WO1997042977A1 - Δ1,6 bicyclo [4,4,0] functional dyes for contrast enhancement in optical imaging - Google Patents
Δ1,6 bicyclo [4,4,0] functional dyes for contrast enhancement in optical imaging Download PDFInfo
- Publication number
- WO1997042977A1 WO1997042977A1 PCT/US1997/007864 US9707864W WO9742977A1 WO 1997042977 A1 WO1997042977 A1 WO 1997042977A1 US 9707864 W US9707864 W US 9707864W WO 9742977 A1 WO9742977 A1 WO 9742977A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- hydrogen
- hydroxyalkyl
- group
- methyl
- Prior art date
Links
- 239000000975 dye Substances 0.000 title claims abstract description 48
- 238000012634 optical imaging Methods 0.000 title description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 34
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 26
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 23
- 125000004181 carboxyalkyl group Chemical group 0.000 claims abstract description 20
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 17
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims abstract description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- 125000002252 acyl group Chemical group 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims abstract description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 238000003384 imaging method Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 2
- IQZPDFORWZTSKT-UHFFFAOYSA-N nitrosulphonic acid Chemical compound OS(=O)(=O)[N+]([O-])=O IQZPDFORWZTSKT-UHFFFAOYSA-N 0.000 claims 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 2
- 125000003396 thiol group Chemical class [H]S* 0.000 abstract description 4
- -1 n-carboxyanhydrides Chemical class 0.000 description 22
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
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- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 7
- 229960004657 indocyanine green Drugs 0.000 description 7
- 230000008685 targeting Effects 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 3
- SGNAVSTUZPHFPI-UHFFFAOYSA-M [I-].C[S+]1C(=NC2=C1C=CC=C2)C Chemical compound [I-].C[S+]1C(=NC2=C1C=CC=C2)C SGNAVSTUZPHFPI-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000004103 aminoalkyl group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 150000002019 disulfides Chemical class 0.000 description 3
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- 239000012467 final product Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 150000002540 isothiocyanates Chemical class 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 125000006850 spacer group Chemical group 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
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- 150000001720 carbohydrates Chemical class 0.000 description 2
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- INGWEZCOABYORO-UHFFFAOYSA-N 2-(furan-2-yl)-7-methyl-1h-1,8-naphthyridin-4-one Chemical compound N=1C2=NC(C)=CC=C2C(O)=CC=1C1=CC=CO1 INGWEZCOABYORO-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- JWUQFQYYMGMPKE-UHFFFAOYSA-N 2-chloro-3-(hydroxymethylidene)cyclohexene-1-carbaldehyde Chemical compound OC=C1CCCC(C=O)=C1Cl JWUQFQYYMGMPKE-UHFFFAOYSA-N 0.000 description 1
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 description 1
- QMYGFTJCQFEDST-UHFFFAOYSA-N 3-methoxybutyl acetate Chemical group COC(C)CCOC(C)=O QMYGFTJCQFEDST-UHFFFAOYSA-N 0.000 description 1
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
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- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MSZJEPVVQWJCIF-UHFFFAOYSA-N butylazanide Chemical compound CCCC[NH-] MSZJEPVVQWJCIF-UHFFFAOYSA-N 0.000 description 1
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- 125000005843 halogen group Chemical group 0.000 description 1
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
Definitions
- the invention is in the field of tomographic imaging. Particularly, the invention is in the field of optical imaging. Most particularly, the invention provides dyes for use in the field of optical imaging. BACKGROUND OF THE INVENTION
- Optical imaging with dyes permit visualization of biological activities (Blasdel, G. G.; Salama, G. Nature 1986, 321, 579, Grinvald, A.; Frostig, E. L. ; Hildesheim, R. Physiological Reviews 1988, 68, 1285, Kauer, J. S. Nature 1988, 331, 166, Lieke, E. E.; Frostig, R. D.; Arieli, A.; Ts'o, D. Y.; Hildesheim, R. and Grinvald, A. Annu. Rev. Physiol. 1989, 51, 543 and reference therein).
- Dyes that are sensitive to physicochemical environments are subject to changes in absorption or emission of light.
- the resulting changes act as optical probes to transform biological activities into optical signals that can be converted into optical images.
- Cyanine dyes with intense absorption and emission in the near-IR region are particularly useful because biological tissues are optically transparent in this region.
- Indocyanine Green (ICG) (I) for example, with absorption maxima at around 810 nm (the isosbestic point of the hemoglobin/deoxyhemoglobin), has been used for monitoring cardiac output, hepatic function, and liver blood flow. After intravenous injection, ICG is rapidly bound by plasma proteins and remains in the blood through one circulation of heart and lungs.
- ICG is then taken up by hepatic parenchymal cells and secreted entirely into the bile (Osol,
- Targeting groups can be introduced to cyanine and indocyanine dyes if essential linkers are present at a convenient site that will not interfere with the optical activity. Conventionally, these spacers have been attached at the nitrogen atom in the heterocyclic moiety. (Mujumdar, R. B.; Ernst, L. A.; Mujumdar, S. R.; Lewis, C. J.; Waggoner, A. S. Bioconjugate Chem. 1993, 4, 105). To effectively label targeting groups, a single spacer between the dye and the targeting group is preferred, and typically involves a multi-step synthesis (Mujumdar, R. B.; Ernst, L. A.; Mujumdar, S. R.; Lewis, C. J. ; Waggoner, A. S. Bioconjugate Chem. 1993, 4, 105).
- the present invention overcomes the technical problems mentioned previously by incorporating a bifunctional spacer, and imposing rigidity on the polyene portion of the cyanine and indocyanine dyes.
- This invention provides functional dyes of the general formula:
- R1, R2, and R 5 may be the same or different and are selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxyl, hydroxyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxyalkyl, C 1 -C 10 aryl, carboxyl, C 1 -C 10 carboxylalkyl, halogen, nitro, C 1 -C 10 alkoxycarbonyl, mercapto, C 1 -C 10 mercaptoalkyl, C 1 -C 10 alkylthio, sulfonate, and -(CH 2 ) m - N(R 6 )(R 7 ) wherein R 6 and R 7 are independently hydrogen or C 1 -C 10 alkyl, C 1 -C 10 acyl, and R 6 and R 7 are capable of forming 5, 6, or 7 membered rings which may optionally be substituted with -O-, -NR 8 , or
- electron donating or electron withdrawing functional groups such as alkyl, alkoxyl, alkylthio, halogen, cyano, alkoxycarbonyl, and nitro can be substituted at the appropriate electron-rich or electron deficient centers at the polyene portion of the molecule.
- the cyanine dyes are generally prepared from condensation reaction between quaternary salts of heterocyclic base and the keto-aldehyde (Keyes, G. H. U.S. Patent 2 251 286, 1941 ;
- the bicyclic cyanine dyes of the present invention can be prepared by the condensation of the thiazolium (2) and the diketone (3).
- Asymmetric dyes with linkage groups can be prepared in a similar manner with additional synthetic steps (Mujumdar, R. B.; Ernst, L. A.; Mujumdar, S. R.; Lewis, C. J.; Waggoner, A. S. Bioconjugate Chem. 1993, 4, 105).
- the starting materials for the bicyclic key intermediate 4 can be prepared by the well known procedures as illustrated in Schemes 1-3.
- the present invention describes the use of ring template strategy to synthesize stable cyanine dyes with desirable photophysical and targeting properties. Simple condensation between a quaternary salt of a heterocyclic base and the cyclic 1 ,5-dicarbonyl compounds will give desirable dye products that are conformationally rigid. The extended conjugated ⁇ system through this centrally located ring(s) will give intensely colored materials.
- the dye moiety can effectively label biological materials.
- the ring system may also contain Group III, IV, V or VI elements in order to further shift the absorption maxima to longer wavelength.
- the ring system can also be a fused ring structure with five, six or seven membered rings.
- the ring structure can also be substituted with acid halides, active esters, alcohols, aldehydes, amines, aryl halides, carboxylic acids, n- carboxy anhydrides, disulfides, hydrazides, iodoacetamides, isothiocyanates, imadates, maleimides, nitrenes, sulfonyl chloride and so forth that are essential for conjugation with targeting groups (biomolecules).
- Biomolecules for use with the dyes refer to all natural and synthetic molecules that play a role in biological systems. Biomolecules include hormones, amino acids, peptides, peptidomimetics, glycomimetics, vitamins, carbohydrates, proteins, deoxyribonucleic acid
- Biomolecules include insulins, prostaglandins, growth factors, liposomes and nucleic acid probes.
- synthetic polymers include polylysine, aborols, dendrimers, and cyclodextrins.
- the advantages of using biomolecules include enhanced tissue targeting through specificity and delivery. Coupling of the dyes to biomolecules can be accomplished by several known methods (e.g., Krejcarek and Tucker Biochem. Biophys. Res. Comm, 30, 581 (1977); Hnatowich, et al.
- nucleophilic group is reacted with an electrophilic group to form a covalent bond between the biomolecule and the dye.
- nucleophilic groups include amines, anilines, alcohols, phenols, thiols and hydrazines.
- Electrophilic group examples include halides, disulfides, epoxides, maleimides, acid chlorides, anhydrides, mixed anhydrides, activated esters, imidates, isocyanates and isothiocyanates.
- alkyl groups for use with the invention include methyl, ethyl, propyl, isopropyl, butyl, cyclohexyl, heptyl and octyl.
- Suitable alkoxyl groups include methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptoxyl and octoxyl.
- Hydroxyalkyl groups suitable for use with the invention include both mono and poly hydroxyalkyls such as hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, tris (hydroxymethyl) methyl and 2-hydroxy-1-hydroxymethyl-ethyI.
- Suitable alkoxyalkyl groups include methoxymethyl, 2,3-dimethoxypropyl, tris (methoxymethyl) methyl, and 2-methoxy- 1-methoxymethyl-ethyl.
- Amino groups suitable for use with the invention include aminoalkyl such as amino methyl, amino ethyl, amino propyl, hydroxy amino such as 1-amino-2,3 propandiol, 1-amino-2-ethanol,and 1-amino-3-propanol and amino acids such as alanine, aspartic acid, glycine and lysine.
- Carboxyalkyls include acetate, hexanoate, propionate, and butyrate.
- Aryl groups include phenyl and naphthyl.
- Alkoxycarbonyl include methyl ester, ethyl ester, propyl ester and butyl ethyl ester.
- Halogen groups include chlorine, fluorine, bromine and iodine.
- Alkylamido groups include groups such as methyl amido, ethyl amido, propyl amido and, butyl amide.
- Alkylthio groups include methyl thio, ethyl thio, propyl thio, and butyl thio.
- Aminoalkyls include NR 6 R 7 where R 6 and R 7 can be hydrogen or C 1 -C 10 alkyl and R 6 and R 7 are capable of forming 5, 6, or 7 membered rings which can be further substituted by a heteroatom such as O, -NR 8 or S, wherein R 8 is hydrogen, alkyl, alkoxyl, hydroxyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylamido, aryl, carboxyl, carboxyalkyl, halogen, nitro, alkoxycarbonyl, mercapto, alkylthio and alkyl sulfonate.
- the compositions of the invention can be formulated into diagnostic compositions for enteral or parenteral administration.
- compositions contain an effective amount of the dye along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated.
- parenteral formulations advantageously contain a sterile aqueous solution or suspension of dye according to this invention.
- Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
- Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
- Formulations for enteral administration may vary widely, as is well known in the art.
- such formulations are liquids which include an effective amount of the dye in aqueous solution or suspension.
- Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like.
- Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.
- the diagnostic compositions are administered in doses effective to achieve the desired enhancement. Such doses may vary widely, depending upon die particular dye employed, the organs or tissues which are the subject of the imaging procedure, the imaging procedure, the imaging equipment being used, and the like.
- the diagnostic compositions of the invention are used in the conventional manner.
- compositions may be administered to a patient, typically a warm-blooded animal, either systemically or locally to the organ or tissue to be imaged, and the patient then subjected to the imaging procedure.
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Abstract
This invention provides functional dyes of general formula (1), wherein R1, R2, and R5 may be the same or different and are selected from the group consisting of hydrogen, C¿1?-C10 alkyl, C1-C10 alkoxyl, hydroxyl, C1-C10 hydroxyalkyl, C1-C10 alkoxyalkyl, C1-C10 aryl, carboxyl, C1-C10 carboxylalkyl, halogen, nitro, C1-C10 alkoxycarbonyl, mercapto, C1-C10 mercaptoalkyl, C1-C10 alkylthio, sulfonate, and -(CH2)m-N(R?6)(R7¿) wherein R?6 and R7¿ are independently hydrogen or C¿1?-C10 alkyl, C1-C10 acyl, and R?6 and R7¿ are capable of forming 5, 6, or 7 membered rings which may optionally be substituted with -O-, -NR8, or -S-; R?3 and R4¿ may be the same or different and are selected from the group consisting of C¿1?-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxyalkyl, C1-C10 aryl, C1-C10 carboxylalkyl, C1-C10 alkyl sulfonate, mercapto alkyl and -(CH2)mN(R?6)(R7); W1 and W2¿ may be the same or different and are selected from the group consisting of -S-, -O-, -Se-, -Te-, -NR8 and C(R9)(R10); and m is about 0-10; R?8, R9, and R10¿ are independently hydrogen, C¿1?-C10 alkyl, C1-C10 alkoxy, C1-C10 mercaptoalkyl, hydroxyl, C1-C10 hydroxyalkyl, C1-C10 alkoxyalkyl, C1-C10 aryl, C1-C10 carboxylalkyl, C1-C10 alkoxycarbonyl, C1-C10 alkylthio, and -(CH2)m-N(R?6)(R7¿); and A is selected from the group consisting of -(CH¿2?)-, -O-, -S-, or -NR?8¿. Also provided are methods of using dyes of the invention comprising administering a diagnostically effective amount of the dye to a patient and visualizing the dye.
Description
Δ1,6 BICYCLO [4,4,0] FUNCTIONAL DYES FOR
CONTRAST ENHANCEMENT IN OPTICAL IMAGING
FIELD OF THE INVENTION
The invention is in the field of tomographic imaging. Particularly, the invention is in the field of optical imaging. Most particularly, the invention provides dyes for use in the field of optical imaging. BACKGROUND OF THE INVENTION
Optical imaging with dyes permit visualization of biological activities (Blasdel, G. G.; Salama, G. Nature 1986, 321, 579, Grinvald, A.; Frostig, E. L. ; Hildesheim, R. Physiological Reviews 1988, 68, 1285, Kauer, J. S. Nature 1988, 331, 166, Lieke, E. E.; Frostig, R. D.; Arieli, A.; Ts'o, D. Y.; Hildesheim, R. and Grinvald, A. Annu. Rev. Physiol. 1989, 51, 543 and reference therein). Dyes that are sensitive to physicochemical environments (such as pressure, cell membrane potential, ion concentration, acidity, partial pressure of oxygen and etc.), are subject to changes in absorption or emission of light. The resulting changes act as optical probes to transform biological activities into optical signals that can be converted into optical images.
Cyanine dyes with intense absorption and emission in the near-IR region (600-1300 nm) are particularly useful because biological tissues are optically transparent in this region. Indocyanine Green (ICG) (I) for example, with absorption maxima at around 810 nm (the isosbestic point of the hemoglobin/deoxyhemoglobin), has been used for monitoring cardiac output, hepatic function, and liver blood flow. After intravenous injection, ICG is rapidly bound by plasma proteins and remains in the blood through one circulation of heart and lungs.
ICG is then taken up by hepatic parenchymal cells and secreted entirely into the bile (Osol,
A.; Pratt, R. The United States Dispensatory Philadelphia, Toronto: J. B. Lippincott Company, 1973, 615).
Despite ICG's promising application, aqueous solutions of indocyanine green rapidly decomposes when irradiated with incandescent light. Also, ICG itself does not localize in any particular tissue.
Additional problems also arise from the photo-instability of the long olefin chain (Matsuoka, M. In Infrared Absorbing Dyes; Plenum: New York, 1990; Chapter 3). Cyanine dyes with shorter olefin chains are relatively stable, but their absorption and emission do not fall within the optical window (600 - 1300 nm) necessary for optical imaging.
There is a need to design stable dyes that possess desirable photophysical properties, stability, and targeting ability. The present invention overcomes the technical problems mentioned previously by incorporating a bifunctional spacer, and imposing rigidity on the polyene portion of the cyanine and indocyanine dyes.
SUMMARY OF THE INVENTION
This invention provides functional dyes of the general formula:
Cyanine dyes are symmetric molecules with two heterocyclic base groups linked by a conjugated carbon chain. These dyes absorb intensely from the visible to near-infrared (NIR) region, depending strongly on the length of the carbon chain. Bathochromic shift is often found when number of C=C unit increases (Matsuoka, M. In Infrared Absorbing Dyes; Plenum: New York, 1990; Chapter 2 & 3). Other structural variations that cause bathochromic shift can also be introduced into these dyes. Typically, electron donating or electron withdrawing functional groups such as alkyl, alkoxyl, alkylthio, halogen, cyano, alkoxycarbonyl, and nitro can be substituted at the appropriate electron-rich or electron deficient centers at the polyene portion of the molecule.
The cyanine dyes are generally prepared from condensation reaction between quaternary salts of heterocyclic base and the keto-aldehyde (Keyes, G. H. U.S. Patent 2 251 286, 1941 ;
Heseltine, D. W.; Brooker, L. G. S. U.S. Patent 2 895 955, 1959; Reynolds, G. A.; Drexhage, K. H. J. Org. Chem. 1977, 42, 885). The bicyclic cyanine dyes of the present invention can be prepared by the condensation of the thiazolium (2) and the diketone (3). Asymmetric dyes with linkage groups can be prepared in a similar manner with additional synthetic steps (Mujumdar, R. B.; Ernst, L. A.; Mujumdar, S. R.; Lewis, C. J.; Waggoner, A. S. Bioconjugate Chem. 1993, 4, 105). The starting materials for the bicyclic key intermediate 4 can be prepared by the well known procedures as illustrated in Schemes 1-3.
Recently, Narayanan and Patonay have demonstrated the synthesis of new cyanine dyes using 2-chloro-1-formyl-3-(hydroxymethylene) cyclohex-1-ene as a template (Narayanan, N.; Patonay, G. J. Org. Chem. 1995, 60, 2391). Several symmetric dyes were prepared in high yields. Like croconium dyes, the central part of these dyes contain a cyclic ring with one C=C bond and a chloride atom. Their results show that introduction of a croconic moiety into the conjugating bridge significantly shift the absorption to longer wavelengths.
The present invention describes the use of ring template strategy to synthesize stable cyanine dyes with desirable photophysical and targeting properties. Simple condensation between a quaternary salt of a heterocyclic base and the cyclic 1 ,5-dicarbonyl compounds will give desirable dye products that are conformationally rigid. The extended conjugated π system through this centrally located ring(s) will give intensely colored materials. With appropriate coupling groups such as acid halides, active esters, alcohols, aldehydes, amines, aryl halides, carboxylic acids, n-carboxyanhydrides, disulfides, hydrazides, iodoacetamides, isothiocyanates, imadates, maleimides, nitrenes, sulfonyl chlorides and so forth, the dye moiety can effectively label biological materials. The ring system may have at least one C=C bond. The ring system may also contain Group III, IV, V or VI elements in order to further shift the absorption maxima to longer wavelength. The ring system can also be a fused ring structure with five, six or seven membered rings. The ring structure can also be substituted with acid halides, active esters, alcohols, aldehydes, amines, aryl halides, carboxylic acids, n- carboxy anhydrides, disulfides, hydrazides, iodoacetamides, isothiocyanates, imadates, maleimides, nitrenes, sulfonyl chloride and so forth that are essential for conjugation with targeting groups (biomolecules).
Biomolecules for use with the dyes refer to all natural and synthetic molecules that play a role in biological systems. Biomolecules include hormones, amino acids, peptides, peptidomimetics, glycomimetics, vitamins, carbohydrates, proteins, deoxyribonucleic acid
(DNA), ribonucleic acid (RNA), lipids, albumins, polyclonal antibodies, receptor molecules,
receptor binding molecules, monoclonal antibodies and aptamers. Specific examples of biomolecules include insulins, prostaglandins, growth factors, liposomes and nucleic acid probes. Examples of synthetic polymers include polylysine, aborols, dendrimers, and cyclodextrins. The advantages of using biomolecules include enhanced tissue targeting through specificity and delivery. Coupling of the dyes to biomolecules can be accomplished by several known methods (e.g., Krejcarek and Tucker Biochem. Biophys. Res. Comm, 30, 581 (1977); Hnatowich, et al. Science, 220, 613 (1983). Typically, a nucleophilic group is reacted with an electrophilic group to form a covalent bond between the biomolecule and the dye. Examples of nucleophilic groups include amines, anilines, alcohols, phenols, thiols and hydrazines. Electrophilic group examples include halides, disulfides, epoxides, maleimides, acid chlorides, anhydrides, mixed anhydrides, activated esters, imidates, isocyanates and isothiocyanates.
Examples of suitable alkyl groups for use with the invention include methyl, ethyl, propyl, isopropyl, butyl, cyclohexyl, heptyl and octyl. Suitable alkoxyl groups include methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptoxyl and octoxyl. Hydroxyalkyl groups suitable for use with the invention include both mono and poly hydroxyalkyls such as hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, tris (hydroxymethyl) methyl and 2-hydroxy-1-hydroxymethyl-ethyI. Suitable alkoxyalkyl groups include methoxymethyl, 2,3-dimethoxypropyl, tris (methoxymethyl) methyl, and 2-methoxy- 1-methoxymethyl-ethyl. Amino groups suitable for use with the invention include aminoalkyl such as amino methyl, amino ethyl, amino propyl, hydroxy amino such as 1-amino-2,3 propandiol, 1-amino-2-ethanol,and 1-amino-3-propanol and amino acids such as alanine, aspartic acid, glycine and lysine. Carboxyalkyls include acetate, hexanoate, propionate, and butyrate. Carbohydrates, monosaccharides, and polysaccharides such as glucose, maltose, lactose and amylose. Aryl groups include phenyl and naphthyl. Alkoxycarbonyl include methyl ester, ethyl ester, propyl ester and butyl ethyl ester. Halogen groups include chlorine, fluorine, bromine and iodine. Alkylamido groups include groups such as methyl amido, ethyl amido, propyl amido and, butyl amide. Alkylthio groups include methyl thio, ethyl thio, propyl thio, and butyl thio. Aminoalkyls include NR6R7 where R6 and R7 can be hydrogen or C1-C10 alkyl and R6 and R7 are capable of forming 5, 6, or 7 membered rings which can be
further substituted by a heteroatom such as O, -NR8 or S, wherein R8 is hydrogen, alkyl, alkoxyl, hydroxyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylamido, aryl, carboxyl, carboxyalkyl, halogen, nitro, alkoxycarbonyl, mercapto, alkylthio and alkyl sulfonate. The compositions of the invention can be formulated into diagnostic compositions for enteral or parenteral administration. These compositions contain an effective amount of the dye along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated. For example, parenteral formulations advantageously contain a sterile aqueous solution or suspension of dye according to this invention. Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration. Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
Formulations for enteral administration may vary widely, as is well known in the art. In general, such formulations are liquids which include an effective amount of the dye in aqueous solution or suspension. Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like. Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities. The diagnostic compositions are administered in doses effective to achieve the desired enhancement. Such doses may vary widely, depending upon die particular dye employed, the organs or tissues which are the subject of the imaging procedure, the imaging procedure, the imaging equipment being used, and the like. The diagnostic compositions of the invention are used in the conventional manner. The compositions may be administered to a patient, typically a warm-blooded animal, either systemically or locally to the organ or tissue to be imaged, and the patient then subjected to the imaging procedure. The following examples illustrate the specific embodiments of the invention described in this document. As would be apparent to skilled artisans, various changes and modifications are
possible and are contemplated within the scope of the invention described.
EXAMPLES
Example I Synthesis of bicyclic cyanine dye wherein A is a -CH2- group and R5 and R9 are hydrogens.
A mixture of compound 4 (2.2g, 10mmole) and 2mL of triethylamine in 10mL of acetonitrile is added with 1 ,2-dimethylbenzothiazolium iodide (3.0g, 10.3mmole). The reaction mixture is slowly heated to reflux for 16 hours. The final product is purified by recrystallization or chromatography.
Example II
Synthesis of bicyclic cyanine dye wherein A is -O-, and R5 and R9 are hydrogens.
A mixture of Compound 5 (2.2g, 10mmole) and 2mL of triethylamine in 10mL of acetonitrile is added with 1,2-dimethylbenzothiazolium iodide (3.0g, 10.3 mmole). The reaction mixture is slowly heated to reflux for 16 hours. The final product is purified by recrystallization or chromatography.
Example III
Synthesis of cyanine dye wherein A is -N, R5 is -H, and R8 is -(CH2)CO2CH3 group. A mixture of compound 6 (2.4g, 10mmole) and 2mL of triethylamine in 10mL of acetonitrile is added with 1,2-dimethylbenzothiazolium iodide (2.9g, 10.3 mmole). The reaction mixture is slowly heated to reflux for 16 hours. The final product is purified by recrystallization or chromatography. Although the invention has been described with respect to specific modifications, the details thereof are not to be construed as limitations, for it will be apparent that various equivalents, changes and modifications may be resorted to without departing from the spirit and scope thereof, and it is understood that such equivalent embodiments are to be included therein.
Claims
What is claimed is: 1. A diagnostic composition comprising a compound of the formula:
R8 , R9, and R10 are independently hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 mercaptoalkyl, hydroxyl, C1-C10 hydroxyalkyl, C1-C10 alkoxyalkyl, C1-C10 aryl, C1-C10 carboxylalkyl, C1-C10 alkoxycarbonyl, C1-C10 alkylthio, and -(CH2)m-N(R6)(R7); and A is selected from the group consisting of -(CH2)-, -O-, -S-, or -NR8. Also provided are methods of using dyes of the invention comprising administering a diagnostically effective amount of the dye to a patient and visualizing the dye.
2. The composition of claim 1 wherein R1, R2 and R5 are independently hydrogen, C1- C10 alkyl, hydroxyl, C1-C10 alkoxyl, carboxyl, halogen, nitro, sulfonate, or -(CH2)m-N(R6)(R7) wherein m is about 0-10; R3 and R4 are independently C1-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 carboxyalkyl, or -(CH2)m- N(R6)(R7); R6 and R7 are independently hydrogen, C1-C10 alkyl, C1-C10 acyl, and hydroxyalkyl; W1 and W2 are independently -S- or -C(R9)(R10) wherein R9 and R10 are independently hydrogen, C1-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 carboxyalkyl or -(CH2)m-N(R6)(R7); m is about 1-10; R8 is hydrogen, C1-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 carboxyalkyl or -(CH2)m-N(R6)(R7); and A may be - (CH2)m or -(CH2)mN(R6)(R7).
3. The composition of claim 2 wherein R1 is hydrogen; R2 is hydrogen; R3 is methyl;
R4 is methyl; R5 is methoxycarbonyl; W1 is -S-; W2 is -S-; and A is -CH2-.
4. The composition of claim 2 wherein R1 is hydrogen; R2 is hydrogen; R3 is methyl;
R4 is methyl; R5 is methoxycarbonyl; W1 is -S-; W2 is -S-; and A is -O-.
5. The composition of claim 2 wherein R1 is hydrogen; R2 is hydrogen; R3 is methyl;
R4 is methyl; W1 is -S-; W2 is -S-; and A is -NR8, wherein -R8 is carboxymethyl. 6. A method of imaging a patient comprising the administration of a diagnostically effective amount of a compound of the formula:
6, or 7 membered rings which may optionally be substituted with -O-, -NR8, or -S-; R3 and R4 may be the same or different and are selected from the group consisting of C1-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxyalkyl, C1-C10 aryl, C1-C10 carboxylalkyl, C1-C10 alkyl sulfonate, mercapto alkyl and -(CH2)mN(R6)(R7); W1 and W2 may be the same or different and are selected from the group consisting of -S-, -O-,-Se-, -Te-, -NR8 and C(R9)(R10); and m is about 0-10;
R8 , R9, and R10 are independently hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 mercaptoalkyl, hydroxyl, C1-C10 hydroxyalkyl, C1-C10 alkoxyalkyl, C1-C10 aryl, C1-C10 carboxylalkyl, C1-C10 alkoxycarbonyl, C1-C10 alkylthio, and -(CH2)m-N(R6)(R7); and A is selected from the group consisting of -(CH2)-, -O-, -S-, or -NR8. Also provided are methods of using dyes of the invention comprising administering a diagnostically effective amount of the dye to a patient and visualizing the dye.
7. The method of claim 9 wherein R1, R2 and R5 are independently hydrogen, C1-C10 alkyl, hydroxyl, C1-C10 alkoxyl, carboxyl, halogen, nitro, sulfonate, or -(CH2)m- N(R6)(R7) wherein m is about 0-10; R3 and R4 are independently C1-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 carboxyalkyl or -(CH2)m-N(R6)(R7); R6 and R7 are independently hydrogen, C1-C10 alkyl, C1-C10 acyl, and hydroxyalkyl; X is -O-, - NR8 or -S-; W1 and W2 are independently -S- or -C(R9)(R10) wherein R9 and R10 are independently hydrogen, C1-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 carboxyalkyl, or - (CH2)m-N(R6)(R7); m is about 1-10; R8 is hydrogen, C1-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 carboxyalkyl, or -(CH2)n,-N(R6)(R7); and A may be -(CH2)m or - (CH2)mN(R6)(R7).
8. The method of claim 10 wherein R1 is hydrogen; R2 is hydrogen; R3 is methyl; R4 is methyl; R5 is methoxycarbonyl; W1 is -S-; W2 is -S-; and A is -CH2-.
9. The method of claim 11 wherein R1 is hydrogen; R2 is hydrogen; R3 is methyl; R4 is methyl; R5 is methoxycarbonyl; W1 is -S-; W2 is -S-; and A is -O-.
10. The method of claim 12 wherein R1 is hydrogen; R2 is hydrogen; R3 is methyl; R4 is methyl; W1 is -S-; W2 is -S-; and A is -NR8, wherein R8 is carboxymethyl.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97924641A EP0959906B1 (en) | 1996-05-13 | 1997-05-09 | Delta 1,6 bicyclo [4,4,0] functional dyes for contrast enhancement in optical imaging |
| DE69725007T DE69725007T2 (en) | 1996-05-13 | 1997-05-09 | DELTA 1.6 BICYCLO (4,4,0) BASED DYES FOR CONTRAST ENHANCEMENT IN OPTICAL IMAGE GENERATION |
| DK97924641T DK0959906T3 (en) | 1996-05-13 | 1997-05-09 | Delta 1.6 bicyclo [4.4,0] functional colors for contrast enhancement by optical imaging |
| AT97924641T ATE249843T1 (en) | 1996-05-13 | 1997-05-09 | DELTA 1.6 BICYCLO (4,4,0) BASED DYES FOR CONTRAST ENHANCEMENT IN OPTICAL IMAGING |
| JP09540962A JP2000510147A (en) | 1996-05-13 | 1997-05-09 | Δ ▲ 1,6 bicyclo [4,4,0] -functional dye for enhancing contrast in optical imaging |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/649,850 | 1996-05-13 | ||
| US08/649,850 US5672333A (en) | 1996-05-13 | 1996-05-13 | Delta1,6 bicyclo 4,4,0! functional dyes for contrast enhancement in optical imaging |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997042977A1 true WO1997042977A1 (en) | 1997-11-20 |
Family
ID=24606485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/007864 WO1997042977A1 (en) | 1996-05-13 | 1997-05-09 | Δ1,6 bicyclo [4,4,0] functional dyes for contrast enhancement in optical imaging |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5672333A (en) |
| EP (1) | EP0959906B1 (en) |
| JP (1) | JP2000510147A (en) |
| AT (1) | ATE249843T1 (en) |
| CA (1) | CA2254900A1 (en) |
| DE (1) | DE69725007T2 (en) |
| DK (1) | DK0959906T3 (en) |
| ES (1) | ES2202619T3 (en) |
| PT (1) | PT959906E (en) |
| WO (1) | WO1997042977A1 (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7547721B1 (en) | 1998-09-18 | 2009-06-16 | Bayer Schering Pharma Ag | Near infrared fluorescent contrast agent and fluorescence imaging |
| JP2000095758A (en) | 1998-09-18 | 2000-04-04 | Schering Ag | Near-infrared, fluorescent contrast medium, and its production |
| US20030180221A1 (en) * | 1998-09-18 | 2003-09-25 | Schering Ag | Near infrared fluorescent contrast agent and fluorescence imaging |
| US6167297A (en) | 1999-05-05 | 2000-12-26 | Benaron; David A. | Detecting, localizing, and targeting internal sites in vivo using optical contrast agents |
| US6180086B1 (en) | 2000-01-18 | 2001-01-30 | Mallinckrodt Inc. | Hydrophilic cyanine dyes |
| US6939532B2 (en) | 2000-01-18 | 2005-09-06 | Mallinckrodt, Inc. | Versatile hydrophilic dyes |
| US6395257B1 (en) * | 2000-01-18 | 2002-05-28 | Mallinckrodt Inc. | Dendrimer precursor dyes for imaging |
| US7198778B2 (en) * | 2000-01-18 | 2007-04-03 | Mallinckrodt Inc. | Tumor-targeted optical contrast agents |
| US6180087B1 (en) | 2000-01-18 | 2001-01-30 | Mallinckrodt Inc. | Tunable indocyanine dyes for biomedical applications |
| US7790144B2 (en) * | 2000-01-18 | 2010-09-07 | Mallinckrodt Inc. | Receptor-avid exogenous optical contrast and therapeutic agents |
| US20080233050A1 (en) * | 2000-01-18 | 2008-09-25 | Mallinckrodt Inc. | Diagnostic and therapeutic optical agents |
| US6748259B1 (en) | 2000-06-15 | 2004-06-08 | Spectros Corporation | Optical imaging of induced signals in vivo under ambient light conditions |
| US20040180809A1 (en) * | 2000-10-16 | 2004-09-16 | Mallinckrodt Inc. | Tissue-specific exogenous optical agents |
| US20070092450A1 (en) * | 2000-10-16 | 2007-04-26 | Mallinckrodt Inc. | Tissue-specific exogenous optical agents |
| US20040143190A1 (en) * | 2003-01-22 | 2004-07-22 | Schnitzer Mark J. | Mapping neural and muscular electrical activity |
| US20100022449A1 (en) * | 2006-03-09 | 2010-01-28 | Mallinckrodt Inc. | Receptor-avid exogenous optical contrast and therapeutic agents |
| US20110177006A1 (en) * | 2008-09-29 | 2011-07-21 | Raghavan Rajagopalan | Dithienofuran Dyes for Imaging and Therapy |
| EP2350206A2 (en) * | 2008-09-29 | 2011-08-03 | Mallinckrodt Inc. | Dithienopyrrole dyes for imaging and therapy |
| CA2737912A1 (en) * | 2008-09-29 | 2010-04-01 | Mallinckrodt Inc. | Fused ring thiophene dyes for imaging and therapy |
| WO2010121003A1 (en) | 2009-04-16 | 2010-10-21 | Mallinckrodt Inc. | Pyrazine derivatives for optical imaging and therapy |
| WO2010132554A2 (en) | 2009-05-12 | 2010-11-18 | Mallinckrodt Inc. | Diaza heterocyclic compounds for phototherapy |
| WO2010132515A1 (en) | 2009-05-12 | 2010-11-18 | Mallinckrodt Inc. | Compounds containing acyclic n-n bonds for phototherapy |
| WO2011031955A2 (en) | 2009-09-11 | 2011-03-17 | Mallinckrodt Inc. | Optical monitoring of leukemia |
| WO2011035140A1 (en) | 2009-09-18 | 2011-03-24 | Paka Pulmonary Pharmaceuticals, Inc. | Methods and compositions for delivery of contrast moieties to the lungs |
| WO2011060113A1 (en) | 2009-11-11 | 2011-05-19 | Mallinckrodt Inc. | Sulfenamide compounds for phototherapy |
| WO2011084571A2 (en) | 2009-12-16 | 2011-07-14 | Mallinckrodt Inc. | Azide derivatives for phototherapy |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4762701A (en) * | 1986-10-31 | 1988-08-09 | Smithkline Beckman Corporation | In vivo cellular tracking |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2682498A1 (en) * | 1991-10-15 | 1993-04-16 | Kodak Pathe | Colouring agents containing thioether macrocycles |
| EP0565121B1 (en) * | 1992-04-09 | 1999-07-14 | Fuji Photo Film Co., Ltd. | Silver halide photographic light-sensitive material |
| DE4301106A1 (en) * | 1993-01-18 | 1994-07-21 | Agfa Gevaert Ag | Color photographic recording material |
| BR9506899A (en) * | 1994-02-28 | 1997-09-09 | Imation Corp | Hot-reveal photothermographic element |
-
1996
- 1996-05-13 US US08/649,850 patent/US5672333A/en not_active Expired - Lifetime
-
1997
- 1997-05-09 ES ES97924641T patent/ES2202619T3/en not_active Expired - Lifetime
- 1997-05-09 JP JP09540962A patent/JP2000510147A/en not_active Withdrawn
- 1997-05-09 DK DK97924641T patent/DK0959906T3/en active
- 1997-05-09 EP EP97924641A patent/EP0959906B1/en not_active Expired - Lifetime
- 1997-05-09 DE DE69725007T patent/DE69725007T2/en not_active Expired - Lifetime
- 1997-05-09 PT PT97924641T patent/PT959906E/en unknown
- 1997-05-09 CA CA002254900A patent/CA2254900A1/en not_active Abandoned
- 1997-05-09 AT AT97924641T patent/ATE249843T1/en not_active IP Right Cessation
- 1997-05-09 WO PCT/US1997/007864 patent/WO1997042977A1/en active IP Right Grant
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4762701A (en) * | 1986-10-31 | 1988-08-09 | Smithkline Beckman Corporation | In vivo cellular tracking |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0959906B1 (en) | 2003-09-17 |
| EP0959906A4 (en) | 1999-12-22 |
| DK0959906T3 (en) | 2003-12-08 |
| PT959906E (en) | 2004-01-30 |
| ATE249843T1 (en) | 2003-10-15 |
| CA2254900A1 (en) | 1997-11-20 |
| DE69725007D1 (en) | 2003-10-23 |
| EP0959906A1 (en) | 1999-12-01 |
| JP2000510147A (en) | 2000-08-08 |
| ES2202619T3 (en) | 2004-04-01 |
| DE69725007T2 (en) | 2004-07-08 |
| US5672333A (en) | 1997-09-30 |
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