Near-infrared nerve-sparing fluorophores
The compounds provided herein are phenoxazines that can be used as far red to near-infrared nerve-sparing fluorescent compounds in medical procedures.
1. A compound of
(a) Formula I(a)
wherein R 4 and R 7 are independently selected from CH 3 and halogen; and each of R 3a , R 3b , R 8a , and R 8b are independently selected from hydrogen and C 1 -C 4 alkyl;
(b) Formula I(b)
wherein
R 3a and R 3b in each instance are independently selected from hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 3a and R 3b is not hydrogen; or R 3a and R 3b together with the nitrogen atom to which they are bound form a 5- or 6-membered nitrogen-containing ring; and
R 8a and R 8b in each instance are independently selected from hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 8a and R 8b is not hydrogen; or R 8a and R 8b together with the nitrogen to which they are bound form a 5- or 6-membered nitrogen-containing ring optionally substituted by 1, 2, 3, or 4 C 1 -C 4 alkyl substituents;
(c) Formula I(c)
wherein
R 3a and R 3b in each instance are independently selected from hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 3a and R 3b is not hydrogen; or R 3a and R 3b together with the nitrogen atom to which they are bound form a 5- or 6-membered nitrogen-containing ring; and
R 8a and R 8b in each instance are independently selected from hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 8a and R 8b is not hydrogen; or R 8a and R 8b together with the nitrogen to which they are bound form a 5- or 6-membered nitrogen-containing ring optionally substituted by 1, 2, 3, or 4 C 1 -C 4 alkyl substituents;
(d) Formula I(d)
wherein
R 3a and R 3b in each instance are independently selected from hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 3a and R 3b is not hydrogen; or R 3a and R 3b together with the nitrogen atom to which they are bound form a 5- or 6-membered nitrogen-containing ring; and
R 8a and R 8b in each instance are independently selected from hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 8a and R 8b is not hydrogen; or R 8a and R 8b together with the nitrogen to which they are bound form a 5- or 6-membered nitrogen-containing ring optionally substituted by 1, 2, 3, or 4 C 1 -C 4 alkyl substituents;
(e) Formula I(e)
wherein
R 3a and R 3b are independently selected from the group of hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 3a and R 3b is not hydrogen; or R 3a and R 3b together with the nitrogen atom to which they are bound form a 5- or 6-membered nitrogen-containing ring;
R 7 is selected from the group of hydrogen, halogen, oxygen, or C 1 -C 4 alkyl; and
R 8a and R 8b are independently selected from the group of hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 8a and R 8b is not hydrogen; or R 8a and R 8b together with the nitrogen to which they are bound form a 5- or 6-membered nitrogen-containing ring optionally substituted by 1, 2, 3, or 4 C 1 -C 4 alkyl substituents;
or R 8b is selected from the group of hydrogen and C 1 -C 4 alkyl, and R 8a together with the nitrogen to which it is bound and R 7 forms a fused 6-membered ring having one nitrogen heteroatom and one oxygen heteroatom, wherein each nitrogen heteroatom is optionally substituted by 1, 2, 3, or 4 C 1 -C 4 alkyl substituents;
with the proviso that the compounds of Formula I do not include N3,N3,N7,N7-tetraethyl-10H-phenoxazine-3,7-diamine; N3,N7-diethyl-10H-phenoxazine-3,7-diamine; N3,N3,N7,N7-tetramethyl-10H-phenoxazine-3,7-diamine; and N7,N7-diethyl-N3,N3,2-trimethyl-10H-phenoxazine-3,7-diamine; or
(f) Formula I(f)
wherein
R 3a and R 3b are independently selected from the group of hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 8a and R 3b is not hydrogen; or R 8a and R 3b together with the nitrogen to which they are bound form a 5- or 6-membered nitrogen-containing ring optionally substituted by 1, 2, 3, or 4 C 1 -C 4 alkyl substituents;
or R 3b is selected from the group of hydrogen and C 1 -C 4 alkyl, and R 3a together with the nitrogen to which it is bound and R 4 forms a fused 6-membered ring having one nitrogen heteroatom and one oxygen heteroatom, wherein each nitrogen heteroatom is optionally substituted by 1, 2, 3, or 4 C 1 -C 4 alkyl substituents;
R 4 is selected from the group of hydrogen, halogen, oxygen, or C 1 -C 4 alkyl; and
R 8a and R 8b are independently selected from the group of hydrogen and C 1 -C 4 alkyl, with the proviso that at least one of R 3a and R 3b is not hydrogen; or R 3a and R 3b together with the nitrogen atom to which they are bound form a 5- or 6-membered nitrogen-containing ring;
with the proviso that the compounds of Formula I do not include N3,N3,N7,N7-tetraethyl-10H-phenoxazine-3,7-diamine; N3,N7-diethyl-10H-phenoxazine-3,7-diamine; N3,N3,N7,N7-tetramethyl-10H-phenoxazine-3,7-diamine; and N7,N7-diethyl-N3,N3,2-trimethyl-10H-phenoxazine-3,7-diamine.
2. A compound selected from the group consisting of:
3. A compound selected from the group consisting of:
4. A compound selected from the group consisting of:
5. A compound selected from the group consisting of:
6. 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.
7. A method of imaging one or more nerves in a target area in a subject, the method comprising contacting the target area in the subject with a compound of claim 2 and detecting the compound in the target area using fluorescence or near-infrared imaging.
8. The method of claim 7 , wherein the target area in the subject is contacted with the compound by direct administration.
9. The method of claim 7 , wherein the target area in the subject is contacted with the compound by systemic administration.
10. A method of imaging one or more nerves in a target area in a subject, the method comprising contacting the target area in the subject with a compound of claim 3 and detecting the compound in the target area using fluorescence or near-infrared imaging.
11. A method of imaging one or more nerves in a target area in a subject, the method comprising contacting the target area in the subject with a compound of claim 4 and detecting the compound in the target area using fluorescence or near-infrared imaging.
12. A method of imaging one or more nerves in a target area in a subject, the method comprising contacting the target area in the subject with a compound of claim 5 and detecting the compound in the target area using fluorescence or near-infrared imaging.
13. A compound of Formula II:
wherein:
R 1 , R 2 , R 4 , R 5 , and R 6 are each independently selected from the group of hydrogen or C 1 -C 4 alkyl;
X is selected from the group of —C(H)—, —CH 2 —, —CH(C 1 -C 4 alkyl)-, —C(C 1 -C 4 alkyl)-, —N(H)—, —N(C 1 -C 4 alkyl)-, and —O—;
Y is selected from the group of —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH—, —CH(C 1 -C 4 alkyl)-CH 2 —, —C(C 1 -C 4 alkyl) 2 -CH 2 —, —CH(C 1 -C 4 alkyl)-CH—, and —C(C 1 -C 4 alkyl) 2 -CH—;
the dashed line ( ) represents an optional double bond that exists when X is selected from —C(H)— or —C(C 1 -C 4 alkyl)- and Y is selected from —CH 2 —CH—, —CH(C 1 -C 4 alkyl)-CH—, and —C(C 1 -C 4 alkyl) 2 -CH—;
R 3a and R 3b are each independently selected from the group of hydrogen or C 1 -C 4 alkyl, with the proviso that at least one of R 3a and R 3b is not hydrogen, or R 3a and R 3b together with the nitrogen atom to which they are bound form a 5- or 6-membered nitrogen containing ring; and
R 8b is selected from the group of hydrogen and C 1 -C 4 alkyl.
14. A method of imaging one or more nerves in a target area in a subject, the method comprising contacting the target area in the subject with a compound of claim 13 and detecting the compound in the target area using fluorescence or near-infrared imaging.
15. A compound of Formula IV:
wherein:
R 2 , R 4 , R 5 , and R 6 are each independently selected from hydrogen and C 1 -C 4 alkyl; and
R 3a and R 3b are each independently hydrogen or C 1 -C 4 alkyl, with the proviso that at least one of R 3a and R 3b is not hydrogen, or R 3a and R 3b together with the nitrogen atom to which they are bound form a 5- or 6-membered nitrogen containing ring.
16. A method of imaging one or more nerves in a target area in a subject, the method comprising contacting the target area in the subject with a compound of claim 15 and detecting the compound in the target area using fluorescence or near-infrared imaging.