Modified pyrazine derivatives and uses thereof
View Patent ↗In some embodiments, the invention provides modified pyrazine derivatives containing a central pyrazine ring with two secondary amine groups attached directly to the central pyrazine ring and two amino carbonyl groups attached directly to the central pyrazine ring. The secondary amine groups are terminated by alkyl groups containing from 1 to 6 carbons. The amino carbonyl groups can be terminated by a wide range of substituents including, but not limited to, alkyl and alkylene groups, polyether groups, including poly(ethylene glycol) groups, secondary and tertiary amine groups, polyhydroxylated alkyl groups, amino carbonyl groups, amino thioketone groups, and combinations thereof. In some embodiments, the invention provides modified pyrazine derivatives useful as optical agents in a wide variety of biomedical imaging procedures, including diagnostic and imaging procedures. In an embodiment, for example, modified pyrazine derivatives are provided which are useful in monitoring organ and system functioning, for example in monitoring renal system functioning.
1. A compound being of the formula (FX1):
wherein:
each of R 1 and R 2 is —(CH 2 ) a (CH 2 CH 2 O) b R 3 , —(CH 2 CH 2 O) b R 3 , —(CH 2 ) c (CH 2 CH 2 O) d (CH 2 ) e NR 4 CONR 5 (CH 2 ) f (CH 2 CH 2 O) b R 6 , —(CH 2 ) c (CH 2 CH 2 O) d (CH 2 ) e NR 4 CSNR 5 (CH 2 ) f (CH 2 CH 2 O) b R 6 , —(CH 2 ) c (CH 2 CH 2 O) d (CH 2 ) e CONR 4 (CH 2 ) f (CH 2 CH 2 O) b R 6 , —(CH 2 ) c (CH 2 CH 2 O) d (CH 2 ) e NR 4 SO 2 (CH 2 ) f (CH 2 CH 2 O) b R 6 , —(CH 2 ) c (CH 2 CH 2 O) d (CH 2 ) e SO 2 NR 4 (CH 2 ) f (CH 2 CH 2 O) b R 6 , —(CH 2 ) c (CH 2 CH 2 O) d (CH 2 ) e NR 4 CO(CH 2 ) f (CH 2 CH 2 O) b R 6 , —(CH 2 ) c (CH 2 CH 2 O) d (CH 2 ) e NR 4 CO 2 (CH 2 ) f (CH 2 CH 2 O) b R 6 , —(CH 2 ) c (CH 2 CH 2 O) d (CH 2 ) e OC(O)NR 4 (CH 2 ) f (CH 2 CH 2 O) b R 6 , or —(CH 2 ) a Y 1 ;
each Y 1 is independently —OR 3 , —(CHOH) c R 7 , —NR 8 R 9 , —CONR 8 R 9 , —NHCO(CH 2 ) a (CH 2 CH 2 O) b R 6 or —NHCO(CHOH) c R 7 ;
each of R 3 , R 4 , R 5 , R 6 and R 7 is independently —H or C 1 -C 6 alkyl;
each of R 8 and R 9 is independently —H, C 1 -C 3 alkyl, —(CH 2 ) a (CHOH) c R 7 or —(CH 2 ) a (CH 2 CH 2 O) b R 6 ;
each of a, c, e and f is independently an integer from 0 to 10;
each b is independently an integer from 1 to 120;
each d is independently an integer from 0 to 120; and
each of m and n is independently an integer from 0 to 5.
2. The compound of claim 1 , wherein m is 1, 2, or 3.
3. The compound of claim 1 having formula (FX2), (FX3), (FX12), or (FX13):
4. The compound of claim 1 , having formula (FX4), (FX5), (FX6), (FX7), (FX8), (FX9), (FX10), or (FX11):
5. The compound of claim 1 , wherein each R 3 is independently C 1 -C 3 alkyl.
6. The compound of claim 1 , wherein each R 3 is C 1 alkyl.
7. The compound of claim 1 , having formula (FX14) or (FX15):
8. The compound of claim 1 , wherein each R 4 is independently —H.
9. The compound of claim 1 , wherein each R 6 is independently C 1 -C 3 alkyl.
10. The compound of claim 1 , wherein each b or d is independently an integer from 2 to 50.
11. The compound of claim 1 , wherein each a, c, e or f is independently an integer from 0 to 6.
12. The compound of claim 1 having formula (FX16) or (FX17):
13. A method of using a compound of claim 1 in an optical imaging, diagnostic, visualization, monitoring, surgical, biomedical or therapeutic procedure, wherein the procedure comprises:
(i) administering a diagnostically effective amount of the compound to a subject, wherein the compound is differentially separated from a bodily fluid of the subject by an organ, tissue or system in the subject; and
(ii) detecting the administered compound.
14. A method of using a compound of claim 1 in an optical imaging, diagnostic, visualization, monitoring, surgical, biomedical or therapeutic procedure, wherein the procedure comprises:
administering an effective amount of a renally excretable compound of claim 1 to a subject;
exposing a tissue of the subject's renal system having the administered compound to electromagnetic radiation, thereby generating emitted electromagnetic radiation from the compound;
detecting the emitted electromagnetic radiation from the compound, thereby visualizing or imaging at least a portion of the renal system of the subject.
15. The compound of claim 1 , wherein the compound has plasma binding of less than 10%.
16. The compound of claim 1 for use in a biomedical procedure for assessing physiological function of an organ, tissue or system.
17. The compound of claim 14 , wherein the at least a portion of the renal system comprises a ureter, bladder or urethra of the subject.
18. A pharmaceutical composition comprising:
the compound of claim 1 ; and
a pharmaceutically acceptable excipient.
19. A pharmaceutical composition comprising:
the compound of claim 1 ; and one or more additional therapeutic agents or diagnostic agents.
20. The method of claim 14 , wherein the compound has plasma binding of less than 10%.