Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-27
2002-04-23
Raymond, Richard L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S410000, C534S015000, C534S016000, C534S010000, C540S145000, C424S009610
Reexamination Certificate
active
06376483
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds useful as photoselective compounds in photodynamic therapy and a process for producing 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 long wavelength absorptions in the 750-850 nm range, 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.
Chlorins are compounds that differ from porphyrins in that one of the pyrrole rings has been reduced.
Bacteriochlorins, iso-bacteriochlorins, and bacteriopurpurins are a subclass of porphyrins in which two of the pyrrole rings have been reduced. Bacteriochlorins have opposing pyrrole rings reduced, and iso-bacteriochlorins have adjacent pyrrole rings reduced.
Bacteriopurpurins differ from bacteriochlorins in that they have one or more 5-membered iso-cyclic rings fused to the macrocyclic ring.
Reduction of the pyrrolic rings in the porphyrin macrocycle has a pronounced effect on the absorption spectra of the reduced compounds. Bacteriochlorins and bacteriopurpurins have large band I absorptions that absorb light in the region of 720-850 nm. Thus, bacteriochlorins and bacteriopurpurins are classes of photoselective compounds that have great potential for use in photodynamic therapy.
Unfortunately, stable bacteriochlorins and bacteriopurpurins are notoriously difficult to synthesize from porphyrins or other chlorin intermediates. Many naturally occurring bacteriochlorins tend to be unstable in the presence of oxygen and light and are rapidly converted back to porphyrins and chlorins.
Accordingly, there is a need for stable photoselective compounds that absorb light at a wavelength where light penetration through tissues is optimal for specific disease indications.
More particularly, there is a need for a photoselective compound that absorbs light in the 750-850 nm range.
There is a further need for a process capable of producing stable bacteriochlorins and bacteriopurpurins.
SUMMARY OF THE INVENTION
To achieve the advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, provided are bacteriochlorins of the following formulae:
bacteriopurpurins of the following formulae:
and bacteriochlorins of the following formulae:
wherein in each of the above and following formulae:
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, and R
12
are independently sele from hydrogen, halogen atoms, unsubstituted or substituted alkyl, C
3
-C
6
cycloalkyl, acetyl, aryl, alkenyl, alkynyl, amides, esters, NR
13
R
14
, CN, OH, OR
13
, CHO, (CH
2
)
n
OH, (CH
2
)
n
SH, (CH
2
)
n
O-alkoxy, (CH
2
)
n
SR
13
, (CH
2
)
n
OR
13
, (CH
2
)
n
CO
2
R
13
, (CH
2
)
n
CONHR
13
, (CH
2
)
n
CON(R
13
)(R
14
), CO
2
R
13
, CONHR
13
, CONR
13
R
14
, SR
13
, SO
3
H, SO
3
R
13
, SO
2
NHR
13
, SO
2
N(R
13
)(R
14
), and SO
2
N(R
13
)(R
14
)(R
15
)+X
−
;
R
13
, R
14
, and R
15
are independently selected from hydrogen, a physiologically acceptable salt, unsubstituted or substituted C
1
-C
6
alkyl, aryl, alkenyl, or alkynyl, and a functional group having a molecular weight less than or equal to about 100,000 daltons;
n is an integer ranging from 1 to 4;
R
20
is an unsubstituted or substituted C
1
-C
6
alkyl;
M is two hydrogens or a metal ion selected from Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Gd, Hf, Ho, In, La, Lu, Mn, Mo, Nd, Ni, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, TI, Tm, U, V, Y, Yb, Zn, and Zr;
Also provided is a process for producing the compounds of formulae IA and IB comprising reacting the corresponding meso-acrylate porphyrin precursor in a solvent with a base catalyst for a time and at a temperature sufficient to form the compounds of formulae IA and IB:
Another process is provided for producing the compounds of formulae IIA and IIB comprising reacting the corresponding meso-acrylate porphyrin precursor in a solvent with a base catalyst for a time and at a temperature sufficient to form the compounds of formulae IIA and IIB:
Furthermore, a process is provided for producing the compounds of formulae IIIA and IIIB comprising reacting the corresponding meso-acrylate porphyrin precursor in a solvent with hydrogen and a hydrogenation catalyst for a time and at a temperature sufficient to form the compound of formulae IIIA and IIIB:
Selective hydrogenation and purification can also produce:
Additional advantages of the invention will be set forth in the detailed description which follows, and in part will be obvious from the description or may be learned by practice of the invention. The advantages of the invention can be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
The compounds of the present invention are useful for the photodiagnosis and phototherapy of tumor, cancer and malignant tissue (hereinafter referred to as “tumor”).
When a human or animal having tumor is treated with doses of a compound of the present invention and when appropriate light rays or electromagnetic waves are applied, the compound emits light (i.e., it fluoresces). Thereby the existence, position and size of the tumor can be detected. This is called photodiagnosis.
When the tumor is irradiated with light of proper wavelength and intensity, the compound is activated to exert a cell killing effect against the tumor. This is called phototherapy.
Compounds intended for photodiagnosis and phototherapy ideally should have the following properties:
(a) non-toxic at normal therapeutic dosage unless and until activated by light;
(b) selectively photoactive;
(c) when light rays or electromagnetic waves are applied, they emit characteristic and detectable fluorescence;
(d) when irradiated with light rays or when electromagnetic waves are applied, they are act
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Miravant Pharmaceuticals, Inc.
Raymond Richard L.
LandOfFree
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