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 compound being of the formula (FX1):
wherein:
R 1 and R 3 are each independently —(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.
2. The compound of claim 1 , being of the formula (FX2), (FX3), (FX5), or (FX6):
3. The compound 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.
4. The compound of claim 1 , wherein the compound is of the formula (FX7), (FX8), (FX9), (FX10), (FX11), (FX12), (FX14), (FX15), or (FX16):
5. The compound of claim 1 , being of formula (FX18):
wherein d and h are independently integers selected from the range of 1 to 120.
6. The compound of claim 5 , 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 .
7. The compound of claim 1 , being of formula (FX19):
wherein d and h are independently integers selected from the range of 1 to 120.
8. The compound of claim 7 , wherein each d and h are independently integers selected from the range of 2 to 50 or the range of 2 to 24.
9. The compound of claim 7 , 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.
10. The compound of claim 1 , being of formula (FX20) or (FX21):
wherein d and h are independently integers selected from the range of 1 to 120.
11. The compound of claim 10 , wherein each a is independently 0, 2 or 3, each b is independently 2 to 50, and R 5 is C 1 -C 3 alkyl.
12. A method of using a compound of claim 1 in an optical imaging, diagnostic, visualization, monitoring, surgical, biomedical or therapeutic procedure, wherein the procedure comprises:
administering a diagnostically effective amount of the compound to a subject, wherein the compound is differentially separated from a bodily fluid of the subject by an organ, tissue or system in the subject; and
detecting the administered compound.
13. A method of using a compound of claim 1 in an optical imaging, diagnostic, visualization, monitoring, surgical, biomedical or therapeutic procedure, wherein the procedure comprises:
administering an effective amount of a renally excretable compound of claim 1 to a subject;
exposing a tissue of the subject's renal system having the administered compound to electromagnetic radiation, thereby generating emitted electromagnetic radiation from the compound;
detecting the emitted electromagnetic radiation from the compound, thereby visualizing or imaging at least a portion of the renal system of the subject.
14. The method of claim 13 , wherein the procedure comprises determining if the administered compound is substantially retained in tissue of the subject's renal system.
15. The method of claim 12 , wherein the compound has plasma binding of less than 10%.
16. The method of claim 13 the biomedical procedure assesses physiological function of an organ, tissue or system.
17. The method of claim 13 , wherein the at least a portion of the renal system comprises a ureter, bladder or urethra of the subject.
18. A pharmaceutical composition comprising:
the compound of claim 1 ; and
a pharmaceutically acceptable excipient.
19. A pharmaceutical composition comprising:
the compound of claim 1 ; and
one or more additional therapeutic agents or diagnostic agents.
20. The method of claim 13 , wherein the compound has plasma binding of less than 10%.