WO2001042368A1 - Phtalocyanines substituees et leurs precurseurs - Google Patents

Phtalocyanines substituees et leurs precurseurs Download PDF

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Publication number
WO2001042368A1
WO2001042368A1 PCT/GB2000/004708 GB0004708W WO0142368A1 WO 2001042368 A1 WO2001042368 A1 WO 2001042368A1 GB 0004708 W GB0004708 W GB 0004708W WO 0142368 A1 WO0142368 A1 WO 0142368A1
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Prior art keywords
substituted
optionally substituted
alkyl
phthalocyanine
formula
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PCT/GB2000/004708
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English (en)
Inventor
Michael John Cook
Martin James Heeney
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Gentian As
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Priority claimed from GBGB9929064.5A external-priority patent/GB9929064D0/en
Priority claimed from GBGB0025817.8A external-priority patent/GB0025817D0/en
Application filed by Gentian As filed Critical Gentian As
Priority to CA002394891A priority Critical patent/CA2394891A1/fr
Priority to PL00355851A priority patent/PL355851A1/xx
Priority to HU0301099A priority patent/HUP0301099A3/hu
Priority to EP00985506A priority patent/EP1238016A1/fr
Priority to AU21922/01A priority patent/AU2192201A/en
Priority to EEP200200298A priority patent/EE200200298A/xx
Priority to JP2001543656A priority patent/JP2003516421A/ja
Publication of WO2001042368A1 publication Critical patent/WO2001042368A1/fr
Priority to NO20022663A priority patent/NO20022663L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B47/00—Porphines; Azaporphines
    • C09B47/04—Phthalocyanines abbreviation: Pc
    • C09B47/045—Special non-pigmentary uses, e.g. catalyst, photosensitisers of phthalocyanine dyes or pigments
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B47/00—Porphines; Azaporphines
    • C09B47/04—Phthalocyanines abbreviation: Pc
    • C09B47/06—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide
    • C09B47/067—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide from phthalodinitriles naphthalenedinitriles, aromatic dinitriles prepared in situ, hydrogenated phthalodinitrile
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B47/00—Porphines; Azaporphines
    • C09B47/04—Phthalocyanines abbreviation: Pc
    • C09B47/06—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide
    • C09B47/067—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide from phthalodinitriles naphthalenedinitriles, aromatic dinitriles prepared in situ, hydrogenated phthalodinitrile
    • C09B47/0673—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide from phthalodinitriles naphthalenedinitriles, aromatic dinitriles prepared in situ, hydrogenated phthalodinitrile having alkyl radicals linked directly to the Pc skeleton; having carbocyclic groups linked directly to the skeleton

Definitions

  • This invention relates to a process for the preparation of phthalonitrile sulfonate esters, a process for the preparation of substituted phthalonitriles using said phthalonitrile sulfonate esters, a process for the preparation of substituted phthalocyanines using said substituted phthalonitriles, a process for the preparation of phthalonitrile halides, a process for the preparation of substituted phthalocyanines using said phthalonitrile halides, novel phthalonitrile sulfonate esters, novel substituted phthalonitriles, novel substituted phthalocyanines and certain uses of said novel substituted phthalocyanines.
  • 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.
  • GB-B-2,229,190 discloses a group of non-peripherally substituted phthalocyanines, at least some of which, in thin films such as for example Langmuir-Blodgett films, in the liquid crystalline state, or when dissolved or dispersed in a carrier material, are transparent in the visible region and yet strong absorbers of UV or IR radiation. Hence they are capable of absorbing energy emitted by lasers and thus useful in laser addressed applications such as laser addressed optical storage devices and projection displays. Alteration of the substituents and the central ion M is a means for tuning the wavelength of absorption by the substituted phthalocyanines to match the wavelengths of the lasers.
  • GB-B-2,295,547 discloses the use of a similar group of non-peripherally substituted phthalocyanines as photosensitizers in photodynamic therapy.
  • EP-A-0, 906,758 discloses a variety of zinc-phthalocyanines substituted with hydrophilic substituents linked to the phthalocyanine ring via an oxygen atom as phototherapeutic or photodiagnostic agents.
  • dye compounds are administered to a tumour-bearing subject. These dye substances may be taken up by the tumour at least to a certain extent. Upon selective irradiation with an appropriate light source the tumour tissue is destroyed via the dye mediated photo-generation of cytotoxic species such as singlet oxygen or free radicals such as hydroxy or superoxide.
  • Alkoxy-substituted phthalonitriles have been synthesised by alkylation of hydroxy- substituted phthalonitriles (see Scheme 2) or nucleophilic aromatic substitution of nitro- or chloro-substituted phthalonitriles (Scheme 3).
  • Scheme 2 alkylation of hydroxy- substituted phthalonitriles
  • Scheme 3 nucleophilic aromatic substitution of nitro- or chloro-substituted phthalonitriles
  • a hydroxy-substituted phthalonitrile may be treated with a suitable base and a haloalkane to yield an alkoxy-substituted pthalonitrile.
  • a nitro- or chloro- substituted phthalonitrile may be treated with a suitable base and an alcohol to yield an alkoxy-substituted pthalonitrile.
  • the resulting 2,5-dialkylfuran may be treated with fumaronitrile followed by a suitable base to yield a 3,6- dialkylphthalonitrile.
  • thiophene may be 2,5-alkylated using suitable base and a haloalkane.
  • the resulting 2,5- dialkylthiophene may be oxidised to yield the corresponding 1,1 -dioxide. This may be reacted with fumaronitrile to yield a 3,6-dialkylphthalonitrile.
  • Substituted phthalocyanines have been prepared by the cyclisation of appropriately substituted phthalonitriles.
  • a substituted phthalonitrile may be reductively cyclised into a substituted phthalocyanine by treatment with a suitable base.
  • the substituted phthalocyanine may be metallated by treatment with a suitable metal compound.
  • the substituted phthalonitrile may be reductively cyclised directly into the metallated substituted phthalocyanine by treatment with a suitable metal compound in the presence of a suitable base.
  • a major disadvantage of the prior art syntheses of substituted phthalocyanines is that a large variety of potentially useful substituents cannot be introduced into phthalocyanine by these prior art syntheses, because their functionality is incompatible with the required reaction conditions.
  • the present invention provides a new synthetic route to substituted phthalocyanines via cyclisation of substituted phthalonitriles, prepared by substitution reactions of phthalonitrile sulfonate esters.
  • aryl iodides, bromides, triflates as well as nonaflates M. Rottlander, P. Knochel, J. Org. Chem., 1998, vol. 63, page 4523; B.H. Lipshutz, D.J. Buzard, C.S.
  • m are the same or different and each m is 0, 1 , 2, 3 or 4, provided that not all four m are 0 simultaneously;
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl optionally substituted;
  • p are the same or different and each p is 0, 1, 2 or 3;
  • R 3 are the same or different and each R 3 is -F, -Cl, -Br or -I;
  • M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
  • R 6 is either C ⁇ -C 12 alkyl, optionally substituted with one or more of -F and/or -Cl, or aryl, optionally substituted with one or more of -CH 3 , -NO 2 , -OCH 3 , -F, -Cl and/or -Br; and when m is 2, 3 or 4, R 6 are the same or different;
  • alkyl is defined as a hydrocarbon with a 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 a sp hybridised aromatic ⁇ -carbon, which may optionally be substituted. Examples of aryls are
  • Heteroaryl is defined as an aromatic hydrocarbon with a sp 2 hybridised aromatic ⁇ -carbon, which comprises at least one heteroatom N, O or S as part of the aromatic ringsystem, and which may optionally be substituted. Examples of heteroaryls are
  • Alkynyl is defined as a hydrocarbon with a 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, -Cl, -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, -Cl, -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 alkynyl group may be substituted with -F, -Cl, -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, -Cl, -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 Cj-Cio alkyl, C 2 -C 10 alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R ) 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) or (V), or ⁇ to either one of the two cyano groups in a compound of formula (IV), (VI) or (VII).
  • a substituent is defined as
  • peripheral when it is not “non-peripheral".
  • 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 formulas (I) and (V) 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 or X may be adjacent to each other or opposite each other.
  • a non-mixed or a mixed phthalocyanine may be obtained.
  • M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In, Ga, Fe, Ge, a lanthanide, Si with two axial substituents or 2H. More preferably, is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
  • the phthalocyanine (I) is a non-mixed phthalocyanine or if the phthalocyanine (I) is substituted with -S-R 5 , the sum of m and p is not 4 or 8.
  • the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V).
  • a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked.
  • the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R 1 , R 8 and/or R 9 .
  • R , R , R and p are defined as in the first aspect of the present invention, and m is 1, 2, 3 or 4,
  • R is defined as in the first aspect of the present invention.
  • the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula (III) with an organozinc reagent R'ZnX or an organocopper reagent R'CuX catalysed by palladium or nickel, wherein R 1 is defined as in the first aspect of the present invention and X is a halogen.
  • the halogen is Cl, Br or I.
  • the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula (III) with a trialkylborane B(R') 3 catalysed by palladium, wherein R 1 are the same or different and each R is C ⁇ -C 20 alkyl optionally substituted; -R 4 -O-R 5 ; -R 4 -S-R 5 ; -R 4 -N-(R 5 ) 2 ; -R 4 -P-(R 5 ) 2 ; -R 4 -aryl optionally substituted; -R 4 -heteroaryl optionally substituted; -R 4 -COR 5 ; -R 4 -COOR 5 or
  • B(R') 3 is 9-BBN, i.e. R'BCCHHM).
  • the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula
  • R are the same or different and each R is Cj-Cio alkyl optionally substituted and both R 7 together with -O-B-O- may form a ring.
  • R ] B(OR 7 ) 2 is R'B ⁇ C ⁇ CH ⁇ C ⁇ O-), R ⁇ -OCH Z CH J O-) or
  • the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a coupling of the sulfonate ester of formula (III) with a coupling partner R1H catalysed by palladium, wherein R 1 is C 2 -C 20 terminally alkenyl optionally substituted or C 2 -C 20 terminally alkynyl optionally substituted.
  • R 1 are the same or different and each R 1 is C ⁇ -C 2 o alkyl, optionally substituted with one or more of -F, -Cl, -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, -Cl, -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
  • R 1 are the same or different and each R 1 is CrC 20 alkyl, optionally substituted with one or more of -F, -Cl, -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 ; -R 4 -aryl, optionally substituted with one or more of C ⁇ -C 10 alkyl, C 2 -C ⁇ o alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR 5 ,
  • R 1 may be a peripheral or a non-peripheral substituent.
  • at least one R 1 is a non-peripheral substituent.
  • the compound of formula (I) and/or (IV) may be 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.
  • the compound of formula (I) and/or (IV) 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 via substituent R .
  • R , R , R and p are defined as in the first aspect of the present invention, and m is 1, 2, 3 or 4,
  • R is Preferably, R 6 are the same or different and each R 6 is -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -C 8 H 17 , -CHC1 2 , -CF 3 , -C 4 F 9 , -C 6 H 5 , -(C 6 H 4 )-4-CH 3 , -(C 6 H 4 )-2-NO 2 , -(C 6 H 4 )-3-NO 2 , -(C 6 H 4 )-4-NO 2 , -(C 6 H 4 )-2-Br, -(C 6 H 4 )-4-Br, -(C 6 H 4 )-4-Cl, -(C 6 H4)-4-F, -(C 6 H 3 )-2,5-Cl 2 , -(C 6 H 3 )-3,4-Cl 2 , -(C 6 H4)-4
  • p 0.
  • n are the same or different and each m is 0, 1, 2, 3 or 4;
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl optionally substituted;
  • R 2 are the same or different and each R 2 is
  • p are the same or different and each p is 0, 1 , 2 or 3;
  • R are the same or different and each R is -F, -Cl, -Br or -I;
  • R are the same or different and each R is C ⁇ -C 20 alkyl optionally substituted;
  • q 1 or 2;
  • R 9 are the same or different and each R 9 is -Cl, -Br, -I, -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted; and
  • M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
  • R 10 are the same or different and each R 10 is -Cl, -Br or -I, into a substituted phthalonitrile of formula (VII)
  • R are the same or diffferent and each R is -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted;
  • R 9 being -Cl, -Br or -I into an R 9 being -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted, or -heteroaryl optionally substituted.
  • a non-mixed or a mixed phthalocyanine may be obtained.
  • M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In,
  • M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -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, -Cl, -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 ) ; C 2 -C 20 al
  • R 1 are the same or different and each R 1 is Cj-C 2 o alkyl, optionally substituted with one or more of -F, -Cl, -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 ; -R 4 -aryl, optionally substituted with one or more of C ⁇ -C 10 alkyl, C 2 -C ⁇ 0 alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -
  • At least one R 1 is not C ⁇ -C 20 alkyl non-substituted.
  • R 1 may be a peripheral or a non-peripheral substituent.
  • at least one R 1 is a non-peripheral substituent.
  • the compound of formula (V) may be 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.
  • the compound of formula (V) 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 via substituent R 1 .
  • the phthalocyanine (V) is a non-mixed phthalocyanine or if the phthalocyanine (V) is substituted with -S-R 5 , the sum of m and p is not 4 or 8.
  • R 2 is
  • p 0.
  • R are the same or different and each R is C ⁇ -C 20 alkyl optionally substituted with -OH. More preferably, R are the same or different and each R is C ⁇ -C 20 alkyl. Even more preferably, R 8 are the same or different and each R 8 is C]-C 10 alkyl.
  • R 9 are the same or different and each R 9 is -Br, -I, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted.
  • the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V).
  • a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked.
  • the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R 1 , R 8 and/or R 9 .
  • R are the same or different and each R is C ⁇ -C 20 alkyl optionally substituted with -OH. More preferably, R 8 are the same or different and each R 8 is C ⁇ -C 20 alkyl. Even more preferably, R 8 are the same or different and each R 8 is C J -CIQ alkyl.
  • n 1, 2, 3 or 4;
  • R 6 is either C]-C 12 alkyl, optionally substituted with one or more of -F and/or -Cl, or aryl, optionally substituted with -CH 3 , -NO 2 , -OCH 3 , -F, -Cl and/or -Br; and when m is 2, 3 or 4, R are the same or different; p is 0, 1, 2 or 3; and
  • R ,3 is either -F, -Cl, -Br or -I; and when p is 2 or 3, R are the same or different.
  • R is N
  • R are the same or different and each R is -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -C 8 H 17 , -CHC1 2 , -CF 3 , -C 4 F 9 , -C 6 H 5 , -(C 6 __ 4 )-4-CH 3 , -(C 6 H 4 )-2-NO 2 , -(C 6 H 4 )-3-NO 2 , -(C 6 H 4 )-4-NO 2 , -(C 6 H 4 )-2-Br, -(C 6 H 4 )-4-Br, -(C 6 H 4 )-4-Cl, -(C 6 H 4 )-4-F, -(C 6 H 3 )-2,5-Cl 2 , -(C 6 H 3 )-3,4-Cl 2 , -(C 6 H 3 )
  • p 0.
  • n 1, 2, 3 or 4;
  • R is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -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, -Cl, -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 alkynyl, optionally substituted
  • -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; and when m is 2, 3 or 4, R 1 , -R 4 - and -R 5 are the same or different;
  • p 0, 1, 2 or 3;
  • R is either -F, -Cl, -Br or -I; and when p is 2 or 3, R are the same or different;
  • R 1 is C ⁇ -C 20 alkyl non-substituted, -CF 3 , -OR 5 , -CH 2 OR 5 or -S-aryl, m is 3 or 4 or p is 1 , 2 or 3.
  • At least one R 1 is not C ⁇ -C 20 alkyl non-substituted.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -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, -Cl, -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, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2
  • 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, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; C 2 -C 2 o alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; C2-C 20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; -OR 5 ; -SR 5 ; -SO 2 R 5 ;
  • R 1 are the same or different and each R 1 is C 1 -C 20 alkyl substituted with at least one or more of -F, -Cl, -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 2 o alkynyl; -S-R 5 ; -N-(R 5 ) 2 ; -aryl, optionally 25 substituted with one or more of C1-C 10 alkyl, C 2 -C ⁇ 0 alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR
  • R 1 are the same or different and each R 1 is C 1 -C 20 alkyl fully substituted with -F, -Cl and/or -Br; C 2 -C 2 o alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; or -aryl, optionally substituted with one or more of -CH 3 , -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH and/or -NH 2 ; where -R 5 are the same or different and each -R 5 is C1-C2 0 alkyl, C 2 -C 20 alkenyl, aryl, heteroaryl or H, or two -R 5 together form a saturated or unsaturated ring.
  • R 1 may be a peripheral or a non-peripheral substituent.
  • at least one R 1 is a non-peripheral substituent.
  • the compound of formula (IV) may be 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.
  • the compound of formula (IV) 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 via substituent R 1 .
  • R 2 is A .
  • p 0.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -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, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , 5 -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R
  • R are the same or different and each R is
  • 25 p are the same or different and each p is 0, 1, 2 or 3; provided that not all four m and all four p are 0 simultaneously;
  • R are the same or different and each R is either -F, -Cl, -Br or -I;
  • 30 M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
  • R 1 provided that when all R 1 are the same and are C ⁇ -C 20 alkyl non-substituted, -CF 3 ,
  • the substituted phthalocyanine (I) of the eighth aspect of the present invention may be a non-mixed or a mixed phthalocyanine. 10
  • At least one R 1 is not C ⁇ -C 20 alkyl non-substituted.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 ,
  • C 2 -C 20 alkenyl optionally substituted with one or more of -F, -Cl, -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, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -Si(R 5 ) 3 , - ILtN, -C 4 H 3 S and/or -C 6 H 5 ; -OR 5 ; -SR 5 ;
  • each -R 5 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, aryl, hetereoaryl or H, or two -R 5 together form a saturated or unsaturated ring.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 30 and/or -NHR 5 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; C 2 -C 2 o alkynyl, optionally substituted with one or more of -F, -Cl, -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 ;
  • 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, -Cl, -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 10 substituted with one or more of C ⁇ -C ⁇ 0 alkyl, C 2 -C ⁇ 0 alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR 5
  • R 1 are the same or different and each R 1 is Cj-C 2 o alkyl fully substituted with -F, -Cl and/or -Br; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; or -aryl, optionally substituted with one or more of-CH 3 , -NO , -OCH 3 , -F, -Cl, -Br, -OH and/or -NH ; where -R 5 are the same or different and each -R 5 is C ⁇ -C 20 alkyl, C 2 -C 2 o alkenyl, aryl, heteroaryl or H, or two -R 5 together form a saturated or unsaturated ring.
  • R 1 may be a peripheral or a non-peripheral substituent.
  • at least one R 1 is a non-peripheral substituent.
  • the compound of formula (I) may be substituted with or conjugated to an amino
  • the compound 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 via substituent R 1 .
  • the phthalocyanine (I) is a non-mixed phthalocyanine or if the phthalocyanine (I) is substituted with -S-R 5 , the sum of m and p is not 4 or 8.
  • R 2 is ⁇ .
  • p 0.
  • M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In,
  • M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
  • R 1 are the same or different and each R 1 is C 2 -C 20 alkyl fully substituted with -F, -Cl and/or -Br; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; or -aryl, optionally substituted with one or more of -CH 3 , -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH and/or -NH 2 ; where -R 5 are the same or different and each -R 5 is C]-C 20 alkyl, C 2 -C 20 alkenyl, aryl, hetereoaryl or H, or two -R together form a saturated or unsaturated ring; A R 2 is ⁇ ; and
  • M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
  • the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V).
  • a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked.
  • the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R 1 , R 8 and/or R 9 .
  • the substituted phthalocyanine is conjugated to a carrier or entrapped or embedded in a macromolecular carrier.
  • the carrier is an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a saccharide, a polysaccharide or a polymer.
  • the substituted phthalocyanine is conjugated to a carrier, it is preferably conjugated to the carrier via substituent R 1 , R 8 or R 9 .
  • the macromolecular carrier is a polypeptide
  • the polypeptide is preferably an antibody.
  • the substituted phthalocyanine is preferably entrapped or embedded in a solid polymer or conjugated to a soluble polymer.
  • the solid polymer is selected from polyesters, poly(orthoesters), polyanhydrides, tyrosine derived pseudo-poly(amino acids) or polyphosphazenes, or the soluble polymer is selected from N-(2-hydroxypropyl)methacrylamide (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 the photodynamic therapy of a human or animal disease.
  • 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 hyperproliferation 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, hyperplasia, intimal hyperplasia, benign prostate hyperplasia, psoriasis, mycosis fungoides, eczema, actinic keratosis or lichen planus.
  • the source of illumination 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 phototherapeutic agent for the use in photodynamic therapy.
  • the phototherapeutic agent is used for the treatment of a disease characterised by benign or malignant cellular hyperproliferation.
  • 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, hyperplasia, 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, hyperplasia, 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 phthalocyanine (I) may be prepared by the cyclisation of a substituted phthalonitrile (IV) either by itself or together with any other phthalonitrile of formula (IV).
  • a phthalonitrile of formula (IV) may in turn 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.
  • the preparation of 3,6- (trifluoromethanesulfonyloxy) phthalonitrile (a triflate), 2,3-dicyano-l,4- (trifluoromethanesulfonyloxy)naphthalene (a triflate) and 3,6- (nonafluorobutanesulfonyloxy)phthalonitrile (a nonaflate) are now described as representative examples of the preparation of phthalonitrile sulfonate esters of formula (III).
  • 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
  • the 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 the previously unknown 3,6-(trifluoromethanesulfonyloxy)phthalonitrile as yellow crystals in good yield.
  • 2,3-dicyano-l,4-(trifluoromethanesulfonyloxy)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 meet 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 the previously unknown 3,6- (nonafluorobutanesulfonyloxy)phthalonitrile.
  • the present invention provides a phthalonitrile sulfonyl ester of formula (III) and a process for its preparation.
  • 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 organocooper 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 N A ⁇ reaction with a nucleophiles (Method E), or coupling with a suitable coupling partner catalysed by palladium (Method F).
  • organozincs are unreactive to a wide range of functional groups (P. Knochel, R.D. Singer, Chem. Rev., 1993, vol. 93, page 2117). This is important since it allows a range of functional groups to be inco ⁇ orated in the reaction, either on the organozinc reagent itself, or on the coupling partner.
  • Functional groups which can be tolerated include ketones, esters, amides, nitriles, acetals, alkenes and alkynes. Besides aryl and alkenyl halides, aryl and alkenyl triflates can also be used as coupling partners (K. Ritter, Synthesis, 1993, page 735; P. Knochel, J.J.A. Perea, P. Jones, Tetrahedron, 1998, vol. 54, page 8275; E. Erdik, Tetrahedron, 1992, vol. 48, page 9577).
  • 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.
  • the organozincs can be prepared by metathesis of a Grignard or organolithium reagent with anhydrous ZnBr 2 or ZnCl 2 in THF. This method was also applied for the generation of decylzinc chloride.
  • This route firstly the MgCl 2 by-product tends to clog the stirrer and makes transfer by cannula problematic and secondly the ZnCl 2 is very hygroscopic and therefore difficult to dry.
  • 1-octynylzinc chloride was successfully prepared by metathesis of 1-octynyllithium with ZnCl 2 at -78°C.
  • 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
  • aryl and heteroarylzinc halides are available by using one of the three methods above (P. Knochel, J.J.A. Perea, P. Jones, Tetrahedron, 1998, vol. 54, page 8275).
  • the direct zinc insertion into iododecane is preferred for the preparation of the simple alkylzinc reagent decylzinc iodide.
  • 1-octynylzinc chloride was best prepared by metathesis of 1-octynyllithium and ZnC ⁇ at -78°C.
  • a more exotic zinc reagent 6-chlorohexylzinc bromide [Cl(CH2) 6 ZnBr] was purchased from the Aldrich chemical company. This was prepared by insertion of Rieke zinc. Rieke zinc as a solution in THF can also be purchased from Aldrich.
  • the Pd(PPh 3 ) 4 catalysed cross-coupling of 3,6-(trifluoromethanesulfonyloxy)- phthalonitrile with decylzinc iodide is described as a representative example of cross- coupling reactions of method A.
  • 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 3 ) 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 «-BuLi (20 mol%) to afford a blood-red Ni(0) catalyst [Ni(PPh 3 ) ].
  • DIBAL or MeMgBr can be used instead of w-BuLi to generate the catalyst (CA. Quesnell, O.B. Familoni, V. Snieckus, Synlett, 1994, page 349).
  • To this catalyst was added 3,6-(trifluoromethanesulfonyloxy)phthalonitrile as a solid at room temperature under a stream of argon.
  • alkynylzinc chloride reagent prepared from an alkynyllithium 5 reagent with ZnCl 2 , led to the preparation of alkynyl-substituted phthalonitriles.
  • 3,6- bis(l'-octynyl)phthalonitrile was prepared by the cross-coupling of 1-octynylzinc chloride.
  • 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 3 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 have been used for the reaction, although some of the most successful such as NaOMe (A. Furstner, G. Seidel, J. Org.
  • 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 AT 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 AT 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 AT conditions could possibly be favoured by using Cs 2 CO 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 animation may be a viable route (A.J. Belfield, Tetrahedron, 1999, vol. 55, page 11399).
  • a non-metallated or metallated substituted phthalocyanine of formula (I) may be prepared from a substituted phthalonitrile of formula (IV) under suitable conditions.
  • 3,6- Bis(dodecylsulfanyl)phthalonitrile was successfully cyclised into both the metal-free and the zinc phthalocyanine 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 also 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.
  • octa-S-aryl phthalocyanines with the eight groups similarly located on the phthalocyanine core, have been prepared by displacement of eight chlorine groups on an octa-chloro phthalocyanine.
  • Such compounds were identified as near infra-red absorbing dyes useful for security printing (EP application no. 85301291.2).
  • 3,6-bis(substituted)phthalonitrile precursors can be similarly cyclotetramerised to give the corresponding metallated or unmetallated phthalocyanine.
  • 3,6-Bis(6'-imidazol-l-yl-hexyl)phthalonitrile provides access to the corresponding zinc octakis(6'-imidazol-l-yl-hexyl)phthalocyanine, a derivative soluble in aqueous acid.
  • 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.
  • [ 1 ,4-diphenyl-8, 11,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II) was prepared by cross cyclotetramerisation of 3,6-diphenylphthalonitrile and 3,6- didecylphthalonitrile and [l,4-bis(4-methoxyphenyl)-8,l 1,15,18,22,25- hexakis(decyl)phthalocyaninato] zinc(II) was prepared by cross cyclotetramerisation of 3 ,6-bis(4-methoxyphenyl)phthalonitrile and 3 ,6-didecylphthalonitrile.
  • l,4-bis(3-methoxyphenyl)phthalonitrile and 3,6-didecylphthalonitrile provide [ 1 ,4-bis(3-methoxyphenyl)-8, 11,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II).
  • the 3,6-didecylphthalonitrile may be used in excess.
  • Byproducts of the reaction include the symmetrically substituted [1,4,8,11,15,18,22,25- octakis(decyl)phthalocyaninato] zinc(II) and the 2:2 mixed substituted phthalocyanines in which the pairs of common substituted isoindole units are either opposite or adjacent.
  • This isomer mixture has been characterised in the case of the mixed cyclisation of 3,6- diphenylphthalonitrile and 3,6-didecylphthalonitrile.
  • 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 in the cases cited 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.
  • mixed phthalocyanines may also be synthesised with, for example, hydroxyalkyl or hydroxyalkoxy side chains on one phthalonitrile and hydrophobic substituents on the other phthalonitrile with the former in excess.
  • a metallated or non-metallated substituted phthalocyanine of formula (I) provides a metallated or non-metallated substituted phthalocyanine of formula (I) and a process for its preparation.
  • a metallated or non-metallated substituted phthalocyanine (V) may be prepared by the cyclisation of a substituted phthalonitrile (VI) or (VII) either by itself or together with any other pthalonitrile of formula (IV).
  • a substituted phthalonitrile of formula (VI) may in turn be prepared from 2,3- dicyanohydroquinone, as shown in Scheme 9.
  • 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.
  • the present invention provides a phthalonitrile halide of formula (VI) and a process for its preparation.
  • 4,5-dibromo-3,6-dibutoxyphthalonitrile and 4-bromo-3,6- dibutoxyphthalonitrile were independently cyclotetramerised, the former to give the octabromo-octabutoxy-phthalocyaninato nickel(II) complex and the latter to give the tetrabromo-octabutoxy-phthalocyaninato zinc complex (as a mixture of regioisomers).
  • Substituted phthalocyanines having one phthalonitrile-monomer different from the other three (1:3 mixed substituted phthalocyanines) may be synthesised, for example, by making use of solid-phase synthetic methods (ret. Letts., 1982, vol. 23(30), pages 3023- 3026; J. Org. Chem., 1991, vol. 56, pages 82-90).
  • solid-phase synthetic methods ret. 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).
  • route B has been followed using cross cyclotetramerisation to yield 1 :3 mixed substituted phthalocyanines.
  • the second fraction contains two components, which are separated on a second column, one of which is the required l,4-dibutoxy-2,3-dibromo-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II), identified by a cluster at 1714 D in the low resolution FAB-mass spectrum, elemental analysis and an ⁇ -NMR spectrum consistent with the expected structure.
  • the pure metal-free compound is isolated by column chromatography.
  • the metal-free compound is readily converted into 1,4- dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato zinc(II) by reaction with zinc acetate.
  • the latter is also obtained by reaction of 3,6-didecylphthalonitrile with 3,6-dibutoxy-4-bromophthalonitrile in DBU in the presence of zinc acetate.
  • Sonogashira coupling is first applied to l,4-dibutoxy-2-bromo-8,l 1,15, 18,22,25- hexakis(decyl)-phthalocyaninato nickel(II) using Et 3 N as solvent.
  • Et 3 N hexakis(decyl)-phthalocyaninato nickel(II)
  • the compound is reacted with trimethylsilylethyne (6 equivalents) at 80°C for 36 hours in the presence of Pd(PPh 3 ) 2 Cl 2 (20 mol%>) and Cul (30 mol%) with additional catalyst added after 24 hours, no cross coupling occurs.
  • Stille coupling procedure satisfactorily converts l,4-dibutoxy-2,3- dibromo-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II) directly into the unprotected ethynylated phthalocyanine in 54%> yield.
  • Stille coupling offers a significant improvement over the Sonogashira method in terms of overall yield.
  • there is less difficulty in separating the fully and partially coupled products which requires careful chromatography in the case of the Sonogashira procedure.
  • Sonogashira coupling using Pd(PPh 3 ) 2 Cl 2 /Cu(I)I as catalyst, or coupling using other catalysts for example Pd 2 (dba) 3 -AsPh 3 , can be undertaken to convert 1 ,4-dibutoxy-2- bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato zinc(II) into corresponding substituted ethynylated derivatives.
  • 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 NH 2 and CO 2 H 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).
  • phthalonitriles of formula (VII) can be cyclotetramerised alone to form further phthalocyanines.
  • 3,6-Dibutoxy-4,5-(tris(isopropyl)silylethynyl)phthalonitrile is converted into the corresponding [octabutoxy- octa(tris(isopropyl)silylethynyl)phthalocyaninato] nickel(II) complex.
  • Reaction of the latter with tetrabutylammonium fluoride removes the TIPS groups to afford the octabutoxy-octaethynyl phthalocyaninato nickel(II) complex.
  • the present invention provides a non-metallated or metallated substituted phthalocyanine of formula (V) and a process for its preparation.
  • phthalocyanines are investigated for liquid crystallinity as a routine element of their characterisation. Hitherto, the columnar mesophase properties of non-peripherally substituted phthalocyanines have been described, both uniformly substituted with either eight alkyl (A.S. Cherodian, A.N. Davies, R.M. Richardson, M.J. Cook, N.B. McKeown, A.J. Thomson, J. Feijoo, G. Ungar, K.J. Harrison, Mol. Cryst. Liq. Cryst., 1991, vol. 196, pages 103-114; M.J. Cook, S.J. Cracknell, K.J. Harrison, J. Mater. Chem., 1991, vol.
  • the first mesophase observed upon cooling gives rise to a "fan-like" birefringence texture characteristic of a discotic hexagonal disordered phase (D hd ) in accordance with the examples referred to above.
  • D hd discotic hexagonal disordered phase
  • l,4-Dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel (II) exhibits a second mesophase, but only during cooling. This phase is mobile and distorts under external pressure. It gives rise to an indistinct texture and has not been identified. It is here denoted as D x .
  • transition temperatures are measured by polarised light microscopy on the first heating and cooling cycle.
  • the higher temperature mesophase is assigned as Dhd-
  • the lower temperature mesophase D x is unknown.
  • the symmetry of the molecule has a marked effect upon the mesophase behaviour.
  • the nona-substituted phthalocyanines are of C s symmetry, whilst the deca-substituted phthalocyanines have C 2v symmetry.
  • the C s phthalocyanines exhibit lower K— »D hd transitions than the analogous C 2v phthalocyanines. This can be attributed to the more symmetrical phthalocyanines forming better packed crystals.
  • the C s phthalocyanines exhibit higher clearing points (K- ⁇ I or D hd ⁇ I) than their C 2v counte ⁇ arts.
  • the D hd mesophase of the C s phthalocyanines is much more mobile and less viscous than for the C v phthalocyanines.
  • the C s phthalocyanines also have a tendency towards supercooling, crystallisation occurring upon standing overnight at room temperature.
  • the C 2v phthalocyanines crystallise directly upon cooling.
  • the transition to the crystal is characterised by a colour change, not a change in texture, the "fans" becoming a lighter green. Replacement of the bromine atoms with unprotected ethynyl groups increases clearing transitions.
  • Substituted phthalocyanines show a multitude of desirable properties and are thus useful for a wide variety of applications.
  • Certain substituted 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. Moreover, in so far as they are fluorophores, they may be used as diagnostic agents for the identification of areas that are pathologically affected.
  • 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. Rosenthal, 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.
  • 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 the pathological condition; e) Possibility of being conjugated to macromolecular carriers, albeit maintaining the characteristics of photosensitization efficiency.
  • 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. Conversely 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.C.H. 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), C.E.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.
  • compositions comprising a substituted phthalocyanine of the 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, intravenous, 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) or (V) optionally conjugated to a carrier for use as a medicament, particularly for use in photodynamic therapy.
  • the present invention further provides a pharmaceutical composition comprising a phthalocyanine of formula (I) or (V) or a pharmaceutically acceptable salt thereof, particularly for use in photodynamic therapy.
  • the present invention further provides use of a substituted phthalocyanine of formula (I) or (V) for the manufacture of a phototherapeutic or photodiagnostic agent.
  • Some substituted phthalocyanines of the present invention in thin films for example Langmuir-Blodgett films and spin coated films, in the liquid crystalline state, or when dissolved or dispersed in a carrier material, are largely transparent in the visible region and are yet strong absorbers of ultraviolet or infra-red radiation, preferably of infrared radiation within the range of 750nm and 870nm and preferably exhibit abso ⁇ tion maxima within that range.
  • Such substituted phthalocyanines can be used in laser addressed applications, in which laser beams are used to scan across the surface of the material to leave a written impression thereon.
  • Gallium arsenide lasers provide laser light at a wavelength of about 850nm, and are most useful for the above applications. With increasing Al content (x ⁇ l), laser wavelength may be reduced down to about 750nm.
  • the high stability of the phthalocyanine ring system suggests further possible uses for the substituted phthalocyanines of the present invention, especially when complexed with central metal ions M, the variable oxidation states of which may give rise to materials with semiconductor, photoconductor or electrochromic properties. Such properties may be exploited in sensors, catalysts and displays.
  • substituted phthalocyanines of the present invention are derived from their stereochemistry and orientational ability, for example some have liquid crystal characteristics, and others may be of value in Langmuir-Blodgett films and spin coated films. Others may absorb electromagnetic radiation and be useful in solution for this pu ⁇ ose, for example in liquid crystals.
  • M is a large metal ion such as Pd or Pt, are as one-dimensional conductors, for example potentially or molecular wires.
  • 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.
  • the present invention provides a material comprising a substituted phthalocyanine of formula (I) or (V), wherein the optical or physical properties of the material may be altered by incident electromagnetic radiation.
  • Figure 1 shows a typical decay and fitted curve for [l,4-bis(3-methoxyphenyl)- 8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample AA35) in toluene/pyridine, excited at 355nm.
  • the residuals (xlO) are shown offset by 20 mV.
  • the ringing observed in the first 2-3 ⁇ s of the decay are due to sensitiser fluorescence.
  • Figure 2 shows a plot showing the linear relationship between singlet oxygen emission intensity and laser energy for samples of perinaphthenone and [l,4-bis(3- methoxyphenyl)-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample
  • Figure 3 shows a plot showing the relationship between the intensity of singlet oxygen signal (normalised for incident laser energy) and the fraction of light absorbed by [1 ,4-bis(3-methoxyphenyl)-8, 11,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample AA35) (1-10- A ).
  • Zinc dust 120 g was stirred in 2% HCl (300ml) for 2 minutes and the acid removed (decanter). The resulting dust was stirred sequentially with 2%> HCl (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 O 5 . Preparation of tt-decylzinc iodide (see B. H. Lipshutz in "Organometallics in Synthesis. A Manual.”, ed. M. Schlosser, John Wiley and Sons, 1994, Chichester):
  • 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.
  • the second fraction was re-chromatographed over silica gel [pretreated with dichloromethane :triethylamine (99:1)] again first eluting with dichloromethane and then dichloromethane :THF (95:5) collecting the first deep blue fraction, which was recrystallised from THF:acetone to give 1,4,8,11,15,18,22,25- octakis(hexylsulfanyl)phthalocyaninato chloroindium(III) (17mg, 3%) as a dark blue/black solid [mp 202-204°C Found: C, 60.66; H.7.11; N, 6.84.
  • the first fraction was unreacted starting material (3.4 mg).
  • the second fraction contained a mixture; subsequent green fractions containing minor amounts of material were discarded.
  • the second fraction was further purified by column chromatography over silica (eluent: petrol/CH 2 Cl 2 98.5:1.5 then 97:3) to afford l,4-dibutoxy-2,3-(2 '-trimethylsilylethynyl)-8,l 1,15, 18,22,25- hexakis(decyl)phthalocyaninato nickel (II) as second fraction (13.2 mg, 35 %>) after recrystallisation from THF-methanol [m.p.
  • tributyl(ethynyl)tin 60 mg, 190 ⁇ mol was added, and the reaction heated at 100°C for 16 hours. The reaction was cooled and the toluene removed under reduced pressure. The residue was triturated with acetone to remove excess tributyl(ethynyl)tin, and the residue was washed from the filter paper with THF.
  • 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 1,4,8,11, 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 first fraction contains [1,4,8,11,15,18,22,25- octakis(decyl)phthalocyaninato] zinc(II) (240mg, 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 tic on silica (eluent: petroleum ether (bp. 40-60°C)/dichloromethane 3:2).
  • the mixture was refluxed for 20 hours in the dark.
  • the solvent was removed under reduced pressure and the residue washed with methanol (3x50ml).
  • the crude product was separated by column chromatography over silica (eluent: petroleum ether (bp. 40-60°C): CH2CI2 4:1).
  • the first fraction contains symmetrical 1,4,8,11,15, 18,22,25-octakis(decyl)phthalocyaninato zinc(II) (300mg).
  • the eluent was changed to petroleum ether (bp. 40-60°C): CH2CI2 (1:1) and a second fraction collected. This fraction was further purified by preparation TLC silica plates (eluent: petroleum ether (bp.
  • the solution was degassed 3 times with Ar, then stirred in the dark in an oil bath at 80°C for 24 hours.
  • the reaction was cooled and again, under an Ar atmosphere, was added bis(triphenylphosphine)- palladium(II) chloride (3.84mg), copper(I) iodide (1.56mg) and 2-methyl-3-butyn-2-ol (15mg, lOeq).
  • the tube was resealed and heated at 80°C for a further 24 hours.
  • the reaction was monitored by TLC. After the starting material was consumed, the reaction was cooled, filtered and washed with diethyl ether until the washings were clear. The organics were combined and concentrated under reduced pressure.
  • 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, l.lmmol) 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 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).
  • 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)phthalocyanine.
  • 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 blue fraction contained [l,4-dibutoxy-2-(p- hydroxymethylphenyl)-8,ll, 15, 18,22, 25-hexakis(decyl)phthalocyaninato] zincfllj, 37 mg (0.022mmol, 90%).
  • the product was purified by column chromatography over silica (eluent: petroleum ether (bp. 40-60°C): dichloromethane 4:1) to remove [1,4,8,11, 15, 18,22,25-octakis(decyl)phthalocyaninato] zinc(II).
  • the eluent was changed to petroleum ether (bp. 40-60°C): dichloromethane 1 :1) and [1, 4-bis(3-methoxyphenyl)-8, 11,15,18,22, 25-hexakis(decyl)phthalocyaninato] zinc(II) was isolated as a green solid and recrystallised from THF/acetone [MALDI ms shows cluster at 1632.
  • 4,5-Dibromo-3,6-dibutoxyphthalonitrile (0.5g, l.l ⁇ mmol) was heated in dry butanol (6ml) under nitrogen.
  • DBU (0.18g, 1.2mmol) was added and reflux continued for 1 hour.
  • Nickel acetate tetrahydrate (0.09g, 0.3mmol) was added and reflux continued for 24 hours. The reaction was cooled and the solvent evaporated under reduced pressure.
  • 4,5-(tris(isopropyl)silylethynyl)-3,6- dibutoxyphthalonitrile (0.51g, 0.81mmol) was reacted with DBU (0.7g, 0.48mmol) and nickel acetate tetrahydrate (0.07g, 0.24mmol) in dry butanol (6ml) for 20 hours.
  • 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-
  • This cell line represents hype ⁇ roliferating cells and is thus a useful model for the rapid cell cycle occurring in psoriasis.
  • DOPC L- ⁇ -dioleoyl- phosphatidylcholine
  • Rotavapor is then connected to a water pump in order to generate reduced pressure and the solvent is evaporated at room temperature.
  • the flask is saturated with nitrogen and 4ml of nitrogen-saturated phosphate buffered saline (PBS) are added.
  • PBS nitrogen-saturated phosphate buffered saline
  • the lipid film containing the phthalocyanine is resuspended by gently shaking in the presence of glass beads.
  • the aqueous suspension is sonicated (10 Hz) for about 30 minutes.
  • the vial is saturated with nitrogen and kept in an ice bath.
  • the liposomes are kept at room temperature overnight.
  • the liposomes have a shelf-life at 4°C of at least three months.
  • they are filtered through a 0.2 ⁇ m filter and the phthalocyanine concentration is measured by diluting a small aliquot of the 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,
  • 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. After 1 hour incubation, the medium was removed, the cells were washed twice with 4ml of
  • PBS devoid of Ca and Mg ions.
  • the cell pellet was homogenised with 2% aqueous sodium dodecylsulphate (SDS) (2ml).
  • SDS sodium dodecylsulphate
  • the suspension thus obtained was divided into two portions: a) 1ml was diluted with a known volume of THF for the determination of the phthalocyanine concentration by spectrophotofluorimetric analysis (excitation at 650 nm, emission collected in the 660-780 nm interval)using a Perkin-Elmer LS50B spectrophotofluorimeter. b) 0.5ml was used for the determination of the protein content by the standard assay with bicinchoninic acid.
  • 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 2+ (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 .
  • 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
  • Fluorescence spectra were recorded using a Hitachi U-4500 Fluorescence 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 pathlength 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 of the 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 of the 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.
  • 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.

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Abstract

La présente invention concerne un procédé permettant la préparation de sulfonates-esters de phtalonitrile, un procédé de préparation de phtalonitriles substitués comprenant l'utilisation de ces sulfonates-esters de phtalonitrile, un procédé de préparation de pthalocyanines substituées comprenant l'utilisation de ces phtalonitriles substitués, un procédé de préparation d'halogénures de phtalonitrile, un procédé de préparation de phtalocyanines substituées comprenant l'utilisation de ces halogénures de phtalonitrile, de nouveaux esters-sulfonates de phtalonitrile, de nouveaux phtalonitriles substitués, de nouvelles pthalocyanines substituées et différentes utilisations de ces nouvelles pthalocyanines substituées.
PCT/GB2000/004708 1999-12-08 2000-12-08 Phtalocyanines substituees et leurs precurseurs WO2001042368A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CA002394891A CA2394891A1 (fr) 1999-12-08 2000-12-08 Phtalocyanines substituees et leurs precurseurs
PL00355851A PL355851A1 (en) 1999-12-08 2000-12-08 Substituted phthalocyanines and their precursors
HU0301099A HUP0301099A3 (en) 1999-12-08 2000-12-08 Substituted phthalocyanines and their precursors
EP00985506A EP1238016A1 (fr) 1999-12-08 2000-12-08 Phtalocyanines substituees et leurs precurseurs
AU21922/01A AU2192201A (en) 1999-12-08 2000-12-08 Substituted phthalocyanines and their precursors
EEP200200298A EE200200298A (et) 1999-12-08 2000-12-08 Asendatud ftalotsüaniinid ja nende lähteühendid, nende valmistamismeetod ja kasutamine, farmatseutiline kompositsioon ja materjal
JP2001543656A JP2003516421A (ja) 1999-12-08 2000-12-08 置換フタロシアニン及びその前駆体
NO20022663A NO20022663L (no) 1999-12-08 2002-06-05 Substituerte ftalocyaniner og deres forlöpere

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GB9929064.5 1999-12-08
GBGB9929064.5A GB9929064D0 (en) 1999-12-08 1999-12-08 Substituted phthalocyanines and their precursors
GB0012348A GB0012348D0 (en) 1999-12-08 2000-05-22 Substituted phthalocyanines and their precursors
GB0012348.9 2000-05-22
GBGB0025817.8A GB0025817D0 (en) 1999-12-08 2000-10-20 Substituted phthalocyanines and their precursors
GB0025817.8 2000-10-20

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CZ303612B6 (cs) * 2010-08-19 2013-01-09 Výzkumný ústav organických syntéz a.s. Sloucenina pro fotodynamickou inaktivaci soucasne grampozitivních bakterií, gramnegativních bakterií a patogenních kvasinek, na bázi derivátu ftalocyaninu, a pouzití této slouceniny
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Publication number Priority date Publication date Assignee Title
US7091373B2 (en) 2002-03-18 2006-08-15 Sumitomo Chemical Company, Limited Production method for biarylalanine
CN100415715C (zh) * 2003-02-11 2008-09-03 杜锡光 紫菜嗪环中具有六个异吲哚结构亚单元的超酞菁类化合物、合成方法及用途
WO2004101516A3 (fr) * 2003-05-14 2005-09-15 Univ Sherbrooke Porphyrazines amphiphiles trisulfonees utilisees dans des applications photodynamiques en medecine
US7541457B2 (en) 2003-05-14 2009-06-02 Universite De Sherbrooke Amphiphilic trisulfonated porphyrazines for photodynamic applications in medicine
AU2004238410B2 (en) * 2003-05-14 2010-07-29 Rsem, Societe En Commandite Amphiphilic trisulfonated porphyrazines for photodynamic applications in medicine
WO2004101516A2 (fr) * 2003-05-14 2004-11-25 UNIVERSITé DE SHERBROOKE Porphyrazines amphiphiles trisulfonees utilisees dans des applications photodynamiques en medecine
CZ303612B6 (cs) * 2010-08-19 2013-01-09 Výzkumný ústav organických syntéz a.s. Sloucenina pro fotodynamickou inaktivaci soucasne grampozitivních bakterií, gramnegativních bakterií a patogenních kvasinek, na bázi derivátu ftalocyaninu, a pouzití této slouceniny
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
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
CN104016995A (zh) * 2014-06-26 2014-09-03 常州大学 八取代全氟烷基钴酞菁化合物及其制备方法
CN108017650A (zh) * 2017-03-08 2018-05-11 先尼科化工（上海）有限公司 一种用于滤光片的酞菁化合物及其制备方法和应用方法
US11015061B2 (en) 2017-04-07 2021-05-25 Yamamoto Chemicals, Inc. Phthalocyanine-based compound and uses of same
US11174274B2 (en) * 2017-04-07 2021-11-16 Yamamoto Chemicals, Inc. Naphthalocyanine compound, method for producing same, and use thereof
CN112279856A (zh) * 2019-07-24 2021-01-29 南方科技大学 一种非外围取代的可溶性金属酞菁及其合成方法和应用、一种钙钛矿太阳能电池
CN112279856B (zh) * 2019-07-24 2021-09-17 南方科技大学 一种非外围取代的可溶性金属酞菁及其合成方法和应用、一种钙钛矿太阳能电池
CN112014383A (zh) * 2020-06-30 2020-12-01 杜旭忠 一种用于均相化学发光的光敏剂及其制备方法和应用
CN112014383B (zh) * 2020-06-30 2024-03-29 杜旭忠 一种用于均相化学发光的光敏剂及其制备方法和应用
CN112812299A (zh) * 2020-12-31 2021-05-18 四川大学 邻苯二甲腈与氨基酸环肽共聚树脂及其制备方法
CN112812299B (zh) * 2020-12-31 2022-03-29 四川大学 邻苯二甲腈与氨基酸环肽共聚树脂及其制备方法

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HUP0301099A3 (en) 2003-11-28
NO20022663D0 (no) 2002-06-05
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EP1238016A1 (fr) 2002-09-11
AU2192201A (en) 2001-06-18
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