COMPOUNDS, CONJUGATES AND COMPOSITIONS OF EPIPOLYTHIODIKETOPIPERAZINES AND POLYTHIODIKETOPIPERAZINES

• US 20160354483A1
• Filed: 05/10/2016
• Published: 12/08/2016
• Est. Priority Date: 12/04/2012
• Status: Active Grant

• Current Assignee: Board of Trustees of The University of Illinois, Massachusetts Institute of Technology
• Original Assignee: Board of Trustees of The University of Illinois, Massachusetts Institute of Technology
• Inventors: Movassaghi, Mohammad, Kim, Justin, Hergenrother, Paul J., Morrison, Karen, Boyer, Nicolas
• Granted Patent: US 10,220,099 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: C07D 513/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07K 5/12 Cyclic peptides with only normal peptide bonds in the ring

Abstract

The present application provides, among other things, compounds, compositions and methods for treating various diseases including cancer.

Claims

1-2. -2. (canceled)

3. A compound having the structure of formula II:

M

L

D)s]_t 

 

II

or a pharmaceutically acceptable salt thereof, wherein;

M is a cell-specific ligand unit;

each L is independently a linker unit;

each D independently has the structure of formula I-c or I-d,

4. The compound of claim 3, wherein the compound has the structure of formula II-a:

5. The compound of claim 3, wherein the compound has the structure of formula II-b:

6. The compound of claim 3, wherein M is an antibody.

8. The compound of claim 3, wherein R^3′

is R.

9. The compound of claim 3, wherein R^3′

is an electron-withdrawing group.

11. The compound of claim 3, wherein L is self-immolative.

12. The compound of claim 3, wherein s is 1.

13. The compound of claim 3, wherein

R^3′

is —

S(O)₂R, —

S(O)₂—

[C(R)₂]_q—

R, —

S(O)₂—

[C(R)₂]_q—

B(OR)₂, —

S(O)₂—

[C(R)₂]_q—

Si(R)₃, —

S(O)₂OR, —

S(O)₂N(R)₂, —

S(O)R, —

C(O)R, —

C(O)OR, —

C(O)N(R)₂, —

C(O)N(R)—

OR, —

P(O)(R)₂, —

P(O)(OR)₂, or —

P(O)[N(R)₂]₂.

14. The compound of claim 3, wherein

R⁸ is —

(S)_m—

R^x wherein m is 1, 2, or 3, and R^x is —

SR, —

C(O)R, —

C(O)OR, —

C(O)N(R)₂, —

C(S)R, —

S(O)R, —

S(O)₂R, or —

S(O)₂N(R)₂; and

R⁹ is —

(S)_p—

R^y wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and R^y is —

SR, —

C(O)R, —

C(O)OR, —

C(O)N(R)₂, —

C(S)R, —

S(O)R, —

S(O)₂R, or —

S(O)₂N(R)₂;

or

R⁸ and R⁹ are taken together to form —

S—

, —

(S)_m—

[C(R)₂]_q—

(S)_p—

, —

(S)_m—

(S)_p—

, —

(S)_m—

C(O)—

(S)_p—

, —

(S)_m—

C(S)—

(S)_p—

, —

(S)_m—

S(O)—

(S)_p—

, or —

(S)_m—

S(O)₂—

(S)_p—

.

15. The compound of claim 3, wherein R⁸ and R⁹ are taken together to form —

S—

, —

(S)_m—

C(R)₂—

(S)_p—

, —

(S)_m—

(S)_p—

, —

(S)_m—

C(O)—

(S)_p—

, —

(S)_m—

C(S)—

(S)_p—

, —

(S)_m—

S(O)—

(S)_p—

, or —

(S)_m—

S(O)₂—

(S)_p—

.

16. A pharmaceutical composition comprising a compound of claim 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 3.

24. The compound claim 3, wherein is a single bond, R⁴ is R or halogen, and R⁵ is hydrogen or an optionally substituted C_1-6 aliphatic.

27. The compound claim 3, wherein:

R⁸ is —

(S)_m—

R^x wherein m is 1 and R^x is —

SR, —

C(O)R; and

R⁹ is —

(S)_p—

R^y wherein p is 1 and R^y is —

SR, —

C(O)R.

28. The compound claim 3, wherein R⁸ and R⁹ are taken together to form —

(S)_m—

(S)_p—

, —

S—

C(O)—

S—

, or —

S—

C(S)—

S—

.

29. The compound claim 3, wherein R³ or R^3′

is —

SO₂R.

30. The compound claim 3, wherein each R⁴ is independently an optionally substituted group selected from phenyl, a 8-14 membered bicyclic or tricyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

7. A compound having the structure of formula III:

M-L

D)s 

 

III

or a pharmaceutically acceptable salt thereof, wherein;

M is a cell-specific ligand unit;

L is a linker unit;

each D independently has the structure of formula I-c or I-d,

10. (canceled)

18-23. -23. (canceled)

25-26. -26. (canceled)

31. (canceled)