Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-09-12
1996-09-17
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540140, 514410, A61K 3140, C07D48722
Patent
active
055568491
DESCRIPTION:
BRIEF SUMMARY
This invention concerns photosensitizers, more particularly it concerns novel transition metal photosensitizers.
BACKGROUND
In the photodynamic therapy of cancer, certain dye compounds (eg, hematoporphyrin derivative, chloroaluminum phthalocyanine sulfonate) are administered to a tumor-bearing subject. To some extent these dye compounds are taken up by the tumor tissue and upon selective irradiation with the appropriate light source the tumor tissue is destroyed via the dye mediated photo-generation of toxic species such as single; oxygen,
A large number of phthalocyanine (Pc) derivatives have been proposed as potential photodynamic therapeutic (PDT) agents. Most biological studies on Pc compounds related to PDT have been conducted with water soluble sulfonated metallo-phthalocyanines (as reported by Rosenthal. I. Photochem Photobiol 53(6). 859-870. (1991). These compounds are generally obtained by sulfonation of the appropriate metallo-phthalocyanine or by template synthesis using the appropriate sulfonated precursors and a metal salt. Both template synthesis and direct sulfonation results in mixtures of Pc's containing a variety of isomers and/or different degrees of sulfonation. This is a particular disadvantage with respect to pharmaceutical applications in that drug regulatory agencies are increasingly stringent in their requirements for substantially pure compounds.
Metallated Pc's have been found to have superior photosensitizing activity compared to metal-free Pc's when the metal is a main group element having a filled d shell (eg. Al. Zn, Sn. In). It has been reported by Chan, W S. et al. Photothem Photobiol. 45, 757-761 (1987), that transition metal complexes of Pc's have been found to be inactive (eg. Cu, Co, Ni. VO, Pal).
There remains a need for novel photosensitizers which can be prepared in isomerically pure form and which show a good level of activity.
The present invention provides novel transition metal phthalocyanine-type derivatives of formula I. ##STR2## wherein M is a second or third row transition metal with a d.sup.6 low-spin electronic configuration, --C.sub.4 H.sub.4 --, nitrile, thiolate, hydrazine, cyanide, thiocyanate, phenolate, sulphide and analine groups having a water-solubilizing moiety, and water-soluble salt or acid form.
Preferably. M is selected from Ru, Rh, Os or Ir. Suitable ligands R incorporate triphenylphosphine or triethylphosphine, and solubilizing groups are suitably sulfonate or carboxylate groups. When R incorporates an amine, it may be a straight or branched chain amine, or an aromatic amine such as pyridine. Preferred R ligands are triphenyl-phosphine mono-, di- or tri-sulfonate, 4-pyridine ethanesulfonate, 3-pyridine sulfonate, triphenylphosphine monocarboxylate, 4-isocyanobenzoate, nicotinic acid, taurine or amino acids.
Preferably, the compound is in salt form, with counterions which are desirably K.sup.+, Na.sup.+ or quaternary ammonium.
The compounds of formula I are novel, and may be prepared by a process comprising reacting a metal phthalocyanine compound of formula II, ##STR3## wherein M, Q and X are as define above, and A is an amine, preferably a pyridine group, CO (carbon monoxide) or a co-ordinating solvent, for example benzonitrile, with a salt of the ligand R, and isolating the product compound of formula I.
Many of the reactants of formula II, and the salts of ligand R, are known from the literature. However, compounds of formula II in which A is ammine, benzonitrile, methylcyanide or another co-ordinating solvent, are believed to be novel and form part of the present invention. Although such compounds may be prepared by methods analogous to those in the art, the invention further provides a method of producing said novel compounds of formula II in which A is benzonitrile by reacting M phthalocyanine bis(ammine) with benzonitrile. The ammine complex may be prepared by reacting MCl.sub.3. xH.sub.2 O, where x is 2 or 3, with phthalonitrile, and then with ammonia.
Suitably, the starting metal phthalocyanine or naphthalocyanine is mixed in an
REFERENCES:
Hedtmann-Rein et al., Inorg. Chem., 26, 2647-51, 1987.
Martinsen et al., Inorg. Chem. 19, 2162-65 1980.
Abrams Michael J.
Bossard Gerald E.
Brooks Robert C.
Vollano Jean F.
Johnson Matthey Public Limited Company
Shah Mukund J.
Sripada Pavanaram K.
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