Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-01-02
2004-08-03
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S317000, C514S699000
Reexamination Certificate
active
06770787
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to heavier halogen atom substituted squaraine based dyes of the formula 1 below
wherein X is a heavier halogen atom and pharmaceutically acceptable derivatives thereof, which can be used in photodynamic therapeutical and industrial applications. The present invention also relates to a process for the preparation of heavier halogen atom substituted squaraine based dyes and use of such dyes as sensitizers for photodynamic, therapeutical and industrial applications.
The present invention also relates to squaraine dyes of formula 1 wherein X is bromine or ioidine or pharmaceutically acceptable derivatives thereof, which can be used as photosensitizers in photodynamic applications for diagnosis and treatment of cancer and other diseases in human beings or animals.
The present invention also relates to squaraine dyes of formula 1 wherein X is a heavy halogen atom or derivatives thereof, which can be used as photosensitizers in photodynamic industrial applications for sterilization of water.
BACKGROUND OF THE INVENTION
Photodynamic therapy is a latest modality for the diagnosis and treatment of cancer and various diseases. The large body of the evidence suggests that photodynamic therapy represents a convenient and effective approach for a variety of cancers. Photodynamic therapy involves the inactivation of living cells by the combined action of light and a chemical (photosensitizer). After intravenous injection, the photosensitizer is selectively retained by the tumor cells. There is more sensitizer in the tumor tissue than in the normal tissues. When irradiated with a light of specific wavelength or laser, the sensitizer produces highly reactive species. These highly reactive species alter the biological tissue and cause the selective destruction of the cancer cells.
The only sensitizer that has been extensively studied is Photofrin (porfime sodium), a hematoporphyrin derivative (HpD), also known as first generation photosensitizer. Photofrin and its commercial variants Photosan, Photogen were the first ones to be approved in clinical use and for which first regulatory authorizations were obtained. However, Photofrin is at the disadvantage of being a mixture of products the composition of which is highly sensitive to the synthetic methodology adopted. It is known to cause cutaneous photosensitivity as an undesirable side effect because of its slow release from the body. Under these circumstances, a patient treated with Photofrin is required to stay in the dark for a long period until it is excreted from the body. Photofrin possess only weak absorption in the red region of spectrum (the molar absorption coefficient being as small as 3000 M
−1
cm
−1
at 630 nm), leading to difficulty in delivering light to some tumor sites and also incomplete light penetration of larger tumors. Therefore, photodynamic therapy using Photofrin is only indicated for cancers developing in the surface layers of less than 10 mm depth. References may be made to Dougherty, T. J.
Photochem. Photobiol.
1987, 45, 879; Kessel, D.; Dougherty, T. J.
Phorphyrin Photosensitization;
Plenum Publishing Corp. New York, 1983; Brown, S. B.; Truscott, T. G.
Chem. Ber,
1993, 29, 955; Andreoni, A., Cubeddu, R.
Phorphyrins in Tumor Phototherapy;
Plenum Publishing Corp.: New York, 1984; Brasseur, N.; Hasarat, A., Langlois, R., Wagner, J. R; Roussean, J.; van Lier J. E.
Photochem. Photobiol.
1987, 45, 581; Spikes, J. D,
Photochem. Photobiol.
1986, 43, 691; Firey, P. A.; Ford, W. E.; Sounik, J. R.; Kenney, M. E.; Rodgers, M. A. J.
J. Am. Chem. Soc.
1988, 110, 7626; Moan, J.
Cancer Lett.
1986, 33, 45; Tralau, C J., Young, A. R.; Walker, N. P. J.; Vernon, D. I.; MacRobert, A. J., Brown, S. B.; Brown, S. G.
Photochem. Photobiol.
1989, 49, 305.
To overcome the drawbacks of the first generation sensitizers, second generation photosensitizers that exhibit strong absorptions in the long wavelength region have been synthesized. Second generation sensitizers that are under evaluation at various clinical phases of photodynamic therapy include chlorins, porphycenes, benzoporphyrins, phthalocyanins, purpurins and aminolevulinic acid-mediated porphyrins. Purpurins possess favorable optical properties and biodistribution patterns but require solubilizing or emulsifying agents such as liposomes or lipoproteins for their photodynamic applications. Chlorins have strong absorption in the red and infrared regions of the spectrum and compete favorably with Photofrin, but skin photosensitivity is a major problem with them. Phthalocyanins and metallophthalocyanins have been found to have strong absorption in the 600-700 nm region, but details of the extent of sulfonation versus the photodynamic activity is not clear. References may be made to U.S. Pat. Nos. 603,267; 5,965,598; 5,889,181; 586,035; 5,789,586; Kostenich, G. A.; Zuravkin, I. N.; Zhavrid, E. A.
J Photochem. Photobiol. B. Biol.
1994, 22, 211; Leach, M. W.; Higgins, R. J.; Autry, S. A.; Boggan, J. E.; Lee, S. -J. H.; Smith, K. M.
Photochem. Photobiol.,
Bai, S.; Liu, C.; Guo, Z.
Proc. SPIE
1993, 1616, 275; Vogel, E.; Kocher, M Schmickler, H.; Lex, J.
Angew. Chem. Int. Ed. Engl.
1986, 25, 197; Leunig, M,; Richert, C.; Gamarra, F.; Lumper, W.; Vogel, E.; Jochani D.; Goetz, A. E.
Br. J. Cancer
1993, 68, 225; Boyle, R. W.; Legnoff, C. C.; Vanheir, J. E.
Br. J. Cancer,
1993, 67, 1177; Wohrl, D.; Shopova, M.; Muller, S.; Muleiv, A. D.; Mantereva, V. N.; Krastev, K. K.
J Photochem. Photobiol. B. Biol.
1993, 21, 155; Morgan, A. R.; Garbo, G. M.; Keck, R. W.; Ericksen, L. D.; Selman, S. H.
Photochem. Photobiol.
1990, 51, 589.
Development of photosensitizers, which have strong absorptions in the long wavelength region, non-toxic to normal tissues, soluble in buffer at physiological pH, can be bleached during the photodynamic treatment and exhibit higher therapeutic efficacy are still desired.
Squaraines form a class of dyes possessing sharp and intense absorption bands in the red to near infra red region. The molar absorption coefficients of these dyes are normally in the range of 500,000 M
−1
cm
−1
. Squaraines find industrial applications in xerographic photoreceptors, solar cells and optical recording devices. However, due to the very low intersystem crossing efficiency of these dyes, their potential as photosensitizers in photodynamic therapeutical applications have not yet been explored. References may be made to U.S. Pat. Nos. 6,001,523; 5,552,253; 5,444,463; Law, K.-Y.
Chem. Rev.
1993, 93, 449; Piechowski, A P; Bird, G. R.; Morel, D L.; Stogryn, E. L.
J. Phy. Chem.
1984, 88, 934.
Accordingly, the use of squaraine based dyes was studied to observe if the problems associated with the prior art could be overcome. It is an objective of this invention to provide a photosensitizer suitable for photodynamic therapeutical applications based on the squaraine moiety. Preliminary investigations by us indicated that halogenation of the squaraine moiety resulted in increased water solubility and intersystem crossing efficiency when compared to the parent unsubstituted squaraine dye. These halogenated dyes exhibited strong absorptions in the near infrared region (>600 nm) and significant bathochromic shifts in presence of microheterogeneous media. Triplet excited states were the main transients involved in these systems, which interact efficiently with molecular oxygen generating biologically highly reactive singlet oxygen in quantitative yields thereby making them potential candidates in phototherapeutical applications. Reference may be made to Ramaiah, D.; Joy, A.; Chandrasekhar, N; Eldho, N. V.; Das, S.; George, M. V.
Photochem. Photobiol.
1997, 65, 783.
However, the yields of these halogenated squaraine dyes were of lower order under stipulated conditions and their efficiency of singlet oxygen (cytotoxic agent) generation in membrane modeling and drug carrier systems like polymers is not known. Moreover, there are no reports on biological properties or the photodynamic therapeutical
Danaboyina Ramaiah
Das Suresh
Epe Bernd
Kalliat Thazhathveetil Arun
Darby & Darby
Killos Paul J.
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