Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-30
2004-09-21
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C534S015000, C534S016000, C540S121000
Reexamination Certificate
active
06794505
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds useful as photoselective agents in photodynamic therapy and procedures for synthesizing such compounds.
BACKGROUND OF THE INVENTION
Photodynamic therapy is a procedure that uses photoselective (light-activated) drugs to target and destroy diseased cells. Photoselective drugs transform light energy into chemical energy in a manner similar to the action of chlorophyll in green plants. The photoselective drugs are inactive until switched on by light of a specific wavelength thereby enabling physicians to target specific groups of cells and control the timing and selectivity of treatment. The result of this process is that diseased cells are destroyed with minimal damage to surrounding normal tissues.
Photodynamic therapy begins with the administration, to a patient, of a preferred amount of a photoselective compound which is selectively taken up and/or retained by the biologic target, i.e., tissue or cells. After the photoselective compound is taken up by the target, a light of the appropriate wavelength to be absorbed by the photoselective compound is delivered to the targeted area. This activating light excites the photoselective compound to a higher energy state. The extra energy of the excited photoselective compound can then be used to generate a biological response in the target area by interaction with oxygen. As a result of the irradiation, the photoselective compound exhibits cytotoxic activity, i.e., it destroys cells. Additionally, by localizing in the irradiated area, it is possible to contain the cytotoxicity to a specific target area. For a more detailed description of photodynamic therapy, see U.S. Pat. Nos. 5,225,433; 5,198,460; 5,171,749; 4,649,151; 5,399,583; 5,459,159; and 5,489,590, the disclosures of which are incorporated herein by reference.
One important factor in the effectiveness of photodynamic therapy for some disease indications is the depth of tissue penetration by the activating light. It would therefore be desirable to find photoselective compounds that absorb at wavelengths in which light penetration through the tissue is deep. Thus, there is a need for photoselective compounds, useful for photodynamic therapy, that possess wavelength absorptions between about 300 and about 850 nm, the latter being a region where light penetration through tissues is optimal.
A large number of naturally occurring and synthetic dyes are currently being evaluated as potential photoselective compounds in the field of photodynamic therapy. Perhaps the most widely studied class of photoselective dyes in this field are the tetrapyrrolic macrocyclic compounds generally called porphyrins.
In general, porphyrins typically have low energy absorptions, called band I absorption at ~620-650 nm, with molar extinction coefficients in the order of 100-10,000M
−1
cm
−1
. Because of this fact, porphyrins have largely been criticized as having less than optimal wavelength and light absorption properties for use in photodynamic therapy.
Chlorins are compounds that differ from porphyrins in that one of the pyrrole rings has been reduced, either by addition of hydrogen or by carbon bond formation.
Regioselective reduction of porphyrins by hydrogen produces chlorins, examples of which are shown below. Unlike porphyrins, chlorins have strong band I absorptions typically in the range of 30,000-80,000M
−1
cm
−1
, and have therefore received much interest in the field of photodynamic therapy. In the compounds shown below, R
1
and R
2
are independently selected from functional groups having a molecular weight less than about 100,000 daltons.
Unfortunately, oxygen is known to oxidize these types of chlorins back to porphyrins, with loss of the valuable high molar extinction coefficients of the longer wavelength band I absorption. For this reason, as well as producing stable pharmaceuticals, several groups have produced chlorins that are produced from porphyrins, via annelation of cyclic ring systems to the reduced pyrrole. Examples of these chlorin types are shown below. In the compounds shown below, R, R
1
, R
2
, and R
3
are independently selected from functional groups having a molecular weight less than about 100,000 daltons.
Fusion of the exocyclic rings has the potential advantage of limiting oxidation of the prepared chlorin. In addition and just as importantly, such compounds generally have improved light absorption profiles with longer wavelength absorptions and higher molar extinction coefficients than porphyrins.
Further, it would be advantageous to derivatize or extend the exocyclic rings of such compounds in order to influence the light absorption profiles of these compounds. By influencing the light absorption properties of these compounds it may be possible to generate molecules that absorb light at a wavelength where light penetration through tissues is optimal for specific disease indications. Further functionalization of such molecules will alter biological properties such as solubility and physiological clearance. For instance, increasing the amphilicity or lipophilicity of the molecules enhances the interaction with polar and nonpolar environments. Therefore, there is great interest in developing stable chlorins with improved light absorption profiles that can be used in the field of photodynamic therapy.
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Phadke Avinash
Robinson Byron C.
Sengupta Dipanjan
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Miravant Pharmaceuticals, Inc.
Raymond Richard L.
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