OSW-1 analogs and conjugates, and uses thereof

Patent metadata

Field	Value
Publication number	US-9790253-B2
Application number	US-201214118589-A
Country	US
Kind code	B2
Filing date	May 18, 2012
Priority date	May 19, 2011
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

Provided are a number of compounds structurally related to OSW-1, a natural compound that binds OSBPs. Also provided are pharmaceutical compositions comprising the OSW-1 analogs, as well as methods for use of these OSW-1 analogs, or pharmaceutically acceptable salts, enantiomers, or stereoisomers thereof in the treatment of atherosclerosis. Alzheimer's disease, and cancer, including p21-deficient cancer. Conjugates of OSW-1 analogs with monoclonal antibodies, including monoclonal antibodies targeted to cancer cells, are also provided. Also provided are pharmaceutical compositions comprising the conjugates, as well as methods for use of these conjugates, in the treatment of cancer, including p21-deficient cancer.

First claim

We claim:

1. A conjugate comprising an antibody, or antigen-binding fragment thereof, covalently linked to a compound of formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 , R 2 , R 3 , and R 6 are independently selected from the group consisting of hydrogen, trialkylsilyl, and

Z is absent or is selected from the group consisting of O and NR 10 ;
n is an integer 0-6;
R is selected from the group consisting of substituted or unsubstituted: alkyl, alkenyl, amino, alloc-protected amino, Fmoc-protected amino, aryl, 5- to 13-membered cycloalkyl or cycloalkenyl group, and 5- to 10-membered cyclic heteroaromatic group comprising 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
R 4 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 5 is selected from the group consisting of hydrogen and acyl; and
R 10 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is not hydrogen.

2. The conjugate of claim 1 , wherein R 4 is hydrogen.

3. The conjugate of claim 1 , wherein R 5 is acetyl.

4. The conjugate of claim 1 , wherein R 6 is para-methoxybenzoyl or 3-phenylpropanoyl.

5. The conjugate of claim 1 , wherein Z is O.

6. The conjugate of claim 5 , wherein R is selected from the group consisting of alkyl and 4-nitrophenyl.

7. The conjugate of claim 5 , wherein n is 0.

8. The conjugate of claim 1 , wherein Z is NH.

9. The conjugate of claim 8 , wherein R is an amino group.

10. The conjugate of claim 9 , wherein n is 6.

11. The conjugate of claim 8 , wherein R is a para-aminoalkylaryl group.

12. The conjugate of claim 11 , wherein n is 1.

13. The conjugate of claim 8 , wherein n is 1; and R is phenyl.

14. The conjugate of claim 1 , wherein Z is absent.

15. The conjugate of claim 14 , wherein R is an amino group.

16. The conjugate of claim 15 , wherein n is 2.

17. The conjugate of claim 14 , wherein R is a 1-imidazolyl group.

18. The conjugate of claim 17 , wherein n is 0.

19. The conjugate of claim 1 , wherein at least one of R 1 , R 2 , and R 3 is tert-butyldimethylsilyl.

20. A conjugate of claim 1 , wherein the antibody, or antigen-binding fragment thereof, and the compound are covalently linked through a cysteine thiol-maleimide Michael addition product, a valine-citrulline p-aminobenzyl linker, or a valine-citrulline p-aminobenzylcarbamate linker.

21. The conjugate of claim 1 , wherein the antibody, or antigen-binding fragment thereof, binds specifically to an antigen expressed on a cancer cell.

22. The conjugate of claim 21 , wherein the cancer cell is p21-deficient.

23. The conjugate of claim 1 , wherein R 1 is

wherein Z is absent or is selected from the group consisting of O and NR 10 .

24. The conjugate of claim 1 , wherein R 2 is

wherein Z is absent or is selected from the group consisting of O and NR 10 .

25. The conjugate of claim 1 , wherein R 3 is

wherein Z is absent or is selected from the group consisting of O and NR 10 .

26. The conjugate of claim 1 , wherein:
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, trialkylsilyl, and

 provided that at least one of R 2 and R 3 is not hydrogen;
R 6 is

Z is absent or is selected from the group consisting of O and NR 10 ;
n is an integer 0-6;
R is selected from the group consisting of substituted or unsubstituted: alkyl, alkenyl, amino, alloc-protected amino, Fmoc-protected amino, aryl, 5- to 13-membered cycloalkyl or cycloalkenyl group, and 5- to 10-membered cyclic heteroaromatic group comprising 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
R 4 is hydrogen;
R 5 is acyl; and
R 10 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl.

27. The conjugate of claim 1 comprising an antibody, or antigen-binding fragment thereof, covalently linked to a compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

28. A pharmaceutical composition, comprising a conjugate of claim 1 ; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

29. A method of killing a mammalian cell, comprising contacting a mammalian cell with an effective amount of a conjugate of claim 1 or a pharmaceutically acceptable salt thereof.

30. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

31. A pharmaceutical composition, comprising a compound of claim 30 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

32. A method of killing a mammalian cell, comprising contacting a mammalian cell with an effective amount of a compound of claim 30 or a pharmaceutically acceptable salt thereof.

33. A conjugate comprising an antibody, or antigen-binding fragment thereof, covalently linked to a compound of claim 30 or a pharmaceutically acceptable salt thereof.

34. A method of killing a mammalian cell, comprising contacting a mammalian cell with an effective amount of a conjugate comprising an antibody, or antigen-binding fragment thereof, covalently linked to a compound of cla

Assignees

• Shair Matthew D
• Burgett Anthony William George
• Harvard College

Inventors

• Shair Matthew D
• Burgett Anthony William George

Classifications

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• C07H15/24

  Condensed ring systems having three or more rings · CPC title

• C07J51/00

  Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07J17/005 Primary

  Glycosides · CPC title