Fluorescent pyrazine derivatives and methods of using the same in assessing renal function
The present invention relates to pyrazine derivatives such as those represented by Formulas I and II. X 1 to X 4 of Formulas I and II may be characterized as electron withdrawing groups, while Y 1 to Y 4 of Formulas I and II 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 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 compound of Formula I wherein:
each of X 1 and X 2 is independently selected from the group consisting of —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —SOR 5 , —SO 2 R 6 , —SO 2 OR 7 and —PO 3 R 8 R 9 ;
each of Y 1 and Y 2 is independently selected from the group consisting of —OR 10 , −SR 11 , 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 9 , and 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, —(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 10 is selected from the group consisting of 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;
with the proviso that if:
each of X 1 and X 2 is independently —CN, —CO 2 R 1 or —CONR 2 R 3 ;
each of Y 1 and Y 2 is
and
Z 1 is a direct bond, then:
each of R 1 , R 2 , and R 3 , are independently not hydrogen, C1-C10 alkyl or C5-C10 aryl; and
the sum of m and n is not 4 or 5.
2. The compound 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
each of R 1 , R 2 , and R 3 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 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 compound 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 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 − ;
m is 1 or 2; and
n is 1.
4. The compound 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; 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 − .