Pyrazine derivatives with extended conjugation and methods of using the same in optical applications

1. A method of optically diagnosing renal function in a patient, comprising the steps of:

administering a pyrazine derivative or a pharmaceutically-acceptable salt thereof to a patient;

exposing the administered pyrazine derivative to visible and/or near infrared light;

detecting spectral energy emanating from the administered pyrazine derivative; and

determining clearance of the pyrazine derivative from the body of the patient;

wherein the administered pyrazine derivative absorbs and emanates spectral energy in the visible and/or near infrared spectrum;

wherein the pyrazine derivative is of the following Formula 1, and wherein:

X is —Ar—Y, —C(R 4 )═C(R 5 )—Ar—Y, —C≡C—Ar—Y, —N═N—Ar—Y, —CO—Ar—Y, —N(R 6 )—Ar—Y, —O—Ar—Y, —S—Ar—Y, —SO—Ar—Y, —SO 2 —Ar—Y, —C(R 4 )═C(R 5 )—Y, or —C≡C—Y;

Ar is phenyl, biphenyl, pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazinyl, triazolyl or thiadiazolyl; with the proviso that if Ar is phenyl, pyrrolyl, or thiopheneyl, then at least one of R 1 , R 2 , and R 3 is other than hydrogen;

each Y is independently hydrogen, C 1 -C 10 alkyl, halo, trihaloalkyl, —CN, —CO 2 R 7 , —CONR 8 R 9 , —COR 10 , —NO 2 , —SOR 11 , —SO 2 R 12 , —SO 2 OR 13 , —PO 3 R 14 R 15 , —OR 16 , —SR 17 , —NR 18 R 19 , —N(R 20 )COR 21 , —P(R 22 ) 3 , —CO(AA) j , or —CONH(PS) k ;

each of, R 1 , R 2 and R 3 is independently hydrogen, C 1 -C 10 alkyl, halo, trihaloalkyl, —CN, —CO 2 R 7 , —CONR 8 R 9 , —COR 10 , —NO 2 , —SOR 11 , —SO 2 R 12 , —SO 2 OR 13 , —PO 3 R 14 R 15 , —OR 16 , —SR 17 , —NR 18 R 19 , —N(R 20 )COR 21 , —P(R 22 ) 3 , —CO(AA) j , —CONH(PS) k , or X;

(AA) j is a polypeptide chain comprising the same or different natural or unnatural α-amino acids linked together by peptide bonds, wherein j is an integer from 1 to 50;

(PS) k is a sulfated or non-sulfated polysaccharide chain comprising the same or different monosaccharide units connected together by glycosidic linkages, wherein k is an integer from 1 to 50;

each of R 4 to R 22 is independently —H, C 1 -C 10 alkyl, —(CH 2 ) a OR 23 , —CH 2 (CHOH) a R 24 , —CH 2 (CHOH) a CO 2 H, —(CHCO 2 H) a CO 2 H, —(CH 2 ) a NR 25 R 26 , —CH[(CH 2 ) b NH 2 ] a CO 2 H, —CH[(CH 2 ) b NH 2 ] a CH 2 OH, —CH 2 (CHNH 2 ) a CH 2 NR 27 R 28 , —(CH 2 CH 2 O) c R 29 , or —(CH 2 ) d CO(CH 2 CH 2 O) c R 30 ;

each of R 23 to R 30 is independently —H or —CH 3 ;

each of a, b, and d is independently an integer from 1 to 10; and

c is an integer from 1 to 100.

2. The method of claim 1 wherein X is —Ar—Y, —C(R 4 )═C(R 5 )—Ar—Y, —C≡C—Ar—Y, —N═N—Ar—Y, —CO—Ar—Y, —N(R 6 )—Ar—Y, —O—Ar—Y, —S—Ar—Y, —SO—Ar—Y, or —SO 2 —Ar—Y.

3. The method of claim 1 wherein X is —Ar—Y.

4. The method of claim 1 wherein X is —C(R 4 )═C(R 5 )—Ar—Y.

5. The method of claim 1 wherein X is —N═N—Ar—Y.

6. The method of claim 1 wherein Ar is phenyl, biphenyl, pyridyl, pyrazinyl, pyrrolyl, furanyl, and thiopheneyl.

7. The method of claim 1 wherein Ar is phenyl, pyridyl, pyrazinyl, pyrrolyl, furanyl, or thiopheneyl.

8. The method of claim 1 wherein Ar is phenyl, pyrrolyl, or furanyl.

9. The method of claim 1 wherein Ar is phenyl.

10. The method of claim 1 wherein Ar is pyrrolyl.

11. The method of claim 1 wherein Ar is furanyl.

12. The method of claim 1 wherein Y is —H, C 1 -C 10 alkyl, halo, trihaloakyl, —CN, —CO 2 R 7 , —CONR 8 R 9 , —COR 10 , —NO 2 , —SO 2 R 12 , —OR 16 , —SR 17 , ——NR 18 R 19 , —N(R 20 )COR 21 , —CO(AA) j , or —CONH(PS) k .

13. The method of claim 1 wherein Y is —H, C 1 -C 10 alkyl, halo, trihaloakyl, —CN, —CO 2 R 7 , —CONR 8 R 9 , —OR 16 , —NR 18 R 19 , or —N(R 20 )COR 21 .

14. The method of claim 1 wherein Y is —H, —CN, —CO 2 R 7 , —CONR 8 R 9 , —OR 16 , —NR 18 R 19 , or —N(R 20 )COR 21 .

15. The method of claim 1 wherein Y is —H, —CO 2 R 7 , —OR 16 , or —NR 18 R 19 .

16. The method of claim 1 wherein Y is —H.

17. The method of claim 1 wherein each of R 1 to R 3 is independently —H, C 1 -C 10 alkyl, —CN, —CO 2 R 7 , —CONR 8 R 9 , —OR 16 , —SR 17 , —NR 18 R 19 , —CO(AA) j , —CONH(PS) k , or X.

18. The method of claim 1 wherein each of R 1 to R 3 is independently —CN, —CO 2 R 7 , —CONR 8 R 9 , —NR 18 R 19 , or X.

19. The method of claim 1 wherein each of R 1 to R 3 is independently —CN, —CONR 8 R 9 , —NR 18 R 19 , or X.

20. The method of claim 1 wherein:

one of R 1 , R 2 , and R 3 is X; and

each of the other two of R 1 , R 2 , and R 3 is independently —CN, —CONR 8 R 9 , or —NR 18 R 19 .

21. The method of claim 1 wherein:

one of R 1 , R 2 , and R 3 is —CN, —CONR 8 R 9 , or —NR 18 R 19 ; and

each of the other two of R 1 , R 2 , and R 3 is X.

22. The method of claim 1 wherein:

each of R 1 and R 3 is independently —H, —OR 16 , —SR 17 , or —NR 18 R 19 ; and

R 2 is —CN, —CO 2 R 7 , —CONR 8 R 9 , —COR 10 , —SO 2 R 12 , —CO(AA) j , —CONH(PS) k , or X.

23. The method of claim 1 wherein each of R 4 to R 21 is independently —H, C 1 -C 10 alkyl, —(CH 2 ) a OR 23 , —CH 2 (CHOH) a R 24 , —CH 2 (CHOH) a CO 2 H, —(CHCO 2 H) a CO 2 H, —(CH 2 ) a NR 25 R 26 , —CH[(CH 2 ) b NH 2 ] a CO 2 H, —CH[(CH 2 ) b NH 2 ] a CH 2 OH, —CH 2 (CHNH 2 ) a CH 2 NR 27 R 28 , —(CH 2 CH 2 O) c R 29 , or —(CH 2 ) d CO(CH 2 CH 2 O) c R 30 .

24. The method of claim 1 wherein each of R 7 to R 21 is independently —H, C 1 -C 10 alkyl, or —(CH 2 ) a OR 23 .

25. The method of claim 1 wherein each of R 7 to R 21 is independently —H or C 1 -C 10 alkyl.

26. The method of claim 1 wherein (AA) j is a polypeptide chain consisting of natural α-amino acids selected from aspartic acid, asparagine, arginine, histidine, lysine, glutamic acid, glutamine, serine, and homoserine.

27. The method of claim 26 wherein j is an integer from 1 to 20.

28. The method of claim 1 wherein (PS) k is a sulfated or non-sulfated polysaccharide chain consisting of glucose, fructose, mannose, and ribose.

29. The method of claim 28 wherein k is an integer from 1 to 20.

30. The method of claim 1 wherein each of a, b, and d is independently an integer from 1 to 6.

31. The method of claim 1 wherein c is an integer from 1 to 20.

32. The method of claim 1 , wherein the pyrazine derivative is any of formula:

33. The method of claim 1 , wherein the pyrazine derivative is any of formula:

34. The method of claim 1 , wherein the pyrazine derivative is any of formula:

35. The method of claim 1 , wherein the pyrazine derivative is any of formula:

36. The method of claim 1 , wherein the pyrazine derivative is any of formula:

37. The method of claim 1 , wherein the pyrazine derivative is any of formula:

38. The method of claim 1 , wherein the pyrazine derivative is any of formula:

39. The method of claim 1 , wherein the pyrazine derivative is any of formula: