Fluorescent pyrazine derivatives and methods of using the same in assessing renal function
View Patent ↗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.
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 , —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 9 , R 11 , 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 ;
each of R 12 to R 15 is independently selected from the group consisting of hydrogen, 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, —(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 independently —NR 12 R 13 or
and
Z 1 is a direct bond, then:
each of R 1 , R 2 , R 3 , R 12 and R 13 is independently not hydrogen, C1-C10 alkyl or C1-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 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 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 − ;
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;
each of Y 1 and Y 2 is independently selected from the group consisting of —NR 12 R 13 and
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 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 − ;
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 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 compound of claim 3 wherein:
each of Y 1 and Y 2 is
6. The compound of claim 2 wherein:
each of X 1 and X 2 is —CO 2 R 1 ;
each of Y 1 and Y 2 is independently selected from the group consisting of —NR 12 R 13 and
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 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 compound 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 compound of claim 6 wherein:
each of Y 1 and Y 2 is