammifères.
PCT/US1987/000819 1986-04-11 1987-04-07 Dihydrorhodamines et leurs derives halogenes Ceased WO1987006138A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85084586A 1986-04-11 1986-04-11
US850,845 1986-04-11

Publications (1)

Publication Number Publication Date
WO1987006138A1 true WO1987006138A1 (fr) 1987-10-22

Family

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Family Applications (1)

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PCT/US1987/000819 Ceased WO1987006138A1 (fr) 1986-04-11 1987-04-07 Dihydrorhodamines et leurs derives halogenes

Country Status (4)

Country Link
EP (1) EP0263877A1 (fr)
JP (1) JPS63503071A (fr)
AU (1) AU7357887A (fr)
WO (1) WO1987006138A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988007986A3 (fr) * 1987-04-17 1988-12-01 Ire Celltarg Sa Composes utiles notamment pour la radiotherapie ou l'imagerie du cancer
EP0353953A3 (fr) * 1988-08-04 1990-11-22 Imperial Chemical Industries Plc Procédé pour réaliser une réaction catalysée enzymatiquement
WO1999015517A1 (fr) * 1997-09-23 1999-04-01 Molecular Probes, Inc. Derives de xanthene sulfone
WO2002079183A1 (fr) * 2001-04-02 2002-10-10 Theratechnologies Inc. Derives halogenes de la rhodamine et leurs applications
WO2006065146A3 (fr) * 2004-12-13 2006-08-31 Ge Healthcare As Agents de contraste fluorescents
US7560574B2 (en) 2001-04-02 2009-07-14 Celmed Biosciences Inc. Halogenated rhodamine derivatives and applications thereof
US9649622B1 (en) * 2016-05-16 2017-05-16 National Taiwan University Of Science And Technology Bimetal oxysulfide solid-solution catalyst and manufacturing method thereof, method for carbon dioxide reduction, method for heavy metal reduction, and method for hydrogenation of organic compounds
US9771262B1 (en) 2016-05-16 2017-09-26 National Taiwan University Of Science And Technology Method for organic compound degradation and method for producing hydrogen

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE44002C (de) * Badische Anilin- und Sodafabrik in Ludwigshafen a. Rh Verfahren zur Darstellung von Farbstoffen aus der Gruppe des Metaam dophenol-Phtaleins
DE49057C (de) * FARBWERKE VORM. Meister, Lucius & Brüning in Höchst a. M Verfahren zur Darstellung von Farbstoffen aus Fluoresceinchlorid
US3728351A (en) * 1968-05-31 1973-04-17 Univ Michigan Radioiodinated quinoline derivatives
US3743713A (en) * 1971-06-22 1973-07-03 Dainabot Radioisotope Labor Lt Preparation of radioactive mono and di-iodosulfobromophthalein
US4067840A (en) * 1976-05-24 1978-01-10 Desoto, Inc. Signal coating suitable for lead-based paint hazard abatement or the like and formulations therefor
US4256727A (en) * 1978-09-18 1981-03-17 The University Of Kentucky Research Foundation Synthesis and use of diagnostic radio-pharmaceuticals comprising radioactive isotopes of bromine with dyes
US4298591A (en) * 1979-04-03 1981-11-03 The United States Of America As Represented By The United States Department Of Energy Instantaneous radioiodination of rose bengal at room temperature and a cold kit therefor
US4306014A (en) * 1979-04-03 1981-12-15 Ricoh Co., Ltd. Photo-sensitive and heat-sensitive composition and recording element using same

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE44002C (de) * Badische Anilin- und Sodafabrik in Ludwigshafen a. Rh Verfahren zur Darstellung von Farbstoffen aus der Gruppe des Metaam dophenol-Phtaleins
DE49057C (de) * FARBWERKE VORM. Meister, Lucius & Brüning in Höchst a. M Verfahren zur Darstellung von Farbstoffen aus Fluoresceinchlorid
US3728351A (en) * 1968-05-31 1973-04-17 Univ Michigan Radioiodinated quinoline derivatives
US3743713A (en) * 1971-06-22 1973-07-03 Dainabot Radioisotope Labor Lt Preparation of radioactive mono and di-iodosulfobromophthalein
US4067840A (en) * 1976-05-24 1978-01-10 Desoto, Inc. Signal coating suitable for lead-based paint hazard abatement or the like and formulations therefor
US4256727A (en) * 1978-09-18 1981-03-17 The University Of Kentucky Research Foundation Synthesis and use of diagnostic radio-pharmaceuticals comprising radioactive isotopes of bromine with dyes
US4298591A (en) * 1979-04-03 1981-11-03 The United States Of America As Represented By The United States Department Of Energy Instantaneous radioiodination of rose bengal at room temperature and a cold kit therefor
US4306014A (en) * 1979-04-03 1981-12-15 Ricoh Co., Ltd. Photo-sensitive and heat-sensitive composition and recording element using same

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Biotechniques, Volume 2, No. 1, issued January/February 1984, (Natick, Massachusetts), PAUL M. GALLOP, "Dynamic Approaches to the Delivery of Reporter Reagents into Living Cells", see pages 32-36. *
Colour Index, third Edition, Volume 4, published 1971 by the Society of Dyers and Colourists (Great Britain), see pages 4417, 4431-4432. *
E.N. ABRAHART "Dyes and their Intermediates", published 1968, by Pergamon Press (London), see pages 223-225. *
Journal of Labelled Compounds and Radiopharmaceuticals, Volume 21, Nos. 11-12, issued 1984 (Engeland), International Symposium on Radiopharmaceutical Chemistry, Tokyo, 9-13 July, 1984 Symposium Abstracts, M.L. THAKUR, "Mitochondria Specific Rhodamine 123: Radioiodination and Preliminary Evaluation as an Agent for Scintigraphy and Radiotherapy of Certain Tumors", see pages 1120-1122. *
The Journal of Nuclear Medicine, Volume 26, issued 1985 (New York), Proceedings of the 32nd Annual Meeting, Poster Session No. 529, S. PADMANABHAN, "Rhodamine-123: Radioiodination and Evaluation as an Agent for Imaging and Radiotherapy of Certain Tumors", see page P124. *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988007986A3 (fr) * 1987-04-17 1988-12-01 Ire Celltarg Sa Composes utiles notamment pour la radiotherapie ou l'imagerie du cancer
EP0353953A3 (fr) * 1988-08-04 1990-11-22 Imperial Chemical Industries Plc Procédé pour réaliser une réaction catalysée enzymatiquement
US5063149A (en) * 1988-08-04 1991-11-05 Imperial Chemical Industries Plc Performing an enzyme-catalyzed reaction
WO1999015517A1 (fr) * 1997-09-23 1999-04-01 Molecular Probes, Inc. Derives de xanthene sulfone
WO2002079183A1 (fr) * 2001-04-02 2002-10-10 Theratechnologies Inc. Derives halogenes de la rhodamine et leurs applications
US7560574B2 (en) 2001-04-02 2009-07-14 Celmed Biosciences Inc. Halogenated rhodamine derivatives and applications thereof
US8383672B2 (en) 2001-04-02 2013-02-26 Kiadis Pharma Canada Inc. Halogenated rhodamine derivatives and applications thereof
WO2006065146A3 (fr) * 2004-12-13 2006-08-31 Ge Healthcare As Agents de contraste fluorescents
US9649622B1 (en) * 2016-05-16 2017-05-16 National Taiwan University Of Science And Technology Bimetal oxysulfide solid-solution catalyst and manufacturing method thereof, method for carbon dioxide reduction, method for heavy metal reduction, and method for hydrogenation of organic compounds
US9771262B1 (en) 2016-05-16 2017-09-26 National Taiwan University Of Science And Technology Method for organic compound degradation and method for producing hydrogen

Also Published As

Publication number Publication date
AU7357887A (en) 1987-11-09
JPS63503071A (ja) 1988-11-10
EP0263877A1 (fr) 1988-04-20

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