US RE43,274 E1Granted

Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy

AssigneeHealth Research, Inc.

InventorsRavindra K. Pandey, William R. Potter, Thomas J. Dougherty

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Abstract

Provided herein are compounds for detection, diagnosis and treatment of target tissues or target compositions, including hyperproliferative tissues such as tumors, using photodynamic methods. In particular, photosensitizer compounds that collect in hyperproliferative tissue are provided. In another embodiment, compounds that absorb light at a wavelength of from about 700 to about 850 nm are provided. In a further embodiment, compounds that are detectable by magnetic resonance imaging are provided.

Claims34

Dependent claims

A compound of the formula:

or a pharmaceutically acceptable derivative thereof, wherein:
R1 and R2 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, —C(O)Ra or —COORa, or —CH(CH3)(ORa) or —CH(CH3)(O(CH2)nXRa) where Ra is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl;
where R2 may be —CH═CH2, —CH(OR20) CH3, —C(O)Me, —(═NR21)CH3 or —CH(NHR21)CH3
where X is an aryl or heteroaryl group;
n is an integer of 0 to 6;
where R20 is methyl, butyl, heptyl, docecyl or 3,5-bis(trifluoromethyl)-benzyl;
and
R21 is 3,5,-bis(trifluoromethyl)benzyl;
R1a and R2a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R3 and R4 are each independently hydrogen or substituted or unsubstituted alkyl;
R3a and R4a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R5 is hydrogen or substituted or unsubstituted alkyl;
R6 and R6a are each independently hydrogen or substituted or unsubstituted alkyl, or together form ═O;
R7 is a covalent bond, alkylene, azaalkyl, or azaaraalkyl or ═NR20 where R20 is 3,5-bis(tri-fluoromethyl)benzyl or —CH2X—R1 or YR1 where Y is an aryl or heteroaryl group;
R8 and R8aare each independently hydrogen or substituted or unsubstituted alkyl or together form ═O;
R9 and R10 are each independently hydrogen, or substituted or unsubstituted alkyl and R9 may be —CH2CH2COOR2 where R2 is an alkyl group that may optionally substituted with one or more fluorine atoms;
each of R1-R10, when substituted, is substituted with one or more substituents each independently selected from Q, where Q is alkyl, haloalkyl, halo, pseudohalo, —COORb where Rb is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl aryl, heteroaryl, araalkyl, or ORc where Rc is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or CONRdRe where Rd and Re are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, or NRfRg where Rf and Rg are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or ═NRh where Rh is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or is an amino acid residue;
each Q is independently unsubstituted or is substituted with one or more substituents each independently selected from Q1, where Q1 is alkyl, haloalkyl, halo, pseudohalo, or —COORb where Rb is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl aryl, heteroaryl, araalkyl, or ORc where Rc is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, or CONRd Re where Rd and Re are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NRfRg where Rf and Rg are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or ═NRh where Rh is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or is an amino acid residue;
with the proviso that the compound contains at least one fluorine atom in at least one 3,5,-bis(trifluoromethyl)benzyl group or in at least one R, R1, or R2 group.

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A compound of the formula:

wherein:
said compound is pharmaceutically acceptable;
R1 and R2 are each independently alkyl, alkenyl, —C(O)Ra or —COORa or —CH(CH3)(ORa) or —CH(CH3)(O(CH2)nXRa) where Ra is hydrogen, alkyl, alkenyl, alkenyl, or cycloalkyl;
where R2 may also be, —C(═NR21)CH3, or —CH(NHR21)CH3;
where X is an aryl or heteroaryl group;
n is an integer of 0 to 6;
R21 is 3,5-bis(trifluoromethyl)benzyl;
R1a and R2a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R3 and R4 are each independently hydrogen or substituted or unsubstituted alkyl;
R3a and R4a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R5 is hydrogen or substituted or unsubstituted alkyl;
R6 and R6a are each independently hydrogen or substituted or unsubstituted alkyl, or together form ═O;
R7 is a covalent bond, alkylene, azaalkyl, or azaaraalkyl or
where R20 is 3,5-bis(trifluoromethyl)benzyl;
R8 and R8a are each independently hydrogen or substituted or unsubstituted alkyl or together form ═O;
R9 and R10 are each independently hydrogen, or substituted or unsubstituted alkyl and R9 may be —CH2CH2COOR2 where R2 is an alkyl group that may be optionally substituted with one or more fluorine atoms;
each of each of R3-R6, R8-R10, R1a-R4a, R6a, and R8a, when substituted, is substituted with one or more substituents each independently selected from Q, where Q is alkyl, haloalkyl, halo or —COORb where Rb is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, araalkyl, or ORc where Rc is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl or CONRdRe where Rd and Re are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NRfRg where Rf and Rg are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl;
each Q is independently unsubstituted or is substituted with one or more substituents each independently selected from Q1, where Q1 is alkyl, haloalkyl, halo, pseudohalo, or —COORb where Rb is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, araalkyl, or ORc where Rc is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or CONRdRe where Rd and Re are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NRfRg where Rf and Rg are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl;
with the proviso that the compound contains at least one 3,5-bis(trifluoromethyl)benzyl group.

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Dependencies are inferred from the claim text.

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Abstract

A compound of the formula:

or a pharmaceutically acceptable derivative thereof, wherein:
R1 and R2 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, —C(O)Ra or —COORa, or —CH(CH3)(ORa) or —CH(CH3)(O(CH2)nXRa) where Ra is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl;
where R2 may be —CH═CH2, —CH(OR20) CH3, —C(O)Me, —(═NR21)CH3 or —CH(NHR21)CH3
where X is an aryl or heteroaryl group;
n is an integer of 0 to 6;
where R20 is methyl, butyl, heptyl, docecyl or 3,5-bis(trifluoromethyl)-benzyl;
and
R21 is 3,5,-bis(trifluoromethyl)benzyl;
R1a and R2a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R3 and R4 are each independently hydrogen or substituted or unsubstituted alkyl;
R3a and R4a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R5 is hydrogen or substituted or unsubstituted alkyl;
R6 and R6a are each independently hydrogen or substituted or unsubstituted alkyl, or together form ═O;
R7 is a covalent bond, alkylene, azaalkyl, or azaaraalkyl or ═NR20 where R20 is 3,5-bis(tri-fluoromethyl)benzyl or —CH2X—R1 or YR1 where Y is an aryl or heteroaryl group;
R8 and R8aare each independently hydrogen or substituted or unsubstituted alkyl or together form ═O;
R9 and R10 are each independently hydrogen, or substituted or unsubstituted alkyl and R9 may be —CH2CH2COOR2 where R2 is an alkyl group that may optionally substituted with one or more fluorine atoms;
each of R1-R10, when substituted, is substituted with one or more substituents each independently selected from Q, where Q is alkyl, haloalkyl, halo, pseudohalo, —COORb where Rb is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl aryl, heteroaryl, araalkyl, or ORc where Rc is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or CONRdRe where Rd and Re are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, or NRfRg where Rf and Rg are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or ═NRh where Rh is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or is an amino acid residue;
each Q is independently unsubstituted or is substituted with one or more substituents each independently selected from Q1, where Q1 is alkyl, haloalkyl, halo, pseudohalo, or —COORb where Rb is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl aryl, heteroaryl, araalkyl, or ORc where Rc is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, or CONRd Re where Rd and Re are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NRfRg where Rf and Rg are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or ═NRh where Rh is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or is an amino acid residue;
with the proviso that the compound contains at least one fluorine atom in at least one 3,5,-bis(trifluoromethyl)benzyl group or in at least one R, R1, or R2 group.

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