Modified pyrazine derivatives and uses thereof
View Patent ↗Provided herein are compounds, preparations and formulations comprising pyrazine derivatives having multiple poly(ethylene glycol) containing substituents. Many of the compounds disclosed herein are excretable by the renal system of a subject or patient and are useful for visualizing the renal system of a subject or patient. Upon excitation by electromagnetic radiation, a number of the compounds disclosed herein exhibit luminescence and are externally detectable when present in the body fluid of a patient or subject. Also provided herein are methods for visualizing the renal system of a subject or patient.
1. A method for use in an optical imaging, medical imaging, diagnostic, visualization, monitoring, surgical, biomedical or therapeutic procedure, wherein the method comprises:
(i) administering an effective amount of a renally excretable compound of the formula (FX1):
wherein:
R 1 and R 3 are each independently —H, —(CH 2 ) a (CH 2 CH 2 O) b R 5 , —(CH 2 CH 2 O) b R 5 , or —(CH 2 ) a Y 1 ;
each Y 1 is independently —OR 6 , —(CHOH) c R 7 , —NR 8 R 9 , —NHCO(CHOH) c R 7 or —NHCO(CH 2 ) a (CH 2 CH 2 O) b R 5 ;
each of R 2 , R 4 , R 5 , R 6 and R 7 are independently —H or C 1 -C 6 alkyl;
R 8 and R 9 are independently —H, C 1 -C 3 alkyl, —(CH 2 ) a (CHOH) c R 7 , or —(CH 2 ) a (CH 2 CH 2 O) b R 5 ;
each a and c is independently an integer selected from the range of 0 to 6;
each b is independently an integer selected from the range of 1 to 120;
each p and q is independently an integer selected from the range of 0 to 120;
each of m and n is independently an integer selected from the range of 3 to 6;
(ii) exposing a tissue of the subject's renal system having the administered compound to electromagnetic radiation, thereby generating emitted electromagnetic radiation from the compound; and
(iii) detecting the emitted electromagnetic radiation from the compound, thereby visualizing or imaging at least a portion of the renal system of the subject.
2. The method of claim 1 , wherein the procedure comprises determining if the administered compound is substantially retained in tissue of the subject's renal system.
3. The method of claim 1 , wherein the compound has plasma binding of less than 10%.
4. The method of claim 1 , wherein the biomedical procedure assesses physiological function of an organ, tissue or system.
5. The method of claim 1 , wherein the at least a portion of the renal system comprises a ureter, bladder or urethra of the subject.
6. The method of claim 1 , wherein the compound is of the formula (FX2), (FX3), (FX4), (FX5), or (FX6):
7. The method of claim 1 , wherein:
each R 5 is independently C 1 -C 3 alkyl;
each b is independently an integer from 2 to 50; and
m and n are each independently 3 or 4.
8. The method of claim 1 , wherein the compound is of the formula (FX7), (FX8), (FX9), (FX10), (FX11), (FX12), (FX13), (FX14), (FX15), or (FX16) or (FX17):
9. The method of claim 1 , wherein the compound is of the formula (FX18):
wherein d and h are independently integers selected from the range of 1 to 120.
10. The method of claim 1 , wherein each d and h are independently integers selected from the range of 2 to 50, wherein each a is 2, and wherein R 8 and R 9 are each —(CH 2 ) a (CHOH) c R 7 .
11. The method of claim 1 , wherein the compound is of the formula (FX19):
wherein d and h are independently integers selected from the range of 1 to 120.
12. The method of claim 1 , wherein each d and h are independently integers selected from the range of 2 to 50 or the range of 2 to 24.
13. The method of claim 1 , wherein Y 1 is —NR 8 R 9 and wherein R 8 and R 9 are each —(CH 2 ) a (CHOH) c R 7 and wherein a is 1 or 2 and c is 2, 3, 4, 5 or 6.
14. The method of claim 1 , wherein the compound is of the formula (FX20) or (FX21):
wherein d and h are independently integers selected from the range of 1 to 120.