Texaphyrin coordination compounds and uses thereof
View Patent ↗Novel coordination polymers, their pharmaceutical formulations, useful for treating atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress, are disclosed.
1. A method for treating a disease or condition in a mammal resulting from the presence of neoplastic tissue, neovascularization, or an atheroma, said method comprising:
administering to a mammal in need of such treatment a therapeutically effective amount of a coordination polymer comprising structural units “A”:
wherein:
M is a trivalent metal cation;
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group —X—Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and
R 5 , R 10 , R 11 , and R 12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl, and
structural unit “B”
2. A method of claim 1 , wherein within structural unit “A”
M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III);
R 1 represents (CH 2 ) 2-4 —OH;
R 2 and R 3 independently represent C 1 -C 3 -alkyl;
R 4 represents ethyl, methyl or propyl;
R 5 , R 6 , R 9 , R 10 , R 11 and R 12 independently represent H or methyl; and
R 7 and R 8 represent O—[(CH 2 ) 2 O] 3 —C 1-2 -alkyl or O—(CH 2 ) 2-4 OH.
3. A method of claim 2 wherein structural unit “A” is represented by
wherein,
M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III).
4. A method of claim 3 wherein said method further comprises treating the area in proximity to the neoplastic tissue with a therapeutic energy means or with a chemotherapeutic agent, or treating the area in proximity to the neovascularization or atheroma with a therapeutic energy means.
5. The method of claim 4 , wherein the optional therapeutic energy means is chosen from photoirradiation, ionizing radiation, neutron irradiation, and ultrasound.
6. A coordination polymer comprising structural units “A”:
wherein:
M is a trivalent metal cation;
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group —X—Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and
R 5 , R 10 , R 11 , and R 12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl, and
structural unit “B”
7. The coordination polymer of claim 6 , wherein within structural unit “A”
wherein,
M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III);
R 1 represents (CH 2 ) 2-4 —OH;
R 2 and R 3 independently represent C 1 -C 3 -alkyl;
R 4 represents ethyl, methyl or propyl;
R 5 , R 6 ; R 9 , R 10 , R 11 and R 12 independently represent H or methyl; and
R 7 and R 8 represent O—[(CH 2 ) 2 O] 3 —C 1-2 -alkyl or O—(CH 2 ) 2-4 OH.
8. The coordination polymer of claim 7 wherein structural unit “A” is represented by
wherein
M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III).
9. A coordination polymer wherein structural unit “A” is represented by
wherein
M independently at each occurrence represents Gd(III) or Lu(III); and structural unit “B” is represented by
10. A coordination polymer wherein structural unit “A” is represented by
wherein
M represents Gd(III); and
structural unit “B” is represented by
11. A coordination polymer wherein structural unit “A” is represented by
wherein
M represents Lu(III); and
structural unit “B” is represented by
12. A process of making a coordination polymer comprising structural units “A”:
wherein:
M is a trivalent metal cation;
AL is an apical ligand;
n is an integer of 1 to 5;
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group —X—Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and
R 5 , R 10 , R 11 , and R 12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; and
structural unit “B”
said method comprising contacting a compound of Formula A
wherein
M is a trivalent metal cation;
AL is an apical ligand;
n is an integer of 1 to 5;
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group —X—Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and
R 5 , R 10 , R 11 , and R 12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl;
with an oxalate salt or an oxalate precursor, to form a coordination polymer comprising structural units “A” and “B”.
13. A process of claim 12 wherein within structural unit “A”
M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III);
R 1 represents (CH 2 ) 2-4 —OH;
R 2 and R 3 independently represent C 1 -C 3 -alkyl;
R 4 represents ethyl, methyl or propyl;
R 5 , R 6 , R 9 , R 10 , R 11 and R 12 independently represent H or methyl; and
R 7 and R 8 represent O—[(CH 2 ) 2 O] 3 —C 1-2 -alkyl or O—(CH 2 ) 2-4 OH.
14. A process of claim 13 wherein structural unit “A” is represented by
and compound of Formula A are represented by
wherein
M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III).
15. A process of claim 14 wherein, the process is carried out at ambient temperature and neutral pH.
16. A process of claim 15 wherein,
the oxalate or oxalate precursor is selected from ascorbate, dehydroascorbate, glyoxal and glyoxylate; and
the process is carried out in the presence of oxygen.
17. A coordination polymer prepared by contacting a compound of Formula A
wherein:
M is a trivalent metal cation;
AL is an apical ligand;
n is an integer of 1 to 5;
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group —X—Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and
R 5 , R 10 , R 11 , and R 12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with an oxalate salt or an oxalate precursor, optionally in the presence of oxygen.
18. A coordination polymer of claim 17 wherein within structural unit “A”
M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III);
R 1 represents (CH 2 ) 2-4 —OH;
R 2 and R 3 independently represent C 1 -C 3 -alkyl;
R 4 represents ethyl, methyl or propyl;
R 5 , R 6 , R 9 , R 10 , R 11 and R 12 independently represent H or methyl; and
R 7 and R 8 represent O—[(CH 2 ) 2 O] 3 —C 1-2 -alkyl or O—(CH 2 ) 2-4 OH.
19. A coordination polymer of claim 18 wherein the oxalate precursor is selected from ascorbate, dehydroascorbate, glyoxal, glyoxalate, oxamate, dimethyloxalate, and oxamide.
20. A method of claim 15 wherein the compound of Formula A is represented by
wherein
M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); and
n represents an integer from 1 to 3.
21. A method of claim 1 wherein the disease or condition in a mammal resulting from the presence of atheroma is atherosclerotic inflammation.
22. A method of claim 21 wherein the atherosclerotic inflammation is in the form of plaque in an artery.
23. A method of claim 22 wherein the plaque is vulnerable plaque and is essentially present along walls of an artery.
24. A method of claim 23 wherein the vulnerable plaque has lipids and is inflamed.
25. A method of claim 24 wherein the coordination polymer is formed within a mammal by first administering to a mammal a compound of structural unit A followed by an oxalate or oxalate precursor is selected from ascorbate, dehydroascorbate, glyoxal and glyoxylate.