ISATIN ANALOGUES AND USES THEREFOR

• US 20090068105A1
• Filed: 08/29/2007
• Published: 03/12/2009
• Est. Priority Date: 08/29/2006
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Welch, Michael J., Mach, Robert H., Rothfuss, Justin, Chu, Wenhua, Zhou, Dong
• Granted Patent: US 8,329,686 B2
• Time in Patent Office: Days
• US Class Current: 424/1.890
• CPC Class Codes: A61K 51/0446 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 51/0455 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

Novel isatin analogues, including isatin analogues comprising Michael Acceptors (IMAs) are disclosed. Further disclosed are methods of synthesis of the isatin analogues, and uses of the analogues, including inhibition of caspase-3 and caspase-7, and in vivo imaging of apoptosis by Positron emission tomography (PET) or Single Photon Emission Computed Tomography (SPECT).

Claims

1. A method of converting an isatin analogue comprising at least one sulfonate ester leaving group into a ketone hydrate isatin analogue, the method comprising contacting the isatin analogue comprising at least one sulfonate ester with a hydroxide XOH, wherein X is a cation.

2. A method in accordance with claim 1, wherein the sulfonate ester leaving group is selected from the group consisting of a mesylate, a triflate, a tosylate and a brosylate.

3. A method in accordance with claim 1, wherein the sulfonate ester leaving group is a mesylate leaving group.

4. A method in accordance with claim 1, wherein X is an inorganic cation selected from the group consisting of Na⁺, K⁺ and Cs⁺.

5. A method in accordance with claim 1, wherein X is an organic cation selected from the group consisting of a tetrabutylammonium cation, a tetraethylammonium cation and a tetramethylammonium cation.

6. A method in accordance with claim 3, wherein the isatin analogue comprising at least one sulfonate ester leaving group has the structure

wherein Z is N or CH, m is an integer from 1 to about 20 and n is an integer from 1 to about 20.

7. A method in accordance with claim 3, wherein the isatin analogue comprising at least one sulfonate ester leaving group has the structure

8. A method in accordance with claim 1, wherein the ketone hydrate isatin analogue has the structure

wherein Z is N or CH, m is an integer from 1 to about 20 and n is an integer from 1 to about 20.

9. A method in accordance with claim 1, wherein the ketone hydrate isatin analogue has the structure

18. A method in accordance with claim 3, wherein the isatin analogue comprising at least one sulfonate ester leaving group has the structure

19. A method in accordance with claim 1, wherein the ketone hydrate isatin analogue has the structure

10. A ketone hydrate isatin analogue of structure

wherein Z is N or CH, m is an integer from 1 to about 20 and n is an integer from 1 to about 20.

11. A ketone hydrate isatin analogue in accordance with claim 10, wherein Z is CH, m=1 and n=2.

12. A method of imaging apoptotic cell death in a mammalian subject, the method comprising:

a) administering to the subject a composition comprising a fluorinated isatin analogue of structure

wherein Z is N or CH, m is an integer from 1 to about 20, n is an integer from 1 to about 20 and the fluoride is an F¹⁸; and

b) subjecting the subject to positron emission tomography (PET) or single photon emission computed tomography (SPECT).

13. A method in accordance with claim 12, wherein Z is CH, m=1 and n=2.

14. A method in accordance with claim 12, wherein the subject is a human.

15. A method in accordance with claim 14, wherein the subject is a human patient having or suspected of having at least one disease selected from the group consisting of ischemia-reperfusion injury (stroke and myocardial infarction), cardiomyopathy, neurodegeneration (Alzheimer'"'"'s Disease, Parkinson'"'"'s Disease, Huntington'"'"'s Disease, ALS), sepsis, Type I diabetes, fulminant liver disease, and allograft rejection.

16. A method in accordance with claim 14, wherein the subject is a human patient having or suspected of having a cancer.

17. A method in accordance with claim 16, wherein the subject is a human patient receiving chemotherapy, radiation therapy, or a combination thereof.

20. A method of converting a ketone hydrate isatin analogue of structure

into a fluorinated isatin analogue of structure

wherein Z is N or CH, m is an integer from 1 to about 20 and n is an integer from 1 to about 20, the method comprising contacting the ketone hydrate with an F¹⁸ fluoride salt.

21. A method in accordance with claim 21, wherein Z is CH, m=1 and n=2.

22. A method of converting a mesylated isatin analogue into a fluorinated isatin analogue, the method comprising:

a) contacting a mesylated isatin analogue of structure

with a hydroxide XOH, wherein X is a cation to yield a ketone hydrate isatin analogue of structure

b) forming a mixture comprising the ketone hydrate, KF and 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane; and

c) heating the mixture.

23. A method in accordance with claim 22, wherein Z is CH, m=1 and n=2.

24. A ketone hydrate isatin analogue of structure

wherein Z is N or CH, m is an integer from 1 to about 20 and n is an integer from 1 to about 20.

25. A ketone hydrate isatin analogue in accordance with claim 24, wherein Z is CH, m=1 and n=2.

26. An isatin analogue of structure

wherein Z is N or CH, m is an integer from 1 to about 20 and n is an integer from 1 to about 20.

27. An isatin analogue in accordance with claim 26, wherein Z is CH, m=1 and n=2.

28. An isatin analogue of structure

wherein Z is N or CH, m is an integer from 1 to about 20 and n is an integer from 1 to about 20.

29. An isatin analogue in accordance with claim 28, wherein Z is CH, m=1 and n=2.

30. An isatin analogue in accordance with claim 28, wherein the F is an F¹⁸.

31. A method of imaging apoptotic cell death in a mammalian subject, the method comprising:

a) administering to the subject a composition comprising a fluorinated isatin analogue of structure

wherein Z is N or CH, m is an integer from 1 to about 20, n is an integer from 1 to about 20 and the fluoride is an F¹⁸; and

b) subjecting the subject to positron emission tomography (PET) or single photon emission computed tomography (SPECT).

32. A method in accordance with claim 31, wherein the subject is a human having or suspected of having at least one disease selected from the group consisting of ischemia-reperfusion injury (stroke and myocardial infarction), cardiomyopathy, neurodegeneration (Alzheimer'"'"'s Disease, Parkinson'"'"'s Disease, Huntington'"'"'s Disease, ALS), sepsis, Type I diabetes, fulminant liver disease, and allograft rejection.

35. A method in accordance with claim 31, wherein Z is CH, m=1 and n=2.

33. A method in accordance with claim 50, wherein the subject is a human patient having or suspected of having a cancer.

34. A method in accordance with claim 33, wherein the subject is a human patient receiving chemotherapy, radiation therapy, or a combination thereof.

36. An Isatin Michael Acceptor (IMA) comprising an isatin analogue in which a keto carbonyl of the isatin ring is substituted with a Michael acceptor.

37. An IMA in accordance with claim 36, wherein the Michael acceptor is a methylenemalononitrile group.

38. An IMA in accordance with claim 36, selected from the group consisting of WC(II)-49, WC(III)-50, WC(III)-51, WC(II)-53, WC(II)-54, WC(II)-62, WC(II)-69, WC(II)-87, WC(II)-92, WC(II)-103, WC(II)-104, WC(II)-128, WC(II)-129 and WC(II)-142.

39. An IMA in accordance with claim 36, wherein the IMA has an IC₅₀ against caspase-3 of less than about 10 nM.

40. An IMA in accordance with claim 38, selected from the group consisting of WC(III)-50, WC(III)-51, WC(II)-69, WC(II)-87, WC(II)-103, WC-(II)-104 and WC(II)-128.

41. A method of inhibiting apoptosis in a subject, the method comprising administering to a subject an Isatin Michael Acceptor (IMA) in accordance with claim 36, at a dose effective for inhibiting caspase activity.

42. A method of synthesizing an Isatin Michael Acceptor (IMA), the method comprising contacting an isatin with dicyanomethane.

43. A method of synthesizing an IMA in accordance with claim 44, wherein the isatin is