CA-IX specific radiopharmaceuticals for the treatment and imaging of cancer
View Patent ↗A compound that recognizes and binds to the CA-IX protein has Formula I, II, III, or IV. The compounds may include a radioactive element for radioimaging or therapeutic applications. Thus, pharmaceutical compositions may be prepared with one or more of the compounds of Formula I, II, III, or IV.
1. A compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein
W is a bond, a (C 1 -C 8 )alkyl, a (C 2 -C 8 )alkenyl, an aryl, a heteroaryl, a —NHC(O),
—C(O)NH, —NH—C(O)—NH—, or —NH—C(S)—NH—;
V is a bond, a (C 1 -C 8 )alkyl, a (C 2 -C 8 )alkenyl, an aryl, a heteroaryl, —NH—C(O)—NH—, or —NH—C(S)—NH—;
NR a R b is a chelator group of Formula:
R t is H, a C 1 -C 8 alkyl group, an ammonium ion, or an alkali or alkaline earth metal ion;
R x and R y is independently hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl;
R v is alkyl;
m is an integer from 0 to 15; and
n is an integer from 0 to 15.
2. The compound of claim 1 , wherein NR a R b is a chelator group of Formula:
3. The compound of claim 1 , wherein R v is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl.
4. The compound of claim 1 , wherein each R t is independently H or tert-butyl.
5. The compound of claim 1 , wherein m is 0 or 1, and n is an integer from 0 to 8.
6. The compound of claim 1 having the structure:
7. The compound of claim 1 , wherein NR a R b is
8. The compound of claim 1 , wherein NR a R b is
9. A complex comprising the compound of claim 1 and a metal selected from the group consisting of Re, Tc, Y, Lu, Ga, and In.
10. The complex of claim 9 , wherein the metal is a radionuclide.
11. The complex of claim 10 , wherein the metal is technetium-99m, rhenium-186m, or rhenium-188m.
12. The complex of claim 9 , wherein NR a R b is
the metal is selected from the group consisting of Y, Ga, Lu, and In.
13. The complex of claim 9 , wherein NR a R b is
14. The complex of claim 9 , which is selected from the group consisting of:
pharmaceutically acceptable salts thereof; and
M is a metal.
15. The complex of claim 14 , wherein M is technetium-99m, rhenium-186m, or rhenium-188m.
16. A compound of Formula II or a pharmaceutically acceptable salt, thereof:
wherein
L is an NR a R b chelator group of formula:
W and X are independently O or S;
p is an integer from 0 to 5;
q is an integer from 0 to 8;
R t is H, a C i -C 8 alkyl group, an ammonium ion, or an alkali or alkaline earth metal ion;
R x and R y is independently hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; and
R y is an alkyl.
17. A complex comprising the compound of claim 16 , where L is the NR a R b chelator group, and a metal.
18. A compound of Formula IV or a pharmaceutically acceptable salt thereof:
wherein
NR a R b is a chelator group of Formula:
Y is O or S;
A is (C 1 -C 8 )alkyl, —(CH 2 ) x —(OCH 2 CH 2 ) y — or —(OCH 2 CH 2 ) y (CH 2 ) x —;
x is an integer from 0 to 3;
y is an integer from 0 to 3;
r is an integer from 0 to 5;
s is an integer from 0 to 10;
R t is H, a C 1 -C 8 alkyl group, an ammonium ion, or an alkali or alkaline earth metal ion;
R x and R y is independently hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; and R v is an alkyl.
19. The compound of claim 18 , wherein r is 0, 1 or 2.
20. The compound of claim 18 , wherein s is 0, 5, or 10.
21. The compound of claim 18 , wherein NR a R b is
22. The compound of claim 18 , wherein NR a R b is
23. A complex comprising the compound of claim 18 and a metal selected from the group consisting of Re, Tc, Y, Lu, Ga, and In.
24. The complex of claim 23 , wherein the metal is a radionuclide.
25. The complex of claim 24 , wherein the metal is technetium-99m, rhenium-186m, or rhenium-188m.
26. The complex of claim 23 , wherein NR a R b is
the metal is Y, Ga, Lu, or In.
27. The complex of claim 23 , wherein NR a R b is
28. The compound of claim 18 , wherein R v is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl.
29. The compound of claim 18 , wherein each R t is independently H or tert-butyl.
30. A pharmaceutical formulation, comprising the compound according to any one of claims 1 , 18 , 19 , 20 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
31. A method of imaging a region in a patient, comprising the steps of: administering to a patient a diagnostically effective amount of a compound of any one of claims 1 , 18 , 19 , 20 , or a pharmaceutically acceptable salt thereof, and obtaining an image of the region of the patient.
32. A pharmaceutical formulation, comprising the complex according to any one of claim 9 , 17 , or 23 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
33. A method of imaging a region in a patient, comprising the steps of: administering to a patient a diagnostically effective amount of a complex of any one of claim 9 , 17 , or 23 , or a pharmaceutically acceptable salt thereof, and obtaining an image of the region of the patient.