Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-02-13
1998-11-10
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514410, A61K 31555, A61K 3140
Patent
active
058344551
DESCRIPTION:
BRIEF SUMMARY
This is a 35 U.S.C. 371 of PCT/GB94/01847 filed Aug. 24, 1994.
This invention relates to photosensitizers, more particularly it relates to their use in photodynamic therapy.
BACKGROUND OF THE INVENTION
In the photodynamic therapy of cancer, dye compounds are administered to a tumour-bearing subject. These dye substances may be taken up, to a certain extent, by the tumour. Upon selective irradiation with an appropriate light source the tumour tissue is destroyed via the dye mediated photo-generation of species such as singlet oxygen or other cytotoxic species such as free radicals, for example hydroxy or superoxide.
A 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 described by I. Rosenthal, Photochem. Photobiol. 53(6), 859-870, 1991. Methods for synthesizing these compounds often results in mixtures of compounds containing a variety of isomers and/or different degrees of sulfonation. Drug regulatory agencies are becoming increasingly stringent in their requirements for substantially pure compounds, hence not being able to produce substantially pure compounds is a particular disadvantage with respect to pharmaceutical applications.
The combination of a sensitizer and electromagnetic radiation for the treatment of cancer is commonly known as photodynamic therapy.
Phthalocyanine has the following formula: ##STR2##
The nomenclature for the numbering of the phenyl ring is also included in the above depiction.
Metallated Pc's have been found to have better photo-sensitizing activity compared to metal-free phthalocyanines when the metal is diamagnetic. Conversely a paramagnetic metal renders the phthalocyanine inactive, see I. Rosenthal and E. Ben-Hur, Phthalocyanines in photobiology in Phthalocyanines, Properties and Applications, Ed., C. C. Leznoff and A. B. P. Lever, V. C. H. Publishers 1989. Photosensitization is a process in which a photochemical reaction is induced to occur by the presence of a substance (the photosensitizer) which absorbs the light but itself is substantially unchanged at the end of the reaction, the absorbed light energy being passed on to the main reactants. For example when hydrogen is exposed to light of wavelength 253.6 nm no absorption of the light takes place and the hydrogen remains completely unaffected. If mercury vapour is added to the hydrogen, the mercury atoms are excited. When such an excited mercury atom collides with a hydrogen molecule, it can transfer some of its energy to the hydrogen, and cause it to dissociate into atoms. The hydrogen has apparently been made sensitive to the light which it does not absorb. In some cases the photosensitizer is broken down and a photoproduct is formed which may also possess suitable PDT properties.
Similarly, oxygen can be made sensitive to the electromagnetic radiation it may not normally absorb by the presence of phthalocyanines or other `complex` organic molecules; some of which may have metals or metal salts incorporated.
Patent WO 93/09124 describes the use of water soluble salt or acid forms of transition metal phthalocyanines for use in photodynamic therapy. In this patent application phthalocyanines containing second or third row transition metals with a d.sup.6 low-spin electronic configuration are disclosed. The compounds exemplified in patent application WO 93/09124 contain Ru.
European Patent Application 0 484 027 A1 describes the use of substituted phthalocyanines for the generation of singlet oxygen.
UK Patent GB 2,229,190 B relates to certain novel substituted phthalocyanines, methods for their preparation and to certain uses thereof.
There are various criteria which have to be met if a compound is to be successful as a photosensitizer for use in photodynamic therapy. Some of these criteria may include the following: infra-red region of the spectrum.
A compound which is tested for PDT applications may exhibit some but not al
REFERENCES:
patent: 5506708 (1996-04-01), Harrison et al.
Cook Michael J
Russell David A
Goldberg Jerome D.
The Secretary of State for Defence in Her Britannic Majesty's Go
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