WO2002096913A1 - Phtalocyanines de di(hydroxy/alcoxy)silicium substituees et utilisations de ces dernieres - Google Patents

Phtalocyanines de di(hydroxy/alcoxy)silicium substituees et utilisations de ces dernieres Download PDF

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WO2002096913A1
WO2002096913A1 PCT/GB2002/002465 GB0202465W WO02096913A1 WO 2002096913 A1 WO2002096913 A1 WO 2002096913A1 GB 0202465 W GB0202465 W GB 0202465W WO 02096913 A1 WO02096913 A1 WO 02096913A1
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phthalocyanine
substituted
substituted phthalocyanine
alkenyl
thf
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PCT/GB2002/002465
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English (en)
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Michael John Cook
Isabelle Fernandes
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Gentian As
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/025—Silicon compounds without C-silicon linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to certain substituted di(hydroxy/alkoxy)silicon phthalocyanines and certain uses thereof, in particular their uses in photodynamic therapy and in photodiagnostics.
  • substituted phthalocyanines show a multitude of desirable properties and are thus useful for a wide variety of applications.
  • the desirable properties of substituted phthalocyanines can often be tuned by manipulation of the substituents on the ring system. In general these substituents fall into two categories, the so-called peripheral (2, 3, 9, 10, 16, 17, 23, 24) and the non-peripheral (1, 4, 8, 11, 15, 18, 22, 25) substituents, as shown in Scheme 1.
  • the central M is a metal or metal compound or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms.
  • the phthalocyanines most commonly synthesised and investigated, are metal free (i.e. M is two hydrogens) or metallated with M being Zn, Cu, Ni, Co, Fe, Mn, Mg and Pb.
  • Di(hydroxy/alkoxy)silicon phthalocyanines have been synthesised very rarely and their properties have to date not been thoroughly investigated and fully appreciated.
  • di(hydroxy/alkoxy)silicon phthalocyanines substituted on the phthalocyanine ring as claimed in the present invention show (a) a higher solubility in a greater range of solvents, notably in methanol and ethanol, (b) a higher extinction coefficient, and (c) improved biological effects, when compared to, for example, the corresponding substituted zinc phthalocyanines, was hitherto unknown, such that their usefulness in the photodynamic therapy and in photodiagnostics has thus far not been recognised.
  • EP-0 337 209 (Mitsui Toatsu Chemicals Inc. and Yamamoto Chemicals Inc.) describes alkylphfhalocyanines which are near-infrared absorbers such that they may usefully be employed in optical recording media, near-infrared absorption filters and liquid crystal display devices. Photodynamic therapy is not mentioned.
  • the phthalocyanines may be metal free or metallated.
  • Si(OH) 2 and Si(OR) 2 wherein R may be alkyl, are listed amongst a large number of possible central metals and metal compounds. Out of 79 example compounds, one has a central Si(OH) 2 , namely:
  • R 1 -CH 2 C 6 H 5
  • R 2 -CH 2 C 6 H 5
  • R 3 -CH 2 C 6 H 5
  • R 4 -CH 2 C 6 H 5 .
  • EP-0 373 643 (Mitsui Toatsu Chemicals Inc. and Yamamoto Chemicals Inc.) describes phthalocyanines which are near-infrared absorbers which may usefully be employed in display/recording materials. Photodynamic therapy is not mentioned.
  • the phthalocyanines may be metal free or metallated.
  • Si(OH) 2 and Si(OR) wherein R may be alkyl, are mentioned amongst a large number of possible central metals and metal compounds. Out of 103 example compounds, three have a central Si(OH) 2 , namely:
  • EP-0 519 423 (Mitsui Toatsu Chemicals Inc. and Yamamoto Chemicals Inc.) describes metallated phthalocyanines useful for the fabrication of colour filters; again photodynamic therapy is not mentioned.
  • Si(OH) 2 is mentioned amongst a large number of possible central metals and metal compounds. Out of 124 example compounds, one has a central Si(OH) 2 , namely:
  • NcSi[OSi(C 6 H ⁇ 3 ) ] 2 and conducted energy transfer experiments showing that energy transfer from the triplet state of NcSi[OSi(C 6 H] 3 ) 3 ] 2 to O 2 to produce singlet oxygen is a reversible reaction, which makes NcSi[OSi(C 6 rI ⁇ 3 ) 3 ] 2 potentially useful as a photosensitizer in the photodynamic therapy of tumours.
  • SiNc[OSi(i-C 4 H ) 2 (n-C ⁇ 8 H 37 )] 2 was thought to be potentially useful as photodynamic sensitizer.
  • WO 92/01753 (Kenney et al.) describes aluminum and silicon phthalocyanines having at least one substituted amine or quaternary ammonium axial ligand attached to the central aluminum or silicon atom. Two aluminum and four silicon phthalocyanines were thought to be potentially useful in the treatment of cancer through photosensitisation. The four silicon phthalocyanines were synthesised as follows:
  • WO 98/14521 (University Hospitals of Cleveland for Kenney et al.) describes the following two synthetic routes to silicon phthalocyanines having at least one silyloxy ligand attached to the central silicon atom.
  • PcSi[OH][OSi(CH 3 ) 2 (CH 2 ) 3 N(CH 3 ) 2 ], PcSi[OH][OSi(CH 3 ) 2 (CH 2 ) 3 I] and PcSi[OSi(CH 3 ) 2 (CH 2 ) 3 I] 2 are said to be useful as dyes and in photodynamic therapy.
  • unsubstituted silicon dihydroxide phthalocyanine PcSi(OH) 2
  • PcSi(OH) 2 unsubstituted silicon dihydroxide phthalocyanine
  • the solubility of a photodynamic agent is, of course, critically important for its effectiveness.
  • Kenney et al. render their silicon-centred phthalocyanines soluble by the introduction of at least one large axial silyloxy ligand.
  • Kenney et al. indicate that they chose to introduce large axial ligands on the central silicon atom in order to avoid having to introduce substituents on the phthalocyanine ring, which is said to be a laborious procedure which often yields mixtures of isomeric compounds.
  • Maree et al. (M.D. Maree, N. Kuznetsova and T. Nyokong, Journal of Photochemistry and Photobiology A: Chemistry, 2001, vol. 140, pages 117-125) prepared a series of silicon octaphenoxyphthalocyanines and studied their photostability and singlet oxygen quantum yields.
  • One of the compounds prepared was silicon dihydroxide octaphenoxyphthalocyanine.
  • Maree et al. concluded that the poor singlet oxygen quantum yield of this silicon dihydroxide phthalocyanine is due to its poor solubility in organic solvents, possibly caused by hydrogen bond attraction between the axial hydroxyl groups.
  • Maree et al. suggest that all silicon dihydroxide phthalocyanines will make poor photodynamic agents, because their poor solubility in organic solvents will give rise to poor quantum yields of singlet oxygen.
  • the other silicon octaphenoxyphthalocyanines prepared by Maree et al. give rise to promising singlet oxygen quantum yields due to their good solubility in organic solvents, which is due to their axial ligands on the central silicon. Maree et al.
  • the present invention provides a number of new substituted di(hydroxy/alkoxy)silicon phthalocyanines and their uses of in photodynamic therapy and in photodiagnostics. In a number of cases the biological activity of the new substituted di(hydroxy/alkoxy)silicon phthalocyanines is compared with that of similarly substituted zinc phthalocyanines.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 2 , -N(
  • R are the same or different and each R is
  • X are the same or different and each X is -H, -CH 3 or -CH 2 CH ,
  • R 2 and all four R 1 -CH 2 C 6 H 5 , or
  • alkyl is defined as a hydrocarbon with an sp 3 hybridised ⁇ -carbon, which may be straight chain or branched, and which may optionally be substituted, and which may comprise at least one double bond and/or at least one triple bond.
  • Aryl is defined as an aromatic hydrocarbon with an sp 2 hybridised aromatic ⁇ -carbon, which may optionally be substituted. Examples of aryls are
  • Alkynyl is defined as a hydrocarbon with an sp hybridised ⁇ -carbon, which may be branched or unbranched, and which may optionally be substituted.
  • alkynyl groups are -C ⁇ C-H, -C ⁇ C-CH 3 , -C ⁇ C-C 6 H 5 and -C ⁇ C-C ⁇ C-H.
  • Terminal alkenyl and terminalally alkynyl refers to terminal “alkenyl” and “alkynyl” groups respectively.
  • an optionally substituted alkyl group may be substituted with one or more of -F, -CI, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 .
  • An optionally substituted alkenyl group may be substituted with one or more of -F, -CI, -Br, -I, -OH, -R 4 -0-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and or -R 4 -N-(R 5 ) 2 .
  • An optionally substituted alkynyl group may be substituted with -F, -CI, -Br, -I, -OH * , -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -R 4 -N-(R 5 ) 2 , -Si(R 5 ) 3 , -C 5 H 4 N, -C 4 H 3 S and or -C 6 H 5 .
  • An optionally substituted aryl group may be substituted with one or more of Cj-Cio alkyl, C 2 -C ⁇ o alkenyl, -NO 2 , -OCH 3 , -CH 2 OH, -F, -CI, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR 5 , -COOR 5 and/or -CON(R 5 ) 2 .
  • An optionally substituted heteroaryl group may be substituted with one or more of C ⁇ -C ⁇ 0 alkyl, C -C] 0 alkenyl, -NO 2 , -OCH 3 , -F, -CI, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR 5 , -COOR 5 and/or -CON(R 5 ) 2 .
  • a "non-peripheral" substituent is defined as a substituent ⁇ to the point of fusion between the pyrrole ring and the R 2 containing aromatic ring in a compound of formula (I), (IA), (IB) or (V), or ⁇ to either one of the two cyano groups in a compound of formula (II), (III), (IV), (VI) or (VII).
  • a substituent is defined as "peripheral” when it is not “non-peripheral”. For example, in Scheme 1 above, the non-peripheral substituents are in positions 1, 4, 8, 11, 15, 18, 22 and 25 and the peripheral substituents are in positions 2, 3, 9, 10, 16, 17, 23 and 24.
  • a substituted phthalocyanine is made up of a core structure and four substituent- units X.
  • the four substituent-units X are shown encircled in Scheme 2 below.
  • a substituted phthalocyanine can be mixed or non-mixed.
  • a non-mixed phthalocyanine is a phthalocyanine made up of four identical substituent-units X.
  • a mixed phthalocyanine is a phthalocyanine made up of at least two different substituent-units, preferably a mixed phthalocyanine is made up of two different substituent-units X 1 and X 2 , wherein the ratio of X*:X 2 may be 1 :3, 2:2 or 3:1. When the ratio of X*:X 2 is 2:2, the pairs of identical substituent-units X 1 or X 2 may be adjacent to each other or opposite each other.
  • the substituted phthalocyanine of the present invention may be a non-mixed or a mixed phthalocyanine.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 and or -N(R 5 ) 3 + ; C 2 -C 20 alkynyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NN(
  • R 1 are the same or different and each R 1 is C]-C 20 alkyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; C 2 -C 20 alkynyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; -OR 5 ; -SR 5 ; -SO 2 R 5 ; -N-(R 5 ) 2 ; -P-(R 5 )
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl substituted with at least one or more of -F, -CI, -Br, -I, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; -N-(R 5 ) 2 ; -aryl, optionally substituted with one or more of d-Cio alkyl, C 2 -C ⁇ 0 alkenyl, -NO 2 , -OCH 3 , -F, -CI, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR 5 , -COR 5
  • R 1 are the same or different and each R 1 is C]-C 20 alkyl fully substituted with -F, -CI and/or -Br; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; -aryl, optionally substituted with one or more of-CH 3 , -NO 2 , -OCH 3 , -F, -CI, -Br, -OH and/or -NH 2 ; -F; -CI; -Br or -I; where -R 5 are the same or different and each -R 5 is C ⁇ -C 20 alkyl, C 2 -C 20 alkenyl, aryl, heteroaryl or H, or two -R 5 together form a saturated or unsaturated ring.
  • At least one R 1 is a non-peripheral substituent.
  • R 1 are the same or different and are attached to the phthalocyanine ring by a carbon atom.
  • R 1 are the same or different and each R 1 is C 1 -C 20 alkyl, optionally substituted with one or more of-F, -CI, -Br, -I, -OH, -OR 5 , and/or -SR 5 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -OR 5 , and/or -SR 5 ; C 2 -C2 0 alkynyl, optionally substituted with one or more of -F, -CI, -Br, -I, -OH, -OR 5 , and/or -SR 5 ; -aryl, optionally substituted with one or more of Ci-Ci 0 alkyl, C 2 -C ⁇ 0 alkenyl, -
  • X is either -H, or X is selected from -Me or -Et. Preferably X is -H.
  • the substituted phthalocyanine of formula (I) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer, preferably the substituted phthalocyanine of formula (I) is substituted or conjugated via R 1 .
  • R 2 is
  • m is 1 or 2.
  • R' nl .
  • the substituted phthalocyanine forms a sandwich complex.
  • the substituted phthalocyanine forms a multimer.
  • the multimer comprises at least two phthalocyanines. More preferably the at least two phthalocyanines forming the multimer are covalently linked, most preferably via R 1 .
  • the substituted phthalocyanine is conjugated to a carrier, or entrapped or embedded in a carrier.
  • the carrier is an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer, most preferably conjugated via R 1 .
  • the carrier is a polypeptide
  • the polypeptide is preferably an antibody.
  • the substituted phthalocyanine is preferably entrapped or embedded in a solid polymer, or preferably conjugated to a soluble polymer.
  • the solid polymer is selected from polyesters, poly(orthoesters), polyanhydrides, tyrosine derived pseudo-poly(amino acids) or polyphosphazenes, or wherein the soluble polymer is selected from N-(2-hydroxypropyl)mefhacrylamide (HMPA) copolymers, polyvinylpyrrolidone (PVP), poly(ethylene glycol) (PEG) polymers, copolymers or block copolymers, amino acid derived polymers or polyesters.
  • the solid or soluble polymer is a biodegradable polymer.
  • the substituted phthalocyanine of the present invention is for use as a medicament.
  • the medicament is for use in photodynamic therapy.
  • the medicament is for use in photodiagnostics.
  • a pharmaceutical composition comprising a substituted phthalocyanine according to the present invention or a pharmaceutically acceptable salt thereof in a mixture or in association with a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition is in a form suitable for topical, subcutaneous, mucosal, parenteral, systemic, intra-articular, intra-venous, intra-muscular, intra-cranial, rectal or oral application.
  • the pharmaceutical composition of the present invention is for use in the photodynamic therapy of a human or animal disease.
  • the human or animal disease is characterised by benign or malignant cellular hype ⁇ roliferation or by areas of neovascularisation.
  • the human or animal disease is a viral, fungal or bacterial disease or a disease caused by prions.
  • the human or animal disease is a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hype ⁇ lasia, intimal hype ⁇ lasia, benign prostate hype ⁇ lasia, psoriasis, mycosis fungoides, eczema, actinic keratosis or lichen planus.
  • composition of the present invention may be for use in photodiagnostics.
  • the pharmaceutical composition of the present invention may be for use in the inactivation of a microorganism.
  • the microorganism comprises Gram positive bacteria, Gram negative bacteria, yeasts, fungi, algae or parasites at any stage in their development.
  • a composition comprising a substituted phthalocyanine according to the present invention for use in the inactivation of a microorganism.
  • the microorganism comprises Gram positive bacteria, Gram negative bacteria, yeasts, fungi, algae or parasites at any stage in their development.
  • the source of illumination for use with the pharmaceutical or non- pharmaceutical composition of the present invention is a laser or a non-coherent light source emitting light of optimal wavelength.
  • a substituted phthalocyanine of the present invention for the manufacture of a photofherapeutic agent for the use in photodynamic therapy.
  • the phototherapeutic agent is used for the treatment of a disease characterised by benign or malignant cellular hype ⁇ roliferation.
  • the phototherapeutic agent is used for the treatment of a viral, fungal or bacterial disease or a disease caused by prions.
  • the phototherapeutic agent is used for the treatment of a disease such as a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hype ⁇ lasia, intimal hype ⁇ lasia, benign prostate hype ⁇ lasia, psoriasis, mycosis fungoides, eczema, actinic keratosis and lichen planus.
  • a disease such as a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hype ⁇ lasia, intimal hype ⁇ lasia, benign prostate hype ⁇ lasia, psoriasis, mycosis fungoides, eczema, actinic keratosis and lichen planus.
  • a substituted phthalocyanine of the present invention for the manufacture of a photodiagnostic agent for the identification of areas that are pathologically affected by cellular hype ⁇ roliferation.
  • a material comprising a substituted phthalocyanine of the present invention, wherein the optical or physical properties of the material may be altered by incident radiation.
  • the incident radiation is electromagnetic radiation. More preferably the incident radiation is electromagnetic radiation with a wavelength in the range of from 200nm to lOOOnm.
  • a substituted di(hydroxy/alkoxy)silicon phthalocyanine (I) may be prepared either by the cyclisation of a substituted phthalonitrile (IV) either by itself or together with any other phthalonitrile of formula (IV), or by the metallation of a metal-free phthalocyanine (V).
  • a substituted di(hydroxy/alkoxy)silicon phthalocyanine (I) may be prepared by trans-metallation of a metallated phthalocyanine such as for example a lithium phthalocyanine (not shown).
  • a metal-free phthalocyanine (V) may be prepared either by the cyclisation of a substituted phthalonitrile (IV) either by itself or together with any other phthalonitrile of formula (IV), or by the de-metallation of a metallated phthalocyanine (not shown), for example a magnesium phthalocyanine.
  • a phthalonitrile of formula (IV) may be prepared from a phthalonitrile sulfonate ester (III), which in turn may be prepared from a suitable phthalonitrile alcohol (II).
  • a phthalonitrile sulfonate ester of formula (III) may be prepared from a phthalonitrile alcohol of formula (II) under suitable conditions.
  • Aryl triflates are usually prepared from phenols in excellent yields by treating them with triflic anhydride in the presence of a base such as triethylamine or pyridine at low temperature (K. Ritter, Synthesis, 1993, page 735; P.J. Stang, M. Hanack, L.R. Subramanian, Synthesis, 1982, page 82).
  • a base such as triethylamine or pyridine at low temperature
  • hydroquinone could be triflated in high yield (91%) by using either 2,6-lutidine or 2,4,6-collodine as the base in the presence of CH 2 C1 2 .
  • 2,6-lutidine or 2,4,6-collodine as the base in the presence of CH 2 C1 2 .
  • triflic anhydride dropwise under argon.
  • a simple aqueous work-up followed by recrystallisation from CH 2 Cl 2 /petrol or EtOAc/cyclohexane afforded 3,6- (trifluoromethanesulfonyloxy)phthalonitrile as yellow crystals in good yield.
  • 2,3-Dicyano- 1 ,4-(trifluoromefhanesulfonyloxy)naphthalene was prepared by a similar procedure.
  • Aryl nonaflates are usually prepared from phenols by treatment with nonafluorobutanesulfonyl fluoride.
  • attempts to nonaflate the 2,3- dicyanohydroquinone under the above conditions all met with failure, possibly due to the poorer leaving group ability of the fluoride anion compared with the triflate anion.
  • sodium hydride as the base in THF led to a clean and high yielding reaction to afford after a simple aqueous work-up 3,6-(nonafluorobutanesulfonyloxy)- phthalonitrile.
  • a substituted phthalonitrile of formula (IV) may be prepared from a sulfonate ester of formula (III) under various conditions, such as for example cross-coupling with an organozinc reagent or an organocopper reagent catalysed by palladium (Method A) or nickel (Method B), cross-coupling with a trialkylborane catalysed by palladium (Method C), cross-coupling with a boronic acid or ester catalysed by palladium (Method D), S A ⁇ reaction with a nucleophiles (Method E), or coupling with a suitable coupling partner catalysed by palladium (Method F).
  • decylzinc iodide was prepared by adding a concentrated solution (ca. 3M) of 1-iododecane in THF to a suspension of zinc dust (3 equivalent) in THF at 40°C.
  • the zinc dust was activated with a few mol% of dibromoethane and TMSC1 prior to the addition of the halide. After 12 hours at 40°C the preparation of decylzinc iodide was complete.
  • organozincs can be prepared by metathesis of a
  • the third method of note is the insertion of more activated zinc (Rieke zinc), prepared by the reduction of zinc halides, into less active alkyl bromides or even aryl bromides.
  • Rieke zinc more activated zinc
  • treatment of ZnCl 2 with finely cut lithium in the presence of naphthalene produces highly reactive zinc which reacts, for example with methyl 3-bromobutyrate in refluxing THF to afford the secondary zinc reagent
  • Lithium chloride was added as a co-catalyst. Although its exact role is not known, it helps to prevent biaryl formation and stabilises the catalyst (M. Fujita, H. Oka, K. Ogura, Tetrahedron Lett., 1995, vol. 36, page 5247; K. Ritter, Synthesis, 1993, page 735).
  • Nickel catalysis (method B) is an attractive alternative to palladium catalysis, both in terms of the cost of the metal and the increased reactivity of Ni(0) towards oxidative insertion into a carbon-halogen or carbon-triflate bond.
  • Snieckus and co-workers have examined the cross-coupling reaction of organotriflates with arylzinc reagents under a variety of conditions (CA. Quesnell, O.B. Familoni, V. Snieckus, Synlett, 1994, page 349). They examined a number of nickel catalysts including Ni(acac) 2 , Ni(acac) 2 /PPh 3 and NiCl 2 (PPh ) 2 .
  • NiCl 2 (PPh 3 ) 2 /2PPh 3 catalysed cross-couplings of 3,6-
  • Ni(0) catalyst was generated in situ by the treatment of NiCl 2 (PPh 3 ) 2 (10 mol%) and PPh 3 (20 mol%) in THF at room temperature with o-BuLi (20 mol%) to afford a blood-red Ni(0) catalyst [Ni(PPh 3 ) 4 ].
  • DIBAL or MeMgBr can be used instead of rc-BuLi to generate the catalyst (CA. Quesnell, O.B.
  • 3,6-bis(6'-chlorohexyl)phthalonitrile was reacted with imidazole to form the 3,6-bis(6'-imidazol-l-yl-hexyl)phthalonitrile.
  • Terminal hydroxy groups at the end of the substituents are readily accessible from some of the functionality described. Conversion of appropriately substituted phthalonitriles can be used to generate dimeric or oligomeric structures by standard reactions, for example terminal alcohol groups reacting with diesters or diacid chlorides.
  • Alkyl boron reagents are readily available from the hydroboration of alkenes, and thus a wide range of alkyl groups can theoretically be introduced.
  • the most common alkyl transfer reagent used is a 9-alkyl-9-BBN derivative, whereupon the primary alkyl group is transferred preferentially. This is prepared from an alkene and 9-BBN.
  • simple trialkylborons, prepared from alkenes and BH is more economical due to the expense of 9-BBN.
  • the cross-coupling involves the treatment of an aryl triflate with a palladium catalyst, a boron reagent and a base at high temperature (50-90°C), typically in a solvent such as THF or 1,4-dioxane.
  • the base is essential for the reaction to proceed, greatly increasing the nucleophilicity of the organoboron and accelerating the subsequent transmetalation step with the organopalladium complex (K. Matos, J.A. Soderquist, J. Org. Chem., 1998, vol. 63, page 461).
  • a variety of bases has been used for the reaction, although some of the most successful such as NaOMe (A. Furstner, G. Seidel, J. Org.
  • Method D Cross-coupling between a phthalonitrile sulfonate ester of formula (III) and a boronic acid or ester catalysed by palladium or nickel to yield a substituted phthalonitrile of formula (IV):
  • the cross-coupling of an aryl compound with a boronic acid or ester is a general method to couple an aromatic ring to an unsaturated coupling partner.
  • the reaction involves the palladium or nickel catalysed coupling of a boronic acid or ester with an aryl halide or triflate under mild base catalysis.
  • the mild conditions allow the inclusion of a wide-range of functionality on either coupling partner.
  • 3,6-diphenylphthalonitrile in 79% yield.
  • 3,6-Bis(4- methoxyphenyl)phthalonitrile and 3,6-bis(3-methoxyphenyl)phthalonitrile were prepared in a similar way by cross-coupling of 3,6-(trifluoromethanesulfonyloxy)phthalonitrile with 4-methoxyphenylboronic acid and 3-methoxyphenylboronic acid respectively.
  • S N A ⁇ Nucleophilic aromatic substitution reactions are unfavourable due to electronic and steric reasons. S N A ⁇ reactions that nevertheless occur are thought to proceed either via a Meisenheimer complex or a benzyne intermediate. Arenes containing strongly electron- withdrawing groups ortho and/or para to the site of substitution may undergo S N A ⁇ reactions via an addition / elimination process (Meisenheimer complex). Treating arenes with a strong base can induce S N A ⁇ reactions via an elimination / addition process (benzyne intermediate).
  • Amino-substituted phthalonitriles may also be synthesised via method E, using amines such as for example piperidine, mo ⁇ holine, pyrrolidine or piperazine as nucleophiles, and has been exemplified using the first one of these.
  • S N A ⁇ conditions could possibly be favoured by using Cs2CO 3 as the base and the nonaflate rather than the triflate (see for example L. Neuville, A. Bigot, M.E.T.H. Dau, J. Zhu, J. Org. Chem., 1999, vol. 64, page 7638).
  • palladium catalysed amination may be a viable route (A.J. Belfield, Tetrahedron, 1999, vol. 55, page 11399).
  • a metallated substituted phthalocyanine of formula (I) or a non-metallated substituted phthalocyanine of formula (V) may be prepared from a substituted phthalonitrile of formula (IV) under suitable conditions.
  • Bis(dodecylsulfanyl)phfhalonitrile was successfully cyclised into both the metal-free and metallated phthalocyanines using NH 3 (g) in DMAE.
  • the cyclisation to form metallated derivatives can also be brought about using DBU as base.
  • Metal free analogues are available by acid catalysed hydrolysis of the magnesium derivatives, exemplified by the demetallation of the octakis(nonylsulfanyl)- phthalocyaninato magnesium(II) derivative.
  • the Q-band of these phthalocyanines is significantly red-shifted, occurring between 780 and 830 nm.
  • 3,6-bis(substituted)phthalonitrile precursors can be similarly cyclotetramerised to give the corresponding metallated or non-metallated phthalocyanines.
  • 1 :3 and 2:2 mixed substituted phthalocyanines may also be prepared making use of methods A to F described above, by cyclising a substituted phthalonitrile of formula (IV) together with any other substituted phthalonitrile (IV) instead of with itself.
  • the phthalonitrile giving rise to three substituent-units may be used in excess.
  • By-products of the reaction include the non-mixed substituted phthalocyanine and the 2:2 mixed substituted phthalocyanines in which the pairs of common substituted isoindole units are either opposite or adjacent.
  • Phthalocyanines bearing functional groups on the pendant aromatic rings can provide access to further derivatives by standard chemistry. For example, demethylation of the methoxy groups by reagents such as BBr 3 would lead to the corresponding phenolic derivatives. These could be used to link two or more phthalocyanine molecules together via diester linkages to form dimeric or oligomeric derivatives.
  • a substituted di(hydroxy/alkoxy)silicon phthalocyanine (IA) or (IB) may also be prepared by the cyclisation of a substituted phthalonitrile (VI) or (VII) either by itself or together with any other phthalonitrile of formula (IV).
  • R 8 are the same or different and each R 8 is C C 2 o alkyl optionally substituted
  • R 10 are the same or different and each R 10 is -CI, -Br or -I
  • R" are the same or different and each R 11 is -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or - heteroaryl optionally substituted.
  • a phthalonitrile halide of formula (VI) may be prepared from 2,3- dicyanohydroquinone by halogenation and subsequent alkylation under suitable conditions.
  • bromination of 2,3-dicyanohydroquinone affords 4,5-dibromo-3,6- dihydroxyphthalonitrile.
  • the use of Guenther's method T. Guenther, Justus Liebigs Ann. Chem., 1906, vol. 349, pages 56-58
  • bromine in acetic acid provides a product which gives a low analysis for bromine.
  • bromination of 2,3-dicyanohydroquinone using NBS Roussel UCLFA, French Patent No. 1313082, 28th December 1962; Chem. Abs., 1962, vol.
  • a substituted di(hydroxy/alkoxy)silicon phthalocyanine of formula (IA) or (IB) may be prepared from a phthalonitrile halide of formula (VI) via two routes. Firstly (route A), the phthalonitrile halide (VI) may be converted into a substituted phthalonitrile (VII), which in turn is cyclised either by itself or together with any other phthalonitrile of formula (IV) to yield a substituted phthalocyanine of formula (IB). Alternatively (route B), the phthalonitrile halide (VI) may be cyclised either by itself or together with any other phthalonitrile of formula (IV) to yield a substituted phthalocyanine halide of formula (IA). The substituted phthalocyanine halide (IA) may optionally be converted into a substituted phthalocyanine of formula (IB).
  • Substituted phthalocyanines having one phthalonitrile-monorner different from the other three (1 :3 mixed substituted phthalocyanines) may be synthesised, for example, by making use of solid-phase synthetic methods (Tet. Letts., 1982, vol. 23(30), pages 3023- 3026; J. Org. Chem., 1991, vol. 56, pages 82-90).
  • solid-phase synthetic methods Tet. Letts., 1982, vol. 23(30), pages 3023- 3026; J. Org. Chem., 1991, vol. 56, pages 82-90.
  • polystyrene-based resins as solid-phase has been discussed (EP-A-0,906,758).
  • phthalocyanines having four identical phthalonitrile-monomers may also be synthesised via solid-phase synthesis.
  • 1 :3 and 2:2 mixed substituted phthalocyanines can in principle be prepared by several methods, for example cross cyclotetramerisation (G. de la Torre, P. Vazquez, F. Agullo- Lopez, T. Torres, J. Chem. Mat., 1998, vol. 8, pages 1671-1683; J. Bakboord, M.J. Cook, E. Hamuryudan, J Porphyrins Phthalocyanines, 2000, vol. 4, pages 510-517).
  • cross cyclotetramerisation G. de la Torre, P. Vazquez, F. Agullo- Lopez, T. Torres, J. Chem. Mat., 1998, vol. 8, pages 1671-1683
  • J. Bakboord, M.J. Cook E. Hamuryudan, J Porphyrins Phthalocyanines, 2000, vol. 4, pages 510-517).
  • route B has been followed using cross cyclotetramerisation to yield 1 :3 mixed substituted phthalocyanines.
  • Two appropriately substituted phthalonitriles (VI) and (IV) are reacted together; the desired product is separated from the resulting mixture by chromatography.
  • the mixed cyclotetramerisation of 4-bromo-3,6-dibutoxyphthalonitrile and 3,6- didecylphthalonitrile was investigated in order to obtain metal-free 1 ,4-dibutoxy-2-bromo- 8,1 l,15,18,22,25-hexakis(decyl)phthalocyanine.
  • Lithium butoxide in butanol was used as base at different temperatures and over different reaction times, with and without the addition of Pd(0) as Pd(PPh 3 ) 4 as a co-catalyst. Ratios of phthalonitriles of 4:1, 3:1 (3,6- didecylphthalonitrile in excess) and 1 :1 were investigated.
  • the pure metal-free compound, 1,4- dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine, is isolated by column chromatography.
  • l,4-Dibutoxy-2,3-dibromo-8,l 1,15,18,22,25-hexakis(decyl)- phthalocyanine may be prepared similarly.
  • the l,4-dibutoxy-2,3-dibromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine and l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine may be converted into their ethynylated derivatives using the Sonogashira coupling method (K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett., 1975, vol. 16, pages 4467-4470; S. Thorand, N. Krause, J. Org. Chem., 1999, vol.
  • the versatility of the Suzuki reaction on the 4-bromo- and 4,5-dibromo-3,6- dibutoxyphthalonitriles in principle provides access to other amino acid derivatives, for example with phenylalanine groups para coupled directly to the phthalonitrile core, preferably using NH2 and CO2H protected derivatives of phenylalanine boronic acid or its ester (see F. Firooznia, C. Gude, K. Chan and Y. Satoh, Tetrahedron Letters, 1998, vol. 39, 3985).
  • Negishi reaction to 4-bromo- and 4,5-dibromo-3,6-dibutoxyphthalonitriles as precursors provides further means of inco ⁇ orating functional groups at the 4- and 4,5-positions of 3,6-dibutoxyphthalonitrile.
  • reactions of 4-bromo-3,6-dibutoxyphthalonitrile with 4- chlorobutylzinc bromide and with 4-ethoxy-4-oxobutylzinc bromide afford the corresponding functionalised phthalonitriles, which are again in principle precursors to other functionally substituted alkyl substituents or can be linked to form dimeric phthalonitriles.
  • the present invention provides a substituted di(hydroxy/alkoxy)silicon phthalocyanine of formula (I) (including substituted di(hydroxy/alkoxy)silicon phthalocyanine of formulas (IA) and (IB)).
  • the substituted di(hydroxy/alkoxy)silicon phthalocyanines of the present invention show a multitude of desirable properties and are thus useful for a wide variety of applications.
  • the substituted di(hydroxy/alkoxy)silicon phthalocyanines of the present invention show high photodynamic properties and a marked abso ⁇ tion in the red region of the visible spectrum.
  • These compounds are thus useful both as such and in the form of conjugates with macromolecular carriers (such as for example polymers or antibodies) in the treatment of viral, fungal or bacterial diseases and diseases characterised by areas of neovascularisation or by benign or malignant cellular hype ⁇ roliferation, in particular diseases such as tumours, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hype ⁇ lasia, intimal hype ⁇ lasia, benign prostate hype ⁇ lasia, psoriasis, mycosis fungoides, eczema, actinic keratosis or lichen planus.
  • they may be used as photodiagnostic agents for the identification
  • organic molecules containing the chromofluorophore macrocycle of the phthalocyanine are photo-activated by irradiation, they are capable of generating hyper- reactive derivatives of oxygen, above all singlet-oxygen or radicals, which are characterised by a high degree of cytotoxicity, and hence are potentially interesting for therapeutic applications, such as photodynamic therapy and/or diagnostic applications (E. Ben-Hur and I. Rosen hal, Int. J. Radiat. Biol., 1985, vol. 47, pages 145-147).
  • Photosensitization is a process in which a photochemical reaction is induced to occur by the presence of a substance (the photosensitizer), which absorbs the light but is itself substantially unchanged at the end of the reaction, the absorbed light energy being passed on to the main reactants.
  • a substance the photosensitizer
  • the photosensitizer absorbs the light but is itself substantially unchanged at the end of the reaction, the absorbed light energy being passed on to the main reactants.
  • the photosensitizer absorbs the light but is itself substantially unchanged at the end of the reaction, the absorbed light energy being passed on to the main reactants.
  • the photosensitizer the photosensitizer
  • the photosensitizer is broken down and a photo-product is formed which may also possess suitable photodynamic properties.
  • oxygen can be made sensitive to the electromagnetic radiation it may not normally absorb by the presence of phthalocyanines or other "complex" organic molecules; some of which may have metals or metal salts inco ⁇ orated.
  • the substituted phthalocyanines are administered to a tumour-bearing subject, where they are taken up by the tumour at least to a certain extent.
  • photodynamic therapy may be carried out in a conventional manner, using light sources and delivery systems that are known in the art (for example see Phys. Med. Biol., 1986, vol. 31(4), pages 327-360).
  • the tumour tissue is destroyed via the dye mediated photogeneration of species such as singlet oxygen or other cytotoxic species such as free radicals, for example hydroxy or superoxide.
  • Phthalocyanines comprising hydroxyl, amine or quaternary ammonium substituents have been described for photosensitization of cancer cells (CC. Leznoff et al., Photochemistry and Photobiology, 1989, vol. 49(3), pages 279-284; D. Wohrle et al., Photochemistry and Photobiology, 1990, vol. 51(3), pages 351-356; D. Wohrle D. et al., Dyes and Pigments, 1992, vol.
  • Minnoch et al. J. Photochem. and Photobiol., 1996, vol. 32(3), pages 159-164
  • Brown et al. Photochem. and Photobiol., 1967, vol. 65(3)
  • a compound is to be successful as a photosensitizer for use in photodynamic therapy, including the following: a) High quantum yield of reactive species, such as singlet-oxygen or radicals; b) Relatively low toxicity to the subject; c) Capacity of being activated by radiation of high wavelength (preferentially in the red or near infra-red region of the spectrum), which is able to penetrate more deeply into the tissues as compared to radiation of shorter wavelength; d) Selective accumulation by the cells that are responsible for a given pathological condition and fast elimination from the tissues that are not affected by the pathological condition; e) Possibility of being conjugated to macromolecular carriers, albeit maintaining the characteristics of photosensitization efficiency; and f) Solubility in suitable solvents to facilitate administration to a patient and physiological uptake and transport within the patient's body.
  • Certain substituted phthalocyanines are induced to act as photosensitizers by incident electromagnetic radiation of a suitable wavelength.
  • the electromagnetic radiation is somewhere in the range of ultra-violet to infra-red, even more preferably it is in the range visible-red to infra-red. Red light shows greater tissue penetration than light of shorter wavelengths.
  • a photosensitizer absorbs laser light of a suitable wavelength, but other light sources may also be used, such as a tungsten halogen lamp.
  • Metallated phthalocyanines have been found to have better photosensitizing activity compared to metal-free phthalocyanines when the metal is diamagnetic
  • Particularly zinc (II) phthalocyanines have been found to be useful in photodynamic therapy.
  • a paramagnetic metal renders the phthalocyanine inactive (I. Rosenthal, E. Ben-Hur, "Phthalocyanines in Photobiology” in “Phthalocyanines, Properties and Applications”, eds., CC Leznoff and A.B.P. Lever, V.CH. Publishers, 1989).
  • Hydrophilic substituents or the conjugation to hydrophilic carriers can accelerate the metabolism of the phthalocyanines, enabling a fast in vivo elimination of the chromophore, and thus preventing the onset of cutaneous phototoxicity.
  • Some substituted phthalocyanines show photodynamic activity even at low oxygen concentration, thus being useful for the specific treatment of anaerobic microorganisms or the treatment of tumour diseases known to be characterised by a hypoxic environment.
  • Substituted phthalocyanines may also be conjugated to carriers to improve their pharmacological characteristics.
  • the carriers are normally chosen from the group consisting of amino acids, fatty acids, nucleic acids, di-, tri- or up to decapeptides, polypeptides, proteins, saccharides, polysaccharides, polymers and antibodies, which may be tailored to attach themselves to the tumour site.
  • Antibodies may be prepared from cultured samples of the tumour. Examples include P.L.A.P. (Placental Alkaline Phosphatase), H.M.F.G. (Human Milk Fat Globulin), CE.A. (Carcino Embryonic Antibody) and H.C.G. (Human Chorionic Gonadotrophin).
  • the phthalocyanine-carrier bond may occur between carboxyl or amine groups or by exploiting other known functional and reactive groups.
  • substituted phthalocyanines of the present invention may be polymerised. Polymerisation may take place across double bonds in unsaturated side chains or by ester or amide formation or any other suitable polymerisation technique, which will be apparent to those skilled in the art. Any polymerisation may be achieved with little or no effect on the phthalocyanine ring itself, as it possesses high stability.
  • compositions comprising a substituted di(hydroxy/alkoxy)silicon phthalocyanine ofthe present invention, as such or in form of a conjugate with a carrier, or a pharmaceutically acceptable salt thereof, in a mixture or in association with a pharmaceutically acceptable carrier, diluent or excipient, may be formulated according to well-known principles and may desirably be in the form of unit dosages determined in accordance with conventional pharmacological methods.
  • the unit dosage forms may provide a daily dosage of active compound in a single dose or in a number of smaller doses. Dosage ranges may be established using conventional pharmacological methods and are expected to lie in the range of from 1 to 60 mg/kg of body weight.
  • compositions may desirably be in a form suitable for topical, subcutaneous, mucosal, parenteral, systemic, intra-articular, intra-venous, intra-muscular, intra-cranial, rectal or oral application.
  • Suitable carriers and diluents are well known in the art and the compositions may include excipients and other components to provide easier or more effective administration.
  • the present invention provides a substituted phthalocyanine of formula (I) optionally conjugated to a carrier for use as a medicament, particularly for use in photodynamic therapy or photodiagnostics.
  • the present invention further provides a pharmaceutical composition comprising a phthalocyanine of formula (I) or a pharmaceutically acceptable salt thereof, particularly for use in photodynamic therapy or photodiagnostics.
  • the present invention further provides use of a substituted phthalocyanine of formula (I) for the manufacture of a phototherapeutic or photodiagnostic agent.
  • the present invention further provides a material comprising a substituted phthalocyanine of formula (I), wherein the optical or physical properties of the material may be altered by incident electromagnetic radiation.
  • Zinc dust 120 g was stirred in 2% HC1 (300ml) for 2 minutes and the acid removed (decanter). The resulting dust was stirred sequentially with 2% HC1 (300 ml), water (3 x 300 ml) and 95%) ethanol (2 x 200ml), the dust being allowed to settle before the waste solvents were decantered. Finally the zinc was washed with diethyl ether (200 ml), filtered and dried under vacuum for 24 hours. The resulting dust was stored over P 2 ⁇ 5 .
  • the drying agent was removed by filtration and the solvent removed under reduced pressure.
  • the residue was purified by column chromatography on silica [eluent: petroleum ether (bp. 40-60°C) / dichloromethane, 1 :1] to remove triphenylphosphine.
  • Dichlorome hane was added to the oil and the organic layer washed with water (2x20ml), brine (20ml) and dried (MgSO 4 ). The drying agent was removed by filtration and the solvent removed under reduced pressure. The product was separated (silica gel, eluent: dichloromefhane, followed by methanol).
  • Method B Prepared as above from l,l-H-2,2-H-perfluorodecyl zinc iodide. After stirring at room temperature for 16 hours, the residue was dissolved in 250ml ether/THF (4:1) and washed with 5% HC1 (40ml). An insoluble precipitate was formed and was filtered. The organic layer was washed with brine (40ml), dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was stirred in acetonitrile (20ml) and filtered.
  • bis(triphenyl)phosphine-nickel(II) dichloride (0.53 g, 0.0008 mol) and triphenylphosphine (0.42 g, 0.0016 mol) were dissolved in dry THF (20 ml).
  • n-BuLi (0.65 ml of a 2.5M solution in hexane, 0.0016 mol) was added dropwise to afford the active red catalyst.
  • Cesium fluoride (0.66g, 4.4mmol), tetrakis(triphenylphosphine)palladium(0) (0.25g, 10mol%) and 2-(4-pyridyl)-4,4,5,5-tetramethyl-l,3-dioxaborolane (0.45g, 2.2mmol) were placed under nitrogen for 10 minutes.
  • 4-Bromo-3,6-dibutoxyphthalonitrile (0.38g, 1.1 mmol) in 1 ,2-dimethoxyethane (DME) (20ml) was added and the mixture was refluxed for 48 hours, adding fresh tetrakis(triphenylphosphine)palladium(0) catalyst (0.25g, 10mol%) every 24 hours.
  • the solvent was removed under reduced pressure and the residue washed with methanol (3x50ml).
  • the crude phthalocyanine mixture was separated by column chromatography over silica (eluent: petrol ether).
  • the first fraction is 1,4,8,1 1,15, 18,22,25-octakis(decyl)phthalocyanine (50mg) identical with an authentic sample.
  • the eluent was then changed to petrol/CH 2 Cl2 (10:1) and a second fraction collected.
  • the solid was filtered and washed with methanol.
  • the product was separated by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C) to remove 1,4,8,1 l,15,18,22,25-octakis(decyl)phthalocyanine).
  • the eluent was changed (petroleum ether (bp.40-60°C)-dichloromethane 9:1) and a second green fraction was collected. This was purified through a second silica column (eluents: petroleum ether (bp. 40-60°C) followed by petroleum ether (bp. 40-60°C)-dichloromethane 19:1).
  • MALDI-MS isotopic cluster at 1582 [M + ].
  • the solvents were removed under reduced pressure and the residue was washed with methanol (3x100ml).
  • the product was separated by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C) to remove 1,4,8,11, 15, 18,22,25-octakis(decyl)phfhalocyanine).
  • the eluent was changed to dichloromethane/petroleum ether (bp. 40-60°C), increasing progressively the amount of dichloromethane from 5 to 25%.
  • the second fraction collected was further purified by column chromatography on silica (same solvent systems used as previously described).
  • the green product was separated by column chromatography on silica (eluent: toluene).
  • the first fraction contained symmetrical 1,4,8,11,15, 18,22,25-octakis(decyl)phfhalocyanine.
  • the second fraction which contained the required product, was collected and was precipitated from toluene by addition of methanol to afford l,4-dibutoxy-2-(p-hydroxymethylphenyl)- 8,11,15, 18,22,25-hexakis(decyl)phthalocyanine as a dark green solid, 100 mg (0.062mmol, 10%).
  • the second green fraction contained 1 ,4-dibutoxy-2-(m- methoxyphenyl)-8,ll,15,18,22,25-hexakis(hexyl)phthalocyanine which was obtained as a green solid after recrystallisation from THF/MeOH (140 mg, 10%) [mp. 132-133°C Found: C, 78.78; H, 8.93; N, 8.64%. C 83 H ⁇ 2 N 8 O 3 requires: C, 78.51; H, 8.89; N, 8.82%.
  • MALDI- MS isotopic cluster at 1270 [M + ].
  • the resulting mixture was poured into methanol (100 ml) and stirred for 5 minutes.
  • the resultant precipitate was collected and dried in air for 10 minutes.
  • the green crude product was then purified by column chromatography (silica gel, eluent: petrol/DCM 7:3).
  • the first fraction contained symmetrical 1,4,8,11, 15, 18,22,25-octakis (decyl) phthalocyanine.
  • the second green fraction contained l,4-dibutoxy-2-(m-methoxyphenyl)-8,l l,15,18,22,25-hexakis(decyl)- phthalocyanine which was obtained as a green solid after recrystallisation from THF/MeOH (180 mg, 14%) [Found: C, 80.26; H, 10.14; N, 6.58%; C 107 H 160 N 8 O 3 requires: C, 80.00; H, 10.04; N, 6.98%.
  • MALDI-MS isotopic cluster at 1606 rjVT].
  • Phthalocyanine derivatives prepared by condensation of 3,6-dibutoxy-4,5-di(m- methoxyphenyl)phfhalonitrile and 3,6-didecylphthalonitrile:
  • the first fraction contained a mixture of symmetrical 1,4,8,11,15,18,22,25- octakis(decyl)phthalocyanine and the expected asymmetrical 3:1 phthalocyanine. Further purification was done for the first fraction by column chromatography (silica gel, eluent: petrol/DCM 7:3).
  • the second green fraction contained l,4-dibutoxy-2,3-di-(m- methoxyphenyl)-8,l l,15,18,22,25-hexakis(decyl)phfhalocyanine (170 mg, 12%) [Found: C, 80.16; H, 9.69; N, 6.20%; C 114 H 166 N 8 O 4 requires: C, 79.95; H, 9.77; N, 6.54%.
  • MALDI-MS isotopic cluster at 1712 [M + ].
  • the second fraction contained an isomeric mixture of 2:2 phthalocyanine derivatives adjacent and opposite. Separation and purification was obtained by column chromatography (silica gel, eluent: petrol/DCM 1 :1).
  • the first green fraction contained 1 ,4, 15, 18-tetrabutoxy-2,3, 16, 17-tetra-(m-methoxyphenyl)-8, 11 ,22,25-tetrakis(decyl)- phthalocyanine which was recrystallised from THF/acetone to afford the product (20 mg, 1.2 %) as green crystals [Found: C, 77.78; H, 8.58; N, 6.09%; C U6 H ⁇ 54 N 8 O 8 requires: C, 77.90; H, 8.68; N, 6.27%.
  • the second green fraction contained 1,4,8,1 l-tetrabutoxy-2,3,9,10-tetra-(m- methoxyphenyl)-15,18,22,25-tetrakis(decyl)phthalocyanine which was obtained (80 mg, 5%) as a green waxy solid [Found: C, 77.96; H, 8.65; N, 6.03%; Cn 6 H ⁇ 5 N 8 O 8 requires: C, 77.90; H, 8.68; N, 6.27%.
  • MALDI-MS isotopic cluster at 1788 [M + ].
  • the third fraction contained another asymmetrical phthalocyanine 1:3. Further purification was obtained using column chromatography (silica gel, eluent: toluene/ethyl acetate 30:1) to afford 1,4,8,1 l,15,18-hexabutoxy-2,3,9,10,16,17-hexa-(m- methoxyphenyl)-22,25-di(decyl)phthalocyanine (90 mg, 6%) as a green waxy solid [Found: C, 75.69; H, 7.98; N, 5.53%; C 118 H 142 N 8 O ⁇ 2 requires: C, 76.02; H, 7.68; N, 6.01%.
  • the fourth fraction was collected by changing the eluent (toluene/THF 20:1) and it was assigned to the symmetrical phthalocyanine which was further purified by column chromatography (silica gel, eluent: petroleum ether/THF 10:1) to afford 1,4,8,1 l,15,18,22,25-octabutoxy-2,3,9,10,16,17,23,24-octa-(m-methoxyphenyl)- phthalocyanine (40 mg, 2.5%) and obtained as a waxy green solid [MALDI-MS: isotopic cluster at 1940 [M + ].
  • the first fraction contained a mixture of symmetrical 1,4,8,11,15,18,22,25- octakis(hexyl)phthalocyanine and the expected asymmetrical 3:1 phthalocyanine. Further purification of the first fraction was achieved by column chromatography (silica gel, eluent: petroleum ether (b.p. 40-60°C)/dichloromethane 7:3) and 1,4,8,11,15,18,22,25- octakis(hexyl)phthalocyanine was collected as the first green fraction.
  • the second fraction was collected and further purified by column chromatography (silica gel, eluent: petroleum ether (b.p. 40-60°C)/dichloromethane 1:1) to isolate the second green fraction containing 1, 4,8, 11 -tetrabutoxy-2, 3,9,10-tetra-(m-methoxyphenyl) ⁇ 15,18,22,25-tetrakis(hexyl)phthalocyanine as a green solid product (90 mg, 7%) [mp. 268- 270°C Found: C, 76.96; H, 7.98; N, 6.89%. C ⁇ 00 H 122 N 8 O 8 requires: C, 76.79; H, 7.86; N, 7.16%.
  • Phthalocyanine derivatives prepared by condensation of 3,6-dibutoxy-4,5-di(4-pyridyl)- phthalonitrile and 3,6-dihexylphthalonitrile:
  • the first fraction contained [1,4,8,1 l,15,18,22,25-octakis(decyl)phfhalocyaninato]zinc(II) (240 mg, 5.8%).
  • the eluent was then changed to petroleum ether (bp. 40-60°C)/dichloromethane (1:1) and a second fraction was collected. This fraction was further purified by preparative TLC on silica (eluent: petroleum ether (bp. 40-60°C)/dichloromethane 3:2).
  • dihydroxysilicon compounds were prepared similarly: [ 1 ,4,8, 11 -tetrabutoxy-2,3,9, 10-tetra-(m-methoxyphenyl)- 15,18,22,25-tetrakis(decyl)- phfhalocyaninato] dihydroxysilicon (compound number 16) [MALDI-MS: isotopic cluster at 1831 (100%, M-H O)], [l,4,15,18-tetrabutoxy-2,3,16,17-tetra-(m-methoxyphenyl)- 8,1 l,22,25-tetrakis(decyl)phthalocyaninato]dihydroxysilicon and [1,4,8,11,15, 18,22,25- octabutoxy-2,3 ,9, 10, 16, 17,23,24-octa-(m-methoxyphenyl)phthalocyaninato]dihydroxy silicon.
  • cells were incubated with the compound of interest, formulated in a liposome suspension, and then exposed to light of a suitable wavelength and energy. The number of viable cells surviving this treatment was registered.
  • the cell line chosen is the HT 1080 fibrosarcoma cell line [ATCC number: CCL-
  • DOPC L- ⁇ -dioleoyl- phosphatidylcholine
  • a stock solution of DOPC in chloroform is prepared at a concentration of 20 mg/ml.
  • the Rotavapor is then connected to a water pump in order to generate reduced pressure and the solvent is evaporated at room temperature. 5.
  • the flask is saturated with nitrogen and 4ml of nitrogen-saturated phosphate buffered saline (PBS) are added.
  • PBS nitrogen-saturated phosphate buffered saline
  • the aqueous suspension is sonicated (10 Hz) for about 30 minutes.
  • the vial is saturated with nitrogen and kept in an ice bath. At the end the liposomes are kept at room temperature overnight.
  • the liposomes have a shelf-life at 4°C of at least three months. Before use, they are filtered through a 0.2 ⁇ m filter and the phthalocyanine concentration is measured by diluting a small aliquot ofthe suspension into a known excess of THF and determining the absorbance of such solution.
  • the cells were routinely cultured with DMEM (Eagle's modified Dulbecco medium added with 100 units/ml penicillin, 100 ⁇ g/ml streptomicin, 0.25 ⁇ m/ml anfotericin, 2mM glutamine) containing 10% FCS (foetal calf serum) and maintained in a humid atmosphere containing 5% CO 2 at a temperature of 37°C. Normally, the cells were detached by using a solution of 0.05% trypsin - 0.02% EDTA in phosphate-buffered saline. The action of trypsin was blocked by addition of FCS. The cell pellet, obtained by centrifugation at 1,000 ⁇ m for 8 minutes was resuspended with DMEM and 10%> FCS and then seeded in 75 cm 2 tissue cultured flasks.
  • DMEM Eagle's modified Dulbecco medium added with 100 units/ml penicillin, 100 ⁇ g/ml streptomicin, 0.25
  • Dulbecco medium containing 10%> FCS (foetal calf serum) and incubated in 25 cm tissue culture flasks. After 24 hours the culture medium was removed and replaced by 5ml DMEM (enriched with 3% FCS) containing either 5 ⁇ M or 10 ⁇ Mof the phthalocyanine.
  • the phthalocyanine was added in an aqueous suspension of DOPC liposomes.
  • PBS devoid of Ca and Mg ions.
  • the cell pellet was homogenised with 2%> aqueous sodium dodecylsulphate (SDS)
  • the amount of phthalocyanine recovered was calculated by inte ⁇ olation with a calibration plot and the uptake was expressed as nmoles of phthalocyanine/mg of cell protein.
  • 1.8x10 cells were seeded in Petri dishes of 7cm diameter, incubated for 24 hours in DMEM containing 10% FCS in a humid atmosphere containing 5% CO 2 and at a temperature of 37°C The medium was removed and replaced by 1ml DMEM containing 2.5 ⁇ M to 10 ⁇ M phthalocyanine which was added in DOPC liposomes. After 1 hour incubation, the cells were washed twice with PBS containing Ca (0.9 mM CaCl 2 • 2 H 2 O) ions and Mg 2+ (0.5 mM MgCl 2 • 2 H 2 O) ions.
  • the light source - Waldmann PDT 1200 (Waldmann Medical Division, Villingen- Schwenningen, Germany) - is a non-coherent light source with a filter allowing light between 600 and 730 nm to pass. A built-in output meter is used to monitor the doses given. The lamp was operated at a fluence rate of 100 mW/cm 2 .
  • the cells in the Petri dish were irradiated (100 mW/cm ) for 1, 5, 10, 15 minutes (6 up to 90 J/cm 2 ) with 1ml PBS containing Ca 2+ and Mg 2+ ions.
  • the irradiated cells were mixed with 2ml DMEM containing 10% FCS and incubated overnight.
  • the photosensitised cells were assayed by the trypan blue test (Reference: C. Milanesi, F. Sorgato, G. Jori, "Photokinetic and ultrastructural studies on po ⁇ hyrin photosensitization of HeLa cells", Int. J. Radiat. Biol., vol. 55, pages 59-69, 1989) and the survival was expressed as the percentage of the survival typical of cells which had been treated by an identical procedure but were not exposed to light.
  • Preliminary studies showed that irradiation of the cells in the absence of the photosensitizer and dark incubation of the cells with phthalocyanines has no effect on cell survival.
  • UV-Vis spectra were recorded using a Hitachi U-3000 Spectrophotometer.
  • the phthalocyanines samples were dissolved in THF, unless otherwise stated, and held in a lcm x 1cm quartz cuvette. The data were recorded at ambient temperature, 20-23 °C
  • Spectrophotometer The phthalocyanines samples were dissolved in THF and held in a lcm x lcm quartz cuvette. The data were recorded at ambient temperature, 20-23°C
  • the samples were held in a lcm x lcm fluorescence cuvette (Hellma).
  • the incident laser energy for each measurement was determined using a pyroelectric detector held behind the sample.
  • the laser energy was adjusted by placing cells containing aqueous sodium nitrite between the CoSO 4 filter and the light guide.
  • Typical pulse energies used here were in the range 25-500 ⁇ J per pulse, as measured using a second, calibrated pyroelectric detector, (Gentec ED- 100). Shot to shot noise was estimated to be ⁇ 10%> and sets of 20 shots gave an average value within ⁇ 3%.
  • Phosphorescence from the sample was collected and passed through an interference filter centred at 1270nm (Infra Red Engineering Ltd) and then focussed onto the active area of a liquid nitrogen cooled germanium photodiode (North Coast EO-817P).
  • the signal form the detector was AC coupled to a digital oscilloscope (Tektronix TDS-320) which digitised and averaged the transients. Typically 32 laser shots were used for each sample. The averaged data was transferred to a PC where it was stored and analysed.
  • Stock solutions of the materials were prepared by taking a small sample of the materials supplied and dissolving them in toluene (Fischer Scientific, Analytical grade) containing l%(v/v) pyridine. The pyridine was added to ensure that the samples did not aggregate. Exact concentrations of these solutions were not determined.
  • Working solutions were prepared by dilution of the stock with toluene to give absorbances of 0.01- 0.100 at 355nm when placed in a UV-Vis spectrometer (ATI-Unicam UV-2) compared to a reference cell containing the pure solvent. UV-Vis spectra were recorded in long pathlengfh cells (2cm) to ensure a more accurate measure of absorbance. Care was taken to avoid high absorbances in the region of the Q-bands (600-750nm) where re-abso ⁇ tion ofthe fluorescence from the sample can lead to error.
  • the data were recorded at ambient temperature, 20-23 °C, and the solutions were aerated.
  • a typical decay is shown below.
  • a plot of A v's incident laser energy was drawn for each solution and the slope determined. The slope is proportional to the singlet oxygen quantum yield and the amount of light absorbed by the sample.
  • the slope ofthe graph for each sample was taken and plotted against (1-10 "A ), where A is the absorbance of the samples at the excitation wavelength. The slope of this graph is then proportional to the singlet oxygen quantum yield.
  • the dominant sources of error in the experiment include the shot-to-shot fluctuations in the laser and errors in the measured sample absorbances. For these reasons we are reporting values to have an error of ⁇ 10%.
  • Fluorescence lifetimes were determined using the method of time-correlated single photon counting (Principles of Fluorescence Spectroscopy 2 nd Ed, j. Lakowicz, Kluwer Academic/ Plenum Press). Samples were excited using the output from a 635nm pulsed diode laser (IBH NanoLed). This produced a 1MHz train of pulses with a FWHM of 200ps. Fluorescence was collected at 90° to the excitation source and the emission wavelength selected by a monochromator (Jobin-Yvon Triax 190) and detected using a cooled red-sensitive photomultiplier/discriminator (IBH TXB-04).
  • the output from the detector was used as the start signal for a time to amplitude converter (Ortec 567) and the stop signal was derived from the laser power supply/driver.
  • the TAC output was processed by a pulse height analyser (Ortec Trump 8K). Typically decays were obtained using a record length of 1024 channels with a time-window of 55ps/channel. Instrument response functions were obtained using a scattering suspension and were typically 45 Ops FWHM. Decays were analysed by the method of iterative reconvolution of the response function with a sum-of-exponentials and the fit optimised by the method of non-linear least-squares analysis. The quality of fit was judged by the reduced chi-squared, randomness of residuals and auto-correlation function (Principles of Fluorescence Spectroscopy 2 nd Ed, J. Lakowicz, Kluwer Academic/ Plenum Press).
  • Rhodamine 101 in acidified ethanol ⁇ f 1.00.
  • Restenosis is the formation of a new blockage in arteries following treatment using balloon angioplasty to open up partially blocked arteries. This formation of a second blockage occurs in less than 6 months in up to 50% of patients treated with balloon angioplasty and represents a major clinical problem.
  • the animal models are performed by introducing a balloon catheter into an artery of the animal and producing a lesion in the artery wall, which is very similar to the clinical procedure.
  • the substance of interest is introduced in the region of the lesion, a light guide (catheter coupled to a light source) is introduced and the photosensitiser is activated. Then the degree of new cellular growth into the blood vessel is measured at intervals of days or weeks.
  • the compounds tested were (a) zinc(II) phthalocyanine, formulated in liposomes as described by the authors of "Local photodynamic therapy with Zn(II)-phthalocyanine in an experimental model of intimal hype ⁇ lasia", and (b) silicon(dihydroxy) octahexyl phthalocyanine (compound 3 as defined in Table 2), formulated as described in the section entitled “Preparation of liposomes" above.
  • the iliac arteries of groups of 3 rabbits were lesioned as described in "Local photodynamic therapy with Zn(II)-phthalocyanine in an experimental model of intimal hype ⁇ lasia” and the animals treated with the compounds, followed by illumination.
  • the degree of intimal hype ⁇ lasia (IH) was evaluated at weekly intervals up to 1 month after PDT treatment (3 rabbits at each time point). Table 3 summarises the results obtained in the above described experiments.
  • apoptosis is applied to a group of characteristic structural and molecular events that separate this type of cell deletion from necrosis. In contrast to necrosis which involves a group of cells simultaneously, apoptosis may occur in a single cell surrounded by a group of viable cells. There is a distinct and precisely localised control over the fate of specific cells in a mixed cell population that undergoes apoptosis.
  • Apoptosis is a selective process for deletion of cells in various biological systems. Similar to proliferation, apoptosis is tightly regulated with both processes playing essential roles in the homeostasis of renewable tissues.
  • apoptosis pathway Diverse groups of molecules are involved in the apoptosis pathway.
  • mediators implicated in apoptosis belong to the aspartate-specific cysteinyl proteases or caspases.
  • caspase-3 A member of this family, caspase-3 (CPP32, apopain, YAMA) has been identified as being a key mediator of apoptosis of mammalian cells.
  • CPP32 cysteinyl proteases
  • YAMA caspase-3
  • selected phthalocyanines were formulated as described in the section entitled "Preparation of liposomes" above.
  • HT 1080 fibrosarcoma cells were treated with the compounds and exposed to light as described in the sections entitled "Cell irradiation studies" and "Light source” above.
  • the activity of caspase-3 was measured in the PDT- treated cells at various post-treatment times, for which an ApoAlert CPP32 kit (Clontech Palo Alto, CA) was used. According to the manufacturer recommended procedure, IO 6 cells were collected by centrifugation, resuspended in 50 ⁇ l of lysis buffer and held on ice for 10 minutes.
  • the caspase-3 activity in the treated cells was expressed as a percentage ofthe fluorescence from untreated cells used as reference.
  • Table 4 shows caspase-3 activity in HT 1080 fibrosarcoma cells irradiated for selected lengths of time in the presence of selected phthalocyanines at a 10 ⁇ M concentration. All measurements were performed at 3 hours after irradiation.
  • Compound numbers are as defined in Table 2.
  • Compounds 3 and 29 are Si(OH) 2 derivatives, compound 8 is a zinc derivative.
  • a mouse model was used in which the compounds were applied onto the dorsal skin of mice.
  • the amount of phthalocyanine taken up by the skin was determined by extracting the skin sample after euthanising the animal. Defined doses of phthalocyanines were applied onto the skin of mice and irradiated with light of defined properties. The biological effects were then observed for a period of up to 10 days.
  • the phthalocyanines tested for skin uptake were zinc(II) octahexyl phthalocyanine (compound 4 as defined in Table 2) and silicon(dihydroxy) octahexyl phthalocyanine (compound 3 as defined in Table 2).
  • mice (body weight 19-21 g) were depilated on the dorsal skin by application of a cream.
  • total volume 20 ⁇ l were dropwise deposited on a predetermined 1 cm 2 skin area, while the mice were kept under light anesthesia (intraperitoneal injection of ketalar). After 5 hours, the area where the phthalocyanine had been deposited was washed with a cotton swab, which was wet with physiological solution (PBS), until no further dyeing of the cotton was noticed. Then the mice were sacrificed by prolonged exposure to ether vapours, the deposition skin area was quickly removed and the phthalocyanine content was quantitatively determined by a spectrophotofluorimetric analytical procedure.
  • the skin (1 cm which was weighed to identify the total mass) was homogenized in a Potter vessel with 2% aqueous SDS (2 ml). The homogenate was magnetically stirred for 1 hour at room temperature. Then 300 ⁇ l of the suspension were 10-fold diluted with THF, centrifuged at 3,000 ⁇ m for 10 minutes, the supernatant was collected and the characteristic phthalocyanine fluorescence emission was measured.

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Abstract

La présente invention concerne certaines phtalocyanines de di(hydroxy/alcoxy)silicium substituées et certaines utilisations de ces dernières, notamment leurs utilisations en thérapie photodynamique et en photodiagnostic.
PCT/GB2002/002465 2001-05-25 2002-05-24 Phtalocyanines de di(hydroxy/alcoxy)silicium substituees et utilisations de ces dernieres WO2002096913A1 (fr)

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GB0112875A GB0112875D0 (en) 2001-05-25 2001-05-25 Substituted di(hudroxy/alkoxy) silicon phthalocyanines and their uses
GB0112875.0 2001-05-25
GB0114398.1 2001-06-13
GB0114398A GB0114398D0 (en) 2001-05-25 2001-06-13 Substituted di(hydroxy/alkoxy)silicon phthalocyanines and their uses

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WO2005099689A1 (fr) * 2004-04-01 2005-10-27 Case Western Reserve University Apport topique de phtalocyanines
US7005518B2 (en) 2002-10-25 2006-02-28 Li-Cor, Inc. Phthalocyanine dyes
US8440641B2 (en) 2009-03-20 2013-05-14 Case Western Reserve University Phthalocyanine salt formulations
JP5277469B1 (ja) * 2012-07-25 2013-08-28 東洋インキＳｃホールディングス株式会社 π型フタロシアニン顔料、該π型フタロシアニン顔料の製造方法および該π型フタロシアニン顔料を用いた着色組成物
CN103864645A (zh) * 2013-12-30 2014-06-18 常州大学 一种二取代全氟烷基邻苯二甲腈化合物及其制备方法
WO2020071470A1 (fr) * 2018-10-05 2020-04-09 山本化成株式会社 Composé de phtalocyanine et son utilisation
EP3541818A4 (fr) * 2016-11-17 2020-07-29 Tampereen Korkeakoulusäätiö SR Photosensibilisateur
WO2022018264A1 (fr) * 2020-07-23 2022-01-27 Technische Universität München Composés ligands contenant du silicium
US11581487B2 (en) 2017-04-26 2023-02-14 Oti Lumionics Inc. Patterned conductive coating for surface of an opto-electronic device
US11985841B2 (en) 2020-12-07 2024-05-14 Oti Lumionics Inc. Patterning a conductive deposited layer using a nucleation inhibiting coating and an underlying metallic coating

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7005518B2 (en) 2002-10-25 2006-02-28 Li-Cor, Inc. Phthalocyanine dyes
WO2005099689A1 (fr) * 2004-04-01 2005-10-27 Case Western Reserve University Apport topique de phtalocyanines
US8211883B2 (en) 2004-04-01 2012-07-03 Case Western Reserve University Topical delivery of phthalocyanines
US8440641B2 (en) 2009-03-20 2013-05-14 Case Western Reserve University Phthalocyanine salt formulations
JP5277469B1 (ja) * 2012-07-25 2013-08-28 東洋インキＳｃホールディングス株式会社 π型フタロシアニン顔料、該π型フタロシアニン顔料の製造方法および該π型フタロシアニン顔料を用いた着色組成物
WO2014017330A1 (fr) * 2012-07-25 2014-01-30 東洋インキＳｃホールディングス株式会社 Pigment phtalocyanine π-conjugué, procédé de production dudit pigment phtalocyanine π-conjugué, et composition colorée préparée en utilisant ledit pigment phtalocyanine π-conjugué
CN103864645A (zh) * 2013-12-30 2014-06-18 常州大学 一种二取代全氟烷基邻苯二甲腈化合物及其制备方法
CN103864645B (zh) * 2013-12-30 2016-08-17 常州大学 一种二取代全氟烷基邻苯二甲腈化合物及其制备方法
EP3541818A4 (fr) * 2016-11-17 2020-07-29 Tampereen Korkeakoulusäätiö SR Photosensibilisateur
US10875871B2 (en) 2016-11-17 2020-12-29 Tampereen Korkeakoulusäätiö SR Photosensitizer
US11581487B2 (en) 2017-04-26 2023-02-14 Oti Lumionics Inc. Patterned conductive coating for surface of an opto-electronic device
WO2020071470A1 (fr) * 2018-10-05 2020-04-09 山本化成株式会社 Composé de phtalocyanine et son utilisation
WO2022018264A1 (fr) * 2020-07-23 2022-01-27 Technische Universität München Composés ligands contenant du silicium
US11985841B2 (en) 2020-12-07 2024-05-14 Oti Lumionics Inc. Patterning a conductive deposited layer using a nucleation inhibiting coating and an underlying metallic coating

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