Pyrazine derivatives and uses thereof in renal monitoring

Abstract

The present invention relates to pyrazine derivatives such as those represented by Formulas I and II below. X 1 to X 4 of the compounds of Formulas I and II may be characterized as electron withdrawing groups. In contrast, Y 1 to Y 4 of the compounds of Formulas I and II may be characterized as electron donating groups. Pyrazine derivatives of the present invention may be utilized in assessing renal function. In particular, an effective amount of a pyrazine derivative of the invention may be administered into a body of a patient. The pyrazine derivative that is in the body may be exposed to visible and/or infrared light to cause spectral energy to emanate from the pyrazine derivative. This emanating spectral energy may be detected and utilized to determine renal function of the patient.

What is claimed is: 
     
       1. A method of using a compound, the method comprising:
 administering the compound into a body of a patient; 
 exposing the compound that is in the body of the patient to visible or infrared red light, thereby causing spectral energy to emanate from the compound; 
 detecting the spectral energy emanated from the compound in the body; and 
 assessing renal function of the patient based on the detected spectral energy, the compound being of Formula I, wherein: 
 
       
         
           
           
               
               
           
         
         each of X 1  and X 2  is independently —CN, —CO 2 R 1 , —CONR 2 R 3 , CO(AA) or —CONH(PS); 
         each of Y 1  and Y 2  is independently —NR 4 R 5  or 
       
       
         
           
           
               
               
           
         
         Z 1  is a single bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, or —SO 2 —; 
         each of R 1  to R 5  and R 18  to R 21  is independently —H, —CH 2 (CHOH) a R 44 , —CH 2 (CHOH) a CO 2 H, —(CHCO 2 H) a CO 2 H, —(CH 2 CH 2 O) c R 49 , —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 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 − , or —(CH 2 ) a PO 3   = ; 
         each of R 44  and R 49  is independently —H or —CH 3 ; 
         AA comprises a single natural or unnatural amino acid or a polypeptide comprising two or more natural and/or unnatural amino acids linked together by peptide bonds and each instance of AA may be the same or different than each other instance; 
         (PS) is a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units connected by glycosidic linkages; and 
         ‘a’ is an integer from 1 to 10, ‘c’ is an integer from 1 to 100, and each of ‘m’ and ‘n’ independently is an integer from 1 to 3. 
       
     
     
       2. The method of  claim 1 , wherein said spectral energy is fluorescence from said compound comprising visible or infrared light. 
     
     
       3. The method of  claim 1 , wherein said step of assessing renal function of the patient based on the detected spectral energy comprises using data indicative of the detected spectral energy and generating an intensity/time profile indicative of clearance of the compound from the body of the patient. 
     
     
       4. The method of  claim 1 , wherein said step of assessing renal function of the patient based on the detected spectral energy comprises:
 comparing differences in which normal and impaired cells of the patient remove the compound from the bloodstream; 
 measuring a rate or an accumulation of the compound in an organ or a tissue of the patient; or 
 obtaining a tomographic image of an organ or a tissue of the patient having the compound associated therewith. 
 
     
     
       5. The method of  claim 1 , wherein each of X 1  and X 2  are —CONR 2 R 3 , and each of Y 1  and Y 2  is —NR 4 R 5 . 
     
     
       6. The method of  claim 5 , wherein each of R 2  and R 4  is —H, and R 3  is —CH 2 (CHOH) a R 44  or —(CH 2 CH 2 O) c R 49 , and R 5  is —H or —(CH 2 CH 2 O) c R 49 . 
     
     
       7. The method of  claim 6 , wherein R 3  is —(CH 2 CH 2 O) c R 49 , and R 5  is —H. 
     
     
       8. The method of  claim 7 , wherein R 49  is —CH 3 , and ‘c’ is an integer from 1 to 20. 
     
     
       9. The method of  claim 1 , wherein each of X 1  and X 2  is —CO 2 R 1 , and each of Y 1  and Y 2  is —NR 4 R 5 . 
     
     
       10. The method of  claim 9 , wherein each of R 1  and R 4  is —H, and R 5  is —CH 2 (CHOH) a R 44  or —(CH 2 CH 2 O) c R 49 . 
     
     
       11. The method of  claim 10 , wherein R 44  is —H, R 49  is —CH 3 , ‘a’ is an integer from 1 to 6, and ‘c’ is an integer from 1 to 20. 
     
     
       12. The method of  claim 1 , wherein each of X 1  and X 2  is —CN, and each of Y 1  and Y 2  is —NR 4 R 5 . 
     
     
       13. The method of  claim 12 , wherein R 4  is —H, and R 5  is —CH 2 (CHOH) a R 44  or —(CH 2 CH 2 O) c R 49 . 
     
     
       14. The method of  claim 13 , wherein R 44  is —H, R 49  is —CH 3 , ‘a’ is an integer from 1 to 6, and ‘c’ is an integer from 1 to 20. 
     
     
       15. The method of  claim 1 , each of X 1  and X 2  is —CONH(PS), and each of Y 1  and Y 2  is —NR 4 R 5 . 
     
     
       16. The method of  claim 15 , wherein each of R 4  and R 5  is independently —H or —CH 2 (CHOH) a R 44 . 
     
     
       17. The method of  claim 16 , wherein each of R 4 , and R 5  is —H. 
     
     
       18. The method of  claim 15 , wherein the one or more monosaccharide units of the polysaccharide chain (PS) are selected from the group consisting of glucose, fructose, mannose, xylose, and ribose. 
     
     
       19. The method of claim 1, wherein at least one of X 1  and X 2  is —CONH(PS) or —CO(AA). 
     
     
       20. The method of claim 1, wherein both X 1  and X 2  are —CO(AA). 
     
     
       21. The method of claim 20, wherein each instance of AA is one or more of D-α-amino acids. 
     
     
       22. The method of claim 21, wherein each instance of AA is a single D-α-amino acid. 
     
     
       23. The method of claim 21, wherein AA is selected from the group consisting of D-aspartic acid, D-asparagine, D-arginine, D-histidine, D-lysine, D-glutamic acid, D-glutamine, D-serine, and D-homoserine. 
     
     
       24. The method of claim 21, wherein AA is selected from the group consisting of D-serine and D-aspartic acid. 
     
     
       25. The method of claim 21, wherein AA is D-serine. 
     
     
       26. The method of claim 20, wherein each instance of AA is one or more of L-α-amino acids. 
     
     
       27. The method of claim 26, wherein each instance of AA is a single L-α-amino acid. 
     
     
       28. The method of claim 26, wherein AA is selected from the group consisting of L-aspartic acid, L-asparagine, L-arginine, L-histidine, L-lysine, L-glutamic acid, L-glutamine, L-serine, and L-homoserine. 
     
     
       29. The method of claim 26, wherein AA is selected from the group consisting of L-serine and L-aspartic acid. 
     
     
       30. The method of claim 26, wherein AA is L-serine. 
     
     
       31. The method of claim 27, wherein AA is L-serine, Y 1  and Y 2  are each —NR 4 R 5  with R 4 ═R 5 ═H. 
     
     
       32. The method of claim 31, wherein the compound of Formula I is combined with at least one pharmaceutically acceptable excipients before administering the compound of Formula I to a patient. 
     
     
       33. The method of claim 32, wherein one of the pharmaceutically acceptable excipients is phosphate buffered saline. 
     
     
       34. A method of using a compound, the method comprising:
 administering the compound into a body of a patient;   exposing the compound that is in the body of the patient to visible or infrared light, thereby causing spectral energy to emanate from the compound;   detecting the spectral energy emanated from the compound in the body; and   assessing renal function of the patient based on the detected spectral energy, wherein the compound is   
       
         
           
           
               
               
           
         
         (2R,2′R)-2,2′-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))-bis(3-hydroxypropanoic acid). 
       
     
     
       35. The method of claim 34, wherein the compound is combined with at least one pharmaceutically acceptable excipients before administering the compound to a patient. 
     
     
       36. The method of claim 35, wherein one of the pharmaceutically acceptable excipients is phosphate buffered saline.