Fluorescent pyrazine derivatives and methods of using the same in assessing renal function
View Patent ↗The present invention relates to pyrazine derivatives represented by Formula I. X 1 and X 2 of Formula I may be characterized as electron withdrawing groups, while Y 1 and Y 2 of Formula I may be characterized as electron donating groups. Pyrazine derivatives of the present invention may be utilized in assessing organ (e.g., kidney) function. In a particular example, an effective amount of a pyrazine derivative that is capable of being renally cleared may be administered into a patient's body. The pyrazine derivative may be capable of one or both absorbing and emanating spectral energy of at least about 400 nm (e.g., visible and/or infrared light). At least some of the derivative that is in the body may be exposed to spectral energy and, in turn, spectral energy may emanate from the derivative. This emanating spectral energy may be detected and utilized to determine renal function of the patient
1. A method of assessing renal function, the method comprising:
administering into a body of a patient an effective amount of a pyrazine derivative that is capable of being renally cleared from the body, wherein the pyrazine derivative is hydrophilic and capable of at least one absorbing and emanating spectral energy of at least about 400 nm;
exposing the pyrazine derivative that is in the body to spectral energy of at least about 400 nm, wherein the exposing causes spectral energy to emanate from the pyrazine derivative;
detecting the spectral energy emanated from the pyrazine derivative in the body; and
assessing renal function of the patient based on the detected spectral energy;
wherein the pyrazine derivative is represented by Formula I, wherein:
X 1 and X 2 are electron withdrawing substituents, each of which is independently selected from the group consisting of —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —SO 2 R 6 , —SO 2 OR 7 and —PO 3 R 8 R 9 ;
Y 1 and Y 2 are electron donating substituents, each of which is independently selected from the group consisting of —OR 10 , —SR 11 , —NR 12 R 13 , —N(R 14 )COR 15 and
Z 1 is selected from the group consisting of a direct bond, —CR 16 R 17 —, —O—, —NR 18 —, —NCOR 19 —, —S—, —SO— and —SO 2 —;
each of R 1 to R 19 is independently selected from the group consisting of hydrogen, C3-C6 polyhydroxylated alkyl, ((CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 , C1-C10 alkyl, C5-C10 aryl, C5-C10 heteroaryl, (CH 2 ) a OH, (CH 2 ) a CO 2 H, (CH 2 ) a SO 3 H, (CH 2 ) a SO 3 − —, (CH 2 ) a OSO 3 H, (CH 2 ) a OSO 3 − —, (CH 2 ) a NHSO 3 H, (CH 2 ) a NHSO 3 − , (CH 2 ) a PO 3 H 2 , (CH 2 ) a PO 3 H, (CH 2 ) a PO 3 = —, (CH 2 ) a OPO 3 H 2 , (CH 2 ) a OPO 3 H − and (CH 2 ) a OPO 3 − ;
R 40 is selected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C5-C10 heteroaryl, (CH 2 ) a OH, (CH 2 ) a CO 2 H, (CH 2 ) a SO 3 H, (CH 2 ) a SO 3 − —, (CH 2 ) a OSO 3 H, (CH 2 ) a OSO 3 − , (CH 2 ) a NHSO 3 H, (CH 2 ) a NHSO 3 − , (CH 2 ) a PO 3 H 2 , (CH 2 ) a PO 3 H − , (CH 2 ) a PO 3 = —, (CH 2 ) a OPO 3 H 2 , (CH 2 ) a OPO 3 H − and (CH 2 ) a OPO 3 ; and
each of a, m and n range from 1 to 6.
2. The method of claim 1 wherein:
each of X 1 and X 2 is independently selected from the group consisting of —CN, —CO 2 R 1 and —CONR 2 R 3 ;
each of Y 1 and Y 2 is independently —NR 12 R 13 or
each of R 1 , R 2 , R 3 , R 12 and R 13 is independently selected from the group consisting of hydrogen, C3-C6 polyhydroxylated alkyl, (CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 , C5-C10 heteroaryl, (CH 2 ) a OH, (CH 2 ) a CO 2 H, (CH 2 ) a CO 2 H, (CH 2 ) a SO 3 H and (CH 2 ) a SO 3 − —;
each of R 16 to R 19 is independently selected from the group consisting of hydrogen, C3-C6 polyhydroxylated alkyl, (CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 , C1-C10 alkyl, C5-C10 aryl, C5-C10 heteroaryl, (CH 2 ) a OH, (CH 2 ) a CO 2 H, (CH 2 ) a SO 3 H and (CH 2 ) a SO 3 − —;
m is 1 or 2; and
n is 1.
3. The method of claim 2 wherein:
each of X 1 and X 2 is —CN;
Z 1 is selected from the group consisting of a direct bond, —O—, —NR 18 —, —NCOR 19 —, —S—, —SO— and —SO 2 —;
each of R 12 and R 13 is independently selected from the group consisting of (CH 2 ) a OH, (CH 2 ) a CO 2 H, (CH 2 ) a SO 3 H, and (CH 2 ) a SO 3 − ; and
each of R 18 and R 19 is independently selected from the group consisting of hydrogen, C1-C10 alkyl, (CH 2 ) a OH, (CH 2 ) a CO 2 H, (CH 2 ) a SO 3 H and (CH 2 ) a SO 3 − —.
4. The method of claim 3 wherein:
each of Y 1 and Y 2 is —NR 12 R 13 ; and
each of R 12 and R 13 is (CH 2 ) a CO 2 H.
5. The method of claim 3 wherein:
each of Y 1 and Y 2 is
6. The method of claim 2 wherein:
each of X 1 and X 2 is —CO 2 R 1 ;
Z 1 is selected from the group consisting of a direct bond, —O—, —NR 18 —, —NCOR 19 —, —S—, —SO— and —SO 2 —;
R 1 is hydrogen;
each of R 12 and R 13 is independently selected from the group consisting of C3-C6 polyhydroxylated alkyl, ((CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 , (CH 2 ) a OH, (CH 2 ) a CO 2 H, (CH 2 ) a SO 3 H and (CH 2 ) a SO 3 − ; and
each of R 18 and R 19 is independently selected from the group consisting of hydrogen, C3-C6 polyhydroxylated alkyl, ((CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 , C1-C10 alkyl, (CH 2 ) a OH, (CH 2 ) a CO 2 H, (CH 2 ) a SO 3 H and (CH 2 ) a SO 3 − —.
7. The method of claim 6 wherein:
each of Y 1 and Y 2 is —NR 12 R 13 ; and
each of R 12 and R 13 is (CH 2 ) a CO 2 H.
8. The method of claim 6 wherein:
each of Y 1 and Y 2 is
9. A method of assessing renal function, the method comprising:
administering into a body of a patient an effective amount of a pyrazine derivative that is capable of being renally cleared from the body, wherein the pyrazine derivative is hydrophilic and capable of at least one absorbing and emanating spectral energy of at least about 400 nm;
exposing the pyrazine derivative that is in the body to spectral energy of at least about 400 nm, wherein the exposing causes spectral energy to emanate from the pyrazine derivative;
detecting the spectral energy emanated from the pyrazine derivative in the body; and
assessing renal function of the patient based on the detected spectral energy;
wherein the pyrazine derivative is selected from the group consisting of the following compounds or a salt thereof:
10. The method of claim 1 , wherein:
at least one of X 1 or X 2 is —CONR 2 R 3 .
11. The method of claim 1 , wherein:
at least one of Y 1 or Y 2 is —NR 12 R 13 .
12. The method of claim 10 , wherein:
at least one of Y 1 or Y 2 is —NR 12 R 13 .
13. The method of claim 10 , wherein:
at least one of R 2 or R 3 is —((CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 —.
14. The method of claim 12 , wherein:
at least one of R 2 or R 3 is —((CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 —.
15. The method of claim 13 , wherein:
a is 6.
16. The method of claim 14 , wherein:
a is 6.
17. The method of claim 13 , wherein:
R 40 is C1-C10 alkyl.
18. The method of claim 14 , wherein:
R 40 is C1-C10 alkyl.
19. The method of claim 15 , wherein:
R 40 is C1-C10 alkyl.
20. The method of claim 16 , wherein:
R 40 is C1-C10 alkyl.
21. The method of claim 10 , wherein:
R 2 is hydrogen, and R 3 is ((CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 .
22. The method of claim 21 , wherein:
at least one of Y 1 or Y 2 is —NR 12 R 13 .
23. The method of claim 22 , wherein:
each of R 12 and R 13 is hydrogen.
24. The method of claim 21 , wherein:
a is 6.
25. The method of claim 22 , wherein:
a is 6.
26. The method of claim 23 , wherein:
a is 6.
27. The method of claim 21 , wherein:
R 40 is C1-C10 alkyl.
28. The method of claim 22 , wherein:
R 40 is C1-C10 alkyl.
29. The method of claim 23 , wherein:
R 40 is C1-C10 alkyl.
30. The method of claim 24 , wherein:
R 40 is C1-C10 alkyl.
31. The method of claim 25 , wherein:
R 40 is C1-C10 alkyl.
32. The method of claim 26 , wherein:
R 40 is C1-C10 alkyl.
33. The method of claim 1 , wherein:
each of X 1 and X 2 is —CONR 2 R 3 .
34. The method of claim 1 , wherein:
each of Y 1 and Y 2 is —NR 12 R 13 .
35. The method of claim 33 , wherein:
each of Y 1 or Y 2 is —NR 12 R 13 .
36. The method of claim 33 , wherein:
at least one of R 2 or R 3 is —((CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 —.
37. The method of claim 35 , wherein:
at least one of R 2 or R 3 is —((CH 2 ) 2 —O—(CH 2 ) 2 —O) a —R 40 —.
38. The method of claim 36 , wherein:
a is 6.
39. The method of claim 37 , wherein:
a is 6.
40. The method of claim 36 , wherein:
R 40 is C1-C10 alkyl.
41. The method of claim 37 , wherein:
R 40 is C1-C10 alkyl.
42. The method of claim 38 , wherein:
R 40 is C1-C10 alkyl.
43. The method of claim 39 , wherein:
R 40 is C1-C10 alkyl.
44. The method of claim 33 , wherein:
R 2 is hydrogen, and R 3 is ((CH 2 ) 2 —O—(CH 2 ) 2 O) a —R 40 .
45. The method of claim 44 , wherein:
each of Y 1 and Y 2 is —NR 12 R 13 —.
46. The method of claim 45 , wherein:
each of R 12 and R 13 is hydrogen.
47. The method of claim 44 , wherein:
a is 6.
48. The method of claim 45 , wherein:
a is 6.
49. The method of claim 46 , wherein:
a is 6.
50. The method of claim 44 , wherein:
R 40 is C1-C10 alkyl.
51. The method of claim 45 , wherein:
R 40 is C1-C10 alkyl.
52. The method of claim 46 , wherein:
R 40 is C1-C10 alkyl.
53. The method of claim 47 , wherein:
R 40 is C1-C10 alkyl.
54. The method of claim 48 , wherein:
R 40 is C1-C10 alkyl.
55. The method of claim 49 , wherein:
R 40 is C1-C10 alkyl.