USRE43274EExpiredUtility
Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy
Est. expiryJun 27, 2022(expired)· nominal 20-yr term from priority
C09B 69/108A61K 41/0071C07D 471/22A61P 35/00C09B 47/00A61K 41/0076
72
PatentIndex Score
1
Cited by
545
References
34
Claims
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.
Claims
exact text as granted — not AI-modified1. A compound of the formula:
or a pharmaceutically acceptable derivative thereof, wherein:
R 1 and R 2 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, —C(O)R a or —COOR a , or —CH(CH 3 )(OR a ) or —CH(CH 3 )(O(CH 2 ) n XR a ) where R a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl; where R 2 may be —CH═CH 2 , —CH(OR 20 ) CH 3 , —C(O)Me, —(═NR 21 )CH 3 or —CH(NHR 21 )CH 3
where X is an aryl or heteroaryl group;
n is an integer of 0 to 6;
where R 20 is methyl, butyl, heptyl, docecyl or 3,5-bis(trifluoromethyl)-benzyl; and
R 21 is 3,5,-bis(trifluoromethyl)benzyl;
R 1a and R 2a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R 3 and R 4 are each independently hydrogen or substituted or unsubstituted alkyl;
R 3a and R 4a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R 5 is hydrogen or substituted or unsubstituted alkyl;
R 6 and R 6a are each independently hydrogen or substituted or unsubstituted alkyl, or together form ═O;
R 7 is a covalent bond, alkylene, azaalkyl, or azaaraalkyl or ═NR 20 where R 20 is 3,5-bis(tri-fluoromethyl)benzyl or —CH 2 X—R 1 or YR 1 where Y is an aryl or heteroaryl group;
R 8 and R 8a are each independently hydrogen or substituted or unsubstituted alkyl or together form ═O;
R 9 and R 10 are each independently hydrogen, or substituted or unsubstituted alkyl and R 9 may be —CH 2 CH 2 COOR 2 where R 2 is an alkyl group that may optionally substituted with one or more fluorine atoms;
each of R 1 -R 10 , when substituted, is substituted with one or more substituents each independently selected from Q, where Q is alkyl, haloalkyl, halo, pseudohalo, —COOR b where R b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl aryl, heteroaryl, araalkyl, or OR c where R c is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or CONR d R e where R d and R e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, or NR f R g where R f and R g are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or ═NR h where R h 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 Q 1 , where Q 1 is alkyl, haloalkyl, halo, pseudohalo, or —COOR b where R b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl aryl, heteroaryl, araalkyl, or OR c where R c is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, or CONR d R e where R d and R e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NR f R g where R f and R g are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or ═NR h where R h 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, R 1 , or R 2 group.
2. The compound of claim 1 , wherein:
R 1 is methyl; R 1a and R 2a together form a covalent bond; R 3 is methyl; R 4 is ethyl; R 3a and R 4a are each independently hydrogen, or together form a covalent bond; R 5 is methyl; R 9 is CH 2 CH 2 COOH or CH 2 CH 2 COOMe; R 10 is methyl.
3. The compound of claim 1 , wherein:
R 2 is CH═CH 2 , CH(OR 20 )CH 3 , C(O)Me, C(═NR 21 )CH 3 or CH(NHR 21 )CH 3 ; where R 20 is methyl, butyl, heptyl, dodecyl or 3,5-bis(trifluoromethyl)benzyl; and R 21 is 3,5-bis(trifluoromethyl)benzyl.
4. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof.
5. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof, wherein:
R is methyl, butyl, heptyl or dodecyl.
6. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof, wherein:
R is methyl, butyl, heptyl or dodecyl.
7. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof.
8. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof, wherein:
R is methyl, butyl, heptyl or dodecyl.
9. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof.
10. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof.
11. The compound of claim 1 having the formula
or a pharmaceutically acceptable derivative thereof, wherein:
X is an aryl or heteroaryl group;
R and R 1 are each independently alkyl, aryl, or heteroaryl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
12. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof, wherein:
X is an aryl or heteroaryl group;
n is an integer from 0 to 6;
R and R 1 are each independently alkyl, aryl, or heteroaryl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
13. The compound of claim 1 having the formula
or a pharmaceutically acceptable derivative thereof, wherein:
X is an aryl or heteroaryl group;
R and R 1 are each independently alkyl, aryl, or heteroaryl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
14. The compound of claim 1 having the formula:
or a pharmaceutically acceptable derivative thereof, wherein:
X is an aryl or heteroaryl group;
n is an integer from 0 to 6;
R and R 1 are each independently alkyl, aryl, or heteroaryl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
15. The compound of claim 1 having the formula
or a pharmaceutically acceptable derivative thereof, wherein:
X and Y are each independently an aryl or heteroaryl group;
n is an integer from 0 to 6;
R and R 1 are each independently alkyl, aryl, or heteroaryl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
16. A pharmaceutical composition, comprising a compound of claim 1 or a pharmaceutically acceptable derivative thereof in a pharmaceutically acceptable carrier.
17. The compound of claim 10 or a pharmaceutically acceptable derivative thereof when used for the detection or treatment or both of hyperproliferative tissue.
18. The compound of claim 11 or a pharmaceutically acceptable derivative thereof when used for the detection or treatment or both of hyperproliferative tissue.
19. The compound of claim 12 or a pharmaceutically acceptable derivative thereof when used for the detection or treatment or both of hyperproliferative tissue.
20. A compound of the formula:
wherein:
said compound is pharmaceutically acceptable;
R 1 and R 2 are each independently alkyl, alkenyl, —C(O)R a or —COOR a or —CH(CH 3 )(OR a ) or —CH(CH 3 )(O(CH 2 ) n XR a ) where R a is hydrogen, alkyl, alkenyl, alkenyl, or cycloalkyl; where R 2 may also be, —C(═NR 21 )CH 3 , or —CH(NHR 21 )CH 3 ;
where X is an aryl or heteroaryl group;
n is an integer of 0 to 6;
R 21 is 3,5-bis(trifluoromethyl)benzyl;
R 1a and R 2a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R 3 and R 4 are each independently hydrogen or substituted or unsubstituted alkyl;
R 3a and R 4a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond;
R 5 is hydrogen or substituted or unsubstituted alkyl;
R 6 and R 6a are each independently hydrogen or substituted or unsubstituted alkyl, or together form ═O;
R 7 is a covalent bond, alkylene, azaalkyl, or azaaraalkyl or
where R 20 is 3,5-bis(trifluoromethyl)benzyl;
R 8 and R 8a are each independently hydrogen or substituted or unsubstituted alkyl or together form ═O;
R 9 and R 10 are each independently hydrogen, or substituted or unsubstituted alkyl and R 9 may be —CH 2 CH 2 COOR 2 where R 2 is an alkyl group that may be optionally substituted with one or more fluorine atoms;
each of each of R 3 -R 6 , R 8 -R 10 , R 1a -R 4a , R 6a , and R 8a , when substituted, is substituted with one or more substituents each independently selected from Q, where Q is alkyl, haloalkyl, halo or —COOR b where R b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, araalkyl, or OR c where R c is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl or CONR d R e where R d and R e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NR f R g where R f and R g 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 Q 1 , where Q 1 is alkyl, haloalkyl, halo, pseudohalo, or —COOR b where R b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, araalkyl, or OR c where R c is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or CONR d R e where R d and R e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NR f R g where R f and R g 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.
21. The compound of claim 20 wherein:
R 1 is methyl; R 1a and R 2a together form a covalent bond; R 3 is methyl; R 4 is ethyl; R 3a and R 4a are each independently hydrogen, or together form a covalent bond; R 5 is methyl; R 9 is CH 2 CH 2 COOMe; R 10 is methyl.
22. The compound of claim 20, wherein:
R 2 is CH═CH 2 , C(O)Me, C(═NR 21 )CH 3 , CH(NHR 21 )CH 3 , and R 21 is 3,5-bis(trifluoromethyl)benzyl.
23. A compound having the formula:
24. A compound having the formula:
wherein R is methyl, butyl, heptyl or dodecyl.
25. A compound having the formula:
wherein R is methyl, butyl, heptyl or dodecyl.
26. A compound having the formula:
27. A compound having the formula:
wherein R is methyl, butyl, heptyl or dodecyl.
28. A compound having the formula:
29. A compound having the formula:
30. A compound having the formula:
wherein:
X is an aryl or heteroaryl group;
R and R 1 are each independently alkyl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
31. A compound having the formula:
wherein:
X is an aryl or heteroaryl group;
n is an integer from 0 to 6;
R and R 1 are each independently alkyl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
32. A compound having the formula:
wherein:
X is an aryl or heteroaryl group;
R and R 1 are each independently alkyl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
33. A compound having the formula:
wherein:
X and Y are each independently an aryl or heteroaryl group;
n is an integer from 0 to 6;
R and R 1 are each independently alkyl groups having 1-20 carbon atoms, wherein at least one of R and R 1 is substituted with at least one fluorine atom; and
R 2 is an alkyl group, optionally substituted with one or more fluorine atoms.
34. A pharmaceutical composition, comprising a compound of claim 20 in a pharmaceutically acceptable carrier.Cited by (0)
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