EP0263877A1 - Dihydrorhodamines et leurs derives halogenes - Google Patents

Dihydrorhodamines et leurs derives halogenes

Info

Publication number
EP0263877A1
EP0263877A1 EP19870903093 EP87903093A EP0263877A1 EP 0263877 A1 EP0263877 A1 EP 0263877A1 EP 19870903093 EP19870903093 EP 19870903093 EP 87903093 A EP87903093 A EP 87903093A EP 0263877 A1 EP0263877 A1 EP 0263877A1
Authority
EP
European Patent Office
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.)
Withdrawn
Application number
EP19870903093
Other languages
German (de)
English (en)
Inventor
Berma Mcdowell Kinsey
Amin I. Kassis
Stanley James Adelstein
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.)
Harvard University
Original Assignee
Harvard University
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 Harvard University filed Critical Harvard University
Publication of EP0263877A1 publication Critical patent/EP0263877A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • 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.
EP19870903093 1986-04-11 1987-04-07 Dihydrorhodamines et leurs derives halogenes Withdrawn EP0263877A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85084586A 1986-04-11 1986-04-11
US850845 1986-04-11

Publications (1)

Publication Number Publication Date
EP0263877A1 true EP0263877A1 (fr) 1988-04-20

Family

ID=25309254

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19870903093 Withdrawn EP0263877A1 (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)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2613937B1 (fr) * 1987-04-17 1989-07-21 Ire Celltarg Sa Ligands specifiques de recepteurs d'hormones steroides utiles pour la therapie ciblee ou l'imagerie medicale notamment du cancer
EP0353953A3 (fr) * 1988-08-04 1990-11-22 Imperial Chemical Industries Plc Procédé pour réaliser une réaction catalysée enzymatiquement
US6130101A (en) * 1997-09-23 2000-10-10 Molecular Probes, Inc. Sulfonated xanthene derivatives
BRPI0204489B8 (pt) * 2001-04-02 2021-05-25 Celmed Biosciences Inc "derivado de rodamina, composição farmacêutica, intermediário, e, processo para a síntese de novos derivados rodamina".
CA2342675A1 (fr) 2001-04-02 2002-10-02 Abdelkrim Habi Derives halogenes de rhodamine et applications de ces composes
EP2025349A3 (fr) * 2004-12-13 2013-03-13 Ge Healthcare As Agents de contraste fluorescents
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
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

Family Cites Families (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
JPS55133032A (en) * 1979-04-03 1980-10-16 Ricoh Co Ltd Photosensitive composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8706138A1 *

Also Published As

Publication number Publication date
WO1987006138A1 (fr) 1987-10-22
JPS63503071A (ja) 1988-11-10
AU7357887A (en) 1987-11-09

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Inventor name: KINSEY, BERMA, MCDOWELL

Inventor name: ADELSTEIN, STANLEY, JAMES

Inventor name: KASSIS, AMIN, I.