Beta-amino pateamine a derivatives and methods for treating chronic lymphocytic leukemia

Patent metadata

Field	Value
Publication number	US-10889596-B2
Application number	US-201716090528-A
Country	US
Kind code	B2
Filing date	Mar 31, 2017
Priority date	Mar 31, 2016
Publication date	Jan 12, 2021
Grant date	Jan 12, 2021

Abstract

Pateamine A derivatives, pharmaceutical compositions that include the derivatives, and methods for treating chronic lymphocytic leukemia using the derivatives.

First claim

The invention claimed is:

1. A compound having formula (I):

or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof,
wherein
X is selected from O, NH, and S; and
Y is selected from R, OR 1 , SR 3 , and N(R 1 )R 2 ,
wherein R is selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O or N atoms, and
wherein R 1 and R 2 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O or N atoms.

2. The compound of claim 1 having formula (II):

or a pharmaceutically acceptable salt thereof,
wherein
X is selected from O, NH, and S; and
Y is selected from R, OR 1 , SR 1 , and N(R 1 )R 2 ,
wherein R is selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O or N atoms, and
wherein R 1 and R 2 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O or N atoms.

3. The compound of claim 1 having formula (III):

wherein A − is a pharmaceutically acceptable counter ion.

4. The compound of claim 2 having formula (IV):

wherein A − is a pharmaceutically acceptable counter ion.

5. The compound of claim 3 , wherein A − is selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, formate, acetate, trifluoroacetate, maleate, fumarate, succinate, tartrate, oxalate, citrate, malate, benzoate, toluenesulfonate, methanesulfonate, and benzenesulfonate.

6. The compound of claim 1 , wherein X is O and Y is R.

7. The compound of claim 1 , wherein X is O and Y is OR 1 .

8. The compound of claim 1 , wherein X is O and Y is N(R 1 )R 2 .

9. The compound of claim 1 , wherein X is O and Y is SR 1 .

10. The compound of claim 1 , wherein X is S and Y is R.

11. The compound of claim 1 , wherein X is S and Y is OR 1 .

12. The compound of claim 1 , wherein X is S and Y is N(R 1 )R 2 .

13. The compound of claim 1 , wherein X is S and Y is SR 1 .

14. The compound of claim 1 , wherein X is NH and Y is R.

15. The compound of claim 1 , wherein X is NH and Y is OR 1 .

16. The compound of claim 1 , wherein X is NH and Y is N(R 1 )R 2 .

17. The compound of claim 1 , wherein X is NH and Y is SR 1 .

18. The compound of claim 1 , wherein the C3-C12 alkyl group in which one or more carbons are replaced with O is selected from —CH 2 —O—CH 3 , —CH 2 CH 2 —O—CH 3 , and -CH 2 CH 2 —O—CH 2 CH 2 —O—CH 3 .

19. The compound of claim 1 , wherein the C3-C12 alkyl group in which one or more carbons are replaced with N is selected from —CH 2 —NH—CH 3 , —CH 2 —N(CH 3 ) 2 , —CH 2 CH 2 —NH—CH 3 , and —CH 2 CH 2 —N(CH 3 ) 2 .

20. A compound having formula (V):

or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof,
wherein
Z is selected from R and OR 1 ,
wherein R is selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O or N atoms, and
wherein R 1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O or N atoms.

21. The compound of claim 20 having formula (VI):

or a pharmaceutically acceptable salt thereof,
wherein
Z is selected from R and OR 1 ,
wherein R is selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O or N atoms, and
wherein R 1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O or N atoms.

22. The compound of claim 20 having formula (VII):

wherein A − is a pharmaceutically acceptable counter ion.

23. The compound of claim 21 having formula (VIII):

wherein A − is a pharmaceutically acceptable counter ion.

24. A compound having formula (IX):

or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof.

25. The compound of claim 24 having formula (IX):

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 24 having formula (XI):

wherein A − is a pharmaceutically acceptable counter ion.

27. The compound of claim 24 having formula (XII):

wherein A − is a pharmaceutically acceptable counter ion.

28. A pharmaceutical composition, comprising a compound of claim 24 , or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. An antibody conjugate for the delivery of a β-amino pateamine derivative, comprising a compound of claim 24 covalently coupled directly or through a linker unit to an antibody or functional fragment thereof.

30. A pharmaceutical composition, comprising the antibody conjugate of claim 29 and a pharmaceutically acceptable carrier.

31. A method for inhibiting growth of chronic lymphocytic leukemia (CLL) cells, comprising contacting CLL cells with a compound of claim 24 , or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof.

32. A method for treating chronic lymphocytic leukemia (CLL), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 24 , or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof.

33. A method for inhibiting growth of chronic lymphocytic leukemia (CLL) cells, comprising contacting CLL cells with an antibody conjugate of claim 29 .

34. A method for treating chronic lymphocytic leukemia (CLL), comprising administering to a subject in need thereof a therapeutically effective amount of an antibody conjugate of claim

Assignees

• Texas A & M Univ Sys

Inventors

• Romo Daniel
• Hull Kenneth G
• Zhu Mingzhao
• Robles Omar

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61K31/429

  condensed with heterocyclic ring systems · CPC title

• C07D513/08 Primary

  Bridged systems · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title