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

Patent metadata

Field	Value
Publication number	US-10370362-B2
Application number	US-201514962242-A
Country	US
Kind code	B2
Filing date	Dec 8, 2015
Priority date	Jun 22, 2006
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

The present invention relates to pyrazine derivatives capable of absorbing and emanating spectral energy in the visible and/or near infrared spectrum. Pyrazine derivatives of the invention may be administered to a patient in the form of a pharmaceutically acceptable composition and utilized in medical (e.g., diagnostic imaging) procedures.

First claim

What is claimed is:

1. An optical diagnostic agent having Formula 1

or pharmaceutically acceptable salt thereof, 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, naphthyl, 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, haloalkyl, —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, haloalkyl, —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; with the proviso that no more than one of R 1 , R 2 and R 3 is a —CN group and at least one of R 1 , R 2 and R 3 comprises a substituted or unsubstituted amino group;
(AA) j is a polypeptide chain comprising the same or different 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 optical diagnostic agent of claim 1 wherein X is -Ar-Y, —C(R 4 )═C(R 5 )-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 optical diagnostic agent of claim 1 wherein X is -Ar-Y.

4. The optical diagnostic agent of claim 1 wherein X is —C(R 4 )═C(R 5 )-Ar-Y.

5. The optical diagnostic agent of claim 1 wherein X is —N═N-Ar-Y.

6. The optical diagnostic agent of claim 1 wherein Ar is phenyl, naphthyl, biphenyl, pyridyl, pyrazinyl, pyrrolyl, furanyl, and thiopheneyl.

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

8. The optical diagnostic agent of claim 1 wherein Ar is phenyl, pyrrolyl, or furanyl.

9. The optical diagnostic agent of claim 1 wherein Ar is phenyl.

10. The optical diagnostic agent of claim 1 wherein Ar is pyrrolyl.

11. The optical diagnostic agent of claim 1 wherein Ar is furanyl.

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

14. The optical diagnostic agent 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 optical diagnostic agent of claim 1 wherein Y is —H, —CO 2 R 7 , —OR 16 , or NR 18 R 19 .

16. The optical diagnostic agent of claim 1 wherein Y is —H.

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

18. The optical diagnostic agent 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 optical diagnostic agent 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 optical diagnostic agent 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 optical diagnostic agent 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 optical diagnostic agent of claim 1 wherein:
each of R 1 and R 3 is independently —OR 16 , —SR 17 , or —NR 18 R 19 ; and
R 2 is —CN, —CO 2 R 7 , —CONR 8 R 9 , —COR m , —SO 2 R 12 , —CO(AA) j , —CONH(PS) k , or X.

23. The optical diagnostic agent 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 optical diagnostic agent 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 optical diagnostic agent of claim 1 wherein each of R 7 to R 21 is independently —H or C 1 -C 10 alkyl.

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

27. The optical diagnostic agent of claim 26 wherein j is an integer from 1 to 20.

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

29. The optical diagnostic agent of claim 28 wherein k is an integer from 1 to 20.

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

31. The optical diagnostic agent of claim 1 wherein c is an integer from 1 to 20.

32. The optical diagnostic agent of claim 1 , wherein the optical diagnostic agent is any of formula:

33. The optical diagnostic agent of claim 1 , wherein the optical diagnostic agent is any of formula:

34. The optical diagnostic agent of claim 1 , wherein the optical diagnostic agent is any of formula:

35. The optical diagnostic agent of claim 1 , wherein the optical diagnostic agent is any of formula:

Assignees

• Medibeacon Inc

Inventors

• Neumann William L
• Rajagopalan Raghavan
• Dorshow Richard B

Classifications

• A61P13/12

  of the kidneys · CPC title

• C07D405/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D241/28

  in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms · CPC title

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• C07D473/18

  one oxygen and one nitrogen atom, e.g. guanine · CPC title