Near-infrared nerve-sparing benzo[c]phenoxazine fluorophores
Provided are near-infrared nerve-sparing fluorescent compounds, compositions comprising them, and methods of their use in medical procedures.
1. A compound of Formula I:
wherein R 1 is selected from hydrogen and C 1 -C 3 alkyl;
R 2 is selected from hydrogen and C 1 -C 3 alkyl;
R 3 is selected from the group of hydrogen, halogen, and C 1 -C 3 alkyl;
or, when R 3 is bound to the 9-position carbon of the 10H-benzo[c]phenoxazine core, R 2 and R 3 , together with the carbon atoms to which they are bonded, form a five-membered or six-membered fused ring, the five-membered or six-membered fused ring optionally containing a ring oxygen heteroatom, and the five-membered or six-membered fused ring being substituted by 0, 1, 2, or 3 C 1 -C 3 alkyl substituents; and
R 4 and R 5 are each independently selected from hydrogen and C 1 -C 3 alkyl.
2. The compound of claim 1 , wherein R 1 is hydrogen; R 2 is C 1 -C 3 alkyl; R 3 is selected from the group of hydrogen, halogen, and C 1 -C 3 alkyl; and R 4 and R 5 are each independently selected from hydrogen and C 1 -C 3 alkyl.
3. The compound of claim 1 , wherein R 1 is hydrogen; R 2 is C 1 -C 3 alkyl; R 3 is selected from the group of hydrogen, F, Cl, and C 1 -C 3 alkyl; and R 4 and R 5 are each independently selected from hydrogen and C 1 -C 3 alkyl.
4. The compound of claim 1 , wherein R 1 is hydrogen; R 2 is C 1 -C 3 alkyl; R 3 is selected from the group of hydrogen, F, Cl, and C 1 -C 3 alkyl; and R 4 and R 5 are each independently C 1 -C 3 alkyl.
5. The compound of claim 1 , wherein R 1 is hydrogen; R 2 is C 1 -C 2 alkyl; R 3 is selected from the group of hydrogen, F, Cl, and C 1 -C 2 alkyl; and R 4 and R 5 are each independently C 1 -C 2 alkyl.
6. The compound of claim 1 , wherein R 1 is selected from hydrogen and C 1 -C 3 alkyl;
R 2 and R 3 , together with the carbon atoms to which they are bonded, form a five-membered or six-membered fused ring, the five-membered or six-membered fused ring optionally containing a ring oxygen heteroatom, and the five-membered or six-membered fused ring being substituted by 0, 1, 2, or 3 C 1 -C 3 alkyl substituents; and
R 4 and R 5 are each independently selected from hydrogen and C 1 -C 3 alkyl.
7. The compound of claim 1 , wherein R 1 is selected from hydrogen and C 1 -C 3 alkyl;
R 2 and R 3 , together with the carbon atoms to which they are bonded, form a five-membered or six-membered fused ring, the five-membered or six-membered fused ring optionally containing a ring oxygen heteroatom, and the five-membered or six-membered fused ring being substituted by 0, 1, 2, or 3 C 1 -C 2 alkyl substituents; and
R 4 and R 5 are each independently selected from hydrogen and C 1 -C 2 alkyl.
8. The compound of claim 1 comprising Formula II:
wherein R 1 is selected from hydrogen and C 1 -C 3 alkyl;
R 2 is selected from hydrogen and C 1 -C 3 alkyl;
R 3 is selected from the group of hydrogen, halogen, and C 1 -C 3 alkyl;
or, when R 3 is bound to the 9-position carbon of the 10H-benzo[c]phenoxazine core, R 2 and R 3 , together with the carbon atoms to which they are bonded, form a five-membered or six-membered fused ring, the five-membered or six-membered fused ring optionally containing a ring oxygen heteroatom, and the five-membered or six-membered fused ring being substituted by 0, 1, 2, or 3 C 1 -C 3 alkyl substituents.
9. The compound of claim 8 , of Formula II, wherein R 1 is hydrogen; R 2 is C 1 -C 3 alkyl; and R 3 is selected from the group of hydrogen, halogen, and C 1 -C 3 alkyl.
10. The compound of claim 8 , of Formula II, wherein R 1 is hydrogen; R 2 is C 1 -C 3 alkyl; and R 3 is selected from the group of hydrogen, F, Cl, and C 1 -C 3 alkyl.
11. The compound of claim 8 , of Formula II, wherein R 1 is hydrogen; R 2 is C 1 -C 2 alkyl; and R 3 is selected from the group of hydrogen, F, Cl, and C 1 -C 2 alkyl.
12. The compound of claim 8 , of Formula II, wherein R 1 is selected from hydrogen and C 1 -C 3 alkyl; and
R 2 and R 3 , together with the carbon atoms to which they are bonded, form a five-membered or six-membered fused ring, the five-membered or six-membered fused ring optionally containing a ring oxygen heteroatom, and the five-membered or six-membered fused ring being substituted by 0, 1, 2, or 3 C 1 -C 3 alkyl substituents.
13. The compound of claim 8 , of Formula II, wherein R 1 is selected from hydrogen and C 1 -C 2 alkyl; and
R 2 and R 3 , together with the carbon atoms to which they are bonded, form a five-membered or six-membered fused ring, the five-membered or six-membered fused ring optionally containing a ring oxygen heteroatom, and the five-membered or six-membered fused ring being substituted by 0, 1, 2, or 3 C 1 -C 2 alkyl substituents.
14. The compound of claim 1 , comprising Formula III:
wherein R 1 is selected from hydrogen and C 1 -C 3 alkyl;
R 4 and R 5 are each independently selected from hydrogen and C 1 -C 3 alkyl;
R 6 , R 7 , and R 8 are each independently hydrogen or C 1 -C 3 alkyl;
X is selected from oxygen and carbon, with carbon atom being optionally substituted by C 1 -C 3 alkyl.
15. The compound of claim 14 , of Formula III, wherein R 1 is selected from hydrogen and C 1 -C 2 alkyl;
R 4 and R 5 are each independently selected from hydrogen and C 1 -C 2 alkyl;
R 6 , R 7 , and R 8 are each independently hydrogen or C 1 -C 2 alkyl; and
X is selected from oxygen and carbon, with carbon atom being optionally substituted by C 1 -C 2 alkyl.
16. The compound of claim 14 , of Formula III, wherein R 1 is selected from hydrogen and —CH 3 ;
R 4 and R 5 are each independently selected from hydrogen and C 1 -C 2 alkyl;
R 6 , R 7 , and R 8 are each independently hydrogen or —CH 3 ; and
X is selected from oxygen and carbon, with carbon atom being optionally substituted by —CH 3 .
17. The compound of claim 1 , having the formula:
wherein R 3 is methyl and R 2 is ethyl;
or, when R 3 is bound to the 9-position carbon of the 10H-benzo[c]phenoxazine core, R 2 and R 3 , together with the carbon atoms to which they are bonded, form a five-membered or six-membered fused ring, the five-membered or six-membered fused ring optionally containing a ring oxygen heteroatom, and the five-membered or six-membered fused ring being substituted by 0, 1, 2, or 3 C 1 -C 3 alkyl substituents.
18. The compound of claim 1 , selected from the group of:
19. A composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
20. A method of imaging a target area in a subject, the method comprising contacting the target area in the subject with a compound of claim 1 and detecting the compound in the target area using fluorescence or near-infrared imaging.