WO2024115524A1 - Porphyrin and phosphonium-porphyrin based compounds for photodynamic therapy and diagnostics - Google Patents

Porphyrin and phosphonium-porphyrin based compounds for photodynamic therapy and diagnostics Download PDF

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Publication number
WO2024115524A1
WO2024115524A1 PCT/EP2023/083438 EP2023083438W WO2024115524A1 WO 2024115524 A1 WO2024115524 A1 WO 2024115524A1 EP 2023083438 W EP2023083438 W EP 2023083438W WO 2024115524 A1 WO2024115524 A1 WO 2024115524A1
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group
compound
alkyl
cancer
dcm
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PCT/EP2023/083438
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French (fr)
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Sebastian M. Marcuccio
Honsue Cho
Christopher D. DONNER
Sacha NOVAKOVIC
Ramesh AILURI
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Rmw Cho Group Limited
Venner Shipley Llp
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Priority claimed from GBGB2217862.8A external-priority patent/GB202217862D0/en
Priority claimed from GBGB2308148.2A external-priority patent/GB202308148D0/en
Application filed by Rmw Cho Group Limited, Venner Shipley Llp filed Critical Rmw Cho Group Limited
Publication of WO2024115524A1 publication Critical patent/WO2024115524A1/en

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    • 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
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent

Definitions

  • the present invention relates to chlorin e6 analogues and their pharmaceutically acceptable salts, and compositions comprising chlorin eP analogues and their pharmaceutically acceptable salts.
  • Chlorin e6 analogues and pharmaceutically acceptable salts thereof are suitable for use in photodynamic therapy, cytoluminescent therapy and photodynamic diagnosis, for example, for treating or detecting a tumour, or for antiviral treatment.
  • the present invention also relates to the use of chlorin e6 analogues and pharmaceutically acceptable salts thereof in the manufacture of a phototherapeutic or photodiagnostic agent, and to a method of photodynamic therapy, cytoluminescent therapy or photodynamic diagnosis, for example, for treating or detecting a tumour, or for antiviral treatment.
  • Porphyrins and their analogues are known photosensitive chemical compounds, which can absorb light photons and emit them at higher wavelengths. There are many applications for such unique properties and PDT (photodynamic therapy) is one of them.
  • PDT photodynamic therapy
  • the first generation comprises heme porphyrins (blood derivatives), and the second for the most part are chlorophyll analogues.
  • the later compounds are known as chlorins and bacteriochlorins.
  • Chlorin e4 has been shown to display good photosensitive activity. It was indicated that chlorin e4 has a protective effect against indomethacin-induced gastric lesions in rats and TAA- or CCI4 -induced acute liver injuries in mice. It was therefore suggested that chlorin e4 may be a promising new drug candidate for anti-gastrelcosis and liver injuiy protection.
  • WO 2009/040411 suggests the use of a chlorin e4 zinc complex in photodynamic therapy and WO 2014/091241 suggests the use of chlorin e4 disodium in photodynamic therapy.
  • a first aspect of the present invention provides a compound of formula (I) or a complex of formula (II): or a pharmaceutically acceptable salt thereof, wherein: -R 1 is selected from -CH 2 OR 2 , -CH 2 SR 2 , -CH 2 S(O)R 2 , -CH 2 S(O) 2 R 2 , -CH 2 N(R 2 ) 2 , -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 ) 2 (preferably -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(S)-OR 3 , -C(S)-SR 3 or -C(S)
  • a second aspect of the present invention provides a compound of formula (I) or a complex of formula (II) according to the first aspect of the invention, for use in medicine.
  • at least one of -R 1 , -R 7 and -R 9 comprises -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, -R ⁇ -[R 8 ]Y, -R ⁇ -[N(R 5 ) 2 (R 5’ )], -R ⁇ -[P(R 5 ) 2 (R 5’ )], -R ⁇ -[R 8’ ], or a saccharidyl group.
  • -R 9 is selected from -N(R 2 ) 2 , -SR 2 , -S(O)R 2 , -S(O) 2 R 2 , or -X.
  • a “hydrocarbyl” substituent group or a hydrocarbyl moiety in a substituent group only includes carbon and hydrogen atoms but, unless stated otherwise, does not include any heteroatoms, such as N, O, S, P or Se in its carbon skeleton.
  • a hydrocarbyl group/moiety may be saturated or unsaturated (including aromatic), and may be straight-chained or branched, or be or include cyclic groups wherein, unless stated otherwise, the cyclic group does not include any heteroatoms, such as N, O, S, P or Se in its carbon skeleton.
  • hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups/moieties and combinations of all of these groups/moieties.
  • hydrocarbyl group is a C 1 - C 60 hydrocarbyl group, more typically a C 1 -C 40 hydrocarbyl group, more typically a C 1 - C 20 hydrocarbyl group. More typically a hydrocarbyl group is a C 1 -C 12 hydrocarbyl group. More typically a hydrocarbyl group is a C 1 -C 10 hydrocarbyl group.
  • a “hydrocarbylene” group is similarly defined as a divalent hydrocarbyl group.
  • An “alkyl” substituent group or an alkyl moiety in a substituent group may be linear (i.e. straight-chained) or branched.
  • alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups/moieties.
  • alkyl does not include “cycloalkyl”.
  • an alkyl group is a C 1 -C 12 alkyl group. More typically an alkyl group is a C 1 -C 6 alkyl group.
  • An “alkylene” group is similarly defined as a divalent alkyl group.
  • an alkylene group is a C 1 -C 42 alkylene group.
  • an alkylene group is a C 1 -C 32 alkylene group, or a C 1 -C 22 alkylene group, or a C 1 -C 12 alkylene group.
  • An “alkenyl” substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds.
  • alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups/ moieties.
  • alkenyl does not include “cycloalkenyl”.
  • an alkenyl group is a C 2 -C 12 alkenyl group. More typically an alkenyl group is a C 2 -C 6 alkenyl group.
  • An “alkenylene” group is similarly defined as a divalent alkenyl group.
  • alkynyl substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds.
  • alkynyl groups/moieties include ethynyl, propargyl, but-1-ynyl and but-2- ynyl.
  • an alkynyl group is a C 2 -C 12 alkynyl group. More typically an alkynyl group is a C 2 -C 6 alkynyl group.
  • An “alkynylene” group is similarly defined as a divalent alkynyl group.
  • a “cyclic” substituent group or a cyclic moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated (including aromatic) and may include one or more heteroatoms, e.g. N, 0, S, P or Se in its carbon skeleton.
  • Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaiyl groups as discussed below.
  • a cyclic group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic.
  • a cyclic group is a 3- to 12-membered cyclic group, which means it contains from 3 to 12 ring atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms.
  • heterocyclic substituent group or a heterocyclic moiety in a substituent group refers to a cyclic group or moiety including one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, 0, S, P or Se in the ring structure.
  • heterocyclic groups include heteroaryl groups as discussed below and nonaromatic heterocyclic groups such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, thietanyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, thianyl and dioxanyl groups.
  • nonaromatic heterocyclic groups such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,
  • a “cycloalkyl” substituent group or a cycloalkyl moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • a “cycloalkenyl” substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon- carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex-1,3-dien-1-yl. Unless stated otherwise, a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • An “aryl” substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring.
  • aryl includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic.
  • aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl.
  • aryl does not include “heteroaryl”.
  • a “heteroaryl” substituent group or a heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety.
  • heteroaryl includes monocyclic aromatic heterocycles and polycyclic fused ring aromatic heterocycles wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic.
  • G O, S or NH.
  • arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule.
  • each hydrogen atom may optionally be replaced by a monovalent substituent independently selected from halo; -CN; -NO 2 ; -N 3 ; -R x ; -OH; -OR x ; -R y -halo; -R y -CN; -R y -NO 2 ; -R y -N 3 ; -R y -R x ; -R y -OH; -R y -OR x ; -SH; -SR x ; -SOR x ; -SO 2 H; -SO 2 R x ; -SO 2 NH 2 ; -SO2NHR x ; -SO2N(R x )2; -R y -SH;
  • a substituted group comprises 1, 2, 3 or 4 substituents, more typically 1, 2 or 3 substituents, more typically 1 or 2 substituents, and more typically 1 substituent.
  • any divalent bridging substituent e.g. -O-, -S-, -NH-, -N(R x )-, -N + (R x ) 2 - or -R y -
  • halo includes fluoro, chloro, bromo and iodo.
  • halo such as a haloalkyl or halomethyl group
  • the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo.
  • the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without the halo prefix.
  • a halomethyl group may contain one, two or three halo substituents.
  • a haloethyl or halophenyl group may contain one, two, three, four or five halo substituents.
  • halomethyl refers to a methyl group substituted with one, two or three fluoro groups.
  • halo-substituted it is to be understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo.
  • the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group said to be halo-substituted.
  • a halo- substituted methyl group may contain one, two or three halo substituents.
  • a halo- substituted ethyl or halo-substituted phenyl group may contain one, two, three, four or five halo substituents.
  • any reference to an element is to be considered a reference to all isotopes of that element.
  • any reference to hydrogen is considered to encompass all isotopes of hydrogen including deuterium and tritium.
  • any reference to a compound or group is to be considered a reference to all tautomers of that compound or group.
  • methoxy, dimethylamino and aminoethyl groups are considered to be hydrocarbyl groups including one or more heteroatoms N, O, S, P or Se in their carbon skeleton.
  • a C x -C y group is defined as a group containing from x to y carbon atoms.
  • a C 1 -C 4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms.
  • Optional substituents and moieties are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituents and/or containing the optional moieties.
  • replacement heteroatoms e.g. N, O, S, P or Se
  • replacement heteroatoms are to be counted as carbon atoms when calculating the number of carbon atoms in a C x -C y group.
  • a morpholinyl group is to be considered a C 6 heterocyclic group, not a C 4 heterocyclic group.
  • the ⁇ electrons of the chlorin ring are delocalised and therefore the chlorin ring can be depicted by more than one resonance structure. Resonance structures are different ways of drawing the same compound. Two of the resonance structures of the chlorin ring are depicted directly below:
  • a complex typically comprises a central metal atom or ion known as the coordination centre and a bound molecule or ion which is known as a ligand.
  • the bond between the coordination centre and the ligand is depicted as shown in the complex on the below left (where the attraction between an anionic ligand and a central metal cation is represented by four dashed lines), but equivalently it could be depicted as shown in the complex on the below right (where the attraction between a ligand molecule and a central metal atom is represented by two covalent bonds and two dashed lines):
  • -[NC 5 H 5 ]Y refers to:
  • X is a halo group selected from fluoro, chloro, bromo, or iodo.
  • X is chloro or bromo.
  • Y is a counter anion selected from halides (for example fluoride, chloride, bromide, or iodide) or other inorganic anions (for example bisulfate, hexafluorophosphate (PF6), nitrate, perchlorate, phosphate, or sulfate) or organic anions (for example acetate, ascorbate, aspartate, benzoate, besylate (benzenesulfonate), bicarbonate, bis(trifluoromethanesulfonyl)imide (TFSI), bitartrate, butyrate, camsylate (camphorsulfonate), carbonate, citrate, decanoate, edetate, esylate (ethanesulfonate), fumarate
  • halides for example fluoride, chloride, bromide, or iodide
  • inorganic anions for example bisulfate, he
  • Y is a counter anion selected from halides (for example fluoride, chloride, bromide, or iodide) or other inorganic anions (for example bisulfate, nitrate, perchlorate, phosphate, or sulfate) or organic anions (for example acetate, aspartate, benzoate, besylate (benzenesulfonate), butyrate, camsylate (camphorsulfonate), citrate, esylate (ethanesulfonate), fumarate, galactarate, gluconate, glutamate, glycolate, 2- hydroxyethanesulfonate, hydroxymaleate, lactate, malate, maleate, mandelate, mesylate (methanesulfonate), napsylate (naphthalene-2-sulfonate), ornithinate, pamoate, pantothenate, propano
  • halides for example fluoride, chloride
  • Y is fluoride, chloride, bromide or iodide. In one embodiment, Y is chloride or bromide.
  • Z is a counter cation selected from inorganic cations (for example lithium, sodium, potassium, magnesium, calcium or ammonium cation) or organic cations (for example amine cations (for example choline or meglumine cation) or amino acid cations (for example arginine cation).
  • M 2+ is a metal cation selected from Zn 2+ , Cu 2+ , Fe 2+ , Pd 2+ or Pt 2+ .
  • M 2+ is Zn 2+ .
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 ) 2 .
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 or -C(S)-N(R 3 ) 2 .
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 ) 2 .
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 ) 2
  • each -R 3 is C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 or -C(S)-N(R 3 ) 2 , and each -R 3 is C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 ) 2 , and each -R 3 is C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is -C(O)-OR 3 and -R 3 is C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ), wherein -R 2 or -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is C 1 -C 4 alkyl (preferably methyl).
  • -R ⁇ - is selected from a C 1 -C 12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe.
  • -R ⁇ - is a C 1 -C 12 alkylene group (preferably a C 1 -C 8 alkylene group, or a C 1 -C 6 alkylene group), a –(CH 2 CH 2 O) m –CH 2 CH 2 – group or a –(CH 2 CH 2 S) m –CH 2 CH 2 – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • An -R 3’ group refers to an -R 3 group attached to the same atom as another -R 3 group. -R 3 and -R 3’ may be the same or different. Preferably -R 3 and -R 3’ are different.
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or -C(S)-N(R 3 )(R 3’ ), wherein -R 2 or -R 3 is selected from -R ⁇ -R ⁇ or -R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -R ⁇ or -R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -R ⁇ or -R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R ⁇ - is a C 1 -C 12 alkylene group (preferably a C 1 -C 8 alkylene group, or a C 1 -C 6 alkylene group), a –(CH 2 CH 2 O) m – group or a –(CH 2 CH 2 S) m – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • the saccharidyl group may optionally be substituted, for example, with a protecting group such as acetyl or a natural amino acid such as valine.
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ), wherein -R 2 or -R 3 is selected from -R ⁇ -R ⁇ or -R ⁇ , and -R ⁇ is a C 1 -C 8 alkyl group optionally substituted with one or more (such as one
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -R ⁇ or -R ⁇ , and -R ⁇ is a C 1 -C 8 alkyl group optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) hydroxyl groups, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -R ⁇ or -R ⁇ , and -R ⁇ is a C 1 -C 8 alkyl group optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) hydroxyl groups, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R ⁇ - is an unsubstituted C 1 -C 6 alkylene group, or an unsubstituted C 1 -C 4 alkylene group, or an unsubstituted C 1 -C 2 alkylene group.
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ); wherein -R 2 or -R 3 is selected from -R ⁇ -H or -R ⁇ -OH; -R ⁇ - is selected from a C1-C12 alkylene group, wherein the alkylene group may optionally be substituted with one or more C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or halo groups, and wherein one or more carbon atoms in the backbone of the
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ); wherein -R 3 is selected from -R ⁇ -H or -R ⁇ -OH; -R ⁇ - is selected from a C 1 -C 12 alkylene group, wherein the alkylene group may optionally be substituted with one or more C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or halo groups, and wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by one or more heteroatoms O or S; and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is -C(O)-N(R 3 )(R 3’ ); wherein -R 3 is selected from -R ⁇ -H or -R ⁇ -OH; -R ⁇ - is selected from a C 1 -C 12 alkylene group, wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by one or more heteroatoms O or S; and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ); wherein -R 2 or -R 3 is -R ⁇ ; -R ⁇ is a C 1 -C 12 alkyl or C 2 -C 12 alkenyl group optionally substituted with one or more (such as one, two, three, four or five) substituents independently selected from halo, -CN, -NO 2 , -N 3 , -OH, -OR x , -SH, -SR x
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ); wherein -R 3 is -R ⁇ ; -R ⁇ is a C 1 -C 12 alkyl group optionally substituted with one or more (such as one, two, three, four or five) substituents independently selected from halo, -CN, -NO 2 , -N 3 , -OH, -OR x , -SH, -SR x , -SOR x , -SO 2 H, -SO 2 R x , -SO 2 NH 2 , -SO 2 NHR x , -SO 2 N(R x ) 2 , -NH 2 , -NHR x , -N(R x ) 2 ,
  • -R 1 is -C(O)-N(R 3 )(R 3’ ); wherein -R 3 is -R ⁇ ; -R ⁇ is a C 1 -C 8 alkyl group optionally substituted with one or more (such as one, two or three) substituents independently selected from halo, -CN, -NO 2 , -N 3 , -OH, -OR x , -SH, -SR x , -SOR x , -SO 2 H, -SO 2 R x , -SO 2 NH 2 , -SO 2 NHR x , -SO 2 N(R x ) 2 , -NH 2 , -NHR x , -N(R x ) 2 , -N + (R x ) 3 , -CHO, -COR x , -COOH, -COOR x , -OCOR x , or
  • -R 1 is selected from -CO-(NR zz -CHR z -CO) v -N(R zz ) 2 and -CO-(NR zz -CHR z -CO) v -OR zz ; wherein each -R z is independently selected from the side chains of natural amino acids; each -R zz is independently selected from hydrogen and C 1 -C 4 alkyl (preferably methyl); and v is 1, 2, 3, 4, 5, 6, 7 or 8.
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ); wherein -R 2 or -R 3 is -R ⁇ ; -R ⁇ is selected from a C 1 -C 20 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ); -R 3’ is H or C 1 -C 4 alkyl (preferably methyl); and -R 2 or -R 3 is selected from -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[R 8 ]Y.
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ );
  • -R 3’ is H or C 1 -C 4 alkyl (preferably methyl);
  • -R 2 or -R 3 is selected from -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[R 8 ]Y; each -R 5 is independently selected from C 1 -C 4 alkyl or phenyl wherein the phenyl is optionally substituted with one, two or three C 1 -C 4 alkyl or C 1 -C 4 alkoxy groups;
  • -R 8 is -[NC 5 H 5 ] optionally substituted with one, two or three C
  • -R 1 is selected from -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ); wherein -R 2 or -R 3 is -R ⁇ -[P(R 5 ) 3 ]Y; each -R 5 is independently selected from phenyl or C 5 -C 6 heteroaryl, wherein the phenyl or C 5 -C 6 heteroaryl may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C 1 -C 4 alky
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ); wherein -R 3 is -R ⁇ -[P(R 5 ) 3 ]Y; each -R 5 is independently selected from phenyl or C 5 -C 6 heteroaryl, wherein the phenyl or C 5 -C 6 heteroaryl may optionally be substituted with one or more C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O(C 1 -C 4 alkyl), -O(C 1 -C 4 haloalkyl), halo, -O-(CH 2 CH 2 O) n -H or -O-(CH 2 CH 2 O) n -CH 3 groups; n is 1, 2, 3 or 4; Y is
  • -R 1 is -C(O)-N(R 3 )(R 3’ ); wherein -R 3 is -R ⁇ -[P(R 5 ) 3 ]Y; each -R 5 is independently selected from phenyl or C 5 -C 6 heteroaryl, wherein the phenyl or C 5 -C 6 heteroaryl may optionally be substituted with one or more C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O(C 1 -C 4 alkyl), -O(C 1 -C 4 haloalkyl), halo, -O-(CH 2 CH 2 O) n -H or -O-(CH 2 CH 2 O) n -CH 3 groups; n is 1, 2, 3 or 4; Y is fluoride, chloride, bromide or iodide; and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R ⁇ - is a C 1 -C 12 alkylene group (preferably a C 1 -C 8 alkylene group, or a C 1 -C 6 alkylene group), a –(CH 2 CH 2 O) m –CH 2 CH 2 – group or a –(CH 2 CH 2 S) m –CH 2 CH 2 – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • -R 1 is -C(O)-OR 3 , wherein -R 3 is selected from hydrogen, C 1 -C 4 alkyl (preferably methyl) or a cation (such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation).
  • a cation such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation.
  • -R 1 is -C(O)-OR 3 , wherein -R 3 is selected from C 1 -C 4 alkyl (preferably methyl) or a cation (such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation).
  • -R 1 is -C(O)-N(R 3 ) 2 .
  • -R 1 is -C(O)-N(C 1 -C 4 alkyl)(R 3 ) or -C(O)-NHR 3 .
  • -R 1 is -C(O)-N(CH 3 )(R 3 ) or -C(O)-NHR 3 . In one embodiment, -R 1 is -C(O)-N(C 1 -C 4 alkyl)(R 3 ). In one embodiment, -R 1 is -C(O)-N(CH 3 )(R 3 ). In one embodiment of the first or second aspect of the present invention, -R 1 is selected from -CH 2 OR 2 , -CH 2 SR 2 , -CH 2 S(O)R 2 , -CH 2 S(O) 2 R 2 , -CH 2 N(R 2 ) 2 , or -R 2 .
  • -R 1 is selected from -CH 2 OR 2 , -CH 2 SR 2 , -CH 2 N(R 2 ) 2 , or -R 2 . In one embodiment, -R 1 is selected from -CH 2 OR 2 , -CH 2 SR 2 , or -CH 2 N(R 2 )2. In one embodiment, -R 1 is selected from -CH 2 OR 2 or -CH 2 SR 2 . In one embodiment, -R 1 is -CH 2 OR 2 . In one embodiment, -R 1 is -R 2 , and -R 2 is -R ⁇ -X.
  • -R 2 is selected from -R ⁇ -H, -R ⁇ , -R ⁇ -R ⁇ , -R ⁇ -OH, -R ⁇ -OR ⁇ , -R ⁇ -SH, -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ , -R ⁇ -S(O) 2 R ⁇ , -R ⁇ -NH 2 , -R ⁇ -NH(R ⁇ ), -R ⁇ -N(R ⁇ ) 2 , -R ⁇ -X, -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[NC 5 H 5 ]Y.
  • -R 2 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ .
  • -R 2 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • -R 2 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ .
  • -R 2 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group.
  • -R 2 is selected from -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-N(R 4 ) 2 , -C(S)-OR 4 , -C(S)-SR 4 or -C(S)-N(R 4 ) 2 .
  • -R 2 is selected from -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-N(R 4 ) 2 or -C(S)-N(R 4 ) 2 . In one embodiment, -R 2 is selected from -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 or -C(O)-N(R 4 ) 2 .
  • -R 2 is -C(O)-N(R 4 )(R 4’ ), wherein -R 4 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 4’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 2 is -C(O)-N(R 4 )(R 4’ ), wherein -R 4 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group, and -R 4’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 2 is -C(O)-N(R 4 )(R 4’ ), wherein -R 4 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 4’ is C 1 -C 4 alkyl (preferably methyl).
  • -R 2 is -C(O)-N(R 4 )(R 4’ ), wherein -R 4 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group, and -R 4’ is C 1 -C 4 alkyl (preferably methyl).
  • An -R 4’ group refers to an -R 4 group attached to the same atom as another -R 4 group.
  • -R 4 and -R 4’ may be the same or different.
  • Preferably -R 4 and -R 4’ are different.
  • -R 2 is -C(O)-N(R 4 ) 2 . In one embodiment, -R 2 is -C(O)-N(C 1 -C 4 alkyl)(R 4 ). In one embodiment, -R 2 is -C(O)-N(CH 3 )(R 4 ).
  • -R 6 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 ) 2 , and each -R 3 is C 1 -C 4 alkyl, preferably each -R 3 is methyl.
  • -R 6 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 ) 2 , and each -R 3 is C 1 -C 4 alkyl, preferably each -R 3 is methyl. In one embodiment, -R 6 is -C(O)-OR 3 , and -R 3 is C 1 -C 4 alkyl, preferably -R 3 is methyl.
  • -R 6 is -C(O)-OR 3 , wherein -R 3 is selected from hydrogen, C 1 -C 4 alkyl (preferably methyl) or a cation (such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation).
  • a cation such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation.
  • -R 6 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ); wherein -R 3 is -R ⁇ ; -R ⁇ is selected from a C 1 -C 20 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; and -R 3’
  • -R 6 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 ) 2
  • each -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • -R 6 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 ) 2
  • each -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • -R 6 is selected from -C(O)-OR 3 or -C(O)-SR 3
  • -R 3 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇
  • -R ⁇ is a saccharidyl group.
  • -R ⁇ - is selected from a C 1 -C 12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe.
  • -R ⁇ - is a C 1 -C 12 alkylene group (preferably a C 1 -C 8 alkylene group, or a C 1 -C 6 alkylene group), a –(CH 2 CH 2 O) m –CH 2 CH 2 – group or a –(CH 2 CH 2 S) m –CH 2 CH 2 – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • -R 6 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 6 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 6 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R ⁇ - is selected from a C 1 -C 12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe.
  • -R ⁇ - is a C 1 -C 12 alkylene group (preferably a C 1 -C 8 alkylene group, or a C 1 -C 6 alkylene group), a –(CH 2 CH 2 O) m –CH 2 CH 2 – group or a –(CH 2 CH 2 S) m –CH 2 CH 2 – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • An -R 3’ group refers to an -R 3 group attached to the same atom as another -R 3 group. -R 3 and -R 3’ may be the same or different. Preferably -R 3 and -R 3’ are different.
  • -R 6 is -C(O)-N(R 3 ) 2 . In one embodiment, -R 6 is -C(O)-N(C 1 -C 4 alkyl)(R 3 ) or -C(O)-NHR 3 . In one embodiment, -R 6 is -C(O)-N(CH3)(R 3 ) or -C(O)-NHR 3 .
  • -R 7 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 ) 2 , and each -R 3 is C 1 -C 4 alkyl, preferably each -R 3 is methyl.
  • -R 7 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 ) 2 , and each -R 3 is C 1 -C 4 alkyl, preferably each -R 3 is methyl. In one embodiment, -R 7 is -C(O)-OR 3 , and -R 3 is C 1 -C 4 alkyl, preferably -R 3 is methyl.
  • -R 7 is -C(O)-OR 3 , wherein -R 3 is selected from hydrogen, C 1 -C 4 alkyl (preferably methyl) or a cation (such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation).
  • a cation such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation.
  • -R 7 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 ) 2 or -C(S)-N(R 3 )(R 3’ ); wherein -R 3 is -R ⁇ ; -R ⁇ is selected from a C 1 -C 20 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; and -R 3’
  • -R 7 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 ) 2 , -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 ) 2
  • each -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • -R 7 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 ) 2
  • each -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • -R 7 is selected from -C(O)-OR 3 or -C(O)-SR 3
  • -R 3 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇
  • -R ⁇ is a saccharidyl group.
  • -R ⁇ - is selected from a C 1 -C 12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe.
  • -R ⁇ - is a C 1 -C 12 alkylene group (preferably a C 1 -C 8 alkylene group, or a C 1 -C 6 alkylene group), a –(CH 2 CH 2 O)m–CH 2 CH 2 – group or a –(CH 2 CH 2 S)m–CH 2 CH 2 – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • -R 7 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 7 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R 7 is selected from -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), wherein -R 3 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group, and -R 3’ is H or C 1 -C 4 alkyl (preferably methyl).
  • -R ⁇ - is selected from a C 1 -C 12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe.
  • -R ⁇ - is a C 1 -C 12 alkylene group (preferably a C 1 -C 8 alkylene group, or a C 1 -C 6 alkylene group), a –(CH 2 CH 2 O) m –CH 2 CH 2 – group or a –(CH 2 CH 2 S) m –CH 2 CH 2 – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • An -R 3’ group refers to an -R 3 group attached to the same atom as another -R 3 group. -R 3 and -R 3’ may be the same or different. Preferably -R 3 and -R 3’ are different.
  • -R 7 is -C(O)-N(R 3 ) 2 . In one embodiment, -R 7 is -C(O)-N(C 1 -C 4 alkyl)(R 3 ) or -C(O)-NHR 3 . In one embodiment, -R 7 is -C(O)-N(CH 3 )(R 3 ) or -C(O)-NHR 3 . In one embodiment of the first or second aspect of the present invention, -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2 .
  • -R 9 is selected from -OR 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2 . In one embodiment, -R 9 is selected from -OR 2 or -SR 2 . In one embodiment, -R 9 is -OR 2 .
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2
  • -R 2 is selected from -H, -C(O)R 4 , -R ⁇ -H, -R ⁇ , -R ⁇ -R ⁇ , -R ⁇ -OH, -R ⁇ -OR ⁇ , -R ⁇ -SH, -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ , -R ⁇ -S(O) 2 R ⁇ , -R ⁇ -NH 2 , -R ⁇ -NH(R ⁇ ), -R ⁇ -N(R ⁇ ) 2 , -R ⁇ -X, -R ⁇ -[N(R 5 ) 3
  • -R 9 is selected from -OR 2 , -SR 2 , -S(O)R 2 or -S(O)2R 2
  • -R 2 is selected from -H, -C(O)R 4 , -R ⁇ -H, -R ⁇ , -R ⁇ -R ⁇ , -R ⁇ -OH, -R ⁇ -OR ⁇ , -R ⁇ -SH, -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ , -R ⁇ -S(O) 2 R ⁇ , -R ⁇ -NH 2 , -R ⁇ -NH(R ⁇ ), -R ⁇ -N(R ⁇ ) 2 , -R ⁇ -X, -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]
  • -R 9 is selected from -OR 2 or -SR 2
  • -R 2 is selected from -H, -C(O)R 4 , -R ⁇ -H, -R ⁇ , -R ⁇ -R ⁇ , -R ⁇ -OH, -R ⁇ -OR ⁇ , -R ⁇ -SH, -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ , -R ⁇ -S(O) 2 R ⁇ , -R ⁇ -NH 2 , -R ⁇ -NH(R ⁇ ), -R ⁇ -N(R ⁇ ) 2 , -R ⁇ -X, -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[NC 5 H 5 ]Y.
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ;
  • -R 2’ is selected from hydrogen or C 1 -C 4 alkyl (preferably hydrogen or methyl);
  • -R 2 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ ; and optionally -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2
  • -R 2 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • optionally -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2
  • -R 2 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇
  • optionally -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 or -SR 2
  • -R 2 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • optionally -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 or -SR 2
  • -R 2 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇
  • optionally -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ; -R 2’ is selected from hydrogen or C 1 -C 4 alkyl (preferably hydrogen or methyl); and -R 2 is -C(O)R 4 .
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ;
  • -R 2’ is selected from hydrogen or C 1 -C 4 alkyl (preferably hydrogen or methyl);
  • -R 2 is -C(O)R 4 ;
  • -R 4 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ ; and
  • -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ;
  • -R 2’ is selected from hydrogen or C 1 -C 4 alkyl (preferably hydrogen or methyl);
  • -R 2 is -C(O)R 4 ;
  • -R 4 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ ; and -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2 , and -R 2 is -C(O)R 4 .
  • -R 9 is selected from -OR 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2
  • -R 2 is -C(O)R 4
  • -R 4 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2 , and -R 2 is -C(O)R 4 , and -R 4 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 or -SR 2
  • -R 2 is -C(O)R 4 .
  • -R 9 is selected from -OR 2 or -SR 2
  • -R 2 is -C(O)R 4
  • -R 4 is selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 or -SR 2
  • -R 2 is -C(O)R 4
  • -R 4 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇
  • -R ⁇ is a saccharidyl group.
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ;
  • -R 2’ is selected from hydrogen or C 1 -C 4 alkyl (preferably hydrogen or methyl);
  • -R 2 is selected from -R ⁇ , -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ ;
  • -R ⁇ is a saccharidyl group; and
  • -R ⁇ - is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S,
  • -R 9 is selected from -OR 2 , -N(R 2 )(R 2’ ) or -SR 2 ; -R 2’ is selected from hydrogen or C 1 -C 4 alkyl (preferably hydrogen or methyl); -R 2 is selected from -R ⁇ , -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ ; -R ⁇ is a saccharidyl group; and -R ⁇ - is selected from a C 1 -C 12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe.
  • the saccharidyl group may optionally be substituted, for example, with a protecting group such as acetyl or a natural amino acid such as valine.
  • Amino acids can be attached to saccharidyl groups, for example, by forming an ester between a carboxylic acid group of the amino acid and a hydroxyl group of the saccharidyl group.
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ;
  • -R 2’ is selected from hydrogen, C 1 -C 4 alkyl or -CO 2 (C 1 -C 4 alkyl);
  • -R 2 is selected from -C(O)R 4 , -C(O)-OR 4 , -C(O)-N(R 4 )(R 4’ ), -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[R 8 ]Y;
  • -R 4’ is selected from hydrogen or C 1 -C 4 alkyl; and
  • -R 4 is selected from -R ⁇ -[N(R 5 )
  • -R 9 is selected from -OR 2 , -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ;
  • -R 2’ is selected from hydrogen, C 1 -C 4 alkyl or -CO 2 (C 1 -C 4 alkyl);
  • -R 2 is selected from -C(O)R 4 , -C(O)-OR 4 , -C(O)-N(R 4 )(R 4’ ), -R ⁇ -[N(R 5 )3]Y, -R ⁇ -[P(R 5 )3]Y, or -R ⁇ -[R 8 ]Y;
  • -R 4’ is selected from hydrogen or C 1 -C 4 alkyl;
  • -R 4 is selected from -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 )
  • -R 9 is selected from -OR 2 or -N(R 2 )(R 2’ ); -R 2’ is selected from hydrogen, C 1 -C 4 alkyl or -CO 2 (C 1 -C 4 alkyl); -R 2 is selected from -C(O)R 4 , -C(O)-OR 4 , -C(O)-N(R 4 )(R 4’ ), -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[R 8 ]Y; -R 4’ is selected from hydrogen or C 1 -C 4 alkyl; -R 4 is selected from -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[R 8 ]Y; each -R 5 is independently selected from C 1 -
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ; and -R 2 is selected from hydrogen, C 1 -C 4 alkyl, -CO(C 1 -C 4 alkyl) or -CO 2 (C 1 -C 4 alkyl).
  • -R 9 is selected from -OR 2 or -N(R 2 ) 2 ; and -R 2 is selected from hydrogen, C 1 -C 4 alkyl, -CO(C 1 -C 4 alkyl) or -CO 2 (C 1 -C 4 alkyl).
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O) 2 R 2 ;
  • -R 2’ is selected from hydrogen or C 1 -C 4 alkyl;
  • -R 2 is selected from -R 4 , -C(O)R 4 , -C(O)-OR 4 or -C(O)-N(R 4 )(R 4’ );
  • -R 4’ is selected from hydrogen or C 1 -C 4 alkyl; and -R 4 is selected from a C 1 -C 12 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three or four carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected
  • -R 9 is selected from -OR 2 or -N(R 2 )(R 2’ ); -R 2’ is selected from hydrogen or C 1 -C 4 alkyl; -R 2 is selected from -R 4 , -C(O)R 4 , -C(O)-OR 4 or -C(O)-N(R 4 )(R 4’ ); -R 4’ is selected from hydrogen or C 1 -C 4 alkyl; and -R 4 is selected from a C1-C12 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three or four carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe.
  • each -R ⁇ - is independently a C 1 -C 12 alkylene group, a –(CH 2 CH 2 O) m – group, a –(CH 2 CH 2 S) m – group, a –(CH 2 CH 2 O) m –CH 2 CH 2 – group or a –(CH 2 CH 2 S) m –CH 2 CH 2 – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • each -R ⁇ - is independently a C 1 -C 12 alkylene group, a –(CH 2 CH 2 O) m – group or a –(CH 2 CH 2 S) m – group, all optionally substituted, wherein m is 1, 2, 3 or 4.
  • each -R ⁇ - is independently a C 1 -C 12 alkylene group or a –(CH 2 CH 2 O) m – group, both optionally substituted, wherein m is 1, 2, 3 or 4.
  • each -R ⁇ - is independently an optionally substituted –(CH 2 CH 2 O)m– group, wherein m is 1, 2, 3 or 4.
  • each -R ⁇ - is independently a C 1 -C 8 alkylene group, or a C 1 -C 6 alkylene group, or a C 2 -C 4 alkylene group, all optionally substituted. In one embodiment of the first or second aspect of the present invention, each -R ⁇ - is independently unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl.
  • each -R ⁇ - is independently unsubstituted or substituted with one or two substituents independently selected from halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In one embodiment, each -R ⁇ - is unsubstituted. In one embodiment of the first or second aspect of the present invention, each -R ⁇ is independently a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • At least one -R ⁇ is independently a C 1 -C 6 alkyl group, or a C 1 -C 4 alkyl group, or a methyl group, all optionally substituted. In one embodiment, each -R ⁇ is independently a C1-C6 alkyl group, or a C 1 -C 4 alkyl group, or a methyl group, all optionally substituted. In one embodiment of the first or second aspect of the present invention, at least one -R ⁇ is independently a saccharidyl group. In one embodiment, each -R ⁇ is independently a saccharidyl group.
  • each -R ⁇ is independently unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In one embodiment, each -R ⁇ is independently unsubstituted or substituted with one or two substituents independently selected from halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In one embodiment, each -R ⁇ is unsubstituted.
  • each -R 3 is independently selected from -R ⁇ -H, -R ⁇ , -R ⁇ -R ⁇ , -R ⁇ -OH, -R ⁇ -OR ⁇ , -R ⁇ -SH, -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ , -R ⁇ -S(O) 2 R ⁇ , -R ⁇ -NH 2 , -R ⁇ -NH(R ⁇ ), -R ⁇ -N(R ⁇ ) 2 , -R ⁇ -X, -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[NC 5 H 5 ]Y.
  • each -R 3 is independently selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ .
  • each -R 3 is independently selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • each -R 3 is independently selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ .
  • each -R 3 is independently selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇
  • -R ⁇ is a saccharidyl group.
  • each -R 4 is independently selected from -R ⁇ -H, -R ⁇ , -R ⁇ -R ⁇ , -R ⁇ -OH, -R ⁇ -OR ⁇ , -R ⁇ -SH, -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ , -R ⁇ -S(O) 2 R ⁇ , -R ⁇ -NH 2 , -R ⁇ -NH(R ⁇ ), -R ⁇ -N(R ⁇ ) 2 , -R ⁇ -X, -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -
  • each -R 4 is independently selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ .
  • each -R 4 is independently selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇
  • -R ⁇ is a saccharidyl group.
  • each -R 4 is independently selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ .
  • each -R 4 is independently selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇
  • -R ⁇ is a saccharidyl group.
  • at least one of -R 2 , -R 3 or -R 4 is independently selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O)2R ⁇
  • -R ⁇ is a saccharidyl group.
  • At least one of -R 2 , -R 3 or -R 4 is independently selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ , and -R ⁇ is a saccharidyl group.
  • a “saccharidyl group” is any group comprising at least one monosaccharide subunit, wherein each monosaccharide subunit may optionally be substituted and/or modified.
  • a saccharidyl group consist of one or more monosaccharide subunits, wherein each monosaccharide subunit may optionally be substituted and/or modified.
  • a carbon atom of a single monosaccharide subunit of each saccharidyl group is directly attached to the remainder of the compound, most typically via a single bond.
  • a first atom or group is “directly attached” to a second atom or group it is to be understood that the first atom or group is covalently bonded to the second atom or group with no intervening atom(s) or group(s) being present.
  • each saccharidyl group is derived from the corresponding saccharide by substitution of a hydroxyl group of the saccharide with the group defined by the remainder of the compound.
  • a single bond between an anomeric carbon of a monosaccharide subunit and a substituent is called a glycosidic bond.
  • a glycosidic group is linked to the anomeric carbon of a monosaccharide subunit by a glycosidic bond.
  • the bond between the saccharidyl group and the remainder of the compound may be a glycosidic or a non- glycosidic bond.
  • the bond between the saccharidyl group and the remainder of the compound is a glycosidic bond, such that the saccharidyl group is a glycosyl group.
  • the glycosidic bond may be in the ⁇ or ⁇ configuration. Typically, such a glycosidic bond is in the ⁇ configuration.
  • a saccharidyl group “contains x monosaccharide subunits”, this means that the saccharidyl group has x monosaccharide subunits and no more.
  • a saccharidyl group “comprises x monosaccharide subunits” this means that the saccharidyl group has x or more monosaccharide subunits.
  • Each saccharidyl group may be independently selected from a monosaccharidyl, disaccharidyl, oligosaccharidyl or polysaccharidyl group. As will be understood, a monosaccharidyl group contains a single monosaccharide subunit.
  • a disaccharidyl group contains two monosaccharide subunits.
  • an “oligosaccharidyl group” contains from 2 to 9 monosaccharide subunits. Examples of oligosaccharidyl groups include trisaccharidyl, tetrasaccharidyl, pentasaccharidyl, hexasaccharidyl, heptasaccharidyl, octasaccharidyl and nonasaccharidyl groups.
  • a “polysaccharidyl group” contains 10 or more monosaccharide subunits (such as 10-50, or 10-30, or 10-20, or 10-15 monosaccharide subunits). Each monosaccharide subunit within a disaccharidyl, oligosaccharidyl or polysaccharidyl group may be the same or different. Each monosaccharide subunit within a disaccharidyl, oligosaccharidyl or polysaccharidyl group may be connected to another monosaccharide subunit within the group via a glycosidic or a non-glycosidic bond.
  • each monosaccharide subunit within a disaccharidyl, oligosaccharidyl or polysaccharidyl group is connected to another monosaccharide subunit within the group via a glycosidic bond, which may be in the ⁇ or ⁇ configuration.
  • Each oligosaccharidyl or polysaccharidyl group may be a linear, branched or macrocyclic oligosaccharidyl or polysaccharidyl group.
  • each oligosaccharidyl or polysaccharidyl group is a linear or branched oligosaccharidyl or polysaccharidyl group.
  • At least one -R ⁇ is a monosaccharidyl or disaccharidyl group. In a further embodiment, at least one -R ⁇ is a monosaccharidyl group.
  • at least one -R ⁇ may be a glycosyl group containing a single monosaccharide subunit, wherein the monosaccharide subunit may optionally be substituted and/or modified.
  • at least one -R ⁇ is a glycosyl group containing a single monosaccharide subunit, wherein the monosaccharide subunit may optionally be substituted.
  • At least one -R ⁇ is a glycosyl group containing a single monosaccharide subunit, wherein the monosaccharide subunit is unsubstituted.
  • at least one -R ⁇ is an aldosyl group, wherein the aldosyl group may optionally be substituted and/or modified.
  • At least one -R ⁇ may be selected from a glycerosyl, aldotetrosyl (such as erythrosyl or threosyl), aldopentosyl (such as ribosyl, arabinosyl, xylosyl or lyxosyl) or aldohexosyl (such as allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl or talosyl) group, any of which may optionally be substituted and/or modified.
  • aldotetrosyl such as erythrosyl or threosyl
  • aldopentosyl such as ribosyl, arabinosyl, xylosyl or lyxosyl
  • aldohexosyl such as allosyl, altrosyl, glucosyl,
  • At least one -R ⁇ is a ketosyl group, wherein the ketosyl group may optionally be substituted and/or modified.
  • at least one -R ⁇ may be selected from an erythrulosyl, ketopentosyl (such as ribulosyl or xylulosyl) or ketohexosyl (such as psicosyl, fructosyl, sorbosyl or tagatosyl) group, any of which may optionally be substituted and/or modified.
  • ketopentosyl such as ribulosyl or xylulosyl
  • ketohexosyl such as psicosyl, fructosyl, sorbosyl or tagatosyl
  • Each monosaccharide subunit may be present in a ring-closed (cyclic) or open-chain (acyclic) form.
  • each monosaccharide subunit in at least one -R ⁇ is present in a ring-closed (cyclic) form.
  • at least one -R ⁇ may be a glycosyl group containing a single ring-closed monosaccharide subunit, wherein the monosaccharide subunit may optionally be substituted and/or modified.
  • at least one -R ⁇ is a pyranosyl or furanosyl group, such as an aldopyranosyl, aldofuranosyl, ketopyranosyl or ketofuranosyl group, any of which may optionally be substituted and/or modified.
  • At least one -R ⁇ is a pyranosyl group, such as an aldopyranosyl or ketopyranosyl group, any of which may optionally be substituted and/or modified.
  • at least one -R ⁇ is selected from a ribopyranosyl, arabinopyranosyl, xylopyranosyl, lyxopyranosyl, allopyranosyl, altropyranosyl, glucopyranosyl, mannopyranosyl, gulopyranosyl, idopyranosyl, galactopyranosyl or talopyranosyl group, any of which may optionally be substituted and/or modified.
  • At least one -R ⁇ is a glucosyl group, such as a glucopyranosyl group, wherein the glucosyl or the glucopyranosyl group may optionally be substituted and/or modified.
  • at least one -R ⁇ is a glucosyl group, wherein the glucosyl group is optionally substituted.
  • at least one -R ⁇ is an unsubstituted glucosyl group.
  • Each monosaccharide subunit may be present in the D- or L-configuration. Typically, each monosaccharide subunit is present in the configuration in which it most commonly occurs in nature.
  • At least one -R ⁇ is a D-glucosyl group, such as a D-glucopyranosyl group, wherein the D-glucosyl or the D-glucopyranosyl group may optionally be substituted and/or modified.
  • at least one -R ⁇ is a D-glucosyl group, wherein the D-glucosyl group is optionally substituted. More typically, at least one -R ⁇ is an unsubstituted D-glucosyl group.
  • a substituted monosaccharidyl group or monosaccharide subunit (a) one or more of the hydroxyl groups of the monosaccharidyl group or monosaccharide subunit are each independently replaced with -H, -F, -CF 3 , -SH, -NH 2 , -N 3 , -CN, -NO 2 , -COOH, -R b , -O-R b , -S-R b , -N(R b ) 2 , -OPO(R b ) 2 , -OSi(R b ) 3 , -O-CO-R b , -O-CO-OR b , -O-CO-N(R b ) 2 , -NR b -CO-R b , -NR b -CO-OR b , or -NR b -CO-N(R b ) 2 ; and
  • -R ⁇ is a saccharidyl group and one or more of the hydroxyl groups of the saccharidyl group are each independently replaced with -O-CO-R b , wherein each -R b is independently C 1 -C 4 alkyl, preferably methyl.
  • -R ⁇ is a saccharidyl group and all of the hydroxyl groups of the saccharidyl group are each independently replaced with -O-CO-R b , wherein each -R b is independently C 1 -C 4 alkyl, preferably methyl.
  • a modified monosaccharidyl group or monosaccharide subunit (a) the ring of the modified monosaccharidyl group or monosaccharide subunit, or what would be the ring in the ring-closed form of the modified monosaccharidyl group or monosaccharide subunit, is partially unsaturated; and/or (b) the ring oxygen of the modified monosaccharidyl group or monosaccharide subunit, or what would be the ring oxygen in the ring-closed form of the modified monosaccharidyl group or monosaccharide subunit, is replaced with -S- or -NR d -, wherein -R d is independently hydrogen, or a substituted or unsubstituted, straight- chained, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl,
  • -R d may be a further monosaccharide subunit or subunits forming part of the disaccharidyl, oligosaccharidyl or polysaccharidyl group, wherein any such further monosaccharide subunit or subunits may optionally be substituted and/or modified.
  • substituted and/or modified monosaccharide subunits include those corresponding to: (i) deoxy sugars, such as deoxyribose, fucose, fuculose and rhamnose, wherein a hydroxyl group of the monosaccharidyl group or monosaccharide subunit has been replaced by -H; (ii) amino sugars, such as glucosamine and galactosamine, wherein a hydroxyl group of the monosaccharidyl group or monosaccharide subunit has been replaced by -NH 2 , most typically at the 2-position; and (iii) sugar acids, containing a -COOH group, such as aldonic acids (e.g.
  • At least one -R ⁇ is a monosaccharidyl group selected from:
  • At least one -RP is:
  • -R 2 , -R 3 or -R 4 is independently selected from -R ⁇ -OR ⁇ , -R ⁇ -SR ⁇ , -R ⁇ -S(O)R ⁇ or -R ⁇ -S(O) 2 R ⁇ (preferably from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ ), and -R ⁇ is selected from:
  • At least one of -R 2 , -R 3 or -R 4 is independently selected from -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, -R ⁇ -[R 8 ]Y, -R ⁇ -[N(R 5 ) 2 (R 5’ )], -R ⁇ -[P(R 5 ) 2 (R 5’ )], or -R ⁇ -[R 8’ ].
  • At least one of -R 2 , -R 3 or -R 4 is independently selected from -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, or -R ⁇ -[R 8 ]Y.
  • at least one of -R 2 , -R 3 or -R 4 is independently selected from:
  • each -R 5 may be the same or different.
  • each -R 5 is the same.
  • each -R 5 is independently unsubstituted or substituted with one or two substituents.
  • each -R 5 is unsubstituted.
  • -R 8 is unsubstituted or substituted with one or two substituents. In one embodiment, -R 8 is unsubstituted. In one embodiment, -R 8 is not substituted at the 4-position of the pyridine ring with a halo group. In one embodiment, -R 8 is unsubstituted at the 4-position of the pyridine ring. In one embodiment, -R 8 is unsubstituted.
  • each of -R 1 , -R 6 , -R 7 and -R 9 independently comprises from 1 to 100 atoms other than hydrogen, preferably from 1 to 80 atoms other than hydrogen, preferably from 1 to 60 atoms other than hydrogen, preferably from 1 to 50 atoms other than hydrogen, and preferably from 1 to 45 atoms other than hydrogen.
  • the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II):
  • -R 1 is selected from: (a) -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 ) 2 , and -R 3 , each independently, is C 1 -C 4 alkyl; preferably -R 1 is -C(O)-OR 3 and -R 3 is C 1 -C 4 alkyl; or (b) -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ); -R 3 is selected from -R ⁇ -OR ⁇ or -R ⁇ -SR ⁇ ; -R ⁇ is a saccharidyl group; and -R 3’ is H or C 1 -C 4 alkyl; -R 6 is selected from: (a) -C(O)-OR 3 , -C(O)-SR 3 or -
  • -R 1 is selected from -CH 2 OR 2 , -CH 2 SR 2 , -CH 2 S(O)R 2 , -CH 2 S(O) 2 R 2 , -CH 2 N(R 2 )(R 2’ ), -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [preferably -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ); more
  • the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II): or a pharmaceutically acceptable salt thereof, wherein: -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [preferably -R 1 is -C(O)-N(R 3 )(R 3’ )]; -R 2 , each independently, is selected from -H, -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-N(R 4 )(R 4’ ), -C(S)-OR 4 , -C(S)-SR 4 , -C(S)-SR
  • each -R 5 may be the same or different; preferably each -R 5 is the same.
  • the compound is a compound of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), (IV), (IW), (IX), (IY), (IZ), (IAA), (IBB) or (ICC):
  • -R 1 is selected from -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ );
  • -R 2 each independently, is selected from -H, -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-N(R 4 )(R 4’ ), -C(S)-OR 4 , -C(S)-SR 4 , -C(S)-N(R 4 )(R 4’ ), -R ⁇ -H, -R ⁇ , -R ⁇ -R ⁇ , -R ⁇ -OH,
  • the compounds of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), (IV), (IW), (IX), (IY), (IZ), (IAA), (IBB), (ICC) and complexes and salts thereof according to the first and second aspect of the present invention comprise a moiety -[(CH 2 ) p O] r -(CH 2 ) s -, wherein: p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5 or 6; and s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • p is 2, 3 or 4; r is 1; and s is 2, 3 or 4.
  • p is 3; r is 1; and s is 3; such that -[(CH 2 ) p O] r -(CH 2 ) s - is -(CH 2 ) 3 -O-(CH 2 ) 3 -.
  • p is 2 or 3; r is 2 or 3; and s is 2 or 3.
  • p is 2; r is 2; and s is 2; such that -[(CH 2 ) p O] r -(CH 2 ) s - is -(CH 2 CH 2 O) 2 -(CH 2 ) 2 -.
  • r is 0; and s is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; such that -[(CH 2 ) p O] r -(CH 2 ) s - is -(CH 2 ) 1-12 -.
  • the first or second aspect of the present invention provides a compound of formula (I’) or a complex of formula (II’):
  • -R 9 is selected from -OR 2 , -N(R 2 ) 2 , -SR 2 , -S(O)R 2 , -S(O) 2 R 2 , or -X;
  • -R 10 , -R 11 and -R 12 each independently, is selected from -OR 3 , -SR 3 or -N(R 3 ) 2 ;
  • -R 2 each independently, is selected from -H, -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-N(R 4 ) 2 , -C(S)-OR 4 , -C(S)-SR 4 , -C(S)-N(R 4 ) 2 , -R ⁇ -H, -R ⁇ , -R ⁇ -R ⁇ , -R ⁇ -OH, -R
  • the first or second aspect of the present invention provides a compound of formula (I’’) or a complex of formula (II’’): or a pharmaceutically acceptable salt thereof, wherein: -U- is -O-, -N(R u )- or -S-; -V- is -CH 2 -, -O-, -N(R v )- or -S-; -W- is -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, -R ⁇ -[R 8 ]Y, -R ⁇ -[N(R 5 ) 2 (R 5’ )], -R ⁇ -[P(R 5 ) 2 (R 5’ )] or -R ⁇ -[R 8’ ]; -R 10 , -R 11 and -R 12 , each independently, is selected from -OH or -
  • -U- is -O-, -N(R u )- or -S-;
  • -V- is -CH 2 -, -O-, -N(R v )- or -S-;
  • -W- is -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y or -R ⁇ -[R 8 ]Y;
  • -R 10 , -R 11 and -R 12 each independently, is selected from -OH or -O-(C 1 -C 4 alkyl);
  • -R ⁇ - is selected from a C 1 -C 12 alkylene group (preferably a C 1 -C 9 alkylene group, preferably a C 2 -C 6 alkylene group), wherein one or more (such as one, two, three or four, preferably one or two) carbon atoms in the backbone of the al
  • -R 1 is selected from -CO 2 H, -C(O)-R 14 -(CH 2 ) x -Me, -C(O)-R 14 -(CH 2 ) x -OH, -C(O)-R 14 -(CH 2 CH 2 O) y -Me or -C(O)-R 14 -(CH 2 CH 2 O) y -H; wherein x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and y is 0, 1, 2, 3, 4, 5 or 6.
  • -R 1 is selected from -CO 2 H, -C(O)-R 14 -(CH 2 ) x -Me or -C(O)-R 14 -(CH 2 CH 2 O) y -Me.
  • x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; preferably, x is 3, 4, 5, 6, 7, 8, 9, 10 or 11.
  • y is 1, 2, 3, 4, 5 or 6; preferably, y is 1, 2, 3 or 4.
  • -R 7 is selected from -CO 2 H, -C(O)-R 14 -(CH 2 ) x -Me, -C(O)-R 14 -(CH 2 ) x -OH, -C(O)-R 14 -(CH 2 CH 2 O) y -Me or -C(O)-R 14 -(CH 2 CH 2 O) y -H; wherein x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and y is 0, 1, 2, 3, 4, 5 or 6.
  • -R 7 is selected from -CO2H, -C(O)-R 14 -(CH 2 )x-Me or -C(O)-R 14 -(CH 2 CH 2 O)y-Me.
  • x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; preferably, x is 3, 4, 5, 6, 7, 8, 9, 10 or 11.
  • y is 1, 2, 3, 4, 5 or 6; preferably, y is 1, 2, 3 or 4.
  • -R 13 is methyl or ethyl.
  • -R 14 - is NH or NMe.
  • -R 14 - is NMe.
  • -R 15 is selected from -(CH 2 ) x -Me, -(CH 2 ) x -OH, -(CH 2 CH 2 O) y -Me or -(CH 2 CH 2 O) y -H; wherein x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and y is 0, 1, 2, 3, 4, 5 or 6.
  • -R 15 is selected from -(CH 2 ) x -Me or -(CH 2 CH 2 O) y -Me.
  • x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; preferably, x is 3, 4, 5, 6, 7, 8, 9, 10 or 11.
  • y is 1, 2, 3, 4, 5 or 6; preferably, y is 1, 2, 3 or 4.
  • M 2+ is a metal cation selected from Zn 2+ , Cu 2+ , Fe 2+ , Pd 2+ or Pt 2+ . In one embodiment, M 2+ is Zn 2+ .
  • the compound of formula (III) or the complex of formula (IV) is in the form of a pharmaceutically acceptable salt, such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) salt.
  • the pharmaceutically acceptable salt is a lithium, sodium, potassium, magnesium, calcium, ammonium, choline, meglumine or arginine salt, or a combination thereof.
  • the pharmaceutically acceptable salt is a lithium, sodium, potassium or meglumine salt, or a combination thereof.
  • the pharmaceutically acceptable salt is a sodium or meglumine salt, or a combination thereof.
  • the pharmaceutically acceptable salt is a mono-sodium salt.
  • the pharmaceutically acceptable salt is a di-sodium salt.
  • the pharmaceutically acceptable salt is a mono-meglumine salt.
  • the pharmaceutically acceptable salt is a di-meglumine salt.
  • the pharmaceutically acceptable salt is a mono-sodium mono- meglumine mixed salt.
  • the compound or complex is:
  • the compound or complex according to the first or second aspect of the invention is in the form of a pharmaceutically acceptable salt.
  • the compound or complex is in the form of an inorganic salt such as a lithium, sodium, potassium, magnesium, calcium or ammonium salt.
  • the compound or complex is in the form of a sodium or potassium salt.
  • the compound is in the form of a sodium salt.
  • the compound or complex is in the form of an organic salt such as an amine salt (for example a choline or meglumine salt) or an amino acid salt (for example an arginine salt).
  • the compound or complex according to the first or second aspect of the invention has at least two chiral centres.
  • the compound or complex of the first or second aspect of the invention is preferably substantially enantiomerically pure, which means that the compound or complex comprises less than 10% of other stereoisomers, preferably less than 5%, preferably less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, all by weight, as measured by XRPD or SFC.
  • the compound or complex according to the first or second aspect of the invention has a HPLC purity of more than 97%, more preferably more than 98%, more preferably more than 99%, more preferably more than 99.5%, more preferably more than 99.8%, and most preferably more than 99.9%.
  • a third aspect of the invention provides a composition comprising a compound or complex according to the first or second aspect of the invention and a pharmaceutically acceptable carrier or diluent.
  • the composition according to the third aspect of the invention further comprises polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the composition comprises 0.01-10% w/w PVP as percentage of the total weight of the composition, preferably 0.1-5% w/w PVP as a percentage of the total weight of the composition, preferably 0.5-5% w/w PVP as a percentage of the total weight of the composition.
  • the PVP is K30.
  • the composition according to the third aspect of the invention further comprises dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • the composition comprises 0.01-99% w/w DMSO as percentage of the total weight of the composition, preferably 40-99% w/w DMSO as a percentage of the total weight of the composition, preferably 65-99% w/w DMSO as a percentage of the total weight of the composition.
  • the composition according to the third aspect of the invention further comprises an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of PD-1 (programmed cell death protein 1), PD-L1 (programmed death ligand 1) or CTLA4 (cytotoxic T-lymphocyte associated protein 4).
  • the immune checkpoint inhibitor is selected from Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab or Ipilimumab.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for use in photodynamic therapy or cytoluminescent therapy.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the treatment of a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the treatment of a benign or malignant tumour.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for use in photodynamic diagnosis.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the detection of an area that is affected by benign or malignant cellular hyperproliferation or by neovascularisation.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the detection of a benign or malignant tumour.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the fluorescent or phosphorescent detection of the diseases listed above, preferably for the fluorescent or phosphorescent detection and quantification of the said diseases.
  • the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are adapted for administration simultaneous with or prior to administration of irradiation or sound, preferably for administration prior to administration of irradiation.
  • the compound or complex according to the first or second aspect of the present invention or the pharmaceutical composition according to the third aspect of the present invention are for use in photodynamic therapy or cytoluminescent therapy, then they are preferably adapted for administration 5 to 100 hours before the irradiation, preferably 6 to 72 hours before the irradiation, preferably 24 to 48 hours before the irradiation. If the compound or complex according to the first or second aspect of the present invention or the pharmaceutical composition according to the third aspect of the present invention are for use in photodynamic diagnosis, then they are preferably adapted for administration 3 to 60 hours before the irradiation, preferably 8 to 40 hours before the irradiation.
  • the irradiation used in the photodynamic therapy, cytoluminescent therapy or photodynamic diagnosis is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm, preferably from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm.
  • the electromagnetic radiation may be administered for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1- 5W, preferably at about 1W.
  • two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm.
  • the irradiation may be provided by a prostate, anal, vaginal, mouth and nasal device for insertion into a body cavity.
  • the irradiation may be provided by interstitial light activation, for example, using a fine needle to insert an optical fibre laser into the lung, liver, lymph nodes or breast.
  • the irradiation may be provided by endoscopic light activation, for example, for delivering light to the lung, stomach, colon, bladder or neck.
  • the pharmaceutical composition according to the third aspect of the present invention may be in a form suitable for oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intratumoral, intraarticular, intraabdominal, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration.
  • the pharmaceutical composition may also be in a form suitable for administration by enema or for administration by injection into a tumour.
  • the pharmaceutical composition is in a form suitable for oral, parenteral (such as intravenous, intraperitoneal, and intratumoral) or airway administration, preferably in a form suitable for oral or parenteral administration, preferably in a form suitable for oral administration.
  • the pharmaceutical composition is in a form suitable for oral administration.
  • the pharmaceutical composition is provided in the form of a tablet, capsule, hard or soft gelatine capsule, caplet, troche or lozenge, as a powder or granules, or as an aqueous solution, suspension or dispersion.
  • the pharmaceutical composition is provided in the form of an aqueous solution, suspension or dispersion for oral administration, or alternatively in the form of a freeze-dried powder which can be mixed with water before administration to provide an aqueous solution, suspension or dispersion for oral administration.
  • the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the compound or complex according to the first or second aspect of the invention, preferably 0.1 to 2 mg/kg/day, preferably about 1 mg/kg/day.
  • the pharmaceutical composition is in a form suitable for parenteral administration.
  • the pharmaceutical composition is in a form suitable for intravenous administration.
  • the pharmaceutical composition is provided in the form of an aqueous solution for parenteral administration, or alternatively in the form of a freeze-dried powder which can be mixed with water before administration to provide an aqueous solution for parenteral administration.
  • the pharmaceutical composition is an aqueous solution or suspension having a pH of from 6 to 8.5.
  • the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the compound or complex according to the first or second aspect of the invention, preferably 0.1 to 2 mg/kg/day, preferably about 1 mg/kg/day.
  • the pharmaceutical composition is in a form suitable for airway administration.
  • the pharmaceutical composition is provided in the form of an aqueous solution, suspension or dispersion for airway administration, or alternatively in the form of a freeze-dried powder which can be mixed with water before administration to provide an aqueous solution, suspension or dispersion for airway administration.
  • the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the compound or complex according to the first or second aspect of the invention, preferably 0.1 to 2 mg/kg/day, preferably about 1 mg/kg/day.
  • a fourth aspect of the present invention provides use of a compound or complex according to the first or second aspect of the present invention in the manufacture of a medicament for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasi
  • the fourth aspect of the present invention also provides use of a compound or complex according to the first or second aspect of the present invention in the manufacture of a phototherapeutic agent for use in photodynamic therapy or cytoluminescent therapy.
  • the phototherapeutic agent is suitable for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperprolife
  • the medicament or the phototherapeutic agent of the fourth aspect of the present invention is suitable for the treatment of a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.
  • the medicament or the phototherapeutic agent of the fourth aspect of the present invention is suitable for the treatment of a benign or malignant tumour.
  • the medicament or the phototherapeutic agent of the fourth aspect of the present invention is suitable for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
  • the fourth aspect of the present invention also provides use of a compound or complex according to the first or second aspect of the present invention in the manufacture of a photodiagnostic agent for use in photodynamic diagnosis.
  • the photodiagnostic agent of the fourth aspect of the present invention is suitable for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular
  • the photodiagnostic agent of the fourth aspect of the present invention is suitable for the detection of an area that is affected by benign or malignant cellular hyperproliferation or by neovascularisation.
  • the photodiagnostic agent of the fourth aspect of the present invention is suitable for the detection of a benign or malignant tumour.
  • the photodiagnostic agent of the fourth aspect of the present invention is suitable for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
  • the photodiagnostic agent of the fourth aspect of the present invention is suitable for the fluorescent or phosphorescent detection of the said diseases, preferably the fluorescent or phosphorescent detection and quantification of the said diseases.
  • the medicament, the phototherapeutic agent or the photodiagnostic agent is adapted for administration simultaneous with or prior to administration of irradiation or sound, preferably for administration prior to administration of irradiation. If the medicament or the phototherapeutic agent is for use in photodynamic therapy or cytoluminescent therapy, then it is preferably adapted for administration 5 to 100 hours before the irradiation, preferably 6 to 72 hours before the irradiation, preferably 24 to 48 hours before the irradiation.
  • the photodiagnostic agent is for use in photodynamic diagnosis, then it is preferably adapted for administration 3 to 60 hours before the irradiation, preferably 8 to 40 hours before the irradiation.
  • the irradiation used in the photodynamic therapy, cytoluminescent therapy or photodynamic diagnosis is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm, preferably from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm.
  • the electromagnetic radiation may be administered for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1- 5W, preferably at about 1W.
  • two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm.
  • the irradiation may be provided by a prostate, anal, vaginal, mouth and nasal device for insertion into a body cavity.
  • the irradiation may be provided by interstitial light activation, for example, using a fine needle to insert an optical fibre laser into the lung, liver, lymph nodes or breast.
  • the irradiation may be provided by endoscopic light activation, for example, for delivering light to the lung, stomach, colon, bladder or neck.
  • a fifth aspect of the present invention provides a method of treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neo
  • the fifth aspect of the present invention also provides a method of photodynamic therapy or cytoluminescent therapy of a human or animal disease, the method comprising administering a therapeutically effective amount of a compound or complex according to the first or second aspect of the present invention to a human or animal in need thereof.
  • the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related ma
  • the method of the fifth aspect of the present invention is a method of treating benign or malignant cellular hyperproliferation or areas of neovascularisation.
  • the method of the fifth aspect of the present invention is a method of treating a benign or malignant tumour.
  • the method of the fifth aspect of the present invention is a method of treating early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
  • the fifth aspect of the present invention also provides a method of photodynamic diagnosis of a human or animal disease, the method comprising administering a diagnostically effective amount of a compound or complex according to the first or second aspect of the present invention to a human or animal.
  • the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant
  • 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 benign or malignant tumour.
  • the human or animal disease is early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancrea
  • the method of photodynamic diagnosis is suitable for the fluorescent or phosphorescent detection of the said diseases, preferably for the fluorescent or phosphorescent detection and quantification of the said diseases.
  • the human or animal is preferably further subjected to irradiation or sound simultaneous with or after the administration of the compound or complex according to the first or second aspect of the invention.
  • the human or animal is subjected to irradiation after the administration of the compound or complex according to the first or second aspect of the invention.
  • the human or animal is preferably subjected to irradiation 5 to 100 hours after administration of the compound or complex according to the first or second aspect of the invention, preferably 6 to 72 hours after administration, preferably 24 to 48 hours after administration.
  • the method is a method of photodynamic diagnosis, then the human or animal is preferably subjected to irradiation 3 to 60 hours after administration of the compound or complex according to the first or second aspect of the invention, preferably 8 to 40 hours after administration.
  • the irradiation is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm, preferably from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm.
  • the electromagnetic radiation may be administered for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1- 5W, preferably at about 1W.
  • two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm.
  • the irradiation may be provided by a prostate, anal, vaginal, mouth and nasal device for insertion into a body cavity.
  • the irradiation may be provided by interstitial light activation, for example, using a fine needle to insert an optical fibre laser into the lung, liver, lymph nodes or breast.
  • the irradiation may be provided by endoscopic light activation, for example, for delivering light to the lung, stomach, colon, bladder or neck.
  • the human or animal is a human.
  • a sixth aspect of the present invention provides a pharmaceutical combination or kit comprising: (a) a compound or complex according to the first or second aspect of the present invention; and (b) an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of PD-1 (programmed cell death protein 1), PD-L1 (programmed death ligand 1) or CTLA4 (cytotoxic T-lymphocyte associated protein 4).
  • the immune checkpoint inhibitor is selected from Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab or Ipilimumab.
  • the combination or kit of the sixth aspect is for use in the treatment of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to PD-1, PD-L1 or CTLA4 inhibition.
  • the combination or kit of the sixth aspect is for use in the treatment of cancer.
  • the cancer is melanoma, lung cancer (e.g. non small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin’s lymphoma.
  • the sixth aspect also provides a use of the combination or kit of the sixth aspect of the invention in the manufacture of a medicament for the treatment of a disease, disorder or condition which is responsive to PD-1, PD-L1 or CTLA4 inhibition.
  • the sixth aspect also provides a use of the combination or kit of the sixth aspect of the invention in the manufacture of a medicament for the treatment of cancer.
  • the cancer is melanoma, lung cancer (e.g. non small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin’s lymphoma.
  • the sixth aspect of the invention also provides a method of treating a disease, disorder or condition which is responsive to PD-1, PD-L1 or CTLA4 inhibition, the method comprising administering a therapeutically effective amount of the combination or kit of the sixth aspect of the present invention to a human or animal in need thereof.
  • the sixth aspect of the invention also provides a method of treating cancer, the method comprising administering a therapeutically effective amount of the combination or kit of the sixth aspect of the present invention to a human or animal in need thereof.
  • the cancer is melanoma, lung cancer (e.g. non small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin’s lymphoma.
  • lung cancer e.g. non small cell lung cancer
  • kidney cancer e.g. non small cell lung cancer
  • kidney cancer e.g. non small cell lung cancer
  • bladder cancer e.g. non small cell lung cancer
  • Hodgkin’s lymphoma e.g., adenoma
  • the compound or complex according to the first or second aspect of the invention, and the immune checkpoint inhibitor may be provided together in one pharmaceutical composition or separately in two pharmaceutical compositions. If provided in two pharmaceutical compositions, these may be administered at the same time or at different times.
  • the combination or kit of the sixth aspect is adapted for administration simultaneous with or prior to administration of irradiation or sound, preferably for administration prior to administration of irradiation.
  • the combination or kit of the sixth aspect is adapted for administration 5 to 100 hours before the irradiation, preferably 6 to 72 hours before the irradiation, preferably 24 to 48 hours before the irradiation.
  • the irradiation used in the photodynamic therapy or cytoluminescent therapy is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm, preferably from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm.
  • the electromagnetic radiation may be administered for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1-5W, preferably at about 1W.
  • two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm.
  • the irradiation may be provided by a prostate, anal, vaginal, mouth and nasal device for insertion into a body cavity.
  • the irradiation may be provided by interstitial light activation, for example, using a fine needle to insert an optical fibre laser into the lung, liver, lymph nodes or breast.
  • the irradiation may be provided by endoscopic light activation, for example, for delivering light to the lung, stomach, colon, bladder or neck.
  • Step 1 To a 100 mL RBF was added chlorin e6 trimethyl ester (1.00 g, 1.566 mmol, 1 eq), THF (40 mL), osmium tetroxide (4 mg, 0.016 mmol, 0.01 eq), deionized water (3 mL), AcOH (3 mL) and sodium periodate (0.737 g, 3.444 mmol, 2.2 eq). The resultant mixture was stirred under nitrogen in the dark at ambient temperature for 19 hours. A further portion of sodium periodate (0.068 g, 0.313 mmol, 0.2 eq) was added and the solution stirred for a further 8 hours.
  • reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (60 mL), transferred to a separatory funnel and washed with brine (30 mL), saturated aqueous NaHCO 3 (30 mL), water (50 mL), before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give chlorin e613-formyl trimethyl ester as a red-brown solid (1.0 g, quantitative).
  • Step 2 To a 250 mL RBF was added chlorin e613-formyl trimethyl ester (850 mg, 1.327 mmol, 1 eq), MeOH (30 mL), DCM (15 mL) and sodium borohydride (100 mg, 2.653 mmol, 2 eq). The resultant mixture was stirred under nitrogen ambient temperature for 1 hour. The reaction mixture was diluted with water (60 mL) and stirred for 10 minutes. The mixture was then extracted with DCM (2 x 30 mL) and the combined DCM layers washed with water (50 mL), before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark red solid.
  • Step 2 To a 50 mL RBF was added chlorin e613-hydroxymethyl trimethyl ester (compound 1) (100 mg, 0.156 mmol, 1 eq), carbonyl diimidazole (76 mg, 0.467 mmol, 3 eq), DCM (5 mL) and 4-dimethylaminopyridine (DMAP) (25 mg, 0.205 mmol, 1.3 eq).
  • the RBF was set over an oil bath and fitted with an air condenser, where stirring (500 rpm) commenced under N 2 at an external temperature of 90 °C. The mixture was left to stir for 72 hours. After this time, the reaction flask was cooled to room temperature and the suspension was filtered through a 2 cm plug of Celite ® , washing through with acetonitrile (250 mL). The faint yellow solution was then evaporated to dryness to leave a dark yellow oil (44.40 g) which was subject to column chromatography (silica gel, 9 x 12 cm) using 6% MeOH in DCM as eluent.
  • Step 2 To a 50 mL RBF was added (3-(3-chloropropoxy)propyl)triphenylphosphonium chloride (4.0 g, 9.23 mmol, 1 eq), NaN 3 (11.08 g, 1.2 eq), NaBr (38 mg, 0.04 eq), tetrapropylammonium bromide (49 mg, 0.02 eq) and water (10 mL). After connecting a water condenser, the flask was heated at 110 °C with stirring for 44 hours. Then the mixture was cooled and EtOAc (50 mL) was added. The mixture was transferred to a separating funnel and washed with water (3 x 30 mL) and brine (30 mL).
  • Step 3 A 3-neck 100 mL RBF was charged with (3-(3-azidopropoxy)propyl) triphenylphosphonium chloride (1.00 g, 2.273 mmol, 1 eq), 10% Pd/C (20 mg), methanol (10 mL) and a stirrer bar.
  • a hydrogen balloon was connected to the middle joint of the flask via a short length air condenser and the side-arm was connected to a 3-way tap.
  • the setup was evacuated and then re-filled with nitrogen (3 times), evacuated and re-filled with hydrogen (2 times).
  • the resulting solution was then stirred (550 rpm) under the hydrogen atmosphere for 2 hours at 35 °C.
  • Step 4 To a 25 mL RBF was added chlorin e613-hydroxymethyl trimethyl ester (compound 1) (60 mg, 0.0934 mmol, 1 eq), carbonyl diimidazole (30 mg, 0.1867 mmol, 2 eq), DCM (4 mL) and DMAP (5 mg, 0.0409 mmol, 0.4 eq). The resultant mixture was stirred under nitrogen for 3 hours with monitoring by TLC. (3-(3- Aminopropoxy)propyl)triphenylphosphonium chloride (193 mg, 0.4668 mmol, 5 eq) dissolved in DCM (1 mL)was added and stirring was continued for 4 days.
  • reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel and washed with water (15 mL), extracted with DCM (2 x 5 mL), before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark green residue.
  • Step 1 A 1-neck 250 mL RBF was charged with chlorin e6 (0.5 g, 1 eq), di-tert-butyl dicarbonate ((Boc) 2 O) (188 mg, 1.03 eq) and DCM (60 ml). DMAP (8 mg, 0.08 eq) was added and the resultant solution was stirred for 2 hours under a nitrogen atmosphere at 40 °C. The resulting black solution was filtered using a cotton plug, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with hexane (2 x 10 ml) and dried to obtain chlorin e6 anhydride as a black solid (475 mg, 98%). It was used in the next step without further purification.
  • Step 2 A 1-neck 250 mL RBF was charged with chlorin e6 anhydride (470 mg, 1 eq), (2- methoxyethyl)methylamine (108 mg, 1.5 eq) and DCM (30 ml). The resultant solution was stirred overnight under a nitrogen atmosphere at 35 °C. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered and washed with diethyl ether (2 x 10 ml).
  • Step 3 Into a 1-neck 250 mL RBF was added chlorin e6 (2-methoxyethyl)methylamine (310 g, 1 eq), potassium carbonate (192 mg, 3 eq), DMF (10 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 300 rpm with an air condenser attached. Methyl iodide (0.072 mL, 3 eq) was then added. The solution was stirred at 25 °C over the weekend. The solvent was removed under reduced pressure at 60 °C to give a dark green solid.
  • Step 4 To a 250 mL RBF was added chlorin e6 (2-methoxyethyl)methylamine dimethyl ester (310 mg, 1 eq), THF (10 mL), osmium tetroxide ( ⁇ 1 mg, 0.01 eq), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (247 mg, 2.6 eq). The resultant mixture was stirred under nitrogen in the dark at ambient temperature overnight.
  • the reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (20 mL), transferred to a separatory funnel and washed with brine (10 mL), saturated NaHCO 3 (10 mL), water (10 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a red-brown powdery solid.
  • the residual dark solid was purified by column chromatography using 1-2% MeOH/DCM and fractions containing the first dark band to elute were combined to give chlorin e613- formyl (2-methoxyethyl)methylamine dimethyl ester as a red-brown powdery solid (210 mg, 68% yield, 93.43% purity by HPLC).
  • Step 5 To a 100 mL RBF was added chlorin e613-formyl (2- methoxyethyl)methylamine dimethyl ester (210 mg, 1 eq), MeOH (5 mL), DCM (2 mL) and sodium borohydride (22 mg, 2 eq). The resultant mixture was stirred under nitrogen at ambient temperature for 1 hour. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected and the aqueous layer further extracted with DCM (10 mL).
  • Step 6 To a 25 mL RBF was added chlorin e613-hydroxymethyl (2- methoxyethyl)methylamine dimethyl ester (compound 9A) (70 mg, 1 eq), carbonyl diimidazole (32 mg, 2 eq), DCM (3 mL) and DMAP (2 mg). The resultant mixture was stirred under nitrogen for 3 hours. (3-Aminopropyl)triphenylphosphonium bromide (200 mg, 5 eq) was added and stirring was continued overnight at ambient temperature.
  • the reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (15 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark green residue ( ⁇ 100 mg).
  • the residue was purified by column chromatography (3 x 12 cm) using 0-6% MeOH/DCM, loaded as a solution in the eluent.
  • Step 1 A 1-neck 250 mL RBF was charged with chlorin e6 anhydride (500 mg, 1 eq), N- methylbutylamine (108 mg, 1.5 eq) and DCM (30 ml). The resultant solution was stirred overnight under a nitrogen atmosphere at 35 °C. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered, washed with diethyl ether (2 x 10 ml) and dried over a rotavapor to obtain chlorin e6 N-methylbutylamine as a bluish green solid (670 mg, quantitative yield, 85.80% purity by HPLC). The crude product was carried over to the next step without further purification.
  • Step 2 Into a 1-neck 250 mL RBF was added chlorin e6 N-methylbutylamine (650 g, 1 eq), potassium carbonate (404 mg, 3 eq), DMF (10 mL) and a stirrer bar. The flask was placed under nitrogen. Methyl iodide (0.150 mL, 2.5 eq) was then added. The solution was stirred at 25 °C overnight. The solvent was removed under reduced pressure at 60 °C to give a dark green solid.
  • chlorin e6 N-methylbutylamine 650 g, 1 eq
  • potassium carbonate 404 mg, 3 eq
  • DMF 10 mL
  • Methyl iodide (0.150 mL, 2.5 eq) was then added. The solution was stirred at 25 °C overnight. The solvent was removed under reduced pressure at 60 °C to give a dark green solid.
  • Step 3 To a 250 mL RBF was added chlorin e6 N-methylbutylamine dimethyl ester (700 mg, 1 eq), THF (10 mL), osmium tetroxide ( ⁇ 2 mg, 0.01 eq), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (561 mg, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight.
  • the reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (20 mL), transferred to a separatory funnel and washed with brine (10 mL), saturated NaHCO 3 (10 mL), water (10 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give chlorin e613-formyl N-methylbutylamine dimethyl ester as a red-brown powdery solid (670 mg, quantitative yield, 85.31% purity by HPLC). The crude product was carried over to the next step without further purification.
  • Step 4 To a 100 mL RBF was added chlorin e613-formyl N-methylbutylamine dimethyl ester (650 mg, 1 eq), MeOH (15 mL), DCM (4 mL) and sodium borohydride (70 mg, 2 eq). The resultant mixture was stirred under nitrogen at ambient temperature for 2 hours. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected and the aqueous layer further extracted with DCM (10 mL).
  • Step 5 To a 100 mL RBF was added chlorin e613-hydroxymethyl N-methylbutylamine dimethyl ester (compound 10A) (140 mg, 1 eq), carbonyl diimidazole (64 mg, 2 eq), DCM (6 mL) and DMAP (2 mg). The resultant mixture was stirred under nitrogen for 3 hours. (3-Aminopropyl)triphenylphosphonium bromide (400 mg, 5 eq) was added and stirring was continued overnight at ambient temperature. After overnight, further carbonyl diimidazole (32 mg) was added and the reaction was then heated at 30 °C (heat block) for a further 3 hours.
  • reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (2 x 10 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark green residue. To this residue was added further carbonyl diimidazole (64 mg), DCM (6 mL) and DMAP (2 mg). The resultant mixture was stirred under nitrogen at 30 °C (external) for 3 hours. Further (3-aminopropyl)triphenylphosphonium bromide (400 mg, 5 eq) was added and stirring was continued overnight at 30 °C.
  • reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue ( ⁇ 150 mg).
  • the residue was purified by column chromatography using 0-6% MeOH/DCM, loaded as a solution in the eluent.
  • Step 2 Into a 1-neck 250 mL RBF was added chlorin e6 N- (methylaminopropyl)triphenylphosphonium bromide (1.0 gm, 1 eq), potassium carbonate (415 mg, 3 eq), DMF (10 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 300 rpm with an air condenser attached. Methyl iodide (0.150 mL, 2.5 eq) was then added. The solution was stirred at 30 °C overnight. The solvent was removed under reduced pressure at 60 °C to give a dark green solid.
  • chlorin e6 N- (methylaminopropyl)triphenylphosphonium bromide 1.0 gm, 1 eq
  • potassium carbonate 415 mg, 3 eq
  • DMF 10 mL
  • Methyl iodide (0.150 mL, 2.5 eq) was then added. The solution was stirred at
  • Step 3 To a 250 mL RBF was added chlorin e6 N- (methylaminopropyl)triphenylphosphonium bromide dimethyl ester (200 mg, 1 eq), THF (10 mL), osmium tetroxide ( ⁇ 1 mg, 0.01 eq), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (247 mg, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight.
  • chlorin e6 N- (methylaminopropyl)triphenylphosphonium bromide dimethyl ester 200 mg, 1 eq
  • THF 10 mL
  • osmium tetroxide ⁇ 1 mg, 0.01 eq
  • deionized water 0.8 mL
  • AcOH 0.8 mL
  • sodium periodate 247 mg, 2.6 eq
  • the reaction mixture was concentrated using a rotary evaporator to remove the THF and then re- dissolved in DCM (20 mL), transferred to a separatory funnel and washed with brine (10 mL), saturated NaHCO 3 (10 mL), water (10 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give chlorin e613-formyl N- (methylaminopropyl)triphenylphosphonium bromide dimethyl ester as a red-brown powdery solid (220 mg, quantitative yield, 72.47% purity by HPLC). The crude product was carried over to the next step without further purification.
  • Step 4 To a 100 mL RBF was added chlorin e613-formyl N- (methylaminopropyl)triphenylphosphonium bromide dimethyl ester (210 mg, 1 eq), MeOH (15 mL), DCM (4 mL) and sodium borohydride (15 mg, 2 eq). The resultant mixture was stirred under nitrogen at ambient temperature for 2 hours. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected and the aqueous layer further extracted with DCM (10 mL).
  • Step 2 A 1-neck 250 mL RBF was charged with chlorin e6 anhydride (2.0 g, 1 eq), (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((3-methylamino)propyl)thio)tetrahydro-2H- pyran-3,4,5-triyl triacetate TFA salt (2.84 g, 1.5 eq), sodium bicarbonate (435 mg, 1.5 eq) and DCM (30 ml). The resultant solution was stirred overnight under a nitrogen atmosphere at 30 °C. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether.
  • chlorin e6 anhydride 2.0 g, 1 eq
  • Step 3 Into a 1-neck 250 mL RBF was added chlorin e6 ⁇ -D-1-thioglucose-N- methylpropylamide conjugate tetraacetate diacid (1.0 gm, 1 eq), potassium carbonate (490 mg, 3 eq), DMF (10 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 300 rpm with an air condenser attached. Methyl iodide (0.218 mL, 2.5 eq) was then added. The solution was stirred at 30 °C overnight. The solvent was removed under reduced pressure at 60 °C to give a dark green solid.
  • Step 4 To a 250 mL RBF was added chlorin e6 ⁇ -D-1-thioglucose-N- methylpropylamide conjugate tetraacetate dimethyl ester (700 mg, 1 eq), THF (25 mL), osmium tetroxide ( ⁇ 2 mg, 0.01 eq), deionized water (2.5 mL), AcOH (2.5 mL) and sodium periodate (373 mg, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight and at 30 °C for one hour.
  • the reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (20 mL), transferred to a separatory funnel and washed with water (10 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give chlorin e6 ⁇ -D-1-thioglucose-N-methylpropylamide conjugate tetraacetate 13-formyl dimethyl ester as a red-brown powdery solid (700 mg, 47.93% purity by HPLC). The crude product was carried over to the next step without further purification.
  • Step 5 To a 100 mL RBF was added chlorin e6 ⁇ -D-1-thioglucose-N- methylpropylamide conjugate tetraacetate 13-formyl dimethyl ester (700 mg, 1 eq), MeOH (20 mL), DCM (8 mL) and sodium borohydride (19 mg, 0.72 eq). The resultant mixture was stirred under nitrogen at ambient temperature for 1 hour. The reaction mixture was concentrated using a rotavapor to give a dark green solid ( ⁇ 800 mg), which was re-dissolved in MeOH (10 mL) and concentrated using a rotavapor at ⁇ 65 °C and 700 mbar (3 cycles). Finally, the solvent MeOH was completely evaporated and crude product obtained ( ⁇ 700 mg).
  • the resultant mixture was stirred under nitrogen at ambient temperature in the dark for 16 hours.
  • the reaction progress was monitored by HPLC.
  • the reaction mixture was transferred to a separatory funnel, diluted with DCM (30 mL) and washed with 0.5 M HCl (20 mL).
  • the organic phase was dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark green film.
  • the solution was diluted with DCM (100 mL), stirred for 15 minutes and filtered through Celite ® (1 cm depth, 6 cm width) washing with DCM until no more color eluted.
  • the solvent was removed under reduced pressure to give crude product as a dark green solid.
  • the crude product was dissolved in EtOAc (300 mL), washed with water (2 x 150 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to give a dark blue/green solid (12.10 g).
  • the dark blue/green solid was purified by column chromatography using a gradient of 0.5-5% MeOH/DCM.
  • Step 2 To a 250 mL RBF was added chlorin e6 triethyl ester (2.01 g, 2.95 mmol, 1 eq), THF (75 mL), osmium tetroxide (7.5 mg, 0.0295 mmol, 0.01 eq), deionized water (6 mL), AcOH (6 mL) and sodium periodate (1.64 g, 7.67 mmol, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature for 3 days. The reaction progress was monitored by HPLC.
  • the reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (90 mL), transferred to a separatory funnel and washed with brine (60 mL), saturated NaHCO 3 (60 mL) and water (75 mL) before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give crude product as a dark blue solid (2.09 g).
  • the crude product was purified by column chromatography using 2% MeOH in DCM as eluent.
  • Step 3 To a 250 mL RBF was added chlorin e613-formyl triethyl ester (850 mg, 1.24 mmol, 1 eq), MeOH (20 mL), DCM (10 mL) and sodium borohydride (94 mg, 2.48 mmol, 2 eq). The resultant mixture was stirred (600 rpm) under nitrogen at ambient temperature for 10 minutes. The reaction mixture was diluted with water (15 mL) and stirred for 10 minutes. The mixture was then extracted with DCM (2 x 30 mL) and the combined DCM layers were washed with water (50 mL) before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give crude product as a dark green solid.
  • Step 2 To a 25 mL RBF was added chlorin e6 N-methylbutylamine diethyl ester (390 mg, 0.540 mmol, 1 eq), THF (6 mL), osmium tetroxide (1.4 mg, 0.0054 mmol, 0.01 eq), deionized water (0.5 mL), AcOH (0.5 mL) and sodium periodate (299 mg, 1.40 mmol, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature for 18 hours.
  • the reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (30 mL), transferred to a separatory funnel and washed with brine (20 mL), saturated NaHCO 3 (20 mL) and water (20 mL) before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a red-blue solid.
  • the red-blue solid was purified by column chromatography using 1-2% MeOH in DCM as eluent.
  • Step 3 To a 50 mL RBF was added chlorin e613-formyl N-methylbutylamine diethyl ester (240 mg, 0.332 mmol, 1 eq), MeOH (9 mL), DCM (3 mL) and sodium borohydride (25 mg, 0.664 mmol, 2 eq). The resultant mixture was stirred (400 rpm) under nitrogen at 25 °C for 2 hours. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected and the aqueous further extracted with DCM (10 mL).
  • Step 1 A 1-neck 1L RBF was charged with chlorin e6 anhydride (6.90 g, 11.9 mmol, 1 eq), N-methyl-3,6,9,12-tetraoxatridecan-1-amine (3.96 g, 17.9 mmol, 1.5 eq) and DCM (400 mL). The resultant solution was stirred (400 rpm) for 18 hours under a nitrogen atmosphere at 35 °C. The resulting dark green solution was concentrated under reduced pressure until ⁇ 10 mL DCM remained, then diethyl ether (100 mL) was added and the mixture swirled by hand in the RBF. The solvent was decanted and a sticky dark green paste remained.
  • Step 2 Into a 1-neck 500 mL RBF was added chlorin e615-N-methyl-3,6,9,12- tetraoxatridecan-1-amine amide (5.50 g, 6.88 mmol, 1 eq), potassium carbonate (4.75 g, 34.4 mmol, 5 eq), DMF (180 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 400 rpm with an air condenser attached. Methyl iodide (2.44 g, 17.2 mmol, 2.5 eq) was then added. The solution was stirred at 25 °C for 18 hours. The reaction progress was monitored by HPLC.
  • Step 3 To a 500 mL RBF was added chlorin e615-N-methyl-3,6,9,12-tetraoxatridecan- 1-amine dimethyl ester amide (3.00 g, 3.62 mmol, 1 eq), THF (120 mL), osmium tetroxide ( ⁇ 9.2 mg, 0.0362 mmol, 0.01 eq), deionized water (12 mL), AcOH (12 mL) and sodium periodate (2.01 g, 9.41 mmol, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at 25 °C for 16 hours. The reaction progress was monitored by HPLC.
  • reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (250 mL), transferred to a separatory funnel and washed with brine (120 mL), saturated NaHCO 3 (120 mL) and water (120 mL) before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give crude product as a dark blue solid (3.53 g).
  • Step 4 To a 100 mL RBF was added chlorin e613-formyl 15-N-methyl-3,6,9,12- tetraoxatridecan-1-amine dimethyl ester amide (1.00 g, 1.20 mmol, 1 eq), MeOH (30 mL), DCM (15 mL) and sodium borohydride (91 mg, 2.40 mmol, 2 eq). The resultant mixture was stirred (600 rpm) under nitrogen at ambient temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (80 mL) and washed with water (80 mL).
  • the DCM layer was collected and the aqueous further extracted with DCM (40 mL). The combined DCM layers were washed with brine (80 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark green solid.
  • the resultant mixture was stirred (600 rpm) under nitrogen for 3 hours at 30 °C.
  • the reaction progress was monitored by TLC.
  • (3- Aminopropyl)triphenylphosphonium bromide (240 mg, 0.600 mmol, 5 eq) was added and stirring was continued for 18 hours at 30 °C.
  • the reaction was monitored by HPLC.
  • the reaction mixture was diluted with DCM (30 mL), transferred to a separatory funnel and washed with water (30 mL) before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark green residue.
  • the residue was purified by column chromatography using 5-9% MeOH/DCM, loaded as a solution in the eluent.
  • Step 1 A 1-neck 1L RBF was charged with chlorin e6 anhydride (7.00 g, 12.1 mmol, 1 eq), N-methyl-1-dodecanamine (4.03 g, 18.2 mmol, 1.5 eq) and DCM (400 mL). The resultant solution was stirred (400 rpm) for 16 hours under a nitrogen atmosphere at 35 °C. The resulting dark green solution was concentrated under reduced pressure until ⁇ 10 mL DCM remained, then hexane (100 mL) was added and the mixture swirled by hand in the RBF. The solvent was decanted and a sticky dark green paste remained.
  • Step 2 Into a 1-neck 500 mL RBF was added chlorin e615-N-methyl-1-dodecanamine amide (7.00 g, 9.00 mmol, 1 eq), potassium carbonate (6.21 g, 45.0 mmol, 5 eq), DMF (220 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 400 rpm with an air condenser attached. Methyl iodide (3.19 g, 22.5 mmol, 2.5 eq) was then added. The solution was stirred at 25 °C for 18 hours. The reaction progress was monitored by HPLC. The solvent was removed under reduced pressure at 70 °C to give crude product as a dark green solid.
  • the crude product was dissolved in DCM (300 mL), washed with water (2 x 150 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to give a dark blue/green solid (10.03 g).
  • the second product fraction from the first column was re-purified by column chromatography using 3% MeOH/DCM as eluent.
  • Step 3 To a 500 mL RBF was added chlorin e615-N-methyl-1-dodecanamine dimethyl ester amide (3.40 g, 4.22 mmol, 1 eq), THF (140 mL), osmium tetroxide ( ⁇ 10.7 mg, 0.0422 mmol, 0.01 eq), deionized water (14 mL), AcOH (14 mL) and sodium periodate (2.35 g, 11.0 mmol, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at 25 °C for 16 hours. The reaction progress was monitored by HPLC.
  • reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (250 mL), transferred to a separatory funnel and washed with brine (120 mL), saturated NaHCO 3 (120 mL) and water (120 mL) before being dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give crude product as a dark blue solid.
  • Step 4 To a 100 mL RBF was added chlorin e613-formyl 15-N-methyl-1-dodecanamine dimethyl ester amide (920 mg, 1.14 mmol, 1 eq), MeOH (30 mL), DCM (15 mL) and sodium borohydride (86 mg, 2.28 mmol, 2 eq). The resultant mixture was stirred (600 rpm) under nitrogen at ambient temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (80 mL) and washed with water (80 mL). The DCM layer was collected and the aqueous further extracted with DCM (40 mL).
  • the solution was allowed to cool to ambient temperature, diluted with water (20 mL) and then filtered through a porosity 3 filter (3 cm diameter) into a 250 mL RBF with a side arm adapter.
  • the reaction flask was rinsed with deionized water ( ⁇ 10 mL) which was passed through the filter to complete the transfer.
  • the filtrate was then freeze dried for 17 hours to give compound 29 as a dark brown fluffy solid (86 mg, 91% yield, 97.76% purity by HPLC).
  • photosensitizers for in vitro studies
  • photosensitizers stock solution 5.5mM in 100% DMSO
  • concentrated excipient solution final 55 ⁇ M photosensitizer in 10% w/v Kollidon-12, 42.4% w/v polysorbate 80, 0.6% w/v citric acid anhydrous, 40% w/v ethanol, 1.0% DMSO.
  • Serial dilutions were prepared in cell culture media (Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F-12)) supplemented with 10% v/v Fetal Bovine Serum, 100U/mL penicillin, 100 ⁇ g/mL streptomycin and the same excipient solution at a constant 1:55 dilution.
  • Cell culture Human ovarian cancer cell line SKOV3 ATCC #HTB-77 was maintained in Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F-12), supplemented with 10% v/v Fetal Bovine Serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin.
  • Monolayer cultures were grown in a humidified incubator at 37°C with 5% CO 2 . Once cells had reached ⁇ 80% confluence, spent media was replaced with media containing photosensitizer at the required concentration and cells were incubated for the desired period of time to allow photosensitizer uptake.
  • Statistical analyses All data were analysed using GraphPad PRISM v8.3.1 (549) (GraphPad Software, CA). Spectral absorbance and viability measurements were normalized in the range 0-100%, with a minimum of 0 and a maximum value determined from the dataset. Dose response was determined using a sigmoidal four-point non-linear regression with variable slope, and IC10 or IC90 calculated for each compound. All data are shown as mean ⁇ SD (where appropriate).
  • Cytotoxicity SKOV3 cells were seeded in 96-well black wall plates (Greiner #655090) at a cell density of 5000 cells in 100 ⁇ l culture medium per well. On reaching ⁇ 60% confluence, media was aspirated and replaced with fresh media containing the relevant chlorin e6 analogue from 0-100 ⁇ M in DMSO. Cells were incubated for a further 24 hours, allowing uptake of chlorin e6 analogues. To test for inherent cytotoxicity (i.e.
  • “dark toxicity”) of the chlorin e6 analogues the culture media was replaced after 24 hours with fresh media containing 10% (v/v) AlamarBlue Cell Viability Reagent (ThermoFisher) and cells incubated at 37°C for 6 hours. Untreated cells were used as a control. Fluorescence (Ex 555nm / Em 596nm) was measured using a Cytation 3 Cell Imaging Multi-Mode Reader (Biotek), and cytotoxicity assessed according to the % viable cells remaining. All measurements were made in quadruplicate. Phototoxicity SKOV3 cells were seeded in 96-well black wall plates (Greiner #655090) at a cell density of 5000 cells in 100 ⁇ l culture medium per well.
  • chlorin e6 analogues were compared against chlorin e4 disodium and Talaporfin sodium, a clinically approved photosensitizer used in the photodynamic treatment of lung cancers.
  • Phototoxicity and dark toxicity values are provided in Table 1. Most chlorin e6 analogues had phototoxicity IC90 values below 10nM (Table 1).
  • chlorin e6 analogues achieved an up to ⁇ 10,000-fold increase in phototoxicity compared to Talaporfin sodium, a clinically approved photosensitizer.
  • Substantial variation in the dark toxicity of the chlorin e6 analogues of the present invention was observed (Table 1). The greater phototoxicity afforded by the chlorin e6 analogues of the present invention, however, is expected to offset any dark toxicity issue through a decreased dose requirement in use.
  • TI Therapeutic Index for Chlorin e6 Analogues
  • TI provides a quantitative measurement to describe relative drug safety, by comparing the drug concentration required for desirable effects versus the concentration resulting in undesirable off-target toxicity.
  • TI was calculated using phototoxicity IC90 vs dark toxicity IC10.
  • the chlorin e6 analogues of the present invention had comparatively significantly improved TIs with substantially greater phototoxicity (Table 1).
  • the chlorin e6 analogues of the present invention have a desirable therapeutic index that is better than a clinically applied photosensitizer.
  • the greater phototoxicity of the chlorin e6 analogues suggests their potential use at a greatly reduced dose in vivo.
  • the chlorin e6 analogues therefore have an acceptable therapeutic profile for clinical application.
  • chlorin e6 analogues of the present invention which carry an ammonium, phosphonium, pyridinium or saccharidyl group (for example a -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y, -R ⁇ -[R 8 ]Y, -R ⁇ -[N(R 5 ) 2 (R 5’ )], -R ⁇ -[P(R 5 ) 2 (R 5’ )], -R ⁇ -[R 8’ ], or saccharidyl group as defined in the description and claims) are particularly preferred, because they have a better phototoxicity compared to similar compounds without such a group.
  • an ammonium, phosphonium, pyridinium or saccharidyl group for example a -R ⁇ -[N(R 5 ) 3 ]Y, -R ⁇ -[P(R 5 ) 3 ]Y
  • Example 3 Investigation of Stability of Chlorin e6 Analogue Salts in Aqueous Solution Procedure Reaction solutions were prepared by dissolving 2-3 mg of the respective chlorin e6 analogue salt in 5 mL of distilled deionised water in a 50 mL test tube fitted with a lid. The solutions were stirred in the test tubes at 30 °C. Air (oxygen) and ambient light were not excluded. Sample HPLC analyses were performed at 0.5, 4 or 66 hours (unless indicated otherwise). The aim was to look for degradation over time. The test results are summarised in table 2 below. Table 2: HPLC purities of chlorin e6 analogue salts in aqueous solution after 0.5, 4 and 66 hours (unless indicated otherwise).
  • Photolon and Photodithiazine are as follows: HPLC method Column and instrument details Instrument: Waters Alliance HPLC with Waters e2695 separations module and Waters 2998 PDA detector Column: YMC-Pack Pro C18 /S-3 ⁇ m /12nm.150 x 4.6mml. D.

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Abstract

The present invention relates to chlorin e6 analogues and their pharmaceutically acceptable salts, and compositions comprising chlorin e6 analogues and their pharmaceutically acceptable salts. Chlorin e6 analogues and pharmaceutically acceptable salts thereof are suitable for use in photodynamic therapy, cytoluminescent therapy and photodynamic diagnosis, for example, for treating or detecting a tumour, or for antiviral treatment. The present invention also relates to the use of chlorin e6 analogues and pharmaceutically acceptable salts thereof in the manufacture of a phototherapeutic or photodiagnostic agent, and to a method of photodynamic therapy, cytoluminescent therapy or photodynamic diagnosis, for example, for treating or detecting a tumour, or for antiviral treatment.

Description

PORPHYRIN AND PHOSPHONIUM-PORPHYRIN BASED COMPOUNDS FOR PHOTODYNAMIC THERAPY AND DIAGNOSTICS
Technical field The present invention relates to chlorin e6 analogues and their pharmaceutically acceptable salts, and compositions comprising chlorin eP analogues and their pharmaceutically acceptable salts. Chlorin e6 analogues and pharmaceutically acceptable salts thereof are suitable for use in photodynamic therapy, cytoluminescent therapy and photodynamic diagnosis, for example, for treating or detecting a tumour, or for antiviral treatment. The present invention also relates to the use of chlorin e6 analogues and pharmaceutically acceptable salts thereof in the manufacture of a phototherapeutic or photodiagnostic agent, and to a method of photodynamic therapy, cytoluminescent therapy or photodynamic diagnosis, for example, for treating or detecting a tumour, or for antiviral treatment.
Figure imgf000002_0001
Background art
Porphyrins and their analogues are known photosensitive chemical compounds, which can absorb light photons and emit them at higher wavelengths. There are many applications for such unique properties and PDT (photodynamic therapy) is one of them. Presently, there are two generations of photosensitizers for PDT. The first generation comprises heme porphyrins (blood derivatives), and the second for the most part are chlorophyll analogues. The later compounds are known as chlorins and bacteriochlorins.
Chlorin e4 has been shown to display good photosensitive activity. It was indicated that chlorin e4 has a protective effect against indomethacin-induced gastric lesions in rats and TAA- or CCI4 -induced acute liver injuries in mice. It was therefore suggested that chlorin e4 may be a promising new drug candidate for anti-gastrelcosis and liver injuiy protection. WO 2009/040411 suggests the use of a chlorin e4 zinc complex in photodynamic therapy and WO 2014/091241 suggests the use of chlorin e4 disodium in photodynamic therapy.
Figure imgf000003_0001
While the conjugation of molecules to triphenylphosphonium cations is known in the literature to enhance delivery to the mitochondria, this is not always guaranteed as demonstrated in a recent paper by Gilson et al (Bioconjugate Chemistry, 2019, vol 30(5), pages 1451-1458). The addition of one triphenylphosphonium cation to the known photodynamic agent chlorin e6 resulted in the derivative accumulating in the lysosomes, while the addition of two triphenylphosphonium cations resulted in distribution to the lysosomes and the mitochondria. The authors concluded that “mitochondrial localized PS did not improve cell killing in this study” and the unconjugated parent chlorin e6 displayed better photodynamic (cell killing) activity than the two triphenylphosphonium conjugated derivatives. There is an ongoing need for better photosensitizers. There is a need for compounds that have a high singlet oxygen quantum yield and for compounds that have a strong photosensitizing ability, preferably in organic and aqueous media. There is also a need for compounds that have a high fluorescence quantum yield. In addition, there is a need for compounds and/or compositions which have a higher phototoxicity, a lower dark toxicity, good stability, good solubility, and/or are easily purified. Summary of the invention A first aspect of the present invention provides a compound of formula (I) or a complex of formula (II):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein: -R1 is selected from -CH2OR2, -CH2SR2, -CH2S(O)R2, -CH2S(O)2R2, -CH2N(R2)2, -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2 (preferably -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2); -R2, each independently, is selected from -H, -C(O)R4, -C(O)-OR4, -C(O)-SR4, -C(O)-N(R4)2, -C(S)-OR4, -C(S)-SR4, -C(S)-N(R4)2, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)] or -Rα-[R8’]; -R3 and -R4, each independently, is selected from -H, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)] or -Rα-[R8’]; -Rα-, each independently, is selected from a C1-C42 alkylene group, wherein the alkylene group may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; -Rβ, each independently, is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O, S, P or Se in its carbon skeleton; -R5, each independently, is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R5’ is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, each substituted with -CO2 ‾, wherein the phenyl or C5-C6 heteroaryl may optionally be further substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2; -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2; -R8 is -[NC5H5] optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R8’ is -[NC5H5] substituted with -CO2 ‾ and optionally further substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X; n is 1, 2, 3, 4, 5 or 6; X is a halo group; Y is a counter anion; Z is a counter cation; and M2+ is a metal cation. A second aspect of the present invention provides a compound of formula (I) or a complex of formula (II) according to the first aspect of the invention, for use in medicine. In one embodiment of the first or second aspect of the present invention, at least one of -R1, -R7 and -R9 comprises -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)], -Rα-[R8’], or a saccharidyl group. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X. In the context of the present specification, a “hydrocarbyl” substituent group or a hydrocarbyl moiety in a substituent group only includes carbon and hydrogen atoms but, unless stated otherwise, does not include any heteroatoms, such as N, O, S, P or Se in its carbon skeleton. A hydrocarbyl group/moiety may be saturated or unsaturated (including aromatic), and may be straight-chained or branched, or be or include cyclic groups wherein, unless stated otherwise, the cyclic group does not include any heteroatoms, such as N, O, S, P or Se in its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups/moieties and combinations of all of these groups/moieties. Typically a hydrocarbyl group is a C1- C60 hydrocarbyl group, more typically a C1-C40 hydrocarbyl group, more typically a C1- C20 hydrocarbyl group. More typically a hydrocarbyl group is a C1-C12 hydrocarbyl group. More typically a hydrocarbyl group is a C1-C10 hydrocarbyl group. A “hydrocarbylene” group is similarly defined as a divalent hydrocarbyl group. An “alkyl” substituent group or an alkyl moiety in a substituent group may be linear (i.e. straight-chained) or branched. Examples of alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups/moieties. Unless stated otherwise, the term “alkyl” does not include “cycloalkyl”. Typically an alkyl group is a C1-C12 alkyl group. More typically an alkyl group is a C1-C6 alkyl group. An “alkylene” group is similarly defined as a divalent alkyl group. Typically an alkylene group is a C1-C42 alkylene group. More typically an alkylene group is a C1-C32 alkylene group, or a C1-C22 alkylene group, or a C1-C12 alkylene group. An “alkenyl” substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds. Examples of alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups/ moieties. Unless stated otherwise, the term “alkenyl” does not include “cycloalkenyl”. Typically an alkenyl group is a C2-C12 alkenyl group. More typically an alkenyl group is a C2-C6 alkenyl group. An “alkenylene” group is similarly defined as a divalent alkenyl group. An “alkynyl” substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds. Examples of alkynyl groups/moieties include ethynyl, propargyl, but-1-ynyl and but-2- ynyl. Typically an alkynyl group is a C2-C12 alkynyl group. More typically an alkynyl group is a C2-C6 alkynyl group. An “alkynylene” group is similarly defined as a divalent alkynyl group.
A “cyclic” substituent group or a cyclic moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated (including aromatic) and may include one or more heteroatoms, e.g. N, 0, S, P or Se in its carbon skeleton. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaiyl groups as discussed below. A cyclic group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic. Typically, a cyclic group is a 3- to 12-membered cyclic group, which means it contains from 3 to 12 ring atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms.
A “heterocyclic” substituent group or a heterocyclic moiety in a substituent group refers to a cyclic group or moiety including one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, 0, S, P or Se in the ring structure. Examples of heterocyclic groups include heteroaryl groups as discussed below and nonaromatic heterocyclic groups such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, thietanyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, thianyl and dioxanyl groups. A “cycloalkyl” substituent group or a cycloalkyl moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings. A “cycloalkenyl” substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon- carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex-1,3-dien-1-yl. Unless stated otherwise, a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings. An “aryl” substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring. The term “aryl” includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless stated otherwise, the term “aryl” does not include “heteroaryl”. A “heteroaryl” substituent group or a heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety. The term “heteroaryl” includes monocyclic aromatic heterocycles and polycyclic fused ring aromatic heterocycles wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic. Examples of heteroaryl groups/moieties include the following:
Figure imgf000008_0001
wherein G = O, S or NH. For the purposes of the present specification, where a combination of moieties is referred to as one group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl. For the purposes of the present specification, in an optionally substituted group or moiety (such as -Rβ): (i) each hydrogen atom may optionally be replaced by a monovalent substituent independently selected from halo; -CN; -NO2; -N3; -Rx; -OH; -ORx; -Ry-halo; -Ry-CN; -Ry-NO2; -Ry-N3; -Ry-Rx; -Ry-OH; -Ry-ORx; -SH; -SRx; -SORx; -SO2H; -SO2Rx; -SO2NH2; -SO2NHRx; -SO2N(Rx)2; -Ry-SH; -Ry-SRx; -Ry-SORx; -Ry-SO2H; -Ry-SO2Rx; -Ry-SO2NH2; -Ry-SO2NHRx; -Ry-SO2N(Rx)2; -NH2; -NHRx; -N(Rx)2; -N+(Rx)3; -Ry-NH2; -Ry-NHRx; -Ry-N(Rx)2; -Ry-N+(Rx)3; -CHO; -CORx; -COOH; -COORx; -OCORx; -Ry-CHO; -Ry-CORx; -Ry-COOH; -Ry-COORx; or -Ry-OCORx; and/or (ii) any two hydrogen atoms attached to the same carbon atom may optionally be replaced by a π-bonded substituent independently selected from oxo (=O), =S, =NH, or =NRx; and/or (iii) any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or moiety, may optionally be replaced by a bridging substituent independently selected from -O-, -S-, -NH-, -N(Rx)-, -N+(Rx)2- or -Ry-; wherein each -Ry- is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or -Rx groups; and wherein each -Rx is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, or wherein any two or three -Rx attached to the same nitrogen atom may, together with the nitrogen atom to which they are attached, form a C2-C7 cyclic group, and wherein any -Rx may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -OH, -NH2, -CN, or oxo (=O) groups. Typically a substituted group comprises 1, 2, 3 or 4 substituents, more typically 1, 2 or 3 substituents, more typically 1 or 2 substituents, and more typically 1 substituent. Unless stated otherwise, any divalent bridging substituent (e.g. -O-, -S-, -NH-, -N(Rx)-, -N+(Rx)2- or -Ry-) of an optionally substituted group or moiety must only be attached to the specified group or moiety and may not be attached to a second group or moiety, even if the second group or moiety can itself be optionally substituted. The term “halo” includes fluoro, chloro, bromo and iodo. Unless stated otherwise, where a group is prefixed by the term “halo”, such as a haloalkyl or halomethyl group, it is to be understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without the halo prefix. For example, a halomethyl group may contain one, two or three halo substituents. A haloethyl or halophenyl group may contain one, two, three, four or five halo substituents. Similarly, unless stated otherwise, where a group is prefixed by a specific halo group, it is to be understood that the group in question is substituted with one or more of the specific halo groups. For example, the term “fluoromethyl” refers to a methyl group substituted with one, two or three fluoro groups. Unless stated otherwise, where a group is said to be “halo-substituted”, it is to be understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group said to be halo-substituted. For example, a halo- substituted methyl group may contain one, two or three halo substituents. A halo- substituted ethyl or halo-substituted phenyl group may contain one, two, three, four or five halo substituents. Unless stated otherwise, any reference to an element is to be considered a reference to all isotopes of that element. Thus, for example, unless stated otherwise any reference to hydrogen is considered to encompass all isotopes of hydrogen including deuterium and tritium. Unless stated otherwise, any reference to a compound or group is to be considered a reference to all tautomers of that compound or group. Where reference is made to a hydrocarbyl or other group including one or more heteroatoms N, O, S, P or Se in its carbon skeleton, or where reference is made to a carbon atom of a hydrocarbyl or other group being replaced by an N, O, S, P or Se atom, what is intended is that:
Figure imgf000011_0001
–CH2– is replaced by –NH–, –PH–, –O–, –S– or –Se–; –CH3 is replaced by –NH2, –PH2, –OH, –SH or –SeH; –CH= is replaced by –N= or –P=; CH2= is replaced by NH=, PH=, O=, S= or Se=; or CH≡ is replaced by N≡ or P≡; provided that the resultant group comprises at least one carbon atom. For example, methoxy, dimethylamino and aminoethyl groups are considered to be hydrocarbyl groups including one or more heteroatoms N, O, S, P or Se in their carbon skeleton. In the context of the present specification, unless otherwise stated, a Cx-Cy group is defined as a group containing from x to y carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms. Optional substituents and moieties are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituents and/or containing the optional moieties. For the avoidance of doubt, replacement heteroatoms, e.g. N, O, S, P or Se, are to be counted as carbon atoms when calculating the number of carbon atoms in a Cx-Cy group. For example, a morpholinyl group is to be considered a C6 heterocyclic group, not a C4 heterocyclic group. The π electrons of the chlorin ring are delocalised and therefore the chlorin ring can be depicted by more than one resonance structure. Resonance structures are different ways of drawing the same compound. Two of the resonance structures of the chlorin ring are depicted directly below:
Figure imgf000012_0001
Typically a complex comprises a central metal atom or ion known as the coordination centre and a bound molecule or ion which is known as a ligand. In the present specification, the bond between the coordination centre and the ligand is depicted as shown in the complex on the below left (where the attraction between an anionic ligand and a central metal cation is represented by four dashed lines), but equivalently it could be depicted as shown in the complex on the below right (where the attraction between a ligand molecule and a central metal atom is represented by two covalent bonds and two dashed lines):
Figure imgf000012_0002
As used herein -[NC5H5]Y refers to:
Figure imgf000012_0003
In one embodiment of the first or second aspect of the present invention, X is a halo group selected from fluoro, chloro, bromo, or iodo. In one embodiment, X is chloro or bromo. In one embodiment of the first or second aspect of the present invention, there is provided a compound of formula (I). In one embodiment of the first or second aspect of the present invention, Y is a counter anion selected from halides (for example fluoride, chloride, bromide, or iodide) or other inorganic anions (for example bisulfate, hexafluorophosphate (PF6), nitrate, perchlorate, phosphate, or sulfate) or organic anions (for example acetate, ascorbate, aspartate, benzoate, besylate (benzenesulfonate), bicarbonate, bis(trifluoromethanesulfonyl)imide (TFSI), bitartrate, butyrate, camsylate (camphorsulfonate), carbonate, citrate, decanoate, edetate, esylate (ethanesulfonate), fumarate, galactarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, β- hydroxybutyrate, 2-hydroxyethanesulfonate, hydroxymaleate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate (methanesulfonate), methylsulfate, mucate, napsylate (naphthalene-2-sulfonate), octanoate, oleate, ornithinate, pamoate, pantothenate, polygalacturonate, propanoate, propionate, salicylate, stearate, succinate, tartrate, teoclate, tetrakis[3,5- bis(trifluoromethyl)phenyl]borate (BARF), tetrakis(pentafluorophenyl)borate (F5- TPB), tetraphenylborate (TPB), tosylate (toluene-p-sulfonate), or triflate (trifluoromethanesulfonate)). In another embodiment of the first or second aspect of the present invention, Y is a counter anion selected from halides (for example fluoride, chloride, bromide, or iodide) or other inorganic anions (for example bisulfate, nitrate, perchlorate, phosphate, or sulfate) or organic anions (for example acetate, aspartate, benzoate, besylate (benzenesulfonate), butyrate, camsylate (camphorsulfonate), citrate, esylate (ethanesulfonate), fumarate, galactarate, gluconate, glutamate, glycolate, 2- hydroxyethanesulfonate, hydroxymaleate, lactate, malate, maleate, mandelate, mesylate (methanesulfonate), napsylate (naphthalene-2-sulfonate), ornithinate, pamoate, pantothenate, propanoate, salicylate, succinate, tartrate, tosylate (toluene-p- sulfonate), or triflate (trifluoromethanesulfonate)). In one embodiment, Y is fluoride, chloride, bromide or iodide. In one embodiment, Y is chloride or bromide. In one embodiment of the first or second aspect of the present invention, Z is a counter cation selected from inorganic cations (for example lithium, sodium, potassium, magnesium, calcium or ammonium cation) or organic cations (for example amine cations (for example choline or meglumine cation) or amino acid cations (for example arginine cation). In one embodiment of the first or second aspect of the present invention, M2+ is a metal cation selected from Zn2+, Cu2+, Fe2+, Pd2+ or Pt2+. In one embodiment, M2+ is Zn2+. In one embodiment of the first or second aspect of the present invention, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2. In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2 or -C(S)-N(R3)2. In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2. In one embodiment of the first or second aspect of the present invention, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2, and each -R3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2 or -C(S)-N(R3)2, and each -R3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2, and each -R3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-OR3 and -R3 is C1-C4 alkyl (preferably methyl). In one embodiment of the first or second aspect of the present invention, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’), wherein -R2 or -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group, and -R3’ is C1-C4 alkyl (preferably methyl). Typically in these embodiments, -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -Rα- is a C1-C12 alkylene group (preferably a C1-C8 alkylene group, or a C1-C6 alkylene group), a –(CH2CH2O)m–CH2CH2– group or a –(CH2CH2S)m–CH2CH2– group, all optionally substituted, wherein m is 1, 2, 3 or 4. An -R3’ group refers to an -R3 group attached to the same atom as another -R3 group. -R3 and -R3’ may be the same or different. Preferably -R3 and -R3’ are different. In one embodiment of the first or second aspect of the present invention, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’), wherein -R2 or -R3 is selected from -Rα-Rβ or -Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’), wherein -R3 is selected from -Rα-Rβ or -Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-Rβ or -Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -Rα- is a C1-C12 alkylene group (preferably a C1-C8 alkylene group, or a C1-C6 alkylene group), a –(CH2CH2O)m– group or a –(CH2CH2S)m– group, all optionally substituted, wherein m is 1, 2, 3 or 4. In any of the embodiments in the three preceding paragraphs, the saccharidyl group may optionally be substituted, for example, with a protecting group such as acetyl or a natural amino acid such as valine. Amino acids can be attached to saccharidyl groups, for example, by forming an ester between a carboxylic acid group of the amino acid and a hydroxyl group of the saccharidyl group. In one embodiment of the first or second aspect of the present invention, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’), wherein -R2 or -R3 is selected from -Rα-Rβ or -Rβ, and -Rβ is a C1-C8 alkyl group optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) -OH or -OAc groups, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’), wherein -R3 is selected from -Rα-Rβ or -Rβ, and -Rβ is a C1-C8 alkyl group optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) hydroxyl groups, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-Rβ or -Rβ, and -Rβ is a C1-C8 alkyl group optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) hydroxyl groups, and -R3’ is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -Rα- is an unsubstituted C1-C6 alkylene group, or an unsubstituted C1-C4 alkylene group, or an unsubstituted C1-C2 alkylene group. In one embodiment of the first or second aspect of the present invention, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’); wherein -R2 or -R3 is selected from -Rα-H or -Rα-OH; -Rα- is selected from a C1-C12 alkylene group, wherein the alkylene group may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by one or more heteroatoms O or S; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’); wherein -R3 is selected from -Rα-H or -Rα-OH; -Rα- is selected from a C1-C12 alkylene group, wherein the alkylene group may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by one or more heteroatoms O or S; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’); wherein -R3 is selected from -Rα-H or -Rα-OH; -Rα- is selected from a C1-C12 alkylene group, wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by one or more heteroatoms O or S; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment of the first or second aspect of the present invention, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’); wherein -R2 or -R3 is -Rβ; -Rβ is a C1-C12 alkyl or C2-C12 alkenyl group optionally substituted with one or more (such as one, two, three, four or five) substituents independently selected from halo, -CN, -NO2, -N3, -OH, -ORx, -SH, -SRx, -SORx, -SO2H, -SO2Rx, -SO2NH2, -SO2NHRx, -SO2N(Rx)2, -NH2, -NHRx, -N(Rx)2, -N+(Rx)3, -CHO, -CORx, -COOH, -COORx, -OCORx, or -NH-CO-CRz-NH2; each -Rx is independently selected from C1-C4 alkyl; -Rz is the side chain of a natural amino acid; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’); wherein -R3 is -Rβ; -Rβ is a C1-C12 alkyl group optionally substituted with one or more (such as one, two, three, four or five) substituents independently selected from halo, -CN, -NO2, -N3, -OH, -ORx, -SH, -SRx, -SORx, -SO2H, -SO2Rx, -SO2NH2, -SO2NHRx, -SO2N(Rx)2, -NH2, -NHRx, -N(Rx)2, -N+(Rx)3, -CHO, -CORx, -COOH, -COORx, -OCORx, or -NH-CO-CRz-NH2; each -Rx is independently selected from C1-C4 alkyl; -Rz is the side chain of a natural amino acid; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’); wherein -R3 is -Rβ; -Rβ is a C1-C8 alkyl group optionally substituted with one or more (such as one, two or three) substituents independently selected from halo, -CN, -NO2, -N3, -OH, -ORx, -SH, -SRx, -SORx, -SO2H, -SO2Rx, -SO2NH2, -SO2NHRx, -SO2N(Rx)2, -NH2, -NHRx, -N(Rx)2, -N+(Rx)3, -CHO, -CORx, -COOH, -COORx, -OCORx, or -NH-CO-CRz-NH2; each -Rx is independently selected from C1-C4 alkyl; -Rz is the side chain of a natural amino acid; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment of the first or second aspect of the present invention, -R1 is selected from -CO-(NRzz-CHRz-CO)v-N(Rzz)2 and -CO-(NRzz-CHRz-CO)v-ORzz; wherein each -Rz is independently selected from the side chains of natural amino acids; each -Rzz is independently selected from hydrogen and C1-C4 alkyl (preferably methyl); and v is 1, 2, 3, 4, 5, 6, 7 or 8. In one embodiment of the first or second aspect of the present invention, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’); wherein -R2 or -R3 is -Rβ; -Rβ is selected from a C1-C20 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment of the first or second aspect of the present invention, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’); -R3’ is H or C1-C4 alkyl (preferably methyl); and -R2 or -R3 is selected from -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y. In one embodiment, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’); -R3’ is H or C1-C4 alkyl (preferably methyl); -R2 or -R3 is selected from -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y; each -R5 is independently selected from C1-C4 alkyl or phenyl wherein the phenyl is optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R8 is -[NC5H5] optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; and Y is a counter ion (preferably a halide). In one embodiment of the first or second aspect of the present invention, -R1 is selected from -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’); wherein -R2 or -R3 is -Rα-[P(R5)3]Y; each -R5 is independently selected from phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; n is 1, 2, 3 or 4; Y is fluoride, chloride, bromide or iodide; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’); wherein -R3 is -Rα-[P(R5)3]Y; each -R5 is independently selected from phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; n is 1, 2, 3 or 4; Y is fluoride, chloride, bromide or iodide; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R1 is -C(O)-N(R3)(R3’); wherein -R3 is -Rα-[P(R5)3]Y; each -R5 is independently selected from phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; n is 1, 2, 3 or 4; Y is fluoride, chloride, bromide or iodide; and -R3’ is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -Rα- is a C1-C12 alkylene group (preferably a C1-C8 alkylene group, or a C1-C6 alkylene group), a –(CH2CH2O)m–CH2CH2– group or a –(CH2CH2S)m–CH2CH2– group, all optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment of the first or second aspect of the present invention, -R1 is -C(O)-OR3, wherein -R3 is selected from hydrogen, C1-C4 alkyl (preferably methyl) or a cation (such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation). In one embodiment, -R1 is -C(O)-OR3, wherein -R3 is selected from C1-C4 alkyl (preferably methyl) or a cation (such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation). In one embodiment of the first or second aspect of the present invention, -R1 is -C(O)-N(R3)2. In one embodiment, -R1 is -C(O)-N(C1-C4 alkyl)(R3) or -C(O)-NHR3. In one embodiment, -R1 is -C(O)-N(CH3)(R3) or -C(O)-NHR3. In one embodiment, -R1 is -C(O)-N(C1-C4 alkyl)(R3). In one embodiment, -R1 is -C(O)-N(CH3)(R3). In one embodiment of the first or second aspect of the present invention, -R1 is selected from -CH2OR2, -CH2SR2, -CH2S(O)R2, -CH2S(O)2R2, -CH2N(R2)2, or -R2. In one embodiment, -R1 is selected from -CH2OR2, -CH2SR2, -CH2N(R2)2, or -R2. In one embodiment, -R1 is selected from -CH2OR2, -CH2SR2, or -CH2N(R2)2. In one embodiment, -R1 is selected from -CH2OR2 or -CH2SR2. In one embodiment, -R1 is -CH2OR2. In one embodiment, -R1 is -R2, and -R2 is -Rα-X. In one embodiment of the first or second aspect of the present invention, -R2 is selected from -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[NC5H5]Y. In one embodiment, -R2 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ. In one embodiment, -R2 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, -R2 is selected from -Rα-ORβ or -Rα-SRβ. In one embodiment, -R2 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group. In one embodiment of the first or second aspect of the present invention, -R2 is selected from -C(O)R4, -C(O)-OR4, -C(O)-SR4, -C(O)-N(R4)2, -C(S)-OR4, -C(S)-SR4 or -C(S)-N(R4)2. In one embodiment, -R2 is selected from -C(O)R4, -C(O)-OR4, -C(O)-SR4, -C(O)-N(R4)2 or -C(S)-N(R4)2. In one embodiment, -R2 is selected from -C(O)R4, -C(O)-OR4, -C(O)-SR4 or -C(O)-N(R4)2. In one embodiment of the first or second aspect of the present invention, -R2 is -C(O)-N(R4)(R4’), wherein -R4 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R4’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R2 is -C(O)-N(R4)(R4’), wherein -R4 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group, and -R4’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R2 is -C(O)-N(R4)(R4’), wherein -R4 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R4’ is C1-C4 alkyl (preferably methyl). In one embodiment, -R2 is -C(O)-N(R4)(R4’), wherein -R4 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group, and -R4’ is C1-C4 alkyl (preferably methyl). An -R4’ group refers to an -R4 group attached to the same atom as another -R4 group. -R4 and -R4’ may be the same or different. Preferably -R4 and -R4’ are different. In one embodiment of the first or second aspect of the present invention, -R2 is -C(O)-N(R4)2. In one embodiment, -R2 is -C(O)-N(C1-C4 alkyl)(R4). In one embodiment, -R2 is -C(O)-N(CH3)(R4). In one embodiment of the first or second aspect of the present invention, -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2, and each -R3 is C1-C4 alkyl, preferably each -R3 is methyl. In one embodiment, -R6 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2, and each -R3 is C1-C4 alkyl, preferably each -R3 is methyl. In one embodiment, -R6 is -C(O)-OR3, and -R3 is C1-C4 alkyl, preferably -R3 is methyl. In one embodiment of the first or second aspect of the present invention, -R6 is -C(O)-OR3, wherein -R3 is selected from hydrogen, C1-C4 alkyl (preferably methyl) or a cation (such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation). In one embodiment of the first or second aspect of the present invention, -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’); wherein -R3 is -Rβ; -Rβ is selected from a C1-C20 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment of the first or second aspect of the present invention, -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2, and each -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, -R6 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2, and each -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, -R6 is selected from -C(O)-OR3 or -C(O)-SR3, and -R3 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group. Typically in these embodiments, -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -Rα- is a C1-C12 alkylene group (preferably a C1-C8 alkylene group, or a C1-C6 alkylene group), a –(CH2CH2O)m–CH2CH2– group or a –(CH2CH2S)m–CH2CH2– group, all optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment of the first or second aspect of the present invention, -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R6 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R6 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -Rα- is a C1-C12 alkylene group (preferably a C1-C8 alkylene group, or a C1-C6 alkylene group), a –(CH2CH2O)m–CH2CH2– group or a –(CH2CH2S)m–CH2CH2– group, all optionally substituted, wherein m is 1, 2, 3 or 4. An -R3’ group refers to an -R3 group attached to the same atom as another -R3 group. -R3 and -R3’ may be the same or different. Preferably -R3 and -R3’ are different. In one embodiment of the first or second aspect of the present invention, -R6 is -C(O)-N(R3)2. In one embodiment, -R6 is -C(O)-N(C1-C4 alkyl)(R3) or -C(O)-NHR3. In one embodiment, -R6 is -C(O)-N(CH3)(R3) or -C(O)-NHR3. In one embodiment of the first or second aspect of the present invention, -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2, and each -R3 is C1-C4 alkyl, preferably each -R3 is methyl. In one embodiment, -R7 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2, and each -R3 is C1-C4 alkyl, preferably each -R3 is methyl. In one embodiment, -R7 is -C(O)-OR3, and -R3 is C1-C4 alkyl, preferably -R3 is methyl. In one embodiment of the first or second aspect of the present invention, -R7 is -C(O)-OR3, wherein -R3 is selected from hydrogen, C1-C4 alkyl (preferably methyl) or a cation (such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) cation). In one embodiment of the first or second aspect of the present invention, -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3, -C(S)-N(R3)2 or -C(S)-N(R3)(R3’); wherein -R3 is -Rβ; -Rβ is selected from a C1-C20 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment of the first or second aspect of the present invention, -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2, and each -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, -R7 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2, and each -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, -R7 is selected from -C(O)-OR3 or -C(O)-SR3, and -R3 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group. Typically in these embodiments, -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -Rα- is a C1-C12 alkylene group (preferably a C1-C8 alkylene group, or a C1-C6 alkylene group), a –(CH2CH2O)m–CH2CH2– group or a –(CH2CH2S)m–CH2CH2– group, all optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment of the first or second aspect of the present invention, -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’) or -C(S)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R7 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R7 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -Rα- is a C1-C12 alkylene group (preferably a C1-C8 alkylene group, or a C1-C6 alkylene group), a –(CH2CH2O)m–CH2CH2– group or a –(CH2CH2S)m–CH2CH2– group, all optionally substituted, wherein m is 1, 2, 3 or 4. An -R3’ group refers to an -R3 group attached to the same atom as another -R3 group. -R3 and -R3’ may be the same or different. Preferably -R3 and -R3’ are different. In one embodiment of the first or second aspect of the present invention, -R7 is -C(O)-N(R3)2. In one embodiment, -R7 is -C(O)-N(C1-C4 alkyl)(R3) or -C(O)-NHR3. In one embodiment, -R7 is -C(O)-N(CH3)(R3) or -C(O)-NHR3. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2 or -S(O)2R2. In one embodiment, -R9 is selected from -OR2, -SR2, -S(O)R2 or -S(O)2R2. In one embodiment, -R9 is selected from -OR2 or -SR2. In one embodiment, -R9 is -OR2. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2 or -S(O)2R2, and -R2 is selected from -H, -C(O)R4, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[NC5H5]Y. In one embodiment, -R9 is selected from -OR2, -SR2, -S(O)R2 or -S(O)2R2, and -R2 is selected from -H, -C(O)R4, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[NC5H5]Y. In one embodiment, -R9 is selected from -OR2 or -SR2, and -R2 is selected from -H, -C(O)R4, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[NC5H5]Y. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -N(R2)2, -N(R2)(R2’), -SR2, -S(O)R2 or -S(O)2R2; -R2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl); -R2 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ; and optionally -Rβ is a saccharidyl group. In one embodiment, -R9 is selected from -OR2, -SR2, -S(O)R2 or -S(O)2R2, and -R2 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and optionally -Rβ is a saccharidyl group. In one embodiment, -R9 is selected from -OR2, -SR2, -S(O)R2 or -S(O)2R2, and -R2 is selected from -Rα-ORβ or -Rα-SRβ, and optionally -Rβ is a saccharidyl group. In one embodiment, -R9 is selected from -OR2 or -SR2, and -R2 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and optionally -Rβ is a saccharidyl group. In one embodiment, -R9 is selected from -OR2 or -SR2, and -R2 is selected from -Rα-ORβ or -Rα-SRβ, and optionally -Rβ is a saccharidyl group. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -N(R2)2, -N(R2)(R2’), -SR2, -S(O)R2 or -S(O)2R2; -R2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl); and -R2 is -C(O)R4. In one embodiment, -R9 is selected from -OR2, -N(R2)2, -N(R2)(R2’), -SR2, -S(O)R2 or -S(O)2R2; -R2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl); -R2 is -C(O)R4; -R4 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ; and -Rβ is a saccharidyl group. In one embodiment, -R9 is selected from -OR2, -N(R2)2, -N(R2)(R2’), -SR2, -S(O)R2 or -S(O)2R2; -R2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl); -R2 is -C(O)R4; -R4 is selected from -Rα-ORβ or -Rα-SRβ; and -Rβ is a saccharidyl group. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -SR2, -S(O)R2 or -S(O)2R2, and -R2 is -C(O)R4. In one embodiment, -R9 is selected from -OR2, -SR2, -S(O)R2 or -S(O)2R2, and -R2 is -C(O)R4, and -R4 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, -R9 is selected from -OR2, -SR2, -S(O)R2 or -S(O)2R2, and -R2 is -C(O)R4, and -R4 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2 or -SR2, and -R2 is -C(O)R4. In one embodiment, -R9 is selected from -OR2 or -SR2, and -R2 is -C(O)R4, and -R4 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, -R9 is selected from -OR2 or -SR2, and -R2 is -C(O)R4, and -R4 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -N(R2)2, -N(R2)(R2’), -SR2, -S(O)R2 or -S(O)2R2; -R2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl); -R2 is selected from -Rβ, -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ; -Rβ is a saccharidyl group; and -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. In one embodiment, -R9 is selected from -OR2, -N(R2)(R2’) or -SR2; -R2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl); -R2 is selected from -Rβ, -Rα-ORβ or -Rα-SRβ; -Rβ is a saccharidyl group; and -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. In any of the embodiments in the five preceding paragraphs, the saccharidyl group may optionally be substituted, for example, with a protecting group such as acetyl or a natural amino acid such as valine. Amino acids can be attached to saccharidyl groups, for example, by forming an ester between a carboxylic acid group of the amino acid and a hydroxyl group of the saccharidyl group. In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -N(R2)2, -N(R2)(R2’), -SR2, -S(O)R2 or -S(O)2R2; -R2’ is selected from hydrogen, C1-C4 alkyl or -CO2(C1-C4 alkyl); -R2 is selected from -C(O)R4, -C(O)-OR4, -C(O)-N(R4)(R4’), -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y; -R4’ is selected from hydrogen or C1-C4 alkyl; and -R4 is selected from -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y. In one embodiment, -R9 is selected from -OR2, -N(R2)(R2’), -SR2, -S(O)R2 or -S(O)2R2; -R2’ is selected from hydrogen, C1-C4 alkyl or -CO2(C1-C4 alkyl); -R2 is selected from -C(O)R4, -C(O)-OR4, -C(O)-N(R4)(R4’), -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y; -R4’ is selected from hydrogen or C1-C4 alkyl; -R4 is selected from -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y; each -R5 is independently selected from C1-C4 alkyl or phenyl wherein the phenyl is optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R8 is -[NC5H5] optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; and Y is a counter ion (preferably a halide). In one embodiment, -R9 is selected from -OR2 or -N(R2)(R2’); -R2’ is selected from hydrogen, C1-C4 alkyl or -CO2(C1-C4 alkyl); -R2 is selected from -C(O)R4, -C(O)-OR4, -C(O)-N(R4)(R4’), -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y; -R4’ is selected from hydrogen or C1-C4 alkyl; -R4 is selected from -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y; each -R5 is independently selected from C1-C4 alkyl or phenyl wherein the phenyl is optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R8 is -[NC5H5] optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -Rα- is selected from a C1-C12 alkylene group, wherein one, two, three or four carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; and Y is a counter ion (preferably a halide). In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2 or -S(O)2R2; and -R2 is selected from hydrogen, C1-C4 alkyl, -CO(C1-C4 alkyl) or -CO2(C1-C4 alkyl). In one embodiment, -R9 is selected from -OR2 or -N(R2)2; and -R2 is selected from hydrogen, C1-C4 alkyl, -CO(C1-C4 alkyl) or -CO2(C1-C4 alkyl). In one embodiment of the first or second aspect of the present invention, -R9 is selected from -OR2, -N(R2)2, -N(R2)(R2’), -SR2, -S(O)R2 or -S(O)2R2; -R2’ is selected from hydrogen or C1-C4 alkyl; -R2 is selected from -R4, -C(O)R4, -C(O)-OR4 or -C(O)-N(R4)(R4’); -R4’ is selected from hydrogen or C1-C4 alkyl; and -R4 is selected from a C1-C12 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three or four carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. In one embodiment, -R9 is selected from -OR2 or -N(R2)(R2’); -R2’ is selected from hydrogen or C1-C4 alkyl; -R2 is selected from -R4, -C(O)R4, -C(O)-OR4 or -C(O)-N(R4)(R4’); -R4’ is selected from hydrogen or C1-C4 alkyl; and -R4 is selected from a C1-C12 alkyl group, wherein the alkyl group may optionally be substituted with one, two, three or four halo groups, and wherein one, two, three or four carbon atoms in the backbone of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe. In one embodiment of the first or second aspect of the present invention, each -Rα- is independently a C1-C12 alkylene group, a –(CH2CH2O)m– group, a –(CH2CH2S)m– group, a –(CH2CH2O)m–CH2CH2– group or a –(CH2CH2S)m–CH2CH2– group, all optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment, each -Rα- is independently a C1-C12 alkylene group, a –(CH2CH2O)m– group or a –(CH2CH2S)m– group, all optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment, each -Rα- is independently a C1-C12 alkylene group or a –(CH2CH2O)m– group, both optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment, each -Rα- is independently an optionally substituted –(CH2CH2O)m– group, wherein m is 1, 2, 3 or 4. In one embodiment of the first or second aspect of the present invention, each -Rα- is independently a C1-C8 alkylene group, or a C1-C6 alkylene group, or a C2-C4 alkylene group, all optionally substituted. In one embodiment of the first or second aspect of the present invention, each -Rα- is independently unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In one embodiment, each -Rα- is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In one embodiment, each -Rα- is unsubstituted. In one embodiment of the first or second aspect of the present invention, each -Rβ is independently a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. In one embodiment of the first or second aspect of the present invention, at least one -Rβ is independently a C1-C6 alkyl group, or a C1-C4 alkyl group, or a methyl group, all optionally substituted. In one embodiment, each -Rβ is independently a C1-C6 alkyl group, or a C1-C4 alkyl group, or a methyl group, all optionally substituted. In one embodiment of the first or second aspect of the present invention, at least one -Rβ is independently a saccharidyl group. In one embodiment, each -Rβ is independently a saccharidyl group. In one embodiment of the first or second aspect of the present invention, each -Rβ is independently unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In one embodiment, each -Rβ is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In one embodiment, each -Rβ is unsubstituted. In one embodiment of the first or second aspect of the present invention, each -R3 is independently selected from -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[NC5H5]Y. In one embodiment, each -R3 is independently selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ. In one embodiment, each -R3 is independently selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, each -R3 is independently selected from -Rα-ORβ or -Rα-SRβ. In one embodiment, each -R3 is independently selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group. In one embodiment of the first or second aspect of the present invention, each -R4 is independently selected from -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[NC5H5]Y. In one embodiment, each -R4 is independently selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ. In one embodiment, each -R4 is independently selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, each -R4 is independently selected from -Rα-ORβ or -Rα-SRβ. In one embodiment, each -R4 is independently selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group. In one embodiment of the first or second aspect of the present invention, at least one of -R2, -R3 or -R4 is independently selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group. In one embodiment, at least one of -R2, -R3 or -R4 is independently selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group. For the purposes of the present invention, a “saccharidyl group” is any group comprising at least one monosaccharide subunit, wherein each monosaccharide subunit may optionally be substituted and/or modified. Typically, a saccharidyl group consist of one or more monosaccharide subunits, wherein each monosaccharide subunit may optionally be substituted and/or modified. Typically, a carbon atom of a single monosaccharide subunit of each saccharidyl group is directly attached to the remainder of the compound, most typically via a single bond. For the purposes of the present specification, where it is stated that a first atom or group is “directly attached” to a second atom or group it is to be understood that the first atom or group is covalently bonded to the second atom or group with no intervening atom(s) or group(s) being present. For example, for the group -(C=O)N(CH3)2, the carbon atom of each methyl group is directly attached to the nitrogen atom and the carbon atom of the carbonyl group is directly attached to the nitrogen atom, but the carbon atom of the carbonyl group is not directly attached to the carbon atom of either methyl group. Typically, each saccharidyl group is derived from the corresponding saccharide by substitution of a hydroxyl group of the saccharide with the group defined by the remainder of the compound. A single bond between an anomeric carbon of a monosaccharide subunit and a substituent is called a glycosidic bond. A glycosidic group is linked to the anomeric carbon of a monosaccharide subunit by a glycosidic bond. The bond between the saccharidyl group and the remainder of the compound may be a glycosidic or a non- glycosidic bond. Typically, the bond between the saccharidyl group and the remainder of the compound is a glycosidic bond, such that the saccharidyl group is a glycosyl group. Where the bond between the saccharidyl group and the remainder of the compound is a glycosidic bond, the glycosidic bond may be in the α or ^ configuration. Typically, such a glycosidic bond is in the ^ configuration. For the purposes of the present invention, where a saccharidyl group “contains x monosaccharide subunits”, this means that the saccharidyl group has x monosaccharide subunits and no more. In contrast, where a saccharidyl group “comprises x monosaccharide subunits”, this means that the saccharidyl group has x or more monosaccharide subunits. Each saccharidyl group may be independently selected from a monosaccharidyl, disaccharidyl, oligosaccharidyl or polysaccharidyl group. As will be understood, a monosaccharidyl group contains a single monosaccharide subunit. Similarly, a disaccharidyl group contains two monosaccharide subunits. As used herein, an “oligosaccharidyl group” contains from 2 to 9 monosaccharide subunits. Examples of oligosaccharidyl groups include trisaccharidyl, tetrasaccharidyl, pentasaccharidyl, hexasaccharidyl, heptasaccharidyl, octasaccharidyl and nonasaccharidyl groups. As used herein, a “polysaccharidyl group” contains 10 or more monosaccharide subunits (such as 10-50, or 10-30, or 10-20, or 10-15 monosaccharide subunits). Each monosaccharide subunit within a disaccharidyl, oligosaccharidyl or polysaccharidyl group may be the same or different. Each monosaccharide subunit within a disaccharidyl, oligosaccharidyl or polysaccharidyl group may be connected to another monosaccharide subunit within the group via a glycosidic or a non-glycosidic bond. Typically each monosaccharide subunit within a disaccharidyl, oligosaccharidyl or polysaccharidyl group is connected to another monosaccharide subunit within the group via a glycosidic bond, which may be in the α or ^ configuration. Each oligosaccharidyl or polysaccharidyl group may be a linear, branched or macrocyclic oligosaccharidyl or polysaccharidyl group. Typically, each oligosaccharidyl or polysaccharidyl group is a linear or branched oligosaccharidyl or polysaccharidyl group. In one embodiment, at least one -Rβ is a monosaccharidyl or disaccharidyl group. In a further embodiment, at least one -Rβ is a monosaccharidyl group. For example, at least one -Rβ may be a glycosyl group containing a single monosaccharide subunit, wherein the monosaccharide subunit may optionally be substituted and/or modified. Typically at least one -Rβ is a glycosyl group containing a single monosaccharide subunit, wherein the monosaccharide subunit may optionally be substituted. More typically, at least one -Rβ is a glycosyl group containing a single monosaccharide subunit, wherein the monosaccharide subunit is unsubstituted. In one embodiment, at least one -Rβ is an aldosyl group, wherein the aldosyl group may optionally be substituted and/or modified. For example, at least one -Rβ may be selected from a glycerosyl, aldotetrosyl (such as erythrosyl or threosyl), aldopentosyl (such as ribosyl, arabinosyl, xylosyl or lyxosyl) or aldohexosyl (such as allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl or talosyl) group, any of which may optionally be substituted and/or modified. In another embodiment, at least one -Rβ is a ketosyl group, wherein the ketosyl group may optionally be substituted and/or modified. For example, at least one -Rβ may be selected from an erythrulosyl, ketopentosyl (such as ribulosyl or xylulosyl) or ketohexosyl (such as psicosyl, fructosyl, sorbosyl or tagatosyl) group, any of which may optionally be substituted and/or modified. Each monosaccharide subunit may be present in a ring-closed (cyclic) or open-chain (acyclic) form. Typically, each monosaccharide subunit in at least one -Rβ is present in a ring-closed (cyclic) form. For example, at least one -Rβ may be a glycosyl group containing a single ring-closed monosaccharide subunit, wherein the monosaccharide subunit may optionally be substituted and/or modified. Typically in such a scenario, at least one -Rβ is a pyranosyl or furanosyl group, such as an aldopyranosyl, aldofuranosyl, ketopyranosyl or ketofuranosyl group, any of which may optionally be substituted and/or modified. More typically, at least one -Rβ is a pyranosyl group, such as an aldopyranosyl or ketopyranosyl group, any of which may optionally be substituted and/or modified. In one embodiment, at least one -Rβ is selected from a ribopyranosyl, arabinopyranosyl, xylopyranosyl, lyxopyranosyl, allopyranosyl, altropyranosyl, glucopyranosyl, mannopyranosyl, gulopyranosyl, idopyranosyl, galactopyranosyl or talopyranosyl group, any of which may optionally be substituted and/or modified. In a further embodiment, at least one -Rβ is a glucosyl group, such as a glucopyranosyl group, wherein the glucosyl or the glucopyranosyl group may optionally be substituted and/or modified. Typically, at least one -Rβ is a glucosyl group, wherein the glucosyl group is optionally substituted. More typically, at least one -Rβ is an unsubstituted glucosyl group. Each monosaccharide subunit may be present in the D- or L-configuration. Typically, each monosaccharide subunit is present in the configuration in which it most commonly occurs in nature. In one embodiment, at least one -Rβ is a D-glucosyl group, such as a D-glucopyranosyl group, wherein the D-glucosyl or the D-glucopyranosyl group may optionally be substituted and/or modified. Typically, at least one -Rβ is a D-glucosyl group, wherein the D-glucosyl group is optionally substituted. More typically, at least one -Rβ is an unsubstituted D-glucosyl group. For the purposes of the present invention, in a substituted monosaccharidyl group or monosaccharide subunit: (a) one or more of the hydroxyl groups of the monosaccharidyl group or monosaccharide subunit are each independently replaced with -H, -F, -Cl, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -SH, -NH2, -N3, -NH=NH2, -CN, -NO2, -COOH, -Rb, -O-Rb, -S-Rb, -Ra-O-Rb, -Ra-S-Rb, -SO-Rb, -SO2-Rb, -SO2-ORb, -O-SO-Rb, -O-SO2-Rb, -O-SO2-ORb, -NRb-SO-Rb, -NRb-SO2-Rb, -NRb-SO2-ORb, -Ra-SO-Rb, -Ra-SO2-Rb, -Ra-SO2-ORb, -SO-N(Rb)2, -SO2-N(Rb)2, -O-SO-N(Rb)2, -O-SO2-N(Rb)2, -NRb-SO-N(Rb)2, -NRb-SO2-N(Rb)2, -Ra-SO-N(Rb)2, -Ra-SO2-N(Rb)2, -N(Rb)2, -N(Rb)3 +, -Ra-N(Rb)2, -Ra-N(Rb)3 +, -P(Rb)2, -PO(Rb)2, -OP(Rb)2, -OPO(Rb)2, -Ra-P(Rb)2, -Ra-PO(Rb)2, -OSi(Rb)3, -Ra-Si(Rb)3, -CO-Rb, -CO-ORb, -CO-N(Rb)2, -O-CO-Rb, -O-CO-ORb, -O-CO-N(Rb)2, -NRb-CO-Rb, -NRb-CO-ORb, -NRb-CO-N(Rb)2, -Ra-CO-Rb, -Ra-CO-ORb, or -Ra-CO-N(Rb)2; and/or (b) one, two or three hydrogen atoms directly attached to a carbon atom of the monosaccharidyl group or monosaccharide subunit are each independently replaced with -F, -Cl, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -OH, -SH, -NH2, -N3, -NH=NH2, -CN, -NO2, -COOH, -Rb, -O-Rb, -S-Rb, -Ra-O-Rb, -Ra-S-Rb, -SO-Rb, -SO2-Rb, -SO2-ORb, -O-SO-Rb, -O-SO2-Rb, -O-SO2-ORb, -NRb-SO-Rb, -NRb-SO2-Rb, -NRb-SO2-ORb, -Ra-SO-Rb, -Ra-SO2-Rb, -Ra-SO2-ORb, -SO-N(Rb)2, -SO2-N(Rb)2, -O-SO-N(Rb)2, -O-SO2-N(Rb)2, -NRb-SO-N(Rb)2, -NRb-SO2-N(Rb)2, -Ra-SO-N(Rb)2, -Ra-SO2-N(Rb)2, -N(Rb)2, -N(Rb)3 +, -Ra-N(Rb)2, -Ra-N(Rb)3 +, -P(Rb)2, -PO(Rb)2, -OP(Rb)2, -OPO(Rb)2, -Ra-P(Rb)2, -Ra-PO(Rb)2, -OSi(Rb)3, -Ra-Si(Rb)3, -CO-Rb, -CO-ORb, -CO-N(Rb)2, -O-CO-Rb, -O-CO-ORb, -O-CO-N(Rb)2, -NRb-CO-Rb, -NRb-CO-ORb, -NRb-CO-N(Rb)2, -Ra-CO-Rb, -Ra-CO-ORb, or -Ra-CO-N(Rb)2; and/or (c) one or more of the hydroxyl groups of the monosaccharidyl group or monosaccharide subunit, together with the hydrogen attached to the same carbon atom as the hydroxyl group, are each independently replaced with =O, =S, =NRb, or =N(Rb)2 +; and/or (d) any two hydroxyl groups of the monosaccharidyl group or monosaccharide subunit are together replaced with -O-Rc-, -S-Rc-, -SO-Rc-, -SO2-Rc-, or -NRb-Rc-; wherein: each -Ra- is independently a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms each independently selected from O, N and S in its carbon skeleton and preferably comprises 1-10 carbon atoms; each -Rb is independently hydrogen, or a substituted or unsubstituted, straight- chained, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms each independently selected from O, N and S in its carbon skeleton and preferably comprises 1-15 carbon atoms; and each -Rc- is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms each independently selected from O, N and S in its carbon skeleton and preferably comprises 1-10 carbon atoms; provided that the monosaccharidyl group or monosaccharide subunit comprises at least one, preferably at least two or at least three, -OH, -O-Rb, -O-SO-Rb, -O-SO2-Rb, -O-SO2-ORb, -O-SO-N(Rb)2, -O-SO2-N(Rb)2, -OP(Rb)2, -OPO(Rb)2, -OSi(Rb)3, -O-CO-Rb, -O-CO-ORb, -O-CO-N(Rb)2, or -O-Rc-. Typically, in a substituted monosaccharidyl group or monosaccharide subunit: (a) one or more of the hydroxyl groups of the monosaccharidyl group or monosaccharide subunit are each independently replaced with -H, -F, -CF3, -SH, -NH2, -N3, -CN, -NO2, -COOH, -Rb, -O-Rb, -S-Rb, -N(Rb)2, -OPO(Rb)2, -OSi(Rb)3, -O-CO-Rb, -O-CO-ORb, -O-CO-N(Rb)2, -NRb-CO-Rb, -NRb-CO-ORb, or -NRb-CO-N(Rb)2; and/or (b) one or two of the hydrogen atoms directly attached to a carbon atom of the monosaccharidyl group or monosaccharide subunit are each independently replaced with -F, -CF3, -OH, -SH, -NH2, -N3, -CN, -NO2, -COOH, -Rb, -O-Rb, -S-Rb, -N(Rb)2, -OPO(Rb)2, -OSi(Rb)3, -O-CO-Rb, -O-CO-ORb, -O-CO-N(Rb)2, -NRb-CO-Rb, -NRb-CO-ORb, or -NRb-CO-N(Rb)2; and/or (c) one hydroxyl group of the monosaccharidyl group or monosaccharide subunit, together with the hydrogen attached to the same carbon atom as the hydroxyl group, is replaced with =O; and/or (d) any two hydroxyl groups of the monosaccharidyl group or monosaccharide subunit are together replaced with -O-Rc- or -NRb-Rc-; wherein: each -Rb is independently hydrogen, or a substituted or unsubstituted, straight- chained, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one, two or three heteroatoms each independently selected from O and N in its carbon skeleton and comprises 1-8 carbon atoms; and each -Rc- is independently a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one, two or three heteroatoms each independently selected from O and N in its carbon skeleton and comprises 1-8 carbon atoms; provided that the monosaccharidyl group or monosaccharide subunit comprises at least two, preferably at least three, -OH, -O-Rb, -OPO(Rb)2, -OSi(Rb)3, -O-CO-Rb, -O-CO-ORb, -O-CO-N(Rb)2, or -O-Rc-. In one embodiment, -Rβ is a saccharidyl group and one or more of the hydroxyl groups of the saccharidyl group are each independently replaced with -O-CO-Rb, wherein each -Rb is independently C1-C4 alkyl, preferably methyl. In one embodiment, -Rβ is a saccharidyl group and all of the hydroxyl groups of the saccharidyl group are each independently replaced with -O-CO-Rb, wherein each -Rb is independently C1-C4 alkyl, preferably methyl. In a modified monosaccharidyl group or monosaccharide subunit: (a) the ring of the modified monosaccharidyl group or monosaccharide subunit, or what would be the ring in the ring-closed form of the modified monosaccharidyl group or monosaccharide subunit, is partially unsaturated; and/or (b) the ring oxygen of the modified monosaccharidyl group or monosaccharide subunit, or what would be the ring oxygen in the ring-closed form of the modified monosaccharidyl group or monosaccharide subunit, is replaced with -S- or -NRd-, wherein -Rd is independently hydrogen, or a substituted or unsubstituted, straight- chained, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms each independently selected from O, N and S in its carbon skeleton and preferably comprises 1-15 carbon atoms. Alternately, where the modified monosaccharide subunit forms part of a disaccharidyl, oligosaccharidyl or polysaccharidyl group, -Rd may be a further monosaccharide subunit or subunits forming part of the disaccharidyl, oligosaccharidyl or polysaccharidyl group, wherein any such further monosaccharide subunit or subunits may optionally be substituted and/or modified. Typically, in a modified monosaccharidyl group or monosaccharide subunit: (a) the ring of the modified monosaccharidyl group or monosaccharide subunit, or what would be the ring in the ring-closed form of the modified monosaccharidyl group or monosaccharide subunit, contains a single C=C; and/or (b) the ring oxygen of the modified monosaccharidyl group or monosaccharide subunit, or what would be the ring oxygen in the ring-closed form of the modified monosaccharidyl group or monosaccharide subunit, is replaced with -NRd-, wherein -Rd is independently hydrogen, or a substituted or unsubstituted, straight-chained, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one, two or three heteroatoms each independently selected from O and N in its carbon skeleton and comprises 1-8 carbon atoms. Typical examples of substituted and/or modified monosaccharide subunits include those corresponding to: (i) deoxy sugars, such as deoxyribose, fucose, fuculose and rhamnose, wherein a hydroxyl group of the monosaccharidyl group or monosaccharide subunit has been replaced by -H; (ii) amino sugars, such as glucosamine and galactosamine, wherein a hydroxyl group of the monosaccharidyl group or monosaccharide subunit has been replaced by -NH2, most typically at the 2-position; and (iii) sugar acids, containing a -COOH group, such as aldonic acids (e.g. gluconic acid), ulosonic acids, uronic acids (e.g. glucuronic acid) and aldaric acids (e.g. gularic or galactaric acid). In one embodiment of the first or second aspect of the present invention, at least one -Rβ is a monosaccharidyl group selected from:
Figure imgf000036_0001
Preferably in the compound or complex according to the first or second aspect of the present invention, at least one -RP is:
Figure imgf000036_0002
In one embodiment of the first or second aspect of the present invention, at least one of
-R2, -R3 or -R4 is independently selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ (preferably from -Rα-ORβ or -Rα-SRβ), and -Rβ is selected from:
Figure imgf000036_0003
Figure imgf000037_0001
In one embodiment of the first or second aspect of the present invention, at least one of -R2, -R3 or -R4 is independently selected from -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)], or -Rα-[R8’]. In one embodiment, at least one of -R2, -R3 or -R4 is independently selected from -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, or -Rα-[R8]Y. In one embodiment, at least one of -R2, -R3 or -R4 is independently selected from:
Figure imgf000038_0001
In the first or second aspect of the present invention, each -R5 may be the same or different. In a preferred embodiment, each -R5 is the same. In one embodiment of the first or second aspect of the present invention, each -R5 is independently unsubstituted or substituted with one or two substituents. In one embodiment, each -R5 is unsubstituted. In one embodiment of the first or second aspect of the present invention, -R8 is unsubstituted or substituted with one or two substituents. In one embodiment, -R8 is unsubstituted. In one embodiment, -R8 is not substituted at the 4-position of the pyridine ring with a halo group. In one embodiment, -R8 is unsubstituted at the 4-position of the pyridine ring. In one embodiment, -R8 is unsubstituted. In one embodiment of the first or second aspect of the present invention, each of -R1, -R6, -R7 and -R9 independently comprises from 1 to 100 atoms other than hydrogen, preferably from 1 to 80 atoms other than hydrogen, preferably from 1 to 60 atoms other than hydrogen, preferably from 1 to 50 atoms other than hydrogen, and preferably from 1 to 45 atoms other than hydrogen. In a particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II):
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof, wherein: -R1 is selected from: (a) -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2, and -R3, each independently, is C1-C4 alkyl; preferably -R1 is -C(O)-OR3 and -R3 is C1-C4 alkyl; or (b) -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’); -R3 is selected from -Rα-ORβ or -Rα-SRβ; -Rβ is a saccharidyl group; and -R3’ is H or C1-C4 alkyl; -R6 is selected from: (a) -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2, and -R3, each independently, is C1-C4 alkyl; preferably -R6 is -C(O)-OR3 and -R3 is C1-C4 alkyl; or (b) -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’); -R3 is selected from -Rα-ORβ or -Rα-SRβ; -Rβ is a saccharidyl group; and -R3’ is H or C1-C4 alkyl; -R7 is selected from: (a) -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)2, and -R3, each independently, is C1-C4 alkyl; preferably -R7 is -C(O)-OR3 and -R3 is C1-C4 alkyl; or (b) -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’); -R3 is selected from -Rα-ORβ or -Rα-SRβ; -Rβ is a saccharidyl group; and -R3’ is H or C1-C4 alkyl; -R9 is selected from -OR2 or -SR2, and -R2 is selected from -Rα-ORβ or -Rα-SRβ, and -Rβ is a saccharidyl group; -Rα- is selected from a C1-C12 alkylene group, wherein the alkylene group may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by one or more heteroatoms O or S; and M2+ is a metal cation. In a particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II):
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof, wherein: -R1 is selected from -CH2OR2, -CH2SR2, -CH2S(O)R2, -CH2S(O)2R2, -CH2N(R2)(R2’), -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’) [preferably -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’); more preferably -R1 is -C(O)-N(R3)(R3’)]; -R2, each independently, is selected from -H, -C(O)R4, -C(O)-OR4, -C(O)-SR4, -C(O)-N(R4)(R4’), -C(S)-OR4, -C(S)-SR4, -C(S)-N(R4)(R4’), -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -[(CH2)pQ]r-(CH2)s-[N(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[P(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[R8]Y, -[(CH2)pQ]r-(CH2)s-[N(R5)2(R5’)], -[(CH2)pQ]r-(CH2)s-[P(R5)2(R5’)] or -[(CH2)pQ]r-(CH2)s-[R8’]; -R3 and -R4, each independently, is selected from -H, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -[(CH2)pQ]r-(CH2)s-[N(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[P(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[R8]Y, -[(CH2)pQ]r-(CH2)s-[N(R5)2(R5’)], -[(CH2)pQ]r-(CH2)s-[P(R5)2(R5’)] or -[(CH2)pQ]r-(CH2)s-[R8’]; wherein at least one of -R2, -R3 and -R4 is selected from -[(CH2)pQ]r-(CH2)s-[N(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[P(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[R8]Y, -[(CH2)pQ]r-(CH2)s-[N(R5)2(R5’)], -[(CH2)pQ]r-(CH2)s-[P(R5)2(R5’)] or -[(CH2)pQ]r-(CH2)s-[R8’]; -R2’, -R3’ and -R4’, each independently, is selected from hydrogen or C1-C6 alkyl [preferably -R2’, -R3’ and -R4’, each independently, is selected from hydrogen or C1-C3 alkyl; more preferably -R2’, -R3’ and -R4’, each independently, is selected from hydrogen or methyl]; -Rα-, each independently, is selected from a C1-C42 alkylene group, wherein the alkylene group may optionally be substituted with one or more (such as one, two, three, four or five) C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more (such as one, two, three, four, five, six, seven, eight, nine or ten) carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; -Rβ, each independently, is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more (such as one, two, three, four or five) heteroatoms N, O, S, P or Se in its carbon skeleton; -R5, each independently, is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more (such as one, two, three, four or five) C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R5’ is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, each substituted with -CO2 ‾, wherein the phenyl or C5-C6 heteroaryl may optionally be further substituted with one or more (such as one, two, three or four) C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’) [preferably -R6 is -C(O)-N(R3)(R3’)]; -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’) [preferably -R7 is -C(O)-N(R3)(R3’)]; -R8 is -[NC5H5] optionally substituted with one or more (such as one, two, three, four or five) C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R8’ is -[NC5H5] substituted with -CO2 ‾ and optionally further substituted with one or more (such as one, two, three or four) C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X; Q is O, S, NH or NMe [preferably Q is O]; X is a halo group; Y is a counter anion; Z is a counter cation; M2+ is a metal cation; n is 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5 or 6; and s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In a particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II):
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof, wherein: -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’) [preferably -R1 is -C(O)-N(R3)(R3’)]; -R2, each independently, is selected from -H, -C(O)R4, -C(O)-OR4, -C(O)-SR4, -C(O)-N(R4)(R4’), -C(S)-OR4, -C(S)-SR4, -C(S)-N(R4)(R4’), -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -[(CH2)pQ]r-(CH2)s-[N(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[P(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[R8]Y, -[(CH2)pQ]r-(CH2)s-[N(R5)2(R5’)], -[(CH2)pQ]r-(CH2)s-[P(R5)2(R5’)] or -[(CH2)pQ]r-(CH2)s-[R8’]; -R3 and -R4, each independently, is selected from -H, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -[(CH2)pQ]r-(CH2)s-[N(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[P(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[R8]Y, -[(CH2)pQ]r-(CH2)s-[N(R5)2(R5’)], -[(CH2)pQ]r-(CH2)s-[P(R5)2(R5’)] or -[(CH2)pQ]r-(CH2)s-[R8’]; wherein at least one of -R2, -R3 and -R4 is selected from -[(CH2)pQ]r-(CH2)s-[N(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[P(R5)3]Y, -[(CH2)pQ]r-(CH2)s-[R8]Y, -[(CH2)pQ]r-(CH2)s-[N(R5)2(R5’)], -[(CH2)pQ]r-(CH2)s-[P(R5)2(R5’)] or -[(CH2)pQ]r-(CH2)s-[R8’]; -R3’ and -R4’, each independently, is selected from hydrogen or C1-C3 alkyl [preferably -R3’ and -R4’, each independently, is selected from hydrogen or methyl]; -Rα-, each independently, is selected from a C1-C42 alkylene group, wherein the alkylene group may optionally be substituted with one or more (such as one, two, three, four or five) C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more (such as one, two, three, four, five, six, seven, eight, nine or ten) carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; -Rβ, each independently, is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more (such as one, two, three, four or five) heteroatoms N, O, S, P or Se in its carbon skeleton; -R5, each independently, is selected from C1-C3 alkyl or phenyl, wherein the phenyl may optionally be substituted with one, two, three, four or five substituents independently selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3; -R5’ is selected from C1-C3 alkyl substituted with -CO2 ‾ or phenyl substituted with -CO2 ‾, wherein the phenyl may optionally be further substituted with one, two, three or four substituents independently selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3; -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’) [preferably -R6 is -C(O)-N(R3)(R3’)]; -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’) [preferably -R7 is -C(O)-N(R3)(R3’)]; -R8 is -[NC5H5] optionally substituted with one, two, three, four or five substituents independently selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3; -R8’ is -[NC5H5] substituted with -CO2 ‾ and optionally further substituted with one, two, three or four substituents independently selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3; -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X; Q is O, S, NH or NMe [preferably Q is O]; X is a halo group; Y is a counter anion; Z is a counter cation; M2+ is a metal cation; n is 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5 or 6; and s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In these two preferred embodiments of the preceding paragraphs, each -R5 may be the same or different; preferably each -R5 is the same. In another preferred embodiment of the first or second aspect of the present invention, the compound is a compound of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), (IV), (IW), (IX), (IY), (IZ), (IAA), (IBB) or (ICC):
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof; wherein: -R1 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’); -R2, each independently, is selected from -H, -C(O)R4, -C(O)-OR4, -C(O)-SR4, -C(O)-N(R4)(R4’), -C(S)-OR4, -C(S)-SR4, -C(S)-N(R4)(R4’), -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, or -Rα-X; -R3 and -R4, each independently, is selected from -H, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, or -Rα-X; -R3’ and -R4’, each independently, is selected from hydrogen or C1-C3 alkyl [preferably -R3’ and -R4’, each independently, is selected from hydrogen or methyl]; -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’); -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)(R3’), -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)(R3’); -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X; -Rα-, each independently, is selected from a C1-C12 alkylene group, wherein the alkylene group may optionally be substituted with one or more (such as one, two, three, four or five) C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more (such as one, two, three, four, five or six) carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; -Rβ, each independently, is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more (such as one, two, three, four or five) heteroatoms N, O, S, P or Se in its carbon skeleton; -Rδ is selected from C1-C3 alkyl; -Rε is selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3; X is a halo group; Y is a counter anion; Z is a counter cation; n is 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; t is 0, 1, 2, 3, 4 or 5; and u is 0, 1, 2, 3 and 4. The compounds of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), (IV), (IW), (IX), (IY), (IZ), (IAA), (IBB), (ICC) and complexes and salts thereof according to the first and second aspect of the present invention comprise a moiety -[(CH2)pO]r-(CH2)s-, wherein: p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5 or 6; and s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In one embodiment, p is 2, 3 or 4; r is 1; and s is 2, 3 or 4. In a preferred embodiment, p is 3; r is 1; and s is 3; such that -[(CH2)pO]r-(CH2)s- is -(CH2)3-O-(CH2)3-. In another embodiment, p is 2 or 3; r is 2 or 3; and s is 2 or 3. In a preferred embodiment, p is 2; r is 2; and s is 2; such that -[(CH2)pO]r-(CH2)s- is -(CH2CH2O)2-(CH2)2-. In yet another embodiment, r is 0; and s is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; such that -[(CH2)pO]r-(CH2)s- is -(CH2)1-12-. In a particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I’) or a complex of formula (II’):
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof, wherein: -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X; -R10, -R11 and -R12, each independently, is selected from -OR3, -SR3 or -N(R3)2; -R2, each independently, is selected from -H, -C(O)R4, -C(O)-OR4, -C(O)-SR4, -C(O)-N(R4)2, -C(S)-OR4, -C(S)-SR4, -C(S)-N(R4)2, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)] or -Rα-[R8’]; -R3 and -R4, each independently, is selected from -H, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)] or -Rα-[R8’]; -Rα-, each independently, is selected from a C1-C42 alkylene group, wherein the alkylene group may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; -Rβ, each independently, is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O, S, P or Se in its carbon skeleton; -R5, each independently, is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R5’ is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, each substituted with -CO2 ‾, wherein the phenyl or C5-C6 heteroaryl may optionally be further substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R8 is -[NC5H5] optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R8’ is -[NC5H5] substituted with -CO2 ‾ and optionally further substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; n is 1, 2, 3, 4, 5 or 6; X is a halo group; Y is a counter anion; Z is a counter cation; and M2+ is a metal cation; provided that either: (i) at least one of -R9, -R10 and -R11 comprises -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)], -Rα-[R8’], or a saccharidyl group; or (ii) -R9 is selected from -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X. In another particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I’’) or a complex of formula (II’’): or a pharmaceutically acceptable salt thereof, wherein: -U- is -O-, -N(Ru)- or -S-; -V- is -CH2-, -O-, -N(Rv)- or -S-; -W- is -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)] or -Rα-[R8’]; -R10, -R11 and -R12, each independently, is selected from -OH or -O-(C1-C4 alkyl); -Rα- is selected from a C1-C12 alkylene group, wherein the alkylene group may optionally be substituted with one or more (such as one, two, three or four) C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more (such as one, two, three or four) carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; -R5, each independently, is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R5’ is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, each substituted with -CO2 ‾, wherein the phenyl or C5-C6 heteroaryl may optionally be further substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R8 is -[NC5H5] optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R8’ is -[NC5H5] substituted with -CO2 ‾ and optionally further substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -Ru is hydrogen or C1-C4 alkyl; -Rv is hydrogen or C1-C4 alkyl; n is 1, 2, 3, 4, 5 or 6; Y is a counter anion; Z is a counter cation; and M2+ is a metal cation. In another particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I’’) or a complex of formula (II’’):
Figure imgf000055_0001
or a pharmaceutically acceptable salt thereof, wherein: -U- is -O-, -N(Ru)- or -S-; -V- is -CH2-, -O-, -N(Rv)- or -S-; -W- is -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y or -Rα-[R8]Y; -R10, -R11 and -R12, each independently, is selected from -OH or -O-(C1-C4 alkyl); -Rα- is selected from a C1-C12 alkylene group (preferably a C1-C9 alkylene group, preferably a C2-C6 alkylene group), wherein one or more (such as one, two, three or four, preferably one or two) carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe (preferably O, NH or NMe, preferably O); -R5, each independently, is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl) or -O(C1-C4 haloalkyl); -R8 is -[NC5H5] optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl) or -O(C1-C4 haloalkyl); -Ru is hydrogen or C1-C4 alkyl; -Rv is hydrogen or C1-C4 alkyl; n is 1, 2, 3, 4, 5 or 6; Y is a counter anion; and M2+ is a metal cation. The first aspect of the present invention further provides a compound of formula (III) or a complex of formula (IV):
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof, wherein: -R1 is selected from -CO2H or -C(O)-R14-R15; -R6 is selected from -CO2H or -CO2R13; -R7 is selected from -CO2H or -C(O)-R14-R15; -R13 is selected from C1-C3 alkyl; -R14- is selected from NH, NMe, O or S; -R15 is selected from C1-C20 alkyl wherein one or more carbon atoms in the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe, and wherein the alkyl group may optionally be substituted with one or more (such as one, two, three, four, five, six, seven or eight) -OH or -NH2 groups; and M2+ is a metal cation; provided that -R1, -R6 and -R7 are not simultaneously -CO2Me. In one embodiment, -R1 is selected from -CO2H, -C(O)-R14-(CH2)x-Me, -C(O)-R14-(CH2)x-OH, -C(O)-R14-(CH2CH2O)y-Me or -C(O)-R14-(CH2CH2O)y-H; wherein x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and y is 0, 1, 2, 3, 4, 5 or 6. Preferably, -R1 is selected from -CO2H, -C(O)-R14-(CH2)x-Me or -C(O)-R14-(CH2CH2O)y-Me. In one embodiment, x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; preferably, x is 3, 4, 5, 6, 7, 8, 9, 10 or 11. In one embodiment, y is 1, 2, 3, 4, 5 or 6; preferably, y is 1, 2, 3 or 4. In one embodiment, -R7 is selected from -CO2H, -C(O)-R14-(CH2)x-Me, -C(O)-R14-(CH2)x-OH, -C(O)-R14-(CH2CH2O)y-Me or -C(O)-R14-(CH2CH2O)y-H; wherein x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and y is 0, 1, 2, 3, 4, 5 or 6. Preferably, -R7 is selected from -CO2H, -C(O)-R14-(CH2)x-Me or -C(O)-R14-(CH2CH2O)y-Me. In one embodiment, x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; preferably, x is 3, 4, 5, 6, 7, 8, 9, 10 or 11. In one embodiment, y is 1, 2, 3, 4, 5 or 6; preferably, y is 1, 2, 3 or 4. In one embodiment, -R13 is methyl or ethyl. In one embodiment, -R14- is NH or NMe. Preferably, -R14- is NMe. In one embodiment, -R15 is selected from -(CH2)x-Me, -(CH2)x-OH, -(CH2CH2O)y-Me or -(CH2CH2O)y-H; wherein x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and y is 0, 1, 2, 3, 4, 5 or 6. Preferably, -R15 is selected from -(CH2)x-Me or -(CH2CH2O)y-Me. In one embodiment, x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; preferably, x is 3, 4, 5, 6, 7, 8, 9, 10 or 11. In one embodiment, y is 1, 2, 3, 4, 5 or 6; preferably, y is 1, 2, 3 or 4. In one embodiment, M2+ is a metal cation selected from Zn2+, Cu2+, Fe2+, Pd2+ or Pt2+. In one embodiment, M2+ is Zn2+. In one embodiment, the compound of formula (III) or the complex of formula (IV) is in the form of a pharmaceutically acceptable salt, such as a lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) salt. Preferably, the pharmaceutically acceptable salt is a lithium, sodium, potassium, magnesium, calcium, ammonium, choline, meglumine or arginine salt, or a combination thereof. Preferably, the pharmaceutically acceptable salt is a lithium, sodium, potassium or meglumine salt, or a combination thereof. Preferably, the pharmaceutically acceptable salt is a sodium or meglumine salt, or a combination thereof. In one embodiment, the pharmaceutically acceptable salt is a mono-sodium salt. In another embodiment, the pharmaceutically acceptable salt is a di-sodium salt. In another embodiment, the pharmaceutically acceptable salt is a mono-meglumine salt. In another embodiment, the pharmaceutically acceptable salt is a di-meglumine salt. In another embodiment, the pharmaceutically acceptable salt is a mono-sodium mono- meglumine mixed salt. Preferably in the compound or complex according to the first or second aspect of the present invention, the compound or complex is:
Figure imgf000058_0001
Figure imgf000059_0001

Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound or complex according to the first or second aspect of the invention is in the form of a pharmaceutically acceptable salt. In one embodiment, the compound or complex is in the form of an inorganic salt such as a lithium, sodium, potassium, magnesium, calcium or ammonium salt. In one embodiment, the compound or complex is in the form of a sodium or potassium salt. In one embodiment, the compound is in the form of a sodium salt. In another embodiment, the compound or complex is in the form of an organic salt such as an amine salt (for example a choline or meglumine salt) or an amino acid salt (for example an arginine salt). The compound or complex according to the first or second aspect of the invention has at least two chiral centres. The compound or complex of the first or second aspect of the invention is preferably substantially enantiomerically pure, which means that the compound or complex comprises less than 10% of other stereoisomers, preferably less than 5%, preferably less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, all by weight, as measured by XRPD or SFC. Preferably, the compound or complex according to the first or second aspect of the invention has a HPLC purity of more than 97%, more preferably more than 98%, more preferably more than 99%, more preferably more than 99.5%, more preferably more than 99.8%, and most preferably more than 99.9%. As used herein the percentage HPLC purity is measured by the area normalisation method. A third aspect of the invention provides a composition comprising a compound or complex according to the first or second aspect of the invention and a pharmaceutically acceptable carrier or diluent. In one embodiment, the composition according to the third aspect of the invention further comprises polyvinylpyrrolidone (PVP). In one embodiment, the composition comprises 0.01-10% w/w PVP as percentage of the total weight of the composition, preferably 0.1-5% w/w PVP as a percentage of the total weight of the composition, preferably 0.5-5% w/w PVP as a percentage of the total weight of the composition. In one embodiment, the PVP is K30. In one embodiment, the composition according to the third aspect of the invention further comprises dimethylsulfoxide (DMSO). In one embodiment, the composition comprises 0.01-99% w/w DMSO as percentage of the total weight of the composition, preferably 40-99% w/w DMSO as a percentage of the total weight of the composition, preferably 65-99% w/w DMSO as a percentage of the total weight of the composition. In one embodiment, the composition according to the third aspect of the invention further comprises an immune checkpoint inhibitor. In one embodiment, the immune checkpoint inhibitor is an inhibitor of PD-1 (programmed cell death protein 1), PD-L1 (programmed death ligand 1) or CTLA4 (cytotoxic T-lymphocyte associated protein 4). In one embodiment, the immune checkpoint inhibitor is selected from Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab or Ipilimumab. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for use in photodynamic therapy or cytoluminescent therapy. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the treatment of a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the treatment of a benign or malignant tumour. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for use in photodynamic diagnosis. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the detection of an area that is affected by benign or malignant cellular hyperproliferation or by neovascularisation. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the detection of a benign or malignant tumour. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for the fluorescent or phosphorescent detection of the diseases listed above, preferably for the fluorescent or phosphorescent detection and quantification of the said diseases. Preferably the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are adapted for administration simultaneous with or prior to administration of irradiation or sound, preferably for administration prior to administration of irradiation. If the compound or complex according to the first or second aspect of the present invention or the pharmaceutical composition according to the third aspect of the present invention are for use in photodynamic therapy or cytoluminescent therapy, then they are preferably adapted for administration 5 to 100 hours before the irradiation, preferably 6 to 72 hours before the irradiation, preferably 24 to 48 hours before the irradiation. If the compound or complex according to the first or second aspect of the present invention or the pharmaceutical composition according to the third aspect of the present invention are for use in photodynamic diagnosis, then they are preferably adapted for administration 3 to 60 hours before the irradiation, preferably 8 to 40 hours before the irradiation. Preferably the irradiation used in the photodynamic therapy, cytoluminescent therapy or photodynamic diagnosis is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm, preferably from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm. The electromagnetic radiation may be administered for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1- 5W, preferably at about 1W. In one embodiment of the present invention, two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm. In another embodiment of the present invention, the irradiation may be provided by a prostate, anal, vaginal, mouth and nasal device for insertion into a body cavity. In another embodiment of the present invention, the irradiation may be provided by interstitial light activation, for example, using a fine needle to insert an optical fibre laser into the lung, liver, lymph nodes or breast. In another embodiment of the present invention, the irradiation may be provided by endoscopic light activation, for example, for delivering light to the lung, stomach, colon, bladder or neck. The pharmaceutical composition according to the third aspect of the present invention may be in a form suitable for oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intratumoral, intraarticular, intraabdominal, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration. The pharmaceutical composition may also be in a form suitable for administration by enema or for administration by injection into a tumour. Preferably the pharmaceutical composition is in a form suitable for oral, parenteral (such as intravenous, intraperitoneal, and intratumoral) or airway administration, preferably in a form suitable for oral or parenteral administration, preferably in a form suitable for oral administration. In one preferred embodiment, the pharmaceutical composition is in a form suitable for oral administration. Preferably the pharmaceutical composition is provided in the form of a tablet, capsule, hard or soft gelatine capsule, caplet, troche or lozenge, as a powder or granules, or as an aqueous solution, suspension or dispersion. More preferably the pharmaceutical composition is provided in the form of an aqueous solution, suspension or dispersion for oral administration, or alternatively in the form of a freeze-dried powder which can be mixed with water before administration to provide an aqueous solution, suspension or dispersion for oral administration. Preferably the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the compound or complex according to the first or second aspect of the invention, preferably 0.1 to 2 mg/kg/day, preferably about 1 mg/kg/day. In another preferred embodiment, the pharmaceutical composition is in a form suitable for parenteral administration. Preferably the pharmaceutical composition is in a form suitable for intravenous administration. Preferably the pharmaceutical composition is provided in the form of an aqueous solution for parenteral administration, or alternatively in the form of a freeze-dried powder which can be mixed with water before administration to provide an aqueous solution for parenteral administration. Preferably the pharmaceutical composition is an aqueous solution or suspension having a pH of from 6 to 8.5. Preferably the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the compound or complex according to the first or second aspect of the invention, preferably 0.1 to 2 mg/kg/day, preferably about 1 mg/kg/day. In another preferred embodiment, the pharmaceutical composition is in a form suitable for airway administration. Preferably the pharmaceutical composition is provided in the form of an aqueous solution, suspension or dispersion for airway administration, or alternatively in the form of a freeze-dried powder which can be mixed with water before administration to provide an aqueous solution, suspension or dispersion for airway administration. Preferably the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg/kg/day of the compound or complex according to the first or second aspect of the invention, preferably 0.1 to 2 mg/kg/day, preferably about 1 mg/kg/day. A fourth aspect of the present invention provides use of a compound or complex according to the first or second aspect of the present invention in the manufacture of a medicament for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. The fourth aspect of the present invention also provides use of a compound or complex according to the first or second aspect of the present invention in the manufacture of a phototherapeutic agent for use in photodynamic therapy or cytoluminescent therapy. Preferably the phototherapeutic agent is suitable for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the medicament or the phototherapeutic agent of the fourth aspect of the present invention is suitable for the treatment of a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation. Preferably the medicament or the phototherapeutic agent of the fourth aspect of the present invention is suitable for the treatment of a benign or malignant tumour. Preferably the medicament or the phototherapeutic agent of the fourth aspect of the present invention is suitable for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. The fourth aspect of the present invention also provides use of a compound or complex according to the first or second aspect of the present invention in the manufacture of a photodiagnostic agent for use in photodynamic diagnosis. Preferably the photodiagnostic agent of the fourth aspect of the present invention is suitable for the detection of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the photodiagnostic agent of the fourth aspect of the present invention is suitable for the detection of an area that is affected by benign or malignant cellular hyperproliferation or by neovascularisation. Preferably the photodiagnostic agent of the fourth aspect of the present invention is suitable for the detection of a benign or malignant tumour. Preferably the photodiagnostic agent of the fourth aspect of the present invention is suitable for the detection of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the photodiagnostic agent of the fourth aspect of the present invention is suitable for the fluorescent or phosphorescent detection of the said diseases, preferably the fluorescent or phosphorescent detection and quantification of the said diseases. Preferably the medicament, the phototherapeutic agent or the photodiagnostic agent is adapted for administration simultaneous with or prior to administration of irradiation or sound, preferably for administration prior to administration of irradiation. If the medicament or the phototherapeutic agent is for use in photodynamic therapy or cytoluminescent therapy, then it is preferably adapted for administration 5 to 100 hours before the irradiation, preferably 6 to 72 hours before the irradiation, preferably 24 to 48 hours before the irradiation. If the photodiagnostic agent is for use in photodynamic diagnosis, then it is preferably adapted for administration 3 to 60 hours before the irradiation, preferably 8 to 40 hours before the irradiation. Preferably the irradiation used in the photodynamic therapy, cytoluminescent therapy or photodynamic diagnosis is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm, preferably from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm. The electromagnetic radiation may be administered for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1- 5W, preferably at about 1W. In one embodiment of the present invention, two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm. In another embodiment of the present invention, the irradiation may be provided by a prostate, anal, vaginal, mouth and nasal device for insertion into a body cavity. In another embodiment of the present invention, the irradiation may be provided by interstitial light activation, for example, using a fine needle to insert an optical fibre laser into the lung, liver, lymph nodes or breast. In another embodiment of the present invention, the irradiation may be provided by endoscopic light activation, for example, for delivering light to the lung, stomach, colon, bladder or neck. A fifth aspect of the present invention provides a method of treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas; the method comprising administering a therapeutically effective amount of a compound or complex according to the first or second aspect of the present invention to a human or animal in need thereof. The fifth aspect of the present invention also provides a method of photodynamic therapy or cytoluminescent therapy of a human or animal disease, the method comprising administering a therapeutically effective amount of a compound or complex according to the first or second aspect of the present invention to a human or animal in need thereof. Preferably the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the method of the fifth aspect of the present invention is a method of treating benign or malignant cellular hyperproliferation or areas of neovascularisation. Preferably the method of the fifth aspect of the present invention is a method of treating a benign or malignant tumour. Preferably the method of the fifth aspect of the present invention is a method of treating early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. The fifth aspect of the present invention also provides a method of photodynamic diagnosis of a human or animal disease, the method comprising administering a diagnostically effective amount of a compound or complex according to the first or second aspect of the present invention to a human or animal. Preferably the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the human or animal disease is characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation. Preferably the human or animal disease is a benign or malignant tumour. Preferably the human or animal disease is early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas. Preferably the method of photodynamic diagnosis is suitable for the fluorescent or phosphorescent detection of the said diseases, preferably for the fluorescent or phosphorescent detection and quantification of the said diseases. In any of the methods of the fifth aspect of the present invention, the human or animal is preferably further subjected to irradiation or sound simultaneous with or after the administration of the compound or complex according to the first or second aspect of the invention. Preferably the human or animal is subjected to irradiation after the administration of the compound or complex according to the first or second aspect of the invention. If the method is a method of photodynamic therapy or cytoluminescent therapy, then the human or animal is preferably subjected to irradiation 5 to 100 hours after administration of the compound or complex according to the first or second aspect of the invention, preferably 6 to 72 hours after administration, preferably 24 to 48 hours after administration. If the method is a method of photodynamic diagnosis, then the human or animal is preferably subjected to irradiation 3 to 60 hours after administration of the compound or complex according to the first or second aspect of the invention, preferably 8 to 40 hours after administration. Preferably the irradiation is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm, preferably from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm. The electromagnetic radiation may be administered for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1- 5W, preferably at about 1W. In one embodiment of the present invention, two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm. In another embodiment of the present invention, the irradiation may be provided by a prostate, anal, vaginal, mouth and nasal device for insertion into a body cavity. In another embodiment of the present invention, the irradiation may be provided by interstitial light activation, for example, using a fine needle to insert an optical fibre laser into the lung, liver, lymph nodes or breast. In another embodiment of the present invention, the irradiation may be provided by endoscopic light activation, for example, for delivering light to the lung, stomach, colon, bladder or neck. In any of the methods of the fifth aspect of the present invention, preferably the human or animal is a human. A sixth aspect of the present invention provides a pharmaceutical combination or kit comprising: (a) a compound or complex according to the first or second aspect of the present invention; and (b) an immune checkpoint inhibitor. In one embodiment, the immune checkpoint inhibitor is an inhibitor of PD-1 (programmed cell death protein 1), PD-L1 (programmed death ligand 1) or CTLA4 (cytotoxic T-lymphocyte associated protein 4). In one embodiment, the immune checkpoint inhibitor is selected from Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab or Ipilimumab. Preferably, the combination or kit of the sixth aspect is for use in the treatment of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to PD-1, PD-L1 or CTLA4 inhibition. Preferably, the combination or kit of the sixth aspect is for use in the treatment of cancer. In one embodiment, the cancer is melanoma, lung cancer (e.g. non small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin’s lymphoma. The sixth aspect also provides a use of the combination or kit of the sixth aspect of the invention in the manufacture of a medicament for the treatment of a disease, disorder or condition which is responsive to PD-1, PD-L1 or CTLA4 inhibition. The sixth aspect also provides a use of the combination or kit of the sixth aspect of the invention in the manufacture of a medicament for the treatment of cancer. In one embodiment, the cancer is melanoma, lung cancer (e.g. non small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin’s lymphoma. The sixth aspect of the invention also provides a method of treating a disease, disorder or condition which is responsive to PD-1, PD-L1 or CTLA4 inhibition, the method comprising administering a therapeutically effective amount of the combination or kit of the sixth aspect of the present invention to a human or animal in need thereof. The sixth aspect of the invention also provides a method of treating cancer, the method comprising administering a therapeutically effective amount of the combination or kit of the sixth aspect of the present invention to a human or animal in need thereof. In one embodiment, the cancer is melanoma, lung cancer (e.g. non small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin’s lymphoma. For the combination or kit of the sixth aspect of the invention, the compound or complex according to the first or second aspect of the invention, and the immune checkpoint inhibitor may be provided together in one pharmaceutical composition or separately in two pharmaceutical compositions. If provided in two pharmaceutical compositions, these may be administered at the same time or at different times. Preferably the combination or kit of the sixth aspect is adapted for administration simultaneous with or prior to administration of irradiation or sound, preferably for administration prior to administration of irradiation. In one embodiment, the combination or kit of the sixth aspect is adapted for administration 5 to 100 hours before the irradiation, preferably 6 to 72 hours before the irradiation, preferably 24 to 48 hours before the irradiation. Preferably the irradiation used in the photodynamic therapy or cytoluminescent therapy is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm, preferably from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm. The electromagnetic radiation may be administered for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1-5W, preferably at about 1W. In one embodiment of the present invention, two sources of electromagnetic radiation are used (for example a laser light and an LED light), both sources adapted to provide irradiation with a wavelength in the range of from 550nm to 750nm, preferably from 600nm to 700nm, preferably from 640nm to 670nm. In another embodiment of the present invention, the irradiation may be provided by a prostate, anal, vaginal, mouth and nasal device for insertion into a body cavity. In another embodiment of the present invention, the irradiation may be provided by interstitial light activation, for example, using a fine needle to insert an optical fibre laser into the lung, liver, lymph nodes or breast. In another embodiment of the present invention, the irradiation may be provided by endoscopic light activation, for example, for delivering light to the lung, stomach, colon, bladder or neck. For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred or optional embodiment of any aspect of the present invention should also be considered as a preferred or optional embodiment of any other aspect of the present invention. Synthetic Experimental Details Synthesis Example 1 (comparative) – synthesis of chlorin e613-hydroxymethyl trimethyl ester (compound 1)
Figure imgf000094_0001
Step 1: To a 100 mL RBF was added chlorin e6 trimethyl ester (1.00 g, 1.566 mmol, 1 eq), THF (40 mL), osmium tetroxide (4 mg, 0.016 mmol, 0.01 eq), deionized water (3 mL), AcOH (3 mL) and sodium periodate (0.737 g, 3.444 mmol, 2.2 eq). The resultant mixture was stirred under nitrogen in the dark at ambient temperature for 19 hours. A further portion of sodium periodate (0.068 g, 0.313 mmol, 0.2 eq) was added and the solution stirred for a further 8 hours. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (60 mL), transferred to a separatory funnel and washed with brine (30 mL), saturated aqueous NaHCO3 (30 mL), water (50 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give chlorin e613-formyl trimethyl ester as a red-brown solid (1.0 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 11.52 (s, 1H), 10.25 (s, 1H), 9.68 (s, 1H), 8.95 (s, 1H), 4.56 (m, 1H), 5.40 (d, 1H), 5.28 (d, 1H), 4.51-4.42 (m, 2H), 4.29 (s, 3H), 3.80-3.72 (m, 8H), 3.67 (s, 3H), 3.59 (s, 3H), 3.31 (s, 3H), 2.67-2.58 (m, 1H), 2.30-2.18 (m, 2H), 1.78-1.69 (m, 7H), -1.31 (brs, 1H), -1.80 (brs, 1H). Step 2: To a 250 mL RBF was added chlorin e613-formyl trimethyl ester (850 mg, 1.327 mmol, 1 eq), MeOH (30 mL), DCM (15 mL) and sodium borohydride (100 mg, 2.653 mmol, 2 eq). The resultant mixture was stirred under nitrogen ambient temperature for 1 hour. The reaction mixture was diluted with water (60 mL) and stirred for 10 minutes. The mixture was then extracted with DCM (2 x 30 mL) and the combined DCM layers washed with water (50 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give a dark red solid. The crude product was re- dissolved in DCM (25 mL) and washed with dilute aqueous NaHCO3 (10 mL) then pH=7 phosphate buffer (10 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give compound 1 as a dark red solid (0.81 g, 94%). 1H NMR (400 MHz, CDCl3) δ 9.70 (brs, 1H), 9.56 (br s, 1H), 8.74 (brs, 1H), 5.90 (m, 2H), 5.36 (d, 1H), 5.23 (d, 1H), 4.40 (m, 4H), 4.25 (s, 3H), 3.78 (m, 7H), 3.70 (s, 3H), 3.68 (s, 3H), 3.65 (s, 3H), 3.60 (s, 3H), 3.45 (m, 3 H), 3.29 (m, 3H), 2.80-2.75 (m, 2H), 2.60-2.50 (m, 5H), 1.78-1.68 (m, 12H), -1.43 (br, 1H), -1.63 (br, 1H). Synthesis Example 2 – synthesis of chlorin e6 trimethyl ester 13-(6- (triphenylphosphonium bromide)hexyl)carbamate (compound 2)
Figure imgf000095_0001
Step 1: To a 50 mL RBF was added (6-((tert-butoxycarbonyl)amino)hexyl) triphenylphosphonium bromide (676 mg, 1.246 mmol, 8 eq), DCM (7 mL) and TFA (1.5 mL). The resultant solution was stirred at ambient temperature for 1 hour and then concentrated on the rotary evaporator. The residue was re-suspended and concentrated twice from chloroform (2 x 40 mL) to give 6-aminohexyltriphenylphosphonium bromide TFA as a viscous oil (0.995 g) which was then dissolved in DCM (2 mL) for the subsequent coupling reaction. Step 2: To a 50 mL RBF was added chlorin e613-hydroxymethyl trimethyl ester (compound 1) (100 mg, 0.156 mmol, 1 eq), carbonyl diimidazole (76 mg, 0.467 mmol, 3 eq), DCM (5 mL) and 4-dimethylaminopyridine (DMAP) (25 mg, 0.205 mmol, 1.3 eq). The resultant mixture was stirred under nitrogen for 3 hours with monitoring by TLC. TEA (455 mg, 4.496 mmol, 29 eq) was added followed by 6- aminohexyltriphenylphosphonium bromide (0.995 g, containing ~0.444 g TFA, in DCM 2 mL) and stirring was continued for 4 days. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with 1 M HCl (2 x 15 mL), pH=7 phosphate buffer (20 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using a gradient of 5-8% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.10 in 5% MeOH/DCM) were combined to give compound 2 as a dark green solid (53 mg, 31% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 9.61 (s, 1H), 8.74 (s, 1H), 7.60-7.50 (m, 9H), 7.50-7.35 (m, 7H), 6.36 (m, 2H), 5.86 (m, 1H), 5.36 (d, 1H), 5.24 (d, 1H), 4.48-4.37 (m, 2H), 4.26 (s, 3H), 3.78 (s, 3H), 3.71 (q, 2H), 3.63 (s, 3H), 3.50-3.40 (m, 5H), 3.30-3.20 (m, 5H), 2.62-2.52 (m, 1H), 2.24-2.14 (m, 2H), 2.06-1.85 (brm, 3H), 1.75-1.70 (m, 4H), 1.70-1.62 (m, 4H), 1.58-1.20 (m, 12H), -1.46 (brs, 1H), -1.66 (brs, 1H). Synthesis Example 3 – synthesis of chlorin e6 trimethyl ester 13-(N-(3-(3- triphenylphosphoniumpropoxy)propyl)chloride)carbamate (compound 3)
Figure imgf000096_0001
Step 1: A 500 mL 3-neck RBF, equipped with a 3 cm stirrer bar was charged with bis(3- chloropropyl)ether (20.00 g, 70.15 mmol, 1.66 eq), triphenyl phosphine (18.40 g, 70.15 mmol, 1 eq), sodium iodide (7.01 g, 46.77 mmol, 0.66 eq) and acetonitrile (340 mL). The RBF was set over an oil bath and fitted with an air condenser, where stirring (500 rpm) commenced under N2 at an external temperature of 90 °C. The mixture was left to stir for 72 hours. After this time, the reaction flask was cooled to room temperature and the suspension was filtered through a 2 cm plug of Celite®, washing through with acetonitrile (250 mL). The faint yellow solution was then evaporated to dryness to leave a dark yellow oil (44.40 g) which was subject to column chromatography (silica gel, 9 x 12 cm) using 6% MeOH in DCM as eluent. Fractions with Rf = 0.35 as visualised by UV in 6% MeOH/DCM were combined and concentrated by rotary evaporation. The resulting residue was purified further by column chromatography (silica gel, 9 x 7 cm). DCM was used as eluent until no further triphenyl phosphine was present as observed by TLC, then the eluent was changed to 10% MeOH in DCM to remove the product from the column. Fractions with Rf = 0.35 as visualised by UV in 6% MeOH/DCM were combined and concentrated by rotary evaporation to give (3-(3-chloropropoxy)propyl) triphenylphosphonium chloride as a faint red solid (18.74 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.87-7.76 (m, 9H), 7.75-7.63 (m, 6H), 3.93-3.80 (m, 2H), 3.75 (td, J = 5.7, 1.3 Hz, 2H), 3.58 (q, J = 6.3 Hz, 4H), 2.05-1.88 (m, 4H). Step 2: To a 50 mL RBF was added (3-(3-chloropropoxy)propyl)triphenylphosphonium chloride (4.0 g, 9.23 mmol, 1 eq), NaN3 (11.08 g, 1.2 eq), NaBr (38 mg, 0.04 eq), tetrapropylammonium bromide (49 mg, 0.02 eq) and water (10 mL). After connecting a water condenser, the flask was heated at 110 °C with stirring for 44 hours. Then the mixture was cooled and EtOAc (50 mL) was added. The mixture was transferred to a separating funnel and washed with water (3 x 30 mL) and brine (30 mL). The combined aqueous layers were extracted with DCM (3 x 20 mL). The combined organic layers were then dried (MgSO4), filtered and concentrated to give (3-(3- azidopropoxy)propyl)triphenylphosphonium chloride as a pale yellow solid (3.20 g, 79%). 1H NMR (400 MHz, CDCl3) δ 7.86-7.77 (m, 9H), 7.73-7.66 (m, 6H), 3.90-3.80 (m, 2H), 3.75 (t, 2H), 3.53 (t, 2H), 3.33 (t, 2H), 1.99-1.89 (m, 2H), 1.82 (p, 2H). Step 3: A 3-neck 100 mL RBF was charged with (3-(3-azidopropoxy)propyl) triphenylphosphonium chloride (1.00 g, 2.273 mmol, 1 eq), 10% Pd/C (20 mg), methanol (10 mL) and a stirrer bar. A hydrogen balloon was connected to the middle joint of the flask via a short length air condenser and the side-arm was connected to a 3-way tap. The setup was evacuated and then re-filled with nitrogen (3 times), evacuated and re-filled with hydrogen (2 times). The resulting solution was then stirred (550 rpm) under the hydrogen atmosphere for 2 hours at 35 °C. Then the solution was filtered through Celite® (0.5 x 3 cm), washing with chloroform (2 x 10 mL) and the solvent then removed under reduced pressure to give (3-(3-aminopropoxy)propyl) triphenylphosphonium chloride as a viscous oil that solidified on standing (1.05 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 7.86-7.76 (m, 9H), 7.73-7.66 (m, 6H), 3.88-3.79 (m, 2H), 3.73 (t, 2H), 3.51 (t, 2H), 2.75 (t, 2H), 1.99-1.87 (m, 2H), 1.68 (p, 2H), 1.41 (brs, 2H). Step 4: To a 25 mL RBF was added chlorin e613-hydroxymethyl trimethyl ester (compound 1) (60 mg, 0.0934 mmol, 1 eq), carbonyl diimidazole (30 mg, 0.1867 mmol, 2 eq), DCM (4 mL) and DMAP (5 mg, 0.0409 mmol, 0.4 eq). The resultant mixture was stirred under nitrogen for 3 hours with monitoring by TLC. (3-(3- Aminopropoxy)propyl)triphenylphosphonium chloride (193 mg, 0.4668 mmol, 5 eq) dissolved in DCM (1 mL)was added and stirring was continued for 4 days. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel and washed with 1 M HCl (2 x 20 mL), pH=7 phosphate buffer (30 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography (3 x 12 cm) using 3-5% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.20 in 5% MeOH/DCM) were combined to give compound 3 as a dark green solid (33 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 9.57 (s, 1H), 8.74 (s, 1H), 7.61-7.50 (m, 6H), 7.48-7.36 (m, 9H), 6.33 (m, 2H), 5.53 (m, 1H), 5.36 (d, 1H), 5.25 (d, 1H), 4.48-4.38 (m, 2H), 4.27 (s, 3H), 3.79 (s, 3H), 3.74 (q, 2H), 3.63 (s, 3H), 3.61-3.50 (m, 7H), 3.49-3.43 (m, 5H), 3.40-3.33 (m, 2H), 3.26 (s, 3H), 2.62-2.52 (m, 1H), 2.25-2.15 (m, 2H), 1.80- 1.60 (m, 14H), 0.90-0.80 (m, 1H), -1.47 (brs, 1H), -1.68 (brs, 1H). Synthesis Example 4 – synthesis of chlorin e6 trimethyl ester 13-(N-(3- triphenylphosphoniumpropyl)bromide)carbamate (compound 4)
Figure imgf000098_0001
To a 25 mL RBF was added chlorin e613-hydroxymethyl trimethyl ester (compound 1) (100 mg, 0.156 mmol, 1 eq), carbonyl diimidazole (50 mg, 0.311 mmol, 2 eq), DCM (4 mL) and DMAP (5 mg, 0.0409 mmol, 0.25 eq). The resultant mixture was stirred under nitrogen at 25 °C for 3 hours. (3-Aminopropyl)triphenylphosphonium bromide (311 mg, 0.778 mmol, 5 eq) was added and stirring was continued overnight at 25 °C. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel and washed with 1 M HCl (2 x 10 mL), pH=7 phosphate buffer (25 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 5-9% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.15 in 5% MeOH/DCM) were combined to give compound 4 as a dark green solid (125 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 9.67 (s, 1H), 8.75 (s, 1H), 9.79 (t, 1H), 7.42- 7.33 (m, 6H), 7.19-7.08 (m, 9H), 6.95-6.86 (m, 1H), 6.75-6.62 (m, 1H), 6.37 (m, 2H), 5.37 (d, 1H), 5.26 (d, 1H), 4.48-4.37 (m, 2H), 4.37 (s, 3H), 3.80 (s, 3H), 3.71 (q, 2H), 3.63 (m, 4H), 3.58 (m, 4H), 3.51 (m, 5H), 3.45 (s, 2H), 3.30 (s, 3H), 2.62-2.53 (m, 1H), 2.26-2.17 (m, 2H), 2.00-1.87 (m, 3H), 1.80-1.60 (m, 10H), -1.45 (brs, 1H), -1.60 (brs, 1H). Synthesis Example 5 – synthesis of chlorin e6 trimethyl ester 13-(N-(2- triphenylphosphoniumethyl)bromide)carbamate (compound 5)
Figure imgf000099_0001
To a 25 mL RBF was added chlorin e613-hydroxymethyl trimethyl ester (compound 1) (90 mg, 0.140 mmol, 1 eq), carbonyl diimidazole (45 mg, 0.280 mmol, 2 eq), DCM (4 mL) and DMAP (5 mg, 0.0409 mmol, 0.3 eq). The resultant mixture was stirred under nitrogen at 22 °C for 3 hours. (2-Aminoethyl)triphenylphosphonium bromide (270 mg, 0.700 mmol, 5 eq) was added and stirring was continued overnight at 22 °C. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel and washed with 1 M HCl (2 x 10 mL), pH=7 phosphate buffer (25 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3-6% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.10 in 5% MeOH/DCM) were combined to give compound 5 as a dark green solid (38 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 9.61 (s, 1H), 8.77 (s, 1H), 7.71 (t, 1H), 7.66- 7.57 (m, 6H), 7.43-7.35 (m, 8H), 6.24 (m, 2H), 5.37 (d, 1H), 5.24 (d, 1H), 4.48-4.38 (m, 2H), 4.26 (s, 3H), 3.88-3.70 (m, 9H), 3.52 (s, 3H), 3.48 (s, 3H), 3.46 (s, 3H), 3.30 (s, 3H), 2.64-2.52 (m, 1H), 2.26-2.17 (m, 2H), 1.90-1.80 (m, 4H), 1.78-1.68 (m, 8H), -1.46 (brs, 1H), -1.64 (brs, 1H). Synthesis Example 6 – synthesis of chlorin e613-(N-methylamino)methyl trimethyl ester (compound 6)
Figure imgf000100_0001
To a 25 mL RBF was added chlorin e613-formyl trimethyl ester (50 mg, 0.078 mmol, 1 eq), DCM (1 mL), methanol (3 mL), TEA (32 mg, 0.312 mmol, 4 eq) and methylamine hydrochloride (11 mg, 0.156 mmol, 2 eq). The resultant mixture was stirred under nitrogen in the dark for 1 hour and then a further portion of methylamine hydrochloride (11 mg, 0.156 mmol, 2 eq) and TEA (32 mg, 0.312 mmol, 4 eq) were added and stirring continued for an additional 1 hour. NaBH4 (15 mg, 0.390 mmol, 5 eq) was added and stirring was continued for 30 minutes. The reaction was acidified with 2 M HCl (1 mL) and stirred for 10 minutes. Phosphate buffer pH=7 (15 mL) was added and the mixture extracted with DCM (2 x 5 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3-7% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.30 in 10% MeOH/DCM) were combined to give compound 6 as a dark green solid (27 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 9.46 (s, 1H), 8.65 (s, 1H), 5.34 (d, 1H), 5.21 (d, 1H), 4.87 (brm, 2H), 4.42-4.34 (m, 2H), 4.25 (s, 3H), 3.77 (m, 4H), 3.70-3.62 (m, 6H), 3.47 (s, 3H), 3.30 (s, 3H), 3.25 (s, 3H), 2.59 (s, 3H), 2.58-2.48 (m, 1H), 2.21-2.09 (m, 2H), 1.77-1.69 (m, 5H), 1.67-1.61 (m, 4H), -1.47 (brs, 1H), -1.70 (brs, 1H). Synthesis Example 7 – synthesis of chlorin e613-(N-methyl-5- triphenylphosphonium bromide pentanamide) trimethyl ester (compound 7)
Figure imgf000101_0001
To a 25 mL RBF was added chlorin e613-(N-methylamino)methyl trimethyl ester (compound 6) (20 mg, 0.0305 mmol, 1 eq), 4-(carboxybutyl)triphenylphosphonium bromide (18 mg, 0.0640 mmol, 2.1 eq), DCM (1 mL) and DMTMM (18 mg, 0.0640 mmol, 2.1 eq). The resultant mixture was stirred under nitrogen at ambient temperature in the dark for 2 hours. The reaction mixture was transferred to a separatory funnel, diluted with DCM (15 mL) and washed with 0.5 M HCl (10 mL). The aqueous layer was re-extracted with DCM (2 x 5 mL) and the combined organics washed with pH 7 phosphate buffer (10 mL) followed by 1 M aqueous NaHCO3 (10 mL). The organic phase was dried (Na2SO4) and concentrated by rotary evaporation to give a blue-black film. The residue was purified by column chromatography using 3-7% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.30 in 10% MeOH/DCM) were combined to give compound 7 as a dark green solid (10 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 9.65 (s, 1H), 8.71 (s, 1H), 7.75-7.67 (m, 7H), 7.57-7.46 (m, 9H), 5.85 (m, 2H), 5.37-5.20 (m, 2H), 4.48-4.37 (m, 2H), 4.26 (s, 3H), 3.88-3.70 (m, 8H), 3.63 (s, 3H), 3.57 (s, 3H), 3.40 (s, 3H), 3.19 (s, 3H), 3.14 (s, 3H), 2.78 (m, 2H), 2.62-2.52 (m, 1H), 2.23-2.12 (m, 4H), 1.90-1.65 (m, 18H), -1.44 (brs, 1H), -1.56 (brs, 1H). Synthesis Example 8 – synthesis of chlorin e6 trimethyl ester 13-(N-methyl-(3- triphenylphosphoniumpropoxy)chloride)carbamate (compound 8)
Figure imgf000102_0001
To a 25 mL RBF was added chlorin e613-(N-methylamino)methyl trimethyl ester (compound 6) (100 mg, 0.152 mmol, 1 eq), carbonyl diimidazole (49 mg, 0.304 mmol, 1.5 eq) and DCM (4 mL). The resultant mixture was stirred under nitrogen for 1 hour. (3-Hydroxypropyl)triphenylphosphonium chloride (108 mg, 0.304 mmol, 1.5 eq) in DCM (2 mL) was added and stirring was continued overnight in the dark at 23 °C. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel and washed with water (15 mL), extracted with DCM (2 x 5 mL), before being dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3-8% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.25 in 7% MeOH/DCM) were combined to give compound 8 as a dark green solid (56 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 9.55 (s, 1H), 8.72 (s, 1H), 7.75-7.60 (m, 5H), 7.55-7.45 (m, 2H), 7.42-7.30 (m, 8H), 5.72-5.68 (m, 2H), 5.40-5.20 (m, 4H), 4.62 (m, 2H), 4.41 (m, 2H), 4.25 (s, 3H), 4.05-3.90 (m, 2H), 3.75 (m, 6H), 3.62 (s, 3H), 3.55 (s, 3H), 3.40 (m, 3H), 3.1 (m, 3H), 2.95 (m, 2H), 2.62-2.50 (m, 1H), 2.25-2.00 (m, 4H), 1.80-1.65 (m, 8H), -1.45 (brs, 1H), -1.58 (brs, 1H). Synthesis Example 9 – synthesis of chlorin e6 (2-methoxyethyl)methylamine dimethyl ester 13-(N-(3-triphenylphosphoniumpropyl)bromide)carbamate (compound 9)
Figure imgf000103_0001
Step 1: A 1-neck 250 mL RBF was charged with chlorin e6 (0.5 g, 1 eq), di-tert-butyl dicarbonate ((Boc)2O) (188 mg, 1.03 eq) and DCM (60 ml). DMAP (8 mg, 0.08 eq) was added and the resultant solution was stirred for 2 hours under a nitrogen atmosphere at 40 °C. The resulting black solution was filtered using a cotton plug, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with hexane (2 x 10 ml) and dried to obtain chlorin e6 anhydride as a black solid (475 mg, 98%). It was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 9.52 (m, 2H), 9.22 (m, 1H), 8.45 (m, 1H), 7.82 (m, 1H), 6.34 (m, 1H), 6.14 (m, 1H), 5.40 (m, 2H), 4.60-4.30 (m, 2H), 3.55 (m, 5H), 3.32 (s, 3H), 3.16 (m, 4H), 2.75-2.50 (m, 2H), 2.35 (m, 2H), 1.95 (m, 1H), 1.75-1.60 (m, 6H), 1.15 (t, 2H), -0.5 (brs, 2H). Step 2: A 1-neck 250 mL RBF was charged with chlorin e6 anhydride (470 mg, 1 eq), (2- methoxyethyl)methylamine (108 mg, 1.5 eq) and DCM (30 ml). The resultant solution was stirred overnight under a nitrogen atmosphere at 35 °C. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered and washed with diethyl ether (2 x 10 ml). The residual black solid was purified by column chromatography using 10-50% MeOH/DCM and fractions containing the first dark band to elute were combined to give chlorin e6 (2- methoxyethyl)methylamine as a bluish green solid (320 mg, 59% yield, 95.33% purity by HPLC). 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.42 (s, 1H), 9.10 (s, 1H), 8.35 (dd, 1H), 6.44 (d, 1H), 6.14 (d, 1H), 5.20 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 2H), 3.85 (m, 3H), 3.65-3.30 (m, 10H), 3.20 (m, 2H), 2.85 (m, 1H), 2.15 (m, 1H), 1.15 (t, 2H), -2.0 (brs, 1H), -2.68 (brs, 1H). Step 3: Into a 1-neck 250 mL RBF was added chlorin e6 (2-methoxyethyl)methylamine (310 g, 1 eq), potassium carbonate (192 mg, 3 eq), DMF (10 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 300 rpm with an air condenser attached. Methyl iodide (0.072 mL, 3 eq) was then added. The solution was stirred at 25 °C over the weekend. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude material was dissolved in DCM (30 mL), washed with water (2 x 10 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product as a dark blue/green solid (350 mg). At this point HPLC analysis indicated a purity of ~96%. The residual blue/green solid was purified by column chromatography using 1-5% MeOH/DCM and fractions containing the first dark band to elute were combined to give chlorin e6 (2-methoxyethyl)methylamine dimethyl ester as a bluish green solid (310 mg, 98% yield, 98.69% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.55 (m, 1H), 8.72 (m, 1H), 8.10-8.00 (m, 2H), 6.44 (d, 1H), 6.14 (d, 1H), 5.50-5.20 (m, 2H), 4.50 (m, 2H), 4.30-4.10 (m, 2H), 3.90-3.65 (m, 5H), 3.65 (s, 3H), 3.60 (m, 6H), 3.45 (m, 6H), 3.30 (s, 3H), 2.95 (s, 3H), 2.85 (s, 3H), 2.60 (m, 1H), 2.20 (m, 2H), 1.75-1.55 (m, 7H), -1.30 (brs, 1H), -1.45 (brs, 1H). Step 4: To a 250 mL RBF was added chlorin e6 (2-methoxyethyl)methylamine dimethyl ester (310 mg, 1 eq), THF (10 mL), osmium tetroxide (~1 mg, 0.01 eq), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (247 mg, 2.6 eq). The resultant mixture was stirred under nitrogen in the dark at ambient temperature overnight. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (20 mL), transferred to a separatory funnel and washed with brine (10 mL), saturated NaHCO3 (10 mL), water (10 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a red-brown powdery solid. The residual dark solid was purified by column chromatography using 1-2% MeOH/DCM and fractions containing the first dark band to elute were combined to give chlorin e613- formyl (2-methoxyethyl)methylamine dimethyl ester as a red-brown powdery solid (210 mg, 68% yield, 93.43% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 10.35 (s, 1H), 9.65 (m, 1H), 8.95 (m, 1H), 8.00 (s, 1H), 5.60-5.30 (m, 2H), 4.50-4.30 (m, 2H), 4.25-4.15 (m, 3H), 3.90-3.40 (m, 14 H), 3.55 (m, 7 H), 3.42 (s, 3H), 3.32 (s, 3H), 2.93 (s, 3H), 2.85 (s, 3H), 2.70-2.60 (m, 2H), 2.50-2.40 (m, 2H), 1.70 (m, 7H), -1.20 (brs, 1H), -1.75 (brs, 1H). Step 5: To a 100 mL RBF was added chlorin e613-formyl (2- methoxyethyl)methylamine dimethyl ester (210 mg, 1 eq), MeOH (5 mL), DCM (2 mL) and sodium borohydride (22 mg, 2 eq). The resultant mixture was stirred under nitrogen at ambient temperature for 1 hour. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected and the aqueous layer further extracted with DCM (10 mL). The combined DCM layers were washed with brine (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green solid (~200 mg). The residue was subjected to column chromatography. The crude product was dissolved in DCM and eluted using a gradient of 1% MeOH/DCM (300 mL), then 2% MeOH/DCM (200 mL), then 3% MeOH/DCM (200 mL). Fractions of ~20 mL size were collected when the first color began to elute. Fractions 6, 7 and 8 containing the product (major dark green spot, Rf = ~0.7 in 5% MeOH/DCM) were combined to give chlorin e613-hydroxymethyl (2-methoxyethyl)methylamine dimethyl ester (compound 9A) as a blue/green solid (110 mg, 52% yield, 97.34% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.60 (m, 1H), 8.78 (m, 1H), 5.90 (s, 2H), 5.50-5.30 (m, 2H), 4.50-4.30 (m, 2H), 4.25-4.15 (m, 3H), 3.70-3.16 (m, 8H), 3.55 (m, 7 H), 3.42 (s, 3H), 3.30 (s, 3H), 3.15 (s, 1H), 2.64-2.50 (m, 1H), 2.50-2.35 (m, 1H), 2.20 (m, 3H), 1.80 (m, 7H), 1.68 (m, 4H), -1.60 (brs, 1H), -1.70 (brs, 1H). Step 6: To a 25 mL RBF was added chlorin e613-hydroxymethyl (2- methoxyethyl)methylamine dimethyl ester (compound 9A) (70 mg, 1 eq), carbonyl diimidazole (32 mg, 2 eq), DCM (3 mL) and DMAP (2 mg). The resultant mixture was stirred under nitrogen for 3 hours. (3-Aminopropyl)triphenylphosphonium bromide (200 mg, 5 eq) was added and stirring was continued overnight at ambient temperature. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (15 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue (~100 mg). The residue was purified by column chromatography (3 x 12 cm) using 0-6% MeOH/DCM, loaded as a solution in the eluent. The major dark green band (Rf = 0.15 in 5% MeOH/DCM) was concentrated to give compound 9 as a dark green solid (65 mg, 58% yield, 97.25% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.78 (m, 1H), 9.65 (m, 1H), 8.75 (m, 1H), 7.48 (t, 1H), 7.25 (m, 9H), 7.00 (m, 9 H), 6.70 (m, 1H), 6.65-6.50 (m, 1H), 6.35 (m, 2H), 5.50-5.30 (m, 2H), 4.45-4.15 (m, 5H), 3.80-3.65 (m, 8H), 3.60-3.40 (m, 18H), 3.32 (s, 3H), 2.70- 2.40 (m, 1H), 2.30-2.00 (m, 2H), 1.80-1.60 (m, 8H) -1.40 (m, 1H), -1.60 (m, 1H). Synthesis Example 10 – synthesis of chlorin e6 N-methylbutylamine dimethyl ester 13-(N-(3-triphenylphosphoniumpropyl)bromide)carbamate (compound 10)
Figure imgf000107_0001
Step 1: A 1-neck 250 mL RBF was charged with chlorin e6 anhydride (500 mg, 1 eq), N- methylbutylamine (108 mg, 1.5 eq) and DCM (30 ml). The resultant solution was stirred overnight under a nitrogen atmosphere at 35 °C. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered, washed with diethyl ether (2 x 10 ml) and dried over a rotavapor to obtain chlorin e6 N-methylbutylamine as a bluish green solid (670 mg, quantitative yield, 85.80% purity by HPLC). The crude product was carried over to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.70 (s, 1H), 9.10 (s, 1H), 8.35 (dd, 1H), 6.44 (d, 1H), 6.14 (d, 1H), 5.70 (m, 1H), 5.30 (m, 1H), 4.60 (m, 1H), 4.40 (m, 1H), 3.85 (m, 3H), 3.65-3.40 (m, 10H), 2.85 (m, 1H), 2.40-2.10 (m, 5H), 1.70 (t, 3H), 1.80-1.50 (m, 10H), 1.25 (m, 4H), 1.00 (t, 2H), 0.90 (t, 4H), 0.80 (t, 1H), -1.90 (brs, 1H), -2.35 (brs, 1H). Step 2: Into a 1-neck 250 mL RBF was added chlorin e6 N-methylbutylamine (650 g, 1 eq), potassium carbonate (404 mg, 3 eq), DMF (10 mL) and a stirrer bar. The flask was placed under nitrogen. Methyl iodide (0.150 mL, 2.5 eq) was then added. The solution was stirred at 25 °C overnight. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude material was dissolved in DCM (30 mL), washed with water (2 x 10 mL), dried (Na2SO4) and concentrated under reduced pressure to give chlorin e6 N-methylbutylamine dimethyl ester as a dark blue/green solid (700 mg, quantitative yield, 86.64% purity by HPLC). The crude product was carried over to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.55 (m, 1H), 8.72 (m, 1H), 8.10-8.00 (m, 2H), 6.44 (d, 1H), 6.14 (d, 1H), 5.50-5.20 (m, 2H), 4.50 (m, 2H), 4.20 (m, 3H), 3.90- 3.60 (m, 6H), 3.65 (s, 3H), 3.55 (m, 4H), 3.45 (m, 6H), 3.30 (s, 3H), 2.95 (s, 3H), 2.85 (s, 3H), 2.60 (m, 1H), 2.20 (m, 2H), 1.75-1.55 (m, 9H), 1.40 (m, 1H), 1.10 (t, 1H), 0.90 (t, 3H), -1.30 (brs, 1H), -1.45 (brs, 1H). Step 3: To a 250 mL RBF was added chlorin e6 N-methylbutylamine dimethyl ester (700 mg, 1 eq), THF (10 mL), osmium tetroxide (~2 mg, 0.01 eq), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (561 mg, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (20 mL), transferred to a separatory funnel and washed with brine (10 mL), saturated NaHCO3 (10 mL), water (10 mL), dried (Na2SO4) and concentrated by rotary evaporation to give chlorin e613-formyl N-methylbutylamine dimethyl ester as a red-brown powdery solid (670 mg, quantitative yield, 85.31% purity by HPLC). The crude product was carried over to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 10.25 (s, 1H), 9.65 (m, 1H), 8.95 (m, 1H), 8.00 (s, 1H), 5.60-5.30 (m, 2H), 4.50-4.30 (m, 2H), 4.25-4.15 (m, 3H), 3.80-3.40 (m, 17 H), 3.42 (s, 3H), 3.32 (s, 3H), 2.93 (s, 3H), 1.85 (m, 3H), 2.70-2.60 (m, 2H), 1.70 (m, 7H), 1.40 (m, 2H), 1.20 (t, 2H), 1.00 (t, 2H), -1.80 (brs, 1H). Step 4: To a 100 mL RBF was added chlorin e613-formyl N-methylbutylamine dimethyl ester (650 mg, 1 eq), MeOH (15 mL), DCM (4 mL) and sodium borohydride (70 mg, 2 eq). The resultant mixture was stirred under nitrogen at ambient temperature for 2 hours. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected and the aqueous layer further extracted with DCM (10 mL). The combined DCM layers were washed with brine (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green solid (~300 mg). The residue was subjected to column chromatography. The crude product was dissolved in DCM and eluted using a gradient of 1% MeOH/DCM (300 mL), then 2% MeOH/DCM (300 mL), then 3% MeOH/DCM (300 mL). Fractions of ~20 mL size were collected when the first color began to elute. Fractions 6, 7 and 8 containing the product (major dark green spot, Rf = ~0.7 in 5% MeOH/DCM) were combined to give chlorin e613- hydroxymethyl N-methylbutylamine dimethyl ester (compound 10A) as blue/green solid (230 mg, 36% yield, 98.49% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.52 (m, 1H), 8.70 (m, 1H), 5.90 (s, 2H), 5.50-5.30 (m, 2H), 4.50-4.30 (m, 2H), 4.20-4.15 (m, 3H), 3.70-3.60 (m, 3H), 3.65 (s, 3 H), 3.55 (m, 4H), 3.45 (m, 6H), 3.30 (s, 3H), 3.05 (s, 1H), 2.64-2.50 (m, 1H), 2.70-2.45 (m, 2H), 2.20 (m, 3H), 1.80 (m, 7H), 1.38 (m, 2H), 1.10 (t, 1H), 0.90 (t, 2H), -1.40 (brs, 1H), -1.70 (brs, 1H). Step 5: To a 100 mL RBF was added chlorin e613-hydroxymethyl N-methylbutylamine dimethyl ester (compound 10A) (140 mg, 1 eq), carbonyl diimidazole (64 mg, 2 eq), DCM (6 mL) and DMAP (2 mg). The resultant mixture was stirred under nitrogen for 3 hours. (3-Aminopropyl)triphenylphosphonium bromide (400 mg, 5 eq) was added and stirring was continued overnight at ambient temperature. After overnight, further carbonyl diimidazole (32 mg) was added and the reaction was then heated at 30 °C (heat block) for a further 3 hours. At this stage, the reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (2 x 10 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. To this residue was added further carbonyl diimidazole (64 mg), DCM (6 mL) and DMAP (2 mg). The resultant mixture was stirred under nitrogen at 30 °C (external) for 3 hours. Further (3-aminopropyl)triphenylphosphonium bromide (400 mg, 5 eq) was added and stirring was continued overnight at 30 °C. Then the reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue (~150 mg). The residue was purified by column chromatography using 0-6% MeOH/DCM, loaded as a solution in the eluent. The major dark green band (Rf = 0.15 in 5% MeOH/DCM) was concentrated to give compound 10 as a dark green solid (62 mg, 28% yield, 98.08% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.70 (m, 1H), 9.55 (m, 1H), 8.65 (m, 1H), 7.38 (t, 1H), 7.15 (m, 5H), 6.90 (m, 8H), 6.70 (m, 1H), 6.65-6.50 (m, 1H), 6.35 (m, 2H), 5.50-5.30 (m, 2H), 4.45-4.10 (m, 5H), 3.80-3.55 (m, 5H), 3.53-3.35 (m, 13H), 3.25 (s, 3H), 2.70-2.40 (m, 1H), 2.30-2.00 (m, 2H), 1.80-1.60 (m, 8H), 1.40 (m, 1H), 1.00 (t, 2H), 0.90 (t, 2H), -1.50 (m, 1H), -1.65 (m, 1H). Synthesis Example 11 – synthesis of chlorin e613-hydroxymethyl N- (methylaminopropyl)triphenylphosphonium bromide dimethyl ester (compound 11)
Figure imgf000110_0001
Step 1: A 1-neck 100 mL RBF was charged with chlorin e6 anhydride (500 mg, 1 eq), (3- (methylamino)propyl)triphenylphosphonium bromide hydrobromide (641 mg, 1.5 eq) and DCM (30 ml). The resultant solution was stirred overnight under a nitrogen atmosphere at 35 °C. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered, washed with diethyl ether (2 x 10 ml) and dried over a rotavapor to obtain chlorin e6 N- (methylaminopropyl)triphenylphosphonium bromide as a blue/green solid (1.20 gm, quantitative yield, 72.47% purity by HPLC). The crude product was carried over to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (m, 1H), 9.10 (m, 1H), 9.10 (s, 1H), 8.35 (m, 1H), 8.00-7.75 (m, 11H), 7.65 (m, 3H), 6.44 (d, 1H), 6.14 (d, 1H), 4.60 (m, 1H), 3.85 (m, 3H), 3.65-3.40 (m, 10H), 2.90 (m, 1H), 2.20-2.15 (m, 2H), 1.80-1.50 (m, 6H), 1.00 (t, 2H), - 1.90 (brm, 1H), -2.40 (brm, 1H). Step 2: Into a 1-neck 250 mL RBF was added chlorin e6 N- (methylaminopropyl)triphenylphosphonium bromide (1.0 gm, 1 eq), potassium carbonate (415 mg, 3 eq), DMF (10 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 300 rpm with an air condenser attached. Methyl iodide (0.150 mL, 2.5 eq) was then added. The solution was stirred at 30 °C overnight. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude material was dissolved in DCM (30 mL), washed with water (2 x 10 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product as a dark blue/green solid (700 mg). At this point HPLC analysis indicated a purity of ~75%. The residual blue/green solid was purified by column chromatography using 2-3% MeOH/DCM and fractions containing the first dark band to elute were combined to give chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide dimethyl ester as a blue/green solid (440 mg, quantitative yield, 99.69% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.50 (s, 1H), 8.70 (s, 1H), 8.10-8.00 (dd, 1H), 7.65 (m, 6H), 7.55 (m, 3H), 7.40 (m, 6H), 6.44 (d, 1H), 6.14 (d, 1H), 5.20 (m, 2H), 4.30 (m, 2H), 4.00-3.90 (m, 5H), 3.70 (m, 3H), 3.65 (s, 3H), 3.55 (s, 3H), 3.40 (s, 3H), 3.30 (s, 3H), 3.20 (s, 3H), 2.60 (m, 1H), 2.20 (m, 4H), 1.70-1.55 (m, 6H), 1.40 (m, 1H), 1.20 (m, 1H), -1.40 (brs, 1H), -1.52 (brs, 1H). Step 3: To a 250 mL RBF was added chlorin e6 N- (methylaminopropyl)triphenylphosphonium bromide dimethyl ester (200 mg, 1 eq), THF (10 mL), osmium tetroxide (~1 mg, 0.01 eq), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (247 mg, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re- dissolved in DCM (20 mL), transferred to a separatory funnel and washed with brine (10 mL), saturated NaHCO3 (10 mL), water (10 mL), dried (Na2SO4) and concentrated by rotary evaporation to give chlorin e613-formyl N- (methylaminopropyl)triphenylphosphonium bromide dimethyl ester as a red-brown powdery solid (220 mg, quantitative yield, 72.47% purity by HPLC). The crude product was carried over to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 11.50 (s, 1H), 10.20 (s, 1H), 9.60 (s, 1H), 9.50 (s, 1H), 8.90 (s, 1H), 7.65 (m, 12H), 7.40 (m, 3H), 5.20 (m, 2H), 4.30 (m, 2H), 4.00-3.90 (m, 5H), 3.70 (m, 8H), 3.65 (s, 3H), 3.55 (s, 3H), 3.40 (s, 3H), 3.30 (s, 3H), 3.25 (s, 3H), 2.60 (m, 4H), 2.20 (m, 4H), 1.70-1.55 (m, 6H), 1.40 (m, 2H), -1.40 (brs, 1H), -1.80 (brs, 1H). Step 4: To a 100 mL RBF was added chlorin e613-formyl N- (methylaminopropyl)triphenylphosphonium bromide dimethyl ester (210 mg, 1 eq), MeOH (15 mL), DCM (4 mL) and sodium borohydride (15 mg, 2 eq). The resultant mixture was stirred under nitrogen at ambient temperature for 2 hours. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected and the aqueous layer further extracted with DCM (10 mL). The combined DCM layers were washed with brine (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green solid (~200 mg). The residue was subjected to column chromatography. The crude product was dissolved in DCM and eluted using a gradient of 1% MeOH/DCM (300 mL), then 2% MeOH/DCM (300 mL), then 3% MeOH/DCM (300 mL). Fractions of ~20 mL size were collected when the first color began to elute. Fractions 6, 7 and 8 containing the product (major dark green spot, Rf = ~0.7 in 5% MeOH/DCM) were combined to give compound 11 as a green solid (45 mg, 21% yield, 90.77% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.40 (m, 1H), 8.65 (s, 1H), 7.80-7.50 (m, 12 H), 7.40 (m, 5H), 5.65 (s, 2H), 5.20 (m, 2H), 4.40-4.20 (m, 2H), 4.05 (m, 4H), 3.70- 3.65 (m, 3H), 3.60 (s, 3 H), 3.55 (m, 4H), 3.35 (m, 3H), 3.30 (s, 3H), 3.10 (s, 1H), 2.60- 2.50 (m, 1H), 2.15 (m, 4H), 1.70 (m, 11H), 1.38 (m, 2H), 0.90 (m, 3H), -1.50 (brs, 1H), - 1.65 (brs, 1H). Synthesis Example 12 – synthesis of chlorin e6 β-D-1-thioglucose-N- methylpropylamide conjugate tetraacetate 13-hydroxymethyl dimethyl ester (compound 12)
Figure imgf000113_0001
Step 1: To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((3-((tert- butoxycarbonyl)(methyl)amino)propyl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.612 g, 1.14 mmol, 1.4 eq) in DCM (5 mL) was added TFA (1 mL). The resultant solution was stirred (420 rpm) for 1 hour at ambient temperature, then concentrated on the rotary evaporator. The residue was resuspended and concentrated twice from chloroform (2 x 10 mL) to give (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((3- methylamino)propyl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate TFA salt as a viscous oil. Step 2: A 1-neck 250 mL RBF was charged with chlorin e6 anhydride (2.0 g, 1 eq), (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((3-methylamino)propyl)thio)tetrahydro-2H- pyran-3,4,5-triyl triacetate TFA salt (2.84 g, 1.5 eq), sodium bicarbonate (435 mg, 1.5 eq) and DCM (30 ml). The resultant solution was stirred overnight under a nitrogen atmosphere at 30 °C. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered, washed with diethyl ether (2 x 10 ml) and dried over a rotavapor. The residual black solid was purified by column chromatography using 2-10% MeOH/DCM and fractions containing the first dark band to elute were combined and concentrated to give chlorin e6 β-D-1- thioglucose-N-methylpropylamide conjugate tetraacetate diacid as a bluish green solid (1.2 g, 34% yield, 96.19% purity by HPLC). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.70 (s, 1H), 9.10 (s, 1H), 8.35 (dd, 1H), 6.44 (d, 1H), 6.14 (d, 1H), 5.70 (m, 1H), 5.30 (m, 1H), 5.00-4.70 (m, 2H), 4.60 (m, 1H), 4.40 (m, 1H), 4.10-3.85 (m, 5H), 3.55 (m, 10H), 2.75 (m, 2H), 2.40-2.10 (m, 5H), 2.00- 1.50 (m, 12H), 1.70 (t, 3H), 1.55 (m, 2H), -1.80 (m, 1H), -2.25 (brs, 1H). Step 3: Into a 1-neck 250 mL RBF was added chlorin e6 β-D-1-thioglucose-N- methylpropylamide conjugate tetraacetate diacid (1.0 gm, 1 eq), potassium carbonate (490 mg, 3 eq), DMF (10 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 300 rpm with an air condenser attached. Methyl iodide (0.218 mL, 2.5 eq) was then added. The solution was stirred at 30 °C overnight. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude material was dissolved in DCM (30 mL), washed with water (2 x 10 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product as a dark blue/green solid (~1.2 g). At this point HPLC analysis indicated a purity of ~65%. The residual blue/green solid was purified by column chromatography using 2-4% MeOH/DCM and fractions containing the first dark band to elute were combined and concentrated to give chlorin e6 β-D-1-thioglucose-N-methylpropylamide conjugate tetraacetate dimethyl ester as a blue/green solid (700 mg, 69% yield, 85.89% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.55 (s, 1H), 8.70 (s, 1H), 8.10-8.00 (dd, 1H), 6.44 (d, 1H), 6.14 (d, 1H), 5.30-5.00 (m, 3H), 4.50-4.00 (m, 8H), 3.80-3.10 (m, 10H), 3.55 (s, 3H), 3.45 (s, 3H), 3.30 (s, 3H), 2.20-2.00 (m, 15H), 1.80 (m, 5H), -1.20-1.52 (m, 2H). Step 4: To a 250 mL RBF was added chlorin e6 β-D-1-thioglucose-N- methylpropylamide conjugate tetraacetate dimethyl ester (700 mg, 1 eq), THF (25 mL), osmium tetroxide (~2 mg, 0.01 eq), deionized water (2.5 mL), AcOH (2.5 mL) and sodium periodate (373 mg, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight and at 30 °C for one hour. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (20 mL), transferred to a separatory funnel and washed with water (10 mL), dried (Na2SO4) and concentrated by rotary evaporation to give chlorin e6 β-D-1-thioglucose-N-methylpropylamide conjugate tetraacetate 13-formyl dimethyl ester as a red-brown powdery solid (700 mg, 47.93% purity by HPLC). The crude product was carried over to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 10.20 (s, 1H), 9.65 (m, 1H), 8.95 (m, 1H), 5.50-5.00 (m, 8H), 4.50-4.00 (m, 12H), 3.90-3.40 (m, 24 H), 3.32 (s, 3H), 2.70-2.60 (m, 2H), 2.30-2.10 (m, 6H), 2.00 (m, 16 H), 1.70 (m, 8H), -1.75 (brs, 1H). Step 5: To a 100 mL RBF was added chlorin e6 β-D-1-thioglucose-N- methylpropylamide conjugate tetraacetate 13-formyl dimethyl ester (700 mg, 1 eq), MeOH (20 mL), DCM (8 mL) and sodium borohydride (19 mg, 0.72 eq). The resultant mixture was stirred under nitrogen at ambient temperature for 1 hour. The reaction mixture was concentrated using a rotavapor to give a dark green solid (~800 mg), which was re-dissolved in MeOH (10 mL) and concentrated using a rotavapor at ~65 °C and 700 mbar (3 cycles). Finally, the solvent MeOH was completely evaporated and crude product obtained (~700 mg). The residue was subjected to column chromatography. The crude product was dissolved in DCM and eluted using a gradient of 1% MeOH/DCM (300 mL), then 2% MeOH/DCM (200 mL), then 3% MeOH/DCM (200 mL). Fractions of ~20 mL size were collected when the first color began to elute. Fractions 6, 7 and 8 containing the product (major dark green spot, Rf = ~0.7 in 5% MeOH/DCM) were combined and concentrated to give compound 12 as a blue/green solid (410 mg, 59% yield, 39.06% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 9.50 (m, 1H), 8.70 (m, 1H), 5.80 (s, 2H), 5.50-4.80 (m, 8H), 4.50-4.00 (m, 12H), 3.70-3.40 (m, 20H), 3.45 (s, 3 H), 3.20 (s, 3H), 2.64-2.50 (m, 2H), 2.30-2.10 (m, 6H), 2.00 (m, 20H), 1.80 (m, 7H), 1.62 (m, 6H), -1.50 - -1.70 (brm, 2H). Synthesis Example 13 – synthesis of chlorin e6 β-D-1-thioglucose-N- methylpropylamide conjugate 13-hydroxymethyl dimethyl ester (compound 13)
Figure imgf000116_0001
To a solution of chlorin e6 β-D-1-thioglucose-N-methylpropylamide conjugate tetraacetate 13-hydroxymethyl dimethyl ester (compound 12) (120 mg, 0.095 mmol, 1 eq) in MeOH (3 mL) and DCM (3 mL) was added NaOMe (4.6 M in MeOH, 0.020 mL, 0.095 mmol, 1 eq), and the mixture stirred (420 rpm) under nitrogen for 1 hour. HPLC analysis after 45 minutes showed conversion to the deacetylated product. The reaction mixture was concentrated by rotary evaporation to give a black film. The residue was purified by column chromatography. The crude product was dissolved in 5% MeOH/DCM and eluted using a gradient of 5-7% MeOH/DCM (to elute a high Rf band) and then 7% ^ 12% MeOH/DCM. Fractions were collected when the first dark band began to elute. Fractions 6-14 were combined and concentrated to give compound 13 as a dark green solid (52 mg, 62% yield, 98.34% purity by HPLC). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (m, 2H), 9.00 (m, 1H), 5.80 (s, 2H), 5.40-5.30 (m, 2H), 5.20-4.90 (m, 2H), 4.45-4.30 (m, 6H), 4.20 (m, 3H), 3.85-3.70 (m, 3H), 3.65 (m, 3H), 3.60-3.40 (m, 12H), 3.30 (s, 3H), 3.20 (d, 3H), 2.70-2.45 (m, 2H), 1.60-1.40 (m, 6H), -1.60 (m, 1H), -1.80 (m, 1H). Synthesis Example 14 – synthesis of chlorin e6 β-D-1-thioglucose-N- methylpropylamide conjugate tetraacetate 13-(3- (triphenylphosphoniumpropyl)bromide)carbamate dimethyl ester (compound 14)
Figure imgf000116_0002
To a 50 mL RBF was added chlorin e6 β-D-1-thioglucose-N-methylpropylamide conjugate tetraacetate 13-hydroxymethyl dimethyl ester (compound 12) (300 mg, 1 eq), carbonyl diimidazole (92 mg, 2 eq), DCM (6 mL) and DMAP (5 mg). The resultant mixture was stirred under nitrogen for 3 hours. (3- Aminopropyl)triphenylphosphonium bromide (573 mg, 5 eq) was added and stirring was continued overnight at ambient temperature. The reaction mixture was concentrated and re-dissolved in 5 mL of 3% MeOH in DCM solution and directly loaded on a column. The residue was purified by column chromatography using 0-6% MeOH/DCM, loaded as a 3% MeOH in DCM solution. The major dark green band (Rf = 0.15 in 5% MeOH/DCM) fractions were concentrated to give compound 14 as a dark green solid (80 mg, 19% yield, 77.81% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.60 (m, 2H), 8.55 (m, 1H), 7.25 (m, 2H), 7.20-7.10 (m, 5H), 7.15-6.85 (m, 8H), 6.25 (s, 2H), 5.40-5.30 (m, 2H), 5.20-4.90 (m, 2H), 4.45-4.00 (m, 6H), 3.70-3.55 (m, 7H), 3.53-3.35 (m, 13H), 3.22 (s, 3H), 2.70-2.40 (m, 2H), 2.25- 2.00 (m, 2H), 2.00-1.85 (m, 15 H), 1.60-1.40 (m, 12H), 0.80 (m, 6H) -1.40 -1.80 (m, 2H). Synthesis Example 15 – synthesis of chlorin e6 N-methylbutylamine 13-N- methylamino dimethyl ester (compound 15)
Figure imgf000117_0001
To a 50 mL RBF was added chlorin e613-formyl N-methylbutylamine dimethyl ester (327 mg, 0.470 mmol, 1 eq), DCM (5 mL), methanol (20 mL), triethylamine (119 mg, 1.18 mmol, 2.5 eq) and methylamine hydrochloride (79 mg, 1.19 mmol, 2.5 eq). The resultant mixture was stirred under nitrogen in the dark for 2.5 hours. Further triethylamine (119 mg, 1.18 mmol, 2.5 eq) and methylamine hydrochloride (79 mg, 1.19 mmol, 2.5 eq) were then added and the reaction stirred for another 1.5 hours. NaBH4 (178 mg, 4.70 mmol, 10 eq) was added and stirring was continued for 16 hours. The reaction was acidified with 2M HCl (~4 mL) and stirred for 10 minutes. Phosphate buffer pH=7 (20 mL) was added and the mixture extracted with DCM (3 x 20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 4-6% MeOH/DCM, loaded as a solution in the eluent. The major fraction (with Rf = 0.30 in 10% MeOH/DCM) was concentrated by rotary evaporation to give compound 15 as a dark blue solid (304 mg, 91%). 1H NMR (400 MHz, Chloroform-d) δ 9.56 (s, 1H), 9.36 (d, J = 2.7 Hz, 1H), 8.62 (d, J = 4.7 Hz, 1H), 5.46-5.24 (m, 2H), 4.73 (s, 2H), 4.43-4.25 (m, 2H), 4.18 (d, J = 6.1 Hz, 3H), 3.83-3.72 (m, 1H), 3.70-3.61 (m, 4H), 3.57 (s, 1H), 3.48 (s, 3H), 3.45 (s, 3H), 3.27 (d, J = 2.2 Hz, 3H), 3.20 (s, 3H), 3.09 (s, 1H), 2.66-2.54 (m, 1H), 2.52 (s, 3H), 2.27-2.11 (m, 2H), 1.93-1.79 (m, 1H), 1.76-1.59 (m, 6H), 1.59-1.48 (m, 1H), 1.43-1.35 (m, 1H), 1.08 (t, J = 7.3 Hz, 1H), 0.95 (t, J = 7.3 Hz, 2H), -1.38 – -1.75 (m, 2H). Synthesis Example 16 – synthesis of chlorin e6 N-methylbutylamine 13-(N-methyl- 5-triphenylphosphonium bromide pentanamide) dimethyl ester (compound 16)
Figure imgf000118_0001
To a 25 mL RBF was added chlorin e6 N-methylbutylamine 13-N-methylamino dimethyl ester (compound 15) (100 mg, 0.141 mmol, 1 eq), 4- (carboxybutyl)triphenylphosphonium bromide (125 mg, 0.282 mmol, 2.2 eq), DCM (6 mL) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (83 mg, 0.282 mmol, 2.2 eq). The resultant mixture was stirred under nitrogen at ambient temperature in the dark for 16 hours. The reaction progress was monitored by HPLC. The reaction mixture was transferred to a separatory funnel, diluted with DCM (30 mL) and washed with 0.5 M HCl (20 mL). The aqueous layer was re-extracted with DCM (10 mL) and the combined organics washed with pH=7 phosphate buffer (20 mL) followed by 1M NaHCO3 (20 mL). The organic phase was dried (Na2SO4) and concentrated by rotary evaporation to give a dark green film. The dark green film was subjected to column chromatography by dissolving in 4% MeOH/DCM and eluting using a gradient of 4-10% MeOH/DCM. Fractions of 25 mL size were collected when the first colour began to elute. Fractions containing the product (major dark green spot, Rf = 0.3 in 10% MeOH/DCM) were combined to give compound 16 as a dark green solid (76 mg, 48%) (97.98% purity by HPLC). 1H NMR (400 MHz, Chloroform-d) δ 9.77 (s, 1H), 9.66 (s, 1H), 8.73 (d, J = 8.9 Hz, 1H), 7.63 (dq, J = 13.2, 7.6 Hz, 6H), 7.50-7.34 (m, 8H), 5.85 (s, 2H), 5.45-5.16 (m, 2H), 4.47- 4.26 (m, 2H), 4.17 (d, J = 6.4 Hz, 3H), 3.85-3.71 (m, 4H), 3.67 (s, 2H), 3.56 (d, J = 7.3 Hz, 4H), 3.46 (d, J = 3.3 Hz, 3H), 3.41 (d, J = 2.8 Hz, 3H), 3.20 (d, J = 2.8 Hz, 3H), 3.16 (s, 3H), 3.09 (s, 1H), 2.76 (t, J = 6.7 Hz, 2H), 2.69-2.45 (m, 1H), 2.33-2.08 (m, 5H), 1.88 (d, J = 7.8 Hz, 1H), 1.82-1.50 (m, 17H), 1.40 (q, J = 7.5 Hz, 1H), 1.33 (s, 1H), 1.22 (d, J = 6.6 Hz, 1H), 1.09 (t, J = 7.3 Hz, 1H), 0.96 (t, J = 7.3 Hz, 2H), -1.53 (d, J = 31.5 Hz, 1H). Synthesis Example 17 – synthesis of chlorin e613-hydroxymethyl triethyl ester (compound 17)
Figure imgf000119_0001
Step 1: Into a 1-neck 500 mL RBF was added chlorin e6 (10.0 g, 0.016 mol, 1 eq), potassium carbonate (8.33 g, 0.060 mol, 3.6 eq), DMF (120 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 300 rpm with an air condenser attached. Ethyl iodide (6.73 mL, 0.083 mmol, 5 eq) was then added. The solution was heated at 40 °C over the weekend. The solution was diluted with DCM (100 mL), stirred for 15 minutes and filtered through Celite® (1 cm depth, 6 cm width) washing with DCM until no more color eluted. The solvent was removed under reduced pressure to give crude product as a dark green solid. The crude product was dissolved in EtOAc (300 mL), washed with water (2 x 150 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark blue/green solid (12.10 g). The dark blue/green solid was purified by column chromatography using a gradient of 0.5-5% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.50 in 5% MeOH/DCM) were combined and concentrated to give chlorin e6 triethyl ester (9.37 g, 82%). 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.57 (s, 1H), 8.76 (s, 1H), 8.06 (dd, 1H), 6.34 (d, 1H), 6.13 (d, 1H), 5.38 (d, 1H), 5.25 (d, 1H), 4.89-4.81 (m, 1H), 4.78-4.69 (m, 1H), 4.50-4.41 (m, 2H), 4.30-4.18 (m, 2H), 4.16-4.04 (m, 2H), 3.79 (q, 2H), 3.60 (s, 3H), 3.48 (s, 3H), 3.30 (s, 3H), 2.58-2.48 (m, 1H), 2.30-2.12 (m, 2H), 1.85-1.70 (m, 7H), 1.66 (t, 3H), 1.22-1.15 (m, 6H), -1.35 (brs, 1H), -1.52 (brs, 1H). Step 2: To a 250 mL RBF was added chlorin e6 triethyl ester (2.01 g, 2.95 mmol, 1 eq), THF (75 mL), osmium tetroxide (7.5 mg, 0.0295 mmol, 0.01 eq), deionized water (6 mL), AcOH (6 mL) and sodium periodate (1.64 g, 7.67 mmol, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature for 3 days. The reaction progress was monitored by HPLC. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (90 mL), transferred to a separatory funnel and washed with brine (60 mL), saturated NaHCO3 (60 mL) and water (75 mL) before being dried (Na2SO4) and concentrated by rotary evaporation to give crude product as a dark blue solid (2.09 g). The crude product was purified by column chromatography using 2% MeOH in DCM as eluent. The fractions containing a red spot with Rf = 0.85 in 5% MeOH in DCM were combined and concentrated by rotary evaporation to give chlorin e613-formyl triethyl ester as a dark blue solid (1.05 g, 52%). 1H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 10.27 (s, 1H), 9.68 (s, 1H), 8.96 (s, 1H), 5.42 (d, J = 18.8 Hz, 1H), 5.27 (d, J = 18.8 Hz, 1H), 4.87 (dq, J = 10.7, 7.1 Hz, 1H), 4.74 (dq, J = 10.8, 7.1 Hz, 1H), 4.54-4.43 (m, 2H), 4.25 (dtt, J = 18.1, 11.0, 7.2 Hz, 2H), 4.17-4.02 (m, 2H), 3.80 (s, 3H), 3.79-3.74 (m, 2H), 3.59 (s, 3H), 3.33 (s, 3H), 2.64-2.53 (m, 1H), 2.31-2.17 (m, 2H), 1.76 (d, J = 7.3 Hz, 3H), 1.72 (t, J = 7.6 Hz, 3H), 1.66 (t, J = 7.2 Hz, 3H), 1.20 (q, J = 7.0 Hz, 7H), -1.32 (s, 1H), -1.82 (s, 1H). Step 3: To a 250 mL RBF was added chlorin e613-formyl triethyl ester (850 mg, 1.24 mmol, 1 eq), MeOH (20 mL), DCM (10 mL) and sodium borohydride (94 mg, 2.48 mmol, 2 eq). The resultant mixture was stirred (600 rpm) under nitrogen at ambient temperature for 10 minutes. The reaction mixture was diluted with water (15 mL) and stirred for 10 minutes. The mixture was then extracted with DCM (2 x 30 mL) and the combined DCM layers were washed with water (50 mL) before being dried (Na2SO4) and concentrated by rotary evaporation to give crude product as a dark green solid. The crude product was purified by silica chromatography (4 × 20 cm) eluting with 2% MeOH/DCM. Fractions containing a spot with Rf = 0.7 in 5% MeOH/DCM were combined and concentrated by rotary evaporation to give compound 17 as a dark green solid (628 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 9.48 (s, 1H), 8.76 (s, 1H), 5.76 (s, 2H), 5.40 (d, 1H), 5.28 (d, 1H), 4.90-4.81 (m, 1H), 4.78-4.70 (m, 1H), 4.51-4.43 (m, 2H), 4.31-4.19 (m, 2H), 4.15-4.05 (m, 2H), 3.74 (q, 2H), 3.59 (s, 3H), 3.39 (s, 3H), 3.25 (s, 3H), 2.59- 2.50 (m, 1H), 2.30-2.21 (m, 1H), 2.20-2.11 (m, 1H), 1.85-1.63 (m, 11H), 1.23-1.16 (m, 7H), -1.49 (brs, 1H), -1.67 (brs, 1H). Synthesis Example 18 – synthesis of chlorin e613- (oxopentyl)triphenylphosphonium bromide triethyl ester (compound 18)
Figure imgf000121_0001
To a 50 mL RBF was added chlorin e613-hydroxymethyl triethyl ester (compound 17) (200 mg, 0.292 mmol, 1 eq), 4-(carboxybutyl)triphenylphosphonium bromide (259 mg, 0.584 mmol, 2 eq), EDC.HCl (112 mg, 0.584 mmol, 2 eq), DMAP (71 mg, 0.584 mmol, 2 eq) and DCM (15 mL). The resultant mixture was stirred (600 rpm) under nitrogen at ambient temperature in the dark. The reaction progress was monitored by TLC. After 1 hour the solvent was removed by rotary evaporation to leave a green oil. The green oil was subjected to column chromatography by dissolving in 3% MeOH/DCM and eluting using a gradient of 3-5% MeOH/DCM. Fractions containing the product (major dark green spot, Rf = 0.15 in 5% MeOH/DCM) were combined to give compound 18 as a dark green solid (290 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 9.57 (s, 1H), 8.78 (s, 1H), 7.31-7.26 (m, 3H), 7.24 (dd, J = 7.1, 1.5 Hz, 3H), 7.20-7.13 (m, 3H), 7.05 (td, J = 7.8, 3.4 Hz, 7H), 6.35 (s, 2H), 5.40 (d, J = 18.8 Hz, 1H), 5.26 (d, J = 18.7 Hz, 1H), 4.85 (dq, J = 10.9, 7.1 Hz, 1H), 4.74 (dq, J = 10.9, 7.2 Hz, 1H), 4.53-4.42 (m, 2H), 4.34-4.18 (m, 2H), 4.16-4.03 (m, 2H), 3.76 (q, J = 7.6 Hz, 2H), 3.72-3.60 (m, 1H), 3.58 (s, 3H), 3.45 (s, 3H), 3.30 (s, 3H), 2.66-2.43 (m, 3H), 2.31-2.05 (m, 4H), 1.76 (d, J = 7.3 Hz, 4H), 1.67 (dt, J = 10.0, 7.4 Hz, 8H), 1.44-1.28 (m, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H), -1.60 (s, 1H), -1.78 (s, 1H). Synthesis Example 19 – synthesis of chlorin e6 triethyl ester 13-(N-(3- triphenylphosphoniumpropyl)bromide)carbamate (compound 19)
Figure imgf000122_0001
To a 25 mL RBF containing chlorin e613-hydroxymethyl triethyl ester (compound 17) (80 mg, 0.1168 mmol, 1 eq), DCM (4 mL) and DMAP (5 mg) was added carbonyl diimidazole (38 mg, 0.2336 mmol, 2 eq). The resultant mixture was stirred under nitrogen for 1 hour at 30 °C. (3-Aminopropyl)triphenylphosphonium bromide (234 mg, 0.5841 mmol, 5 eq) was added and stirring was continued at 30 °C for 3 hours and then at 25 °C overnight. The reaction mixture was diluted with water (5 mL), transferred to a separatory funnel and extracted with DCM (3 x 5 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using a gradient of 4-6% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.15 in 5% MeOH/DCM) were combined to give compound 19 as a dark green solid (96 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 9.67 (s, 1H), 8.76 (s, 1H), 7.44 (t, 1H), 7.37- 7.29 (m, 6H), 7.15-7.04 (m, 9H), 6.90-6.81 (m, 1H), 6.72-6.57 (m, 1H), 6.37 (m, 2H), 5.39 (d, 1H), 5.26 (d, 1H), 4.89-4.80 (m, 1H), 4.78-4.69 (m, 1H), 4.48-4.39 (m, 2H), 4.30-4.18 (m, 2H), 4.14-4.05 (m, 2H), 3.72 (q, 2H), 3.59 (m, 4H), 3.51 (m, 7H), 3.30 (s, 3H), 2.60-2.51 (m, 1H), 2.29-2.15 (m, 2H), 1.80-1.60 (m, 18H), 1.28-1.16 (m, 9H), -1.47 (brs, 1H), -1.66 (brs, 1H). Synthesis Example 20 – synthesis of chlorin e613-hydroxymethyl N- methylbutylamine diethyl ester (compound 20)
Figure imgf000123_0001
Step 1: Into a 1-neck 100 mL RBF was added chlorin e6 N-methylbutylamine (761 mg, 1.14 mmol, 1 eq), potassium carbonate (788 mg, 5.70 mmol, 5 eq), DMF (15 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 400 rpm with an air condenser attached. Ethyl iodide (445 mg, 2.85 mmol, 2.5 eq) was then added. The solution was stirred at 25 °C for 3 days. The reaction progress was monitored by HPLC. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude material was dissolved in DCM (50 mL), washed with water (2 x 20 mL), dried (Na2SO4) and concentrated under reduced pressure to give crude product as a dark blue solid. The crude product was purified by silica gel column chromatography using 1% MeOH in DCM as eluent. Fractions with Rf = 0.5 in 1% MeOH/DCM were combined and concentrated by rotary evaporation to give chlorin e6 N- methylbutylamine diethyl ester as a dark blue solid (400 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 1.4 Hz, 1H), 9.56 (d, J = 6.2 Hz, 1H), 8.73 (d, J = 5.5 Hz, 1H), 8.07 (ddd, J = 17.9, 11.5, 3.6 Hz, 1H), 6.34 (dd, J = 17.8, 1.6 Hz, 1H), 6.12 (dd, J = 11.5, 1.5 Hz, 1H), 5.54-5.25 (m, 2H), 4.78-4.57 (m, 2H), 4.47-4.30 (m, 2H), 4.20-3.96 (m, 2H), 3.84-3.75 (m, 2H), 3.74-3.60 (m, 1H), 3.57 (d, J = 2.0 Hz, 3H), 3.47 (d, J = 2.3 Hz, 3H), 3.44 (s, 2H), 3.30 (d, J = 2.2 Hz, 3H), 3.08 (s, 1H), 2.64-2.42 (m, 1H), 2.30-2.11 (m, 2H), 1.93-1.80 (m, 1H), 1.78-1.69 (m, 6H), 1.69 (s, 1H), 1.60 (td, J = 7.2, 2.8 Hz, 2H), 1.39 (q, J = 7.4 Hz, 1H), 1.22 (t, J = 7.1 Hz, 2H), 1.14 (t, J = 7.2 Hz, 1H), 1.06 (t, J = 7.3 Hz, 1H), 0.96 (t, J = 7.3 Hz, 2H), -1.18 – -1.63 (m, 2H). Step 2: To a 25 mL RBF was added chlorin e6 N-methylbutylamine diethyl ester (390 mg, 0.540 mmol, 1 eq), THF (6 mL), osmium tetroxide (1.4 mg, 0.0054 mmol, 0.01 eq), deionized water (0.5 mL), AcOH (0.5 mL) and sodium periodate (299 mg, 1.40 mmol, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature for 18 hours. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (30 mL), transferred to a separatory funnel and washed with brine (20 mL), saturated NaHCO3 (20 mL) and water (20 mL) before being dried (Na2SO4) and concentrated by rotary evaporation to give a red-blue solid. The red-blue solid was purified by column chromatography using 1-2% MeOH in DCM as eluent. Fractions with spots with Rf = 0.4 in 2% MeOH in DCM were combined and concentrated by rotary evaporation to give chlorin e613-formyl N-methylbutylamine diethyl ester as a dark blue solid (310 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 11.55 (d, J = 2.2 Hz, 1H), 10.27 (s, 1H), 9.66 (s, 1H), 8.95 (s, 1H), 5.57-5.31 (m, 2H), 4.80-4.56 (m, 2H), 4.51-4.34 (m, 2H), 4.24-3.97 (m, 2H), 3.85-3.74 (m, 5H), 3.74-3.61 (m, 1H), 3.57 (s, 3H), 3.47 (s, 2H), 3.45-3.37 (m, 1H), 3.34 (d, J = 1.6 Hz, 3H), 3.09 (s, 1H), 2.72-2.46 (m, 1H), 2.35-2.15 (m, 2H), 1.95-1.83 (m, 1H), 1.80-1.69 (m, 6H), 1.63-1.52 (m, 8H), 1.41 (p, J = 7.4 Hz, 1H), 1.24 (t, J = 7.1 Hz, 2H), 1.13 (dt, J = 21.3, 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 4H), -1.08 – -1.55 (m, 1H), -1.75 (d, J = 16.9 Hz, 1H). Step 3: To a 50 mL RBF was added chlorin e613-formyl N-methylbutylamine diethyl ester (240 mg, 0.332 mmol, 1 eq), MeOH (9 mL), DCM (3 mL) and sodium borohydride (25 mg, 0.664 mmol, 2 eq). The resultant mixture was stirred (400 rpm) under nitrogen at 25 °C for 2 hours. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected and the aqueous further extracted with DCM (10 mL). The combined DCM layers were washed with brine (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green solid (346 mg). The dark green solid was subjected to column chromatography by dissolving in DCM and eluting using 2% MeOH/DCM. Fractions containing a major dark green spot at Rf = ~0.6 in 5% MeOH/DCM were combined to give compound 20 as a dark blue solid (119 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 7.4 Hz, 1H), 9.47 (d, J = 3.4 Hz, 1H), 8.73 (d, J = 6.5 Hz, 1H), 5.77 (s, 2H), 5.55-5.29 (m, 2H), 4.81-4.56 (m, 2H), 4.47-4.30 (m, 2H), 4.21-3.98 (m, 2H), 3.78-3.60 (m, 2H), 3.55 (s, 3H), 3.45 (s, 2H), 3.39 (d, J = 0.9 Hz, 3H), 3.25 (d, J = 1.7 Hz, 3H), 3.08 (s, 1H), 2.67-2.41 (m, 1H), 2.32-2.07 (m, 2H), 1.96- 1.81 (m, 1H), 1.77 (d, J = 7.2 Hz, 3H), 1.71-1.63 (m, 3H), 1.60 (td, J = 7.2, 3.2 Hz, 3H), 1.45-1.32 (m, 1H), 1.22 (t, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 1H), 1.07 (t, J = 7.3 Hz, 1H), 0.95 (t, J = 7.3 Hz, 2H), -1.69 (d, J = 39.4 Hz, 2H). Synthesis Example 21 – synthesis of chlorin e6 N-methylbutylamine diethyl ester 13-(N-(3-triphenylphosphoniumpropyl)bromide)carbamate (compound 21)
Figure imgf000125_0001
To a 25 mL RBF was added chlorin e613-hydroxymethyl N-methylbutylamine diethyl ester (compound 20) (55 mg, 0.0757 mmol, 1 eq), carbonyl diimidazole (24 mg, 0.151 mmol, 2 eq), DCM (4 mL) and DMAP (2 mg). The resultant mixture was stirred (400 rpm) under nitrogen for 3 hours. The reaction progress was monitored by TLC. (3- Aminopropyl)triphenylphosphonium bromide (152 mg, 0.379 mmol, 5 eq) was added and stirring was continued for 27 hours at 30 °C. The reaction progress was monitored by HPLC. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue (103 mg). The residue was purified by column chromatography using 5-8% MeOH/DCM, loaded as a solution in the eluent. Fractions containing the major dark green band (Rf = 0.4 in 10% MeOH/DCM) were combined and concentrated by rotary evaporation to give compound 21 as a dark green solid (31 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 9.77 (d, J = 7.8 Hz, 1H), 9.65 (s, 1H), 8.74 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 57.2 Hz, 1H), 7.24-7.13 (m, 5H), 7.06-6.88 (m, 7H), 6.75 (s, 1H), 6.62 (s, 1H), 6.52 (s, 1H), 6.37 (t, J = 2.9 Hz, 2H), 5.53-5.31 (m, 2H), 4.80-4.58 (m, 1H), 4.50-4.28 (m, 2H), 4.20-3.98 (m, 1H), 3.73 (q, J = 7.4 Hz, 2H), 3.56 (s, 3H), 3.51 (s, 3H), 3.46 (s, 2H), 3.45-3.37 (m, 1H), 3.31 (s, 3H), 3.21 (s, 1H), 3.07 (s, 1H), 2.72-2.44 (m, 1H), 2.34-2.13 (m, 1H), 1.94-1.83 (m, 1H), 1.83-1.48 (m, 26H), 1.46-1.31 (m, 1H), 1.31-1.19 (m, 4H), 1.14 (t, J = 7.1 Hz, 1H), 1.09 (t, J = 7.3 Hz, 1H), 0.94 (t, J = 7.3 Hz, 2H), 0.90-0.78 (m, 1H), -1.33 – -1.90 (m, 2H). Synthesis Example 22 – synthesis of chlorin e6 N-methylbutylamine diethyl ester 13-(oxopentyl)triphenylphosphonium bromide (compound 22)
Figure imgf000126_0001
To a 25 mL RBF was added chlorin e613-hydroxymethyl N-methylbutylamine diethyl ester (compound 20) (55 mg, 0.0757 mmol, 1 eq), 4- (carboxybutyl)triphenylphosphonium bromide (67 mg, 0.151 mmol, 2 eq), EDC.HCl (29 mg, 0.151 mmol, 2 eq), DMAP (18 mg, 0.145 mmol, 2 eq) and DCM (5 mL). The resultant mixture was stirred (600 rpm) under nitrogen at 25 °C. The reaction progress was monitored by TLC. After 2 hours the solvent was removed by rotary evaporation to leave a dark green residue. The residue was subjected to column chromatography by dissolving in 5% MeOH/DCM and eluting using a gradient of 5-7% MeOH/DCM. Fractions containing the product (major dark green spot, Rf = 0.3 in 5% MeOH/DCM) were combined to give compound 22 as a dark green solid (65 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 9.71-9.47 (m, 2H), 8.78 (d, J = 7.0 Hz, 1H), 7.18-6.99 (m, 10H), 6.97-6.80 (m, 6H), 6.35 (d, J = 2.6 Hz, 2H), 5.58-5.30 (m, 2H), 4.81-4.57 (m, 2H), 4.52-4.30 (m, 2H), 4.22-3.95 (m, 2H), 3.77 (q, J = 8.3 Hz, 3H), 3.57 (s, 3H), 3.48 (s, 2H), 3.45 (s, 3H), 3.31 (s, 3H), 3.09 (s, 1H), 2.70-2.44 (m, 3H), 2.34-2.19 (m, 1H), 2.18-2.08 (m, 2H), 1.91 (t, J = 7.9 Hz, 1H), 1.77 (d, J = 7.1 Hz, 3H), 1.72-1.64 (m, 6H), 1.61 (td, J = 7.1, 2.6 Hz, 3H), 1.39 (q, J = 7.4 Hz, 1H), 1.25 (d, J = 7.1 Hz, 5H), 1.18-1.09 (m, 2H), 0.95 (t, J = 7.3 Hz, 2H), -1.76 (d, J = 29.4 Hz, 1H). Synthesis Example 23 – synthesis of chlorin e6 N-methylbutylamine dimethyl ester 13-(oxopentyl)triphenylphosphonium bromide (compound 23)
Figure imgf000127_0001
To a 25 mL RBF was added chlorin e613-hydroxymethyl N-methylbutylamine dimethyl ester (60 mg, 0.0859 mmol, 1 eq), 4-(carboxybutyl)triphenylphosphonium bromide (76 mg, 0.172 mmol, 2 eq), EDC.HCl (33 mg, 0.172 mmol, 2 eq), DMAP (21 mg, 0.172 mmol, 2 eq) and DCM (5 mL). The resultant mixture was stirred (400 rpm) under nitrogen at 25 °C. The reaction progress was monitored by TLC. After 2 hours the solvent was removed by rotary evaporation to leave a dark green residue. The residue was subjected to column chromatography by dissolving in 5% MeOH/DCM and eluting using a gradient of 5-10% MeOH/DCM. Fractions containing the product (major dark green spot, Rf = 0.2 in 5% MeOH/DCM) were combined and concentrated by rotary evaporation to give compound 23 as a dark green solid (80 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 9.56 (d, J = 6.7 Hz, 1H), 8.76 (d, J = 7.1 Hz, 1H), 7.17-7.00 (m, 9H), 6.97-6.86 (m, 6H), 6.34 (d, J = 3.0 Hz, 2H), 5.54-5.32 (m, 2H), 4.49-4.31 (m, 2H), 4.20 (d, J = 6.3 Hz, 3H), 3.76 (q, J = 8.2 Hz, 2H), 3.68 (s, 2H), 3.58 (s, 1H), 3.56 (d, J = 2.3 Hz, 3H), 3.50 (s, 2H), 3.46-3.41 (m, 3H), 3.30 (s, 3H), 3.10 (s, 1H), 2.72-2.45 (m, 2H), 2.34-2.06 (m, 3H), 1.93 (p, J = 7.9 Hz, 1H), 1.81-1.74 (m, 3H), 1.74-1.52 (m, 8H), 1.40 (h, J = 7.4 Hz, 1H), 1.12 (t, J = 7.3 Hz, 1H), 0.96 (t, J = 7.3 Hz, 2H), -1.51 – -1.84 (m, 1H). Synthesis Example 24 – synthesis of chlorin e613-hydroxymethyl 15-N-methyl- 3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (compound 24)
Figure imgf000128_0001
Step 1: A 1-neck 1L RBF was charged with chlorin e6 anhydride (6.90 g, 11.9 mmol, 1 eq), N-methyl-3,6,9,12-tetraoxatridecan-1-amine (3.96 g, 17.9 mmol, 1.5 eq) and DCM (400 mL). The resultant solution was stirred (400 rpm) for 18 hours under a nitrogen atmosphere at 35 °C. The resulting dark green solution was concentrated under reduced pressure until ~10 mL DCM remained, then diethyl ether (100 mL) was added and the mixture swirled by hand in the RBF. The solvent was decanted and a sticky dark green paste remained. The paste was further washed with diethyl ether (2 x 100 mL) until a sticky dark blue solid remained. Residual solvent was removed from the solid by rotary evaporation to give chlorin e615-N-methyl-3,6,9,12-tetraoxatridecan-1- amine amide as a dark blue solid (7.34 g, 77%). 1H NMR (400 MHz, DMSO-d6) δ 9.77-9.67 (m, 2H), 9.10 (d, J = 1.7 Hz, 1H), 8.33 (dd, J = 17.8, 11.7 Hz, 1H), 6.44 (dd, J = 17.7, 1.6 Hz, 1H), 6.16 (dd, J = 11.6, 1.4 Hz, 1H), 5.90- 5.70 (m, 1H), 5.56-5.34 (m, 1H), 4.58 (q, J = 7.4 Hz, 1H), 4.36 (d, J = 10.5 Hz, 1H), 4.08-3.91 (m, 1H), 3.86-3.78 (m, 2H), 3.78-3.73 (m, 0H), 3.65-3.43 (m, 66H), 3.43- 3.34 (m, 7H), 3.23-3.16 (m, 5H), 3.01-2.96 (m, 1H), 2.96-2.91 (m, 2H), 2.71-2.53 (m, 1H), 2.45 (s, 2H), 2.32 (d, J = 4.5 Hz, 1H), 2.25-2.12 (m, 1H), 1.72-1.57 (m, 6H), -1.75 – - 2.03 (m, 1H), -2.28 (s, 1H). Step 2: Into a 1-neck 500 mL RBF was added chlorin e615-N-methyl-3,6,9,12- tetraoxatridecan-1-amine amide (5.50 g, 6.88 mmol, 1 eq), potassium carbonate (4.75 g, 34.4 mmol, 5 eq), DMF (180 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 400 rpm with an air condenser attached. Methyl iodide (2.44 g, 17.2 mmol, 2.5 eq) was then added. The solution was stirred at 25 °C for 18 hours. The reaction progress was monitored by HPLC. The solvent was removed under reduced pressure at 70 °C to give crude product as a dark green solid. The crude product was dissolved in DCM (300 mL), washed with water (2 x 150 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark blue solid (5.82 g). The blue solid was purified by column chromatography using 2-4% MeOH/DCM as eluent. Fractions containing the major band with Rf = 0.4 in 5% MeOH/DCM were combined and concentrated by rotary evaporation to give chlorin e615-N-methyl-3,6,9,12- tetraoxatridecan-1-amine dimethyl ester amide as a dark blue solid (3.10 g, 53%). 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 3.0 Hz, 1H), 9.54 (d, J = 6.9 Hz, 1H), 8.72 (d, J = 6.9 Hz, 1H), 8.11-8.02 (m, 1H), 6.34 (dd, J = 17.8, 1.5 Hz, 1H), 6.12 (dd, J = 11.5, 1.5 Hz, 1H), 5.47-5.23 (m, 2H), 4.45-4.31 (m, 2H), 4.23 (s, 2H), 4.18 (s, 1H), 4.04-3.91 (m, 1H), 3.78 (ttd, J = 9.2, 4.8, 2.7 Hz, 5H), 3.73-3.65 (m, 7H), 3.64 (s, 3H), 3.59-3.52 (m, 8H), 3.46 (d, J = 2.4 Hz, 3H), 3.38 (s, 3H), 3.29 (d, 3H), 3.16 (s, 1H), 2.64-2.38 (m, 1H), 2.26-2.01 (m, 2H), 1.76 (dd, J = 7.2, 3.4 Hz, 3H), 1.74-1.68 (m, 3H), -1.28 (d, J = 25.8 Hz, 1H), -1.44 (d, J = 25.4 Hz, 1H). Step 3: To a 500 mL RBF was added chlorin e615-N-methyl-3,6,9,12-tetraoxatridecan- 1-amine dimethyl ester amide (3.00 g, 3.62 mmol, 1 eq), THF (120 mL), osmium tetroxide (~9.2 mg, 0.0362 mmol, 0.01 eq), deionized water (12 mL), AcOH (12 mL) and sodium periodate (2.01 g, 9.41 mmol, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at 25 °C for 16 hours. The reaction progress was monitored by HPLC. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (250 mL), transferred to a separatory funnel and washed with brine (120 mL), saturated NaHCO3 (120 mL) and water (120 mL) before being dried (Na2SO4) and concentrated by rotary evaporation to give crude product as a dark blue solid (3.53 g). The crude product was purified by column chromatography using 2-2.5% MeOH/DCM and fractions containing the first dark band to elute (Rf = 0.5 in 5% MeOH/DCM) were combined and concentrated by rotary evaporation to give chlorin e613-formyl 15-N-methyl-3,6,9,12-tetraoxatridecan-1- amine dimethyl ester amide as a dark blue solid (2.01 g, 67%). 1H NMR (400 MHz, CDCl3) δ 11.53 (d, J = 2.0 Hz, 1H), 10.23 (d, J = 4.4 Hz, 1H), 9.64 (s, 1H), 8.92 (d, J = 4.7 Hz, 1H), 5.54-5.31 (m, 2H), 4.44 (q, J = 6.8, 6.4 Hz, 1H), 4.39- 4.33 (m, 1H), 4.25 (s, 2H), 4.20 (s, 1H), 4.08-3.94 (m, 1H), 3.88-3.73 (m, 8H), 3.73- 3.68 (m, 5H), 3.66 (d, J = 7.1 Hz, 4H), 3.59 (s, 2H), 3.56 (d, J = 2.4 Hz, 6H), 3.38 (s, 3H), 3.32 (d, J = 1.2 Hz, 3H), 3.17 (s, 1H), 2.69-2.43 (m, 1H), 2.30-2.04 (m, 2H), 1.81- 1.68 (m, 6H), -1.28 (s, 1H), -1.75 (d, J = 17.5 Hz, 1H). Step 4: To a 100 mL RBF was added chlorin e613-formyl 15-N-methyl-3,6,9,12- tetraoxatridecan-1-amine dimethyl ester amide (1.00 g, 1.20 mmol, 1 eq), MeOH (30 mL), DCM (15 mL) and sodium borohydride (91 mg, 2.40 mmol, 2 eq). The resultant mixture was stirred (600 rpm) under nitrogen at ambient temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (80 mL) and washed with water (80 mL). The DCM layer was collected and the aqueous further extracted with DCM (40 mL). The combined DCM layers were washed with brine (80 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green solid. The dark green solid was subjected to column chromatography by dissolving in 2% MeOH in DCM and eluting using a gradient of 2-5% MeOH in DCM. Fractions with a major dark green spot at Rf = ~0.4 in 5% MeOH/DCM were combined and concentrated by rotary evaporation to give compound 24 as a dark green solid (802 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 9.66 (d, J = 2.6 Hz, 1H), 9.43 (d, J = 4.0 Hz, 1H), 8.70 (d, J = 6.2 Hz, 1H), 5.71 (s, 2H), 5.52-5.20 (m, 2H), 4.45-4.31 (m, 2H), 4.22 (s, 2H), 4.18 (s, 1H), 4.06-3.90 (m, 1H), 3.83-3.71 (m, 4H), 3.71-3.65 (m, 5H), 3.63 (d, J = 1.9 Hz, 3H), 3.58-3.52 (m, 8H), 3.38 (d, J = 1.1 Hz, 3H), 3.35 (s, 3H), 3.25 (d, J = 1.5 Hz, 3H), 3.15 (s, 1H), 2.64-2.38 (m, 1H), 2.26-2.13 (m, 1H), 2.13-1.99 (m, 1H), 1.77 (dd, J = 7.2, 3.6 Hz, 3H), 1.69 (t, J = 7.6 Hz, 3H), -1.30 – -1.73 (m, 2H). Synthesis Example 25 – synthesis of chlorin e613-(N-(3- triphenylphosphoniumpropyl)bromide)carbamate 15-N-methyl-3,6,9,12- tetraoxatridecan-1-amine dimethyl ester amide (compound 25)
Figure imgf000131_0001
To a 25 mL RBF was added chlorin e613-hydroxymethyl 15-N-methyl-3,6,9,12- tetraoxatridecan-1-amine dimethyl ester amide (compound 24) (100 mg, 0.120 mmol, 1 eq), carbonyl diimidazole (39 mg, 0.240 mmol, 2 eq), DCM (4 mL) and DMAP (3 mg). The resultant mixture was stirred (600 rpm) under nitrogen for 3 hours at 30 °C. The reaction progress was monitored by TLC. (3- Aminopropyl)triphenylphosphonium bromide (240 mg, 0.600 mmol, 5 eq) was added and stirring was continued for 18 hours at 30 °C. The reaction was monitored by HPLC. The reaction mixture was diluted with DCM (30 mL), transferred to a separatory funnel and washed with water (30 mL) before being dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 5-9% MeOH/DCM, loaded as a solution in the eluent. Fractions with a major dark green spot at Rf = 0.60 in 10% MeOH/DCM were combined and concentrated to give compound 25 as a dark green solid (89 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 9.72 (d, J = 6.0 Hz, 1H), 9.62 (d, J = 3.5 Hz, 1H), 8.71 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 6.3 Hz, 1H), 7.24-7.17 (m, 4H), 7.06-6.91 (m, 7H), 6.82-6.47 (m, 2H), 6.41-6.27 (m, 2H), 5.49-5.25 (m, 2H), 4.46-4.28 (m, 2H), 4.22 (s, 2H), 4.18 (s, 1H), 4.07-3.90 (m, 1H), 3.84-3.65 (m, 8H), 3.64 (s, 2H), 3.59-3.53 (m, 5H), 3.50 (d, J = 2.5 Hz, 3H), 3.46-3.38 (m, 1H), 3.36 (d, J = 9.6 Hz, 2H), 3.30 (s, 2H), 3.15 (s, 1H), 2.69- 2.37 (m, 1H), 2.33-2.12 (m, 1H), 1.77 (s, 1H), 1.71 (dd, J = 7.4, 2.2 Hz, 2H), 1.69-1.61 (m, 2H), -1.37 – -1.92 (m, 1H). Synthesis Example 26 – synthesis of chlorin e613-hydroxymethyl 15-N-methyl-1- dodecanamine dimethyl ester amide (compound 26)
Figure imgf000132_0001
Figure imgf000133_0001
Step 1: A 1-neck 1L RBF was charged with chlorin e6 anhydride (7.00 g, 12.1 mmol, 1 eq), N-methyl-1-dodecanamine (4.03 g, 18.2 mmol, 1.5 eq) and DCM (400 mL). The resultant solution was stirred (400 rpm) for 16 hours under a nitrogen atmosphere at 35 °C. The resulting dark green solution was concentrated under reduced pressure until ~10 mL DCM remained, then hexane (100 mL) was added and the mixture swirled by hand in the RBF. The solvent was decanted and a sticky dark green paste remained. The paste was further washed with hexane (2 x 100 mL) until a dark green solid remained. Residual solvent was removed from the solid by rotary evaporation to give chlorin e615-N-methyl-1-dodecanamine amide as a dark green solid (9.16 g, 97%). 1H NMR (400 MHz, Methanol-d4) δ 9.66 (s, 1H), 9.42 (d, J = 5.2 Hz, 1H), 8.98 (d, J = 4.7 Hz, 1H), 7.86 (ddd, J = 17.8, 11.6, 3.3 Hz, 1H), 6.16-6.04 (m, 1H), 5.94 (dd, J = 19.7, 13.5 Hz, 2H), 4.61-4.52 (m, 1H), 4.40-4.29 (m, 1H), 3.92-3.80 (m, 1H), 3.72-3.62 (m, 2H), 3.57 (d, J = 10.7 Hz, 5H), 3.08 (s, 3H), 3.02 (s, 1H), 2.74 (ddd, J = 22.8, 11.1, 6.4 Hz, 1H), 2.66-2.51 (m, 1H), 2.44-2.33 (m, 1H), 2.33-2.20 (m, 2H), 2.13 (s, 1H), 2.00 (s, 3H), 1.87-1.74 (m, 2H), 1.74-1.56 (m, 7H), 1.43-1.03 (m, 25H), 1.01-0.91 (m, 2H), 0.85 (t, J = 7.1 Hz, 6H), 0.76 (p, J = 7.2 Hz, 2H), 0.52-0.34 (m, 4H), 0.29-0.15 (m, 2H), 0.08 – -0.09 (m, 4H). Step 2: Into a 1-neck 500 mL RBF was added chlorin e615-N-methyl-1-dodecanamine amide (7.00 g, 9.00 mmol, 1 eq), potassium carbonate (6.21 g, 45.0 mmol, 5 eq), DMF (220 mL) and a stirrer bar. The flask was placed under nitrogen and stirred at 400 rpm with an air condenser attached. Methyl iodide (3.19 g, 22.5 mmol, 2.5 eq) was then added. The solution was stirred at 25 °C for 18 hours. The reaction progress was monitored by HPLC. The solvent was removed under reduced pressure at 70 °C to give crude product as a dark green solid. The crude product was dissolved in DCM (300 mL), washed with water (2 x 150 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark blue/green solid (10.03 g). The dark blue/green solid was purified by column chromatography using 2-5% MeOH/DCM as eluent. Two fractions containing the major band with Rf = 0.4 in 5% MeOH/DCM were collected and concentrated by rotary evaporation giving the product as a dark blue solid. The second product fraction from the first column was re-purified by column chromatography using 3% MeOH/DCM as eluent. The first pure fractions containing the major band with Rf = 0.4 in 5% MeOH/DCM were combined with the first fraction from the first column and concentrated by rotary evaporation to give chlorin e615-N-methyl-1- dodecanamine dimethyl ester amide as a dark green solid (3.45 g, 48%). 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 1.7 Hz, 1H), 9.55 (d, J = 6.9 Hz, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.06 (ddd, J = 17.9, 11.5, 4.1 Hz, 1H), 6.34 (dd, J = 17.8, 1.6 Hz, 1H), 6.12 (dd, J = 11.5, 1.5 Hz, 1H), 5.47-5.18 (m, 2H), 4.48-4.27 (m, 2H), 4.20 (d, J = 4.0 Hz, 3H), 3.79 (q, J = 7.7, 2.2 Hz, 2H), 3.67 (s, 3H), 3.59-3.54 (m, 4H), 3.46 (d, J = 2.7 Hz, 5H), 3.30 (d, J = 2.6 Hz, 3H), 3.09 (s, 1H), 2.71-2.46 (m, 1H), 2.33-2.10 (m, 2H), 1.85- 1.61 (m, 8H), 1.45-1.21 (m, 19H), 0.95-0.84 (m, 3H), -1.27 (d, J = 27.7 Hz, 1H), -1.43 (d, J = 28.5 Hz, 1H). Step 3: To a 500 mL RBF was added chlorin e615-N-methyl-1-dodecanamine dimethyl ester amide (3.40 g, 4.22 mmol, 1 eq), THF (140 mL), osmium tetroxide (~10.7 mg, 0.0422 mmol, 0.01 eq), deionized water (14 mL), AcOH (14 mL) and sodium periodate (2.35 g, 11.0 mmol, 2.6 eq). The resultant mixture was stirred (420 rpm) under nitrogen in the dark at 25 °C for 16 hours. The reaction progress was monitored by HPLC. The reaction mixture was concentrated using a rotary evaporator to remove the THF and then re-dissolved in DCM (250 mL), transferred to a separatory funnel and washed with brine (120 mL), saturated NaHCO3 (120 mL) and water (120 mL) before being dried (Na2SO4) and concentrated by rotary evaporation to give crude product as a dark blue solid. The crude product was purified by column chromatography using 2% MeOH/DCM and fractions containing the first dark band to elute (Rf = 0.5 in 5% MeOH/DCM) were combined to give chlorin e613-formyl 15-N-methyl-1- dodecanamine dimethyl ester amide as a dark blue solid (1.88 g, 55%). 1H NMR (400 MHz, CDCl3) δ 11.53 (d, J = 2.8 Hz, 1H), 10.22 (d, J = 2.2 Hz, 1H), 9.63 (d, J = 2.9 Hz, 1H), 8.91 (d, J = 2.7 Hz, 1H), 5.56-5.18 (m, 2H), 4.52-4.28 (m, 2H), 4.19 (d, J = 3.6 Hz, 3H), 3.81-3.72 (m, 5H), 3.68 (s, 2H), 3.56 (d, J = 4.0 Hz, 4H), 3.47 (s, 2H), 3.45-3.36 (m, 1H), 3.31 (d, J = 1.3 Hz, 3H), 3.08 (s, 1H), 2.72-2.44 (m, 1H), 2.34- 2.12 (m, 2H), 1.91-1.79 (m, 1H), 1.78-1.62 (m, 6H), 1.46-1.15 (m, 18H), 0.92-0.80 (m, 3H), -1.28 (d, J = 16.7 Hz, 1H), -1.76 (d, J = 18.5 Hz, 1H). Step 4: To a 100 mL RBF was added chlorin e613-formyl 15-N-methyl-1-dodecanamine dimethyl ester amide (920 mg, 1.14 mmol, 1 eq), MeOH (30 mL), DCM (15 mL) and sodium borohydride (86 mg, 2.28 mmol, 2 eq). The resultant mixture was stirred (600 rpm) under nitrogen at ambient temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (80 mL) and washed with water (80 mL). The DCM layer was collected and the aqueous further extracted with DCM (40 mL). The combined DCM layers were washed with brine (80 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green solid. The dark green solid was subjected to column chromatography by dissolving in 2% MeOH in DCM and eluting using a gradient of 2% MeOH in DCM. Fractions with a major dark green spot at Rf = ~0.4 in 5% MeOH/DCM were combined to give compound 26 as a dark blue solid (688 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 1.2 Hz, 1H), 9.41 (d, J = 3.1 Hz, 1H), 8.69 (d, J = 5.0 Hz, 1H), 5.67 (d, J = 2.9 Hz, 2H), 5.51-5.22 (m, 2H), 4.48-4.30 (m, 2H), 4.19 (d, J = 4.2 Hz, 3H), 3.81-3.71 (m, 2H), 3.67 (s, 2H), 3.59-3.54 (m, 4H), 3.46 (s, 2H), 3.33 (s, 3H), 3.25 (d, J = 2.1 Hz, 3H), 3.09 (s, 1H), 2.69-2.44 (m, 1H), 2.32-2.09 (m, 2H), 1.99 (s, 1H), 1.77 (dd, J = 7.2, 3.3 Hz, 3H), 1.70 (q, J = 6.9, 6.2 Hz, 4H), 1.44-1.20 (m, 18H), 0.94-0.83 (m, 3H), -1.26 – -1.77 (m, 2H). Synthesis Example 27 – synthesis of chlorin e613-(N-(3- triphenylphosphoniumpropyl)bromide)carbamate 15-N-methyl-1-dodecanamine dimethyl ester amide (compound 27)
Figure imgf000135_0001
To a 25 mL RBF was added chlorin e613-hydroxymethyl 15-N-methyl-1-dodecanamine dimethyl ester amide (compound 26) (100 mg, 0.1234 mmol, 1 eq), carbonyl diimidazole (40 mg, 0.2469 mmol, 2 eq), DCM (4 mL) and DMAP (3 mg). The resultant mixture was stirred under nitrogen for 3 hours at 30 °C. (3- Aminopropyl)triphenylphosphonium bromide (247 mg, 0.6172 mmol, 5 eq) was added and stirring was continued for 18 hours at 30 °C. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using a gradient of 3-7% MeOH/DCM. Fractions containing the major dark green spot (Rf = 0.40 in 7% MeOH/DCM) were combined to give compound 27 as a dark green solid (123 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 9.75 (m, 1H), 9.63 (s, 1H), 8.72 (m, 1H), 7.47 (m, 1H), 7.24-7.17 (m, 6H), 7.06-6.91 (m, 9H), 6.81-6.47 (m, 2H), 6.37 (m, 2H), 5.47-5.27 (m, 2H), 4.50-4.30 (m, 2H), 4.22-4.18 (m, 3H), 3.78-3.66 (m, 6H), 3.59-3.53 (m, 5H), 3.52- 3.50 (m, 5H), 3.50-3.48 (m, 3H), 3.47-3.39 (m, 3H), 3.31 (s, 3H), 2.70-2.47 (m, 1H), 2.31-2.12 (m, 2H), 1.92-1.82 (m, 1H), 1.75-1.55 (m, 17H), 1.38-1.20 (m, 22H), -1.35 – - 1.73 (m, 2H). Synthesis Example 28 – synthesis of chlorin e613-hydroxymethyl (2- methoxyethyl)methylamine (compound 28)
Figure imgf000136_0001
To a 50 mL RBF was added chlorin e613-hydroxymethyl (2- methoxyethyl)methylamine dimethyl ester (159 mg, 0.227 mmol, 1 eq), lithium hydroxide monohydrate (29 mg, 0.681 mmol, 3 eq), THF (9 mL) and water (3 mL). The mixture was stirred at 25 °C for 2 hours. The reaction progress was monitored by HPLC. The reaction mixture was diluted in EtOAc (50 mL) and transferred to a separating funnel, then 1M HCl solution (25 mL) was added. After shaking the separating funnel for ~1 minute, pH 7 buffer solution (40 mL) was added and the funnel shaken for ~1 minute. The organic layer was then separated, dried over MgSO4 and concentrated by rotary evaporation to give compound 28 as a dark blue solid (140 mg, 92% yield, 98.12% purity by HPLC). 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 9.42-9.32 (m, 1H), 8.67 (s, 1H), 5.73-5.57 (m, 2H), 5.36-5.02 (m, 1H), 4.96 (s, 1H), 4.45-4.26 (m, 2H), 4.20-3.97 (m, 4H), 3.92- 3.83 (m, 0H), 3.83-3.62 (m, 2H), 3.60 (s, 1H), 3.57 (s, 2H), 3.54 (s, 1H), 3.52 (s, 2H), 3.39 (s, 2H), 3.31 (d, J = 2.3 Hz, 3H), 3.24-3.18 (m, 3H), 3.08 (s, 1H), 2.53 (s, 1H), 2.03 (s, 1H), 1.99-1.83 (m, 1H), 1.77-1.62 (m, 6H), 1.59-1.38 (m, 1H), 1.23-1.20 (m, 1H), -1.65 (s, 1H). Synthesis Example 29 – synthesis of chlorin e613-hydroxymethyl (2- methoxyethyl)methylamine bis(N-methyl-D-glucamine) salt (compound 29)
Figure imgf000137_0001
Into a 25 mL RBF was weighed chlorin e613-hydroxymethyl (2- methoxyethyl)methylamine (compound 28) (60 mg, 0.0893 mmol, 1 eq) followed by distilled deionized water (5 mL) with a stirrer bar. Meglumine (35 mg, 0.179mmol, 2 eq) was added and the mixture was then stirred while being heated at 40 °C for 1 hour. The solution was allowed to cool to ambient temperature, diluted with water (20 mL) and then filtered through a porosity 3 filter (3 cm diameter) into a 250 mL RBF with a side arm adapter. The reaction flask was rinsed with deionized water (~10 mL) which was passed through the filter to complete the transfer. The filtrate was then freeze dried for 17 hours to give compound 29 as a dark brown fluffy solid (86 mg, 91% yield, 97.76% purity by HPLC). 1H NMR (400 MHz, DMSO-d6) δ 9.73 (dd, J = 7.0, 2.8 Hz, 2H), 8.99 (d, J = 4.5 Hz, 1H), 5.77 (s, 2H), 5.47-5.26 (m, 2H), 4.53 (q, J = 7.2 Hz, 1H), 4.31 (dd, J = 20.9, 10.1 Hz, 1H), 4.14 (s, 1H), 3.80 (q, J = 8.0, 6.0 Hz, 2H), 3.72 (q, J = 5.2 Hz, 3H), 3.64 (d, J = 5.3 Hz, 2H), 3.61-3.57 (m, 3H), 3.52 (s, 4H), 3.51-3.49 (m, 3H), 3.45-3.34 (m, 7H), 3.30 (d, J = 7.2 Hz, 5H), 2.95 (s, 1H), 2.72-2.61 (m, 5H), 2.32 (s, 7H), 2.24-1.99 (m, 2H), 1.82 (s, 1H), 1.73-1.58 (m, 6H), -1.63 (d, J = 14.9 Hz, 1H), -1.83 (d, J = 13.0 Hz, 1H). Synthesis Example 30 – synthesis of chlorin e613-hydroxymethyl (2- methoxyethyl)methylamine disodium salt (compound 30)
Figure imgf000138_0001
Into a 100 mL RBF was weighed chlorin e613-hydroxymethyl (2- methoxyethyl)methylamine (compound 28) (60 mg, 0.0893 mmol, 1 eq) followed by distilled deionized water (5mL) with a stirrer bar.0.1M Sodium hydroxide solution (1.70 mL, 0.170 mmol, 1.9 eq) was added and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was then freeze dried overnight (16 hours) to give compound 30 as a dark green fluffy solid (64 mg, quantitative yield, 94.43% purity by HPLC). 1H NMR (400 MHz, DMSO-d6) δ 9.77-9.66 (m, 2H), 9.00 (d, J = 7.2 Hz, 1H), 5.86 (d, J = 16.0 Hz, 1H), 5.76 (d, J = 4.9 Hz, 2H), 5.65 (d, J = 18.4 Hz, 1H), 5.51-5.34 (m, 1H), 4.50 (q, J = 6.9 Hz, 1H), 4.30 (dd, J = 24.4, 10.5 Hz, 1H), 4.20 (s, 2H), 4.15 (s, 1H), 4.03 (t, J = 5.2 Hz, 1H), 3.92-3.74 (m, 3H), 3.52 (d, J = 2.4 Hz, 6H), 3.44 (d, J = 2.3 Hz, 3H), 3.33 (s, 2H), 3.29 (d, J = 3.7 Hz, 3H), 2.97 (s, 1H), 2.43-2.22 (m, 1H), 2.15-1.92 (m, 1H), 1.68 (td, J = 7.6, 1.7 Hz, 3H), 1.60 (d, J = 6.5 Hz, 4H), 1.47-1.19 (m, 1H), -1.65 (d, J = 26.0 Hz, 1H), -1.85 (d, J = 25.8 Hz, 1H). Biological Experimental Details Example 1 – Determination of Solubility of Chlorin e6 Analogues Absorbance maxima were used as a surrogate measure of solubility. The relevant chlorin e6 analogue was diluted to 50 µM in PBS (phosphate buffered saline) solutions containing decreasing amounts of DMSO from 100% to 0%. Where required, polyvinylpyrrolidone (K30) was added to a final concentration of 1% w/v. Absorbance was measured using a Cytation 3 Multimode Plate Reader (Biotek) in spectral scanning mode, with spectra captured between 500-800 nm in 2nm increments. Equivalent blank solutions were also measured and subtracted accordingly. Each spectrum was normalized to have a minimum signal of 0, and a maximum signal in pure DMSO solution (the most soluble state) of 100%. Example 2 – Cytotoxicity, Phototoxicity and Therapeutic Index Preparation of photosensitizer stock solutions Photosensitizers (e.g. chlorin e6 analogue, chlorin e4 disodium (provided by Advanced Molecular Technologies, Scoresby) or Talaporfin sodium (purchased from Focus Bioscience cat# HY-16477-5MG)) were resuspended in 100% dimethylsulfoxide (DMSO) at a concentration of 5.5mM. Samples were stored at 4 °C protected from light. Preparation of photosensitizers for in vitro studies For in vitro experiments, photosensitizers (stock solution 5.5mM in 100% DMSO) were diluted 1:100 in concentrated excipient solution (final 55 µM photosensitizer in 10% w/v Kollidon-12, 42.4% w/v polysorbate 80, 0.6% w/v citric acid anhydrous, 40% w/v ethanol, 1.0% DMSO). Serial dilutions were prepared in cell culture media (Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F-12)) supplemented with 10% v/v Fetal Bovine Serum, 100U/mL penicillin, 100μg/mL streptomycin and the same excipient solution at a constant 1:55 dilution. Cell culture Human ovarian cancer cell line SKOV3 (ATCC #HTB-77) was maintained in Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F-12), supplemented with 10% v/v Fetal Bovine Serum, 100U/mL penicillin and 100μg/mL streptomycin. Monolayer cultures were grown in a humidified incubator at 37°C with 5% CO2. Once cells had reached ~80% confluence, spent media was replaced with media containing photosensitizer at the required concentration and cells were incubated for the desired period of time to allow photosensitizer uptake. Statistical analyses All data were analysed using GraphPad PRISM v8.3.1 (549) (GraphPad Software, CA). Spectral absorbance and viability measurements were normalized in the range 0-100%, with a minimum of 0 and a maximum value determined from the dataset. Dose response was determined using a sigmoidal four-point non-linear regression with variable slope, and IC10 or IC90 calculated for each compound. All data are shown as mean ±SD (where appropriate). Cytotoxicity SKOV3 cells were seeded in 96-well black wall plates (Greiner #655090) at a cell density of 5000 cells in 100 μl culture medium per well. On reaching ~60% confluence, media was aspirated and replaced with fresh media containing the relevant chlorin e6 analogue from 0-100 µM in DMSO. Cells were incubated for a further 24 hours, allowing uptake of chlorin e6 analogues. To test for inherent cytotoxicity (i.e. “dark toxicity”) of the chlorin e6 analogues, the culture media was replaced after 24 hours with fresh media containing 10% (v/v) AlamarBlue Cell Viability Reagent (ThermoFisher) and cells incubated at 37°C for 6 hours. Untreated cells were used as a control. Fluorescence (Ex 555nm / Em 596nm) was measured using a Cytation 3 Cell Imaging Multi-Mode Reader (Biotek), and cytotoxicity assessed according to the % viable cells remaining. All measurements were made in quadruplicate. Phototoxicity SKOV3 cells were seeded in 96-well black wall plates (Greiner #655090) at a cell density of 5000 cells in 100 μl culture medium per well. On reaching ~60% confluence, media was aspirated and replaced with fresh media containing the relevant chlorin e6 analogue from 0-100 µM in DMSO. Cells were incubated for a further 24 hours, allowing uptake of chlorin e6 analogues. To test for phototoxicity, cells incubated with chlorin e6 analogues (0-10 µM in DMSO) had culture media replaced after 24 hours (as above) and were then exposed to a 660nm laser (Invion) or light-emitting diode (LED) panel (Invion) with optical power density at 50mW/cm2 for 5 mins (total 15J/cm2). Laser and LED exposure induce an equivalent response in relation to phototoxicity. Following activation, cells were cultured for a further 24 hours. Media was then replaced with fresh media containing AlamarBlue, and % viable cells remaining assessed as above. Controls included cells treated with chlorin e6 analogues but not activated by laser light; cells without chlorin e6 analogue treatment but with laser light; and untreated controls. All measurements were made in quadruplicate. Toxicity Profile for Chlorin e6 Analogues The phototoxicity and inherent cytotoxicity (i.e. “dark toxicity”) of chlorin e6 analogues were assessed as previously using SKOV3 ovarian cancer cells. For comparative purposes, chlorin e6 analogues were compared against chlorin e4 disodium and Talaporfin sodium, a clinically approved photosensitizer used in the photodynamic treatment of lung cancers. Phototoxicity IC90 values and dark toxicity IC10 values were calculated using a log[inhibitor]-vs normalized response dose curve with variable slope, using the formula Y=100/(1+(IC90/X)^HillSlope (phototoxicity IC90)) or Y=100/(1+(IC10/X)^HillSlope (dark toxicity IC10)). Phototoxicity and dark toxicity values are provided in Table 1. Most chlorin e6 analogues had phototoxicity IC90 values below 10nM (Table 1). These were substantially better than chlorin e4 disodium (IC9021.32 µM) or Talaporfin sodium (IC9022.83 µM); indeed, the best-performing compound (compound 3) achieved 4 orders of magnitude greater phototoxicity compared to Talaporfin sodium. Thus, chlorin e6 analogues achieved an up to ~10,000-fold increase in phototoxicity compared to Talaporfin sodium, a clinically approved photosensitizer. Substantial variation in the dark toxicity of the chlorin e6 analogues of the present invention was observed (Table 1). The greater phototoxicity afforded by the chlorin e6 analogues of the present invention, however, is expected to offset any dark toxicity issue through a decreased dose requirement in use. Therapeutic Index for Chlorin e6 Analogues To evaluate the therapeutic potential of chlorin e6 analogues, the therapeutic index (TI) was calculated. TI provides a quantitative measurement to describe relative drug safety, by comparing the drug concentration required for desirable effects versus the concentration resulting in undesirable off-target toxicity. TI was calculated using phototoxicity IC90 vs dark toxicity IC10. TI values are provided in Table 1. Talaporfin sodium had a low therapeutic index (TI = 0.49) with chlorin e4 disodium only marginally better (TI = 1.89), indicating that whilst their relative cytotoxicity is low, the potential therapeutic window for their use is small. The chlorin e6 analogues of the present invention had comparatively significantly improved TIs with substantially greater phototoxicity (Table 1). Thus, the chlorin e6 analogues of the present invention have a desirable therapeutic index that is better than a clinically applied photosensitizer. Moreover, the greater phototoxicity of the chlorin e6 analogues suggests their potential use at a greatly reduced dose in vivo. The chlorin e6 analogues therefore have an acceptable therapeutic profile for clinical application. Moreover, chlorin e6 analogues of the present invention which carry an ammonium, phosphonium, pyridinium or saccharidyl group (for example a -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)], -Rα-[R8’], or saccharidyl group as defined in the description and claims) are particularly preferred, because they have a better phototoxicity compared to similar compounds without such a group. This can be seen when comparing, for example: ^ compound 1 with compounds 2-5 ^ compound 6 with compounds 7-8 ^ compound 15 with compound 16 ^ compound 17 with compounds 18-19 ^ compound 20 with compounds 21-22 ^ compound 24 with compound 25 Of course, compounds without such groups can be used as intermediates to prepare compounds with such groups. Table 1. Toxicity profile and therapeutic index for Chlorin e6 analogues: * denotes that the phototoxicity was measured by LED
Figure imgf000142_0001
Figure imgf000143_0001
Example 3 – Investigation of Stability of Chlorin e6 Analogue Salts in Aqueous Solution Procedure Reaction solutions were prepared by dissolving 2-3 mg of the respective chlorin e6 analogue salt in 5 mL of distilled deionised water in a 50 mL test tube fitted with a lid. The solutions were stirred in the test tubes at 30 °C. Air (oxygen) and ambient light were not excluded. Sample HPLC analyses were performed at 0.5, 4 or 66 hours (unless indicated otherwise). The aim was to look for degradation over time. The test results are summarised in table 2 below.
Figure imgf000144_0002
Table 2: HPLC purities of chlorin e6 analogue salts in aqueous solution after 0.5, 4 and 66 hours (unless indicated otherwise). The structures of Photolon and Photodithiazine are as follows:
Figure imgf000144_0001
HPLC method Column and instrument details Instrument: Waters Alliance HPLC with Waters e2695 separations module and Waters 2998 PDA detector Column: YMC-Pack Pro C18 /S-3µm /12nm.150 x 4.6mml. D. S/N: 112YB00270 Guard Column: Phenomenex Security Guard Cartridge C184 x 3.0 mm ID PRD-281272 HPLC Method
Figure imgf000144_0003
Mobile Phase: A = 0.05% w/v phosphoric acid in distilled water; B = acetonitrile Injection volume: 5 µL HPLC run length: 35 minutes Detection wavelength: 406 nm Column temperature: 40 °C Conclusion As can be seen from the experimental results, compounds which have an ester or amide group at -R7 (such as a -CO2R13 or -C(O)-R14-R15 group as defined in the description and claims) are more stable in aqueous solution than compounds without such a group. It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

Claims 1. A compound of formula (I) or a complex of formula (II):
Figure imgf000146_0001
or a pharmaceutically acceptable salt thereof, wherein: -R1 is selected from -CH2OR2, -CH2SR2, -CH2S(O)R2, -CH2S(O)2R2, -CH2N(R2)2, -R2, -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2; -R2, each independently, is selected from -H, -C(O)R4, -C(O)-OR4, -C(O)-SR4, -C(O)-N(R4)2, -C(S)-OR4, -C(S)-SR4, -C(S)-N(R4)2, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)] or -Rα-[R8’]; -R3 and -R4, each independently, is selected from -H, -Rα-H, -Rβ, -Rα-Rβ, -Rα-OH, -Rα-ORβ, -Rα-SH, -Rα-SRβ, -Rα-S(O)Rβ, -Rα-S(O)2Rβ, -Rα-NH2, -Rα-NH(Rβ), -Rα-N(Rβ)2, -Rα-X, -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)] or -Rα-[R8’]; -Rα-, each independently, is selected from a C1-C42 alkylene group, wherein the alkylene group may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and wherein one or more carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe; -Rβ, each independently, is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O, S, P or Se in its carbon skeleton; -R5, each independently, is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may optionally be substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R5’ is selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O)n-H, -(CH2CH2O)n-CH3, phenyl or C5-C6 heteroaryl, each substituted with -CO2 ‾, wherein the phenyl or C5-C6 heteroaryl may optionally be further substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R6 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2; -R7 is selected from -C(O)-OR3, -C(O)-SR3, -C(O)-N(R3)2, -C(S)-OR3, -C(S)-SR3 or -C(S)-N(R3)2; -R8 is -[NC5H5] optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R8’ is -[NC5H5] substituted with -CO2 ‾ and optionally further substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O)n-H or -O-(CH2CH2O)n-CH3 groups; -R9 is selected from -OR2, -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X; n is 1, 2, 3, 4, 5 or 6; X is a halo group; Y is a counter anion; Z is a counter cation; and M2+ is a metal cation; provided that either: (i) at least one of -R1, -R7 and -R9 comprises -Rα-[N(R5)3]Y, -Rα-[P(R5)3]Y, -Rα-[R8]Y, -Rα-[N(R5)2(R5’)], -Rα-[P(R5)2(R5’)], -Rα-[R8’], or a saccharidyl group; or (ii) -R9 is selected from -N(R2)2, -SR2, -S(O)R2, -S(O)2R2, or -X.
2. The compound or complex according to claim 1, wherein each -Rα- is independently selected from C1-C6 alkylene.
3. The compound or complex according to any preceding claim, wherein at least one of -R2, -R3 and -R4 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group.
4. The compound or complex according to claim 3, wherein -Rβ is a saccharidyl group selected from:
Figure imgf000148_0001
5. The compound or complex according to claim 4, wherein the saccharidyl group is:
Figure imgf000148_0002
6. The compound or complex according to claim 3, wherein -Rβ is a saccharidyl group selected from:
Figure imgf000148_0003
wherein -R11 is selected from C1-C4 alkyl.
7. The compound or complex according to claim 6, wherein -R11 is methyl.
8. The compound or complex according to any preceding claim, wherein -R1 is -C(O)-OR3, R3 is -Rβ, and -Rβ is a C1-C4 alkyl group.
9. The compound or complex according to any one of claims 1-7, wherein -R1 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl.
10. The compound or complex according to any preceding claim, wherein -R6 is -C(O)-OR3 and -R3 is C1-C4 alkyl.
11. The compound or complex according to any one of claims 1-9, wherein -R6 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl.
12. The compound or complex according to any preceding claim, wherein -R7 is -C(O)-OR3 and -R3 is C1-C4 alkyl.
13. The compound or complex according to any one of claims 1-11, wherein -R7 is selected from -C(O)-OR3, -C(O)-SR3 or -C(O)-N(R3)(R3’), wherein -R3 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group, and -R3’ is H or C1-C4 alkyl.
14. The compound or complex according to any preceding claim, wherein -R9 is selected from -OR2 or -SR2, and -R2 is selected from -Rα-ORβ, -Rα-SRβ, -Rα-S(O)Rβ or -Rα-S(O)2Rβ, and -Rβ is a saccharidyl group.
15. A compound of formula (III) or a complex of formula (IV):
Figure imgf000149_0001
or a pharmaceutically acceptable salt thereof, wherein: -R1 is selected from -CO2H or -C(O)-R14-R15; -R6 is selected from -CO2H or -CO2R13; -R7 is selected from -CO2H or -C(O)-R14-R15; -R13 is selected from C1-C3 alkyl; -R14- is selected from NH, NMe, O or S; -R15 is selected from C1-C20 alkyl wherein one or more carbon atoms in the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH or NMe, and wherein the alkyl group may optionally be substituted with one or more (such as one, two, three, four, five, six, seven or eight) -OH or -NH2 groups; and M2+ is a metal cation; provided that -R1, -R6 and -R7 are not simultaneously -CO2Me.
16. The compound or complex according to any preceding claim, wherein the compound or complex is:
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof.
17. The compound or complex according to any preceding claim, for use in medicine.
18. The compound or complex according to any preceding claim, for use in photodynamic therapy or cytoluminescent therapy.
19. The compound or complex according to any preceding claim, for use in the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
20. The compound or complex according to any preceding claim, for use in the treatment of a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.
21. The compound or complex according to any preceding claim, for use in the treatment of a benign or malignant tumour.
22. The compound or complex according to any preceding claim, for use in the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
23. The compound or complex according to any preceding claim, for use in photodynamic diagnosis.
24. The compound or complex according to any preceding claim, wherein the compound is adapted for administration prior to administration of irradiation.
25. The compound or complex according to claim 24, wherein the irradiation is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm.
26. A pharmaceutical composition comprising a compound or complex according to any preceding claim and a pharmaceutically acceptable carrier or diluent.
27. The pharmaceutical composition according to claim 26, further comprising polyvinylpyrrolidone.
28. The pharmaceutical composition according to claim 26 or 27, further comprising an immune checkpoint inhibitor.
29. The pharmaceutical composition according to claim 28, wherein the immune checkpoint inhibitor is selected from Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab or Ipilimumab.
30. The pharmaceutical composition according to any one of claims 26-29, for use in photodynamic therapy or cytoluminescent therapy.
31. The pharmaceutical composition according to any one of claims 26-30, for use in the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
32. The pharmaceutical composition according to any one of claims 26-31, for use in the treatment of a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.
33. The pharmaceutical composition according to any one of claims 26-32, for use in the treatment of a benign or malignant tumour.
34. The pharmaceutical composition according to any one of claims 26-33, for use in the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
35. The pharmaceutical composition according to claim 26 or 27, for use in photodynamic diagnosis.
36. The pharmaceutical composition according to any one of claims 26-35, wherein the pharmaceutical composition is adapted for administration prior to administration of irradiation.
37. The pharmaceutical composition according to claim 36, wherein the irradiation is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm.
38. The pharmaceutical composition according to any one of claims 26-37, wherein the pharmaceutical composition is in a form suitable for oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intratumoral, intraarticular, intraabdominal, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration.
39. The pharmaceutical composition according to claim 38, wherein the pharmaceutical composition is in a form suitable for oral or parenteral administration.
40. Use of a compound or complex according to any one of claims 1-25, in the manufacture of a medicament for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
41. Use of a compound or complex according to any one of claims 1-25, in the manufacture of a phototherapeutic agent for use in photodynamic therapy or cytoluminescent therapy.
42. The use according to claim 41, wherein the phototherapeutic agent is for the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
43. The use according to any one of claims 40-42, wherein the medicament or the phototherapeutic agent is for the treatment of a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.
44. The use according to any one of claims 40-43, wherein the medicament or the phototherapeutic agent is for the treatment of a benign or malignant tumour.
45. The use according to any one of claims 40-44, wherein the medicament or the phototherapeutic agent is for the treatment of early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
46. Use of a compound or complex according to any one of claims 1-25, in the manufacture of a photodiagnostic agent for use in photodynamic diagnosis.
47. The use according to any one of claims 40-46, wherein the medicament, the phototherapeutic agent or the photodiagnostic agent is adapted for administration prior to administration of irradiation.
48. The use according to claim 47, wherein the irradiation is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm.
49. A method of treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas; the method comprising administering a therapeutically effective amount of a compound or complex according to any one of claims 1-25 to a human or animal in need thereof.
50. A method of photodynamic therapy or cytoluminescent therapy of a human or animal disease, the method comprising administering a therapeutically effective amount of a compound or complex according to any one of claims 1-25 to a human or animal in need thereof.
51. The method according to claim 50, wherein the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious disease; HIV; Aids; infection with sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) flu virus, Dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; a cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; a dermatological condition; acne; psoriasis; a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation; a benign or malignant tumour; early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
52. The method according to any one of claims 49-51, wherein the human or animal disease is characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.
53. The method according to any one of claims 49-52, wherein the human or animal disease is a benign or malignant tumour.
54. The method according to any one of claims 49-53, wherein the human or animal disease is early cancer; cervical dysplasia; soft tissue sarcoma; a germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin’s lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vaginal or other female adnexa, breast, naso-pharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gall bladder, spleen, brain, lymphatic system, bones, skin or pancreas.
55. A method of photodynamic diagnosis of a human or animal disease, the method comprising administering a diagnostically effective amount of a compound or complex according to any one of claims 1-25 to a human or animal.
56. The method according to any one of claims 49-55, wherein the human or animal is subjected to irradiation after the administration of the compound or complex according to any one of claims 1-25.
57. The method according to claim 56, wherein the irradiation is electromagnetic radiation with a wavelength in the range of from 500nm to 1000nm.
58. A pharmaceutical combination or kit comprising: (a) a compound or complex according to any one of claims 1-25; and (b) a co-agent which is an immune checkpoint inhibitor.
59. The pharmaceutical combination or kit according to claim 58, wherein the immune checkpoint inhibitor is selected from Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab or Ipilimumab.
PCT/EP2023/083438 2022-11-28 2023-11-28 Porphyrin and phosphonium-porphyrin based compounds for photodynamic therapy and diagnostics WO2024115524A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028628A2 (en) * 2001-10-03 2003-04-10 Miravant Pharmaceuticals, Inc. Photosensitizing carbamate derivatives
WO2009040411A1 (en) * 2007-09-28 2009-04-02 Photo Diagnostic Devices (Pdd) Limited Photodynamic therapy and diagnosis using a chlorin e4 zinc complex
WO2014091241A1 (en) 2012-12-14 2014-06-19 Rmw Cho Group Limited Chlorin derivative useful in photodynamic therapy and diagnosis
KR20160066773A (en) * 2014-12-03 2016-06-13 인제대학교 산학협력단 Cationic Chlorin and Purpurinimide Derivatives, and Its Chlorin- and Purpurinimide-Polyoxometalate Complexes as Photosensitizer in Photodynamic Therapy
WO2022112537A1 (en) * 2020-11-26 2022-06-02 Rmw Cho Group Limited Photodynamic therapy and diagnosis
US20220281883A1 (en) * 2021-06-29 2022-09-08 Southwest Jiaotong University Chlorin compound, and preparation and use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028628A2 (en) * 2001-10-03 2003-04-10 Miravant Pharmaceuticals, Inc. Photosensitizing carbamate derivatives
WO2009040411A1 (en) * 2007-09-28 2009-04-02 Photo Diagnostic Devices (Pdd) Limited Photodynamic therapy and diagnosis using a chlorin e4 zinc complex
WO2014091241A1 (en) 2012-12-14 2014-06-19 Rmw Cho Group Limited Chlorin derivative useful in photodynamic therapy and diagnosis
KR20160066773A (en) * 2014-12-03 2016-06-13 인제대학교 산학협력단 Cationic Chlorin and Purpurinimide Derivatives, and Its Chlorin- and Purpurinimide-Polyoxometalate Complexes as Photosensitizer in Photodynamic Therapy
WO2022112537A1 (en) * 2020-11-26 2022-06-02 Rmw Cho Group Limited Photodynamic therapy and diagnosis
US20220281883A1 (en) * 2021-06-29 2022-09-08 Southwest Jiaotong University Chlorin compound, and preparation and use thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
D. V. BELYKH ET AL: "Synthesis of potential antitumor agents, dimeric and trimeric chlorins, from methylpheophorbide a", RUSSIAN CHEMICAL BULLETIN, vol. 60, no. 4, 1 April 2011 (2011-04-01), New York, pages 719 - 728, XP055565999, ISSN: 1066-5285, DOI: 10.1007/s11172-011-0112-0 *
GHOSH GOUTAM ET AL: "S,S-Chiral Linker Induced U Shape with a Syn-facial Sensitizer and Photocleavable Ethene Group", PHOTOCHEMISTRY AND PHOTOBIOLOGY, vol. 95, no. 1, 27 January 2019 (2019-01-27), US, pages 293 - 305, XP093141497, ISSN: 0031-8655, Retrieved from the Internet <URL:https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fphp.13000> DOI: 10.1111/php.13000 *
GILSON ET AL., BIOCONJUGATE CHEMISTRY, vol. 30, no. 5, 2019, pages 1451 - 1458
MICHIO KUNIEDA ET AL: "Self-Aggregation of Synthetic Zinc Chlorins Possessing a 13-Ester-Carbonyl Group as Chlorosomal Chlorophyll Models", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, WILEY-VCH, DE, vol. 2006, no. 10, 13 March 2006 (2006-03-13), pages 2352 - 2361, XP072108493, ISSN: 1434-193X, DOI: 10.1002/EJOC.200500909 *
PAVLOV V. YU ET AL: "Synthesis of New Derivatives of protoporphyrin IX and Chlorophyll a", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, 1 January 2005 (2005-01-01), pages 1824 - 1835, XP093141501, Retrieved from the Internet <URL:https://link.springer.com/content/pdf/10.1007/s11178-006-0044-6.pdf> [retrieved on 20240314] *

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